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Pluripotency and its layers of complexity
Cell Regeneration volume 1, Article number: 7 (2012)
Pluripotency is depicted by a self-renewing state that can competently differentiate to form the three germ layers. Different stages of early murine development can be captured on a petri dish, delineating a spectrum of pluripotent states, ranging from embryonic stem cells, embryonic germ cells to epiblast stem cells. Anomalous cell populations displaying signs of pluripotency have also been uncovered, from the isolation of embryonic carcinoma cells to the derivation of induced pluripotent stem cells. Gaining insight into the molecular circuitry within these cell types enlightens us about the significance and contribution of each stage, hence deepening our understanding of vertebrate development. In this review, we aim to describe experimental milestones that led to the understanding of embryonic development and the conception of pluripotency. We also discuss attempts at exploring the realm of pluripotency with the identification of pluripotent stem cells within mouse teratocarcinomas and embryos, and the generation of pluripotent cells through nuclear reprogramming. In conclusion, we illustrate pluripotent cells derived from other organisms, including human derivatives, and describe current paradigms in the comprehension of human pluripotency.
Pluripotency is denoted by the capacity of a self-renewing cell to develop into the three germ layers. The conception of pluripotency emerged in the Classical Greek period where rudimentary methods were employed to examine the development of organs within chick embryos . These observations were left unexplored for two thousand years and awareness was rekindled in the Renaissance period where the invention of the microscope enhanced the resolution of developing embryos. This elicited the establishment of several landmark discoveries and escalated our understanding of vertebrate developmental processes.
The first testimony of pluripotency on a petri dish was portrayed using inbred strains of mice. Spontaneous incidences of teratocarinomas arose at low frequencies in 129 strain of mice . This led to the isolation of pluripotent stem cells that were able to regenerate tumours consisting of the three germ layers . Subsets of pluripotent cell populations came in quick succession, where various cell types within the mouse embryo were isolated and snapshots of distinct developmental stages were captured [4–9]. Other than naturally occurring instances in normal development, artificial states that are reflective of pluripotency have been accomplished. Cells from developing Rana pipiens embryos were demonstrated to undergo nuclear transplantation and revert to a primitive state capable of developing into an entire organism . This highlighted the capacity of a non-pluripotent cell to reset its epigenetic marks and convert to a pluripotent derivative. Termed as nuclear reprogramming, these findings were extended in mice and further exemplified in alternative methods [11–14].
The easy manipulation and cultivation of mouse pluripotent stem cells have provided a convenient platform to study the independent developmental stages. Furthermore, comparison of these pluripotent states and their necessary environmental milieu for sustenance provides indications of developmental cues (reviewed by ). Pluripotent stem cells from various non-rodent and primate species have been achieved either directly from embryos or through nuclear reprogramming, but none are truly reflective of mouse embryonic stem cells that display germline competence (reviewed by Nichols and Smith, 2009c) . Recent studies suggest that conventional human pluripotent cells resemble mouse epiblast stem cells more closely than mouse embryonic stem cells , indicating the possibility of a primitive subset of human pluripotent stem cells which have not been clearly delineated.
This review aims to address these concerns by first describing the milestones established through the study of vertebrate development and pluripotency. This will be followed by the illustration of extrinsic signals and molecular pathways associated to pluripotency. By way of introducing pluripotent stem cells achieved from alternative organisms, we compare the differences between human and mouse pluripotent stem cells and describe recent inferences on a distinct state of human pluripotency.
History of vertebrate development
The development of vertebrates involves the orchestration of a series of steps in a tightly regulated process that determines cell lineage specification into endodermal, ectodermal and mesodermal derivatives. Imprinted into the operational dogma of modern developmental biology, conception of these notions has been accompanied by a history of key observations and controversies.
Originating from examinations of the chick embryo, Aristotle witnessed the development of a palpitating heart, head and eyes, laying ink on a clean palette of embryology . With the proposition of epigenesis, he described development as a sequential process involving the formation of organs to construct a complete organism. Almost two thousand years after these initial recordings, the field was reawakened and the mechanisms behind these phenomena were questioned. To examine the root of development, Girolamo Fibrici performed dissections on cadavers of pregnant mammals, providing comparisons between anatomical structures of uteri . This work was advanced by his student William Harvey who hypothesised the presence of female germ cells within uteri that hold the capacity to constitute a new organism (). Furthermore, identification of budding and subdivision during primary stages of embryonic development of the chick led him to be a strong advocate of epigenesis. These findings revived Aristotle’s theory and provoked collision against preformation views. Preformationism was held as the dominant perception of development, and describes the existence of a miniature organism that expands without increasing complexity within the germ cell. Although epigenesis perceptions were resurrected, it was not received warmly. Transformation of the field of development biology was invoked by subsequent experiments led by Caspar Frederich Wolff and Karl Ernst von Baer. Using plants as a surrogate organism for study, Wolff explained the ability of differentiated plant root to regenerate a new organism. This study was traversed to chick embryos where Wolff studied the formation of embryonic kidneys . Building on the scaffold of information uncovered by his predecessors, von Baer discovered the presence of primitive germ cells and ultimately eclipsed any influence of preformationism .
Beginnings of the notion of pluripotency
Delineating vertebrate developmental processes proposes the presence of pluripotent cells which participate in the contribution of the cellular entirety of an adult organism. The first inkling of pluripotency was established by Hans Driesch who demonstrated that isolation of individual cells within 2-cell embryos culminated in the generation of two small complete larvae . In parallel, Hans Spemann validated the ability of detached cells within 2-cell newt embryos to develop into intact organisms . As Spemann was poised with micro-surgical skills, he extended his findings in embryology through the constriction of developing embryos using baby hair. By restricting the position of the nucleus to one side of the cytoplasm, development of the embryo into its 16-cell state would result in the escape of one cell past the noose, into the opposite end. This led to the formation of twin larvae, suggesting the pluripotent capacity of cells within the developing embryo. These findings illuminated a new era of embryological study and unravelled avenues for the study of pluripotency.
Embryonic carcinoma cells
To reinforce the notion of pluripotency, pluripotent cells have been successfully established on the Petri dish. Teratocarcinomas are tumours discovered in humans and mice ([2, 23]. Inspection of these cellular masses reveals the presence of a plethora of organised structures, including teeth, fingers and hair, suggesting the presence of pluripotent cells within the tumour. This was corroborated through the determination that intraperitoneal injection of a single cell could generate teratocarcinoma consisting of an array of differentiated tissues . Likewise, grafting of mouse embryos into adult mice also leads to the formation of teratomas, reinforcing the existence of all-encompassing cells ([24, 25]). Teratomas in both contexts have been successfully maintained in culture [26–29]. Designated as embryonic carcinoma (EC) cells, these cells exhibit pluripotent properties including the ability to form teratomas in immune-compromised mice and serve as the first platform to study embryonic development of mice in vitro.
Embryonic stem cells
Soon after, the inner cell mass of mouse blastocysts was demonstrated to be sustained on a petri dish, recapitulating an early developmental event in vitro [5, 6]. Labelled as embryonic stem (ES) cells, these cells were competent at contributing to the three germ layers in teratomas, when injected into immune-compromised or syngenic mice. Furthermore, re-introduction of these cells into the mouse blastocyst led to the formation of high percentage chimeras, indicating their ability to participate in normal murine development, a property not frequently shared with EC cells. To satisfy stringent pluripotent stipulations, ES cells were also studied for their ability to contribute to the germline and an intact embryo. The former was approached through the cross of chimeras to phenotypically distinct wildtype mice , whereas the latter was addressed through tetraploid complementation assays [31, 32].
Amenable to modifications, ES cells embody a useful tool for genetic alterations (reviewed in ). With the elucidation of the genetic composition of the mouse in 2002 , the genomic content of ES cells has been frequently disrupted in a precise fashion to study gene function. The capacity for germline transmission results in the establishment of intact mice harbouring any desired genetic mutation in the germline [35–38].
Epiblast stem cells
ES cells represent a subset of cells isolated from the epiblast in pre-implantation blastocysts and depict a primitive developmental stage of the developing embryo. To recapitulate late phases, two independent groups have segregated the columnar epithelial epiblast of the early post-implantation embryo and cultivated it on a petri dish [4, 9]. Termed as Epiblast stem cells (EpiSCs), they behave distinctly from ES cells and are rarely able to generate chimeras. However, both ES cells and EpiSCs are competent in multi-lineage differentiation, where injection of these cells into immune-compromised mice results in the development of teratomas comprised of tissue types characteristic of the three germ layers [4, 9].
Examination of the molecular circuitry within these cells revealed some similarities to ES cells, where the core transcriptional machinery consisting of Oct4, Sox2 and Nanog was expressed [39–41]. However, ES cells and EpiSCs exhibit disparities in transcript and epigenetic levels of markers associated to the inner cell mass and early germ layers , highlighting distinctions in their original developmental stages.
Embryonic germ cells
Pluripotent stem cells divergent from the mouse blastocyst were first derived from primordial germ cells (PGCs) [7, 8]. Emergent at 7 days post coitum (dpc), these cells are represented by a small population of alkaline-phosphatase positive cells . In a span of six days, these cells undergo extensive proliferation every 16 hours to comprise of 25,000 PGCs , and eventually reside in either the testis or ovary of the mouse.
Extraction of PGCs at 8.5-12.5 dpc from the posterior fragment of the embryo and cultivation in the presence of soluble factors such as leukemia inhibitory factor (LIF), steel factor (SF) and fibroblast growth factor (FGF), results in a population of cells that exhibits self-renewal and limitless proliferation ([7, 8, 44, 45]). Coined as embryonic germ (EG) cells, these cells resemble ES cells and are capable of generating chimeras and contributing to the mouse germline [7, 46, 47].
Artificial states of pluripotency
Historical perspectives on the study of vertebrate development illuminated the remarkable capacity of a fertilized oocyte to generate a complete organism. This led to the advent of nuclear reprogramming, denoted by the transition between unrelated cell types triggered by switches in gene patterns. Introduction of a somatic cell nucleus into an enucleated oocyte results in the re-establishment of epigenetic marks, allowing the hybrid cell to generate an organism (; [48, 49]). Termed as Somatic Cell Nuclear Transfer (SCNT), this technique has proved effective across species [11, 50], but is subject to technical competence and coordinated mitotic cycles (reviewed by ).
A similar phenomenon is observed upon the fusion of pluripotent stem cells and somatic cells. The environmental milieu arising from the pluripotent cell seizes control of the cellular transcriptional machinery and leads to the silencing of somatic markers in the fusion cells. The resultant heterokaryon is tetraploid but able to differentiate into all three germ layers [14, 52].
Recently, ectopic expression of four transcription factors was described to revert somatic cells to a pluripotent state . For the ease of nomenclature, these resultant cells were termed as induced pluripotent stem (iPS) cells. Mouse iPS cells are similar to mouse ES cells, and are capable of generating chimeras and contributing to the germline . Traversed across species, human iPS cells have since been obtained [54, 55]. The ability to generate patient specific iPS cells highlights its potential for cell therapy, drug screening and disease modelling (reviewed by ). Comprehensive studies of iPS cells and ES cells reveal minute differences in phosphoproteomic and transcriptomic components that were statistically disregarded . However, epigenomic analysis at high resolution expose subtle differences between iPS cells and ES cells [58, 59] and continuous in vitro culture could incur genomic aberrations [58, 60, 61]. These discrepancies could account for functional disparities such as epigenetic memory [62–64] and immunogenicity , surmising potential for improvement in the derivation of iPS cells which possess qualities that are identical to ES cells.
Chemicals and pathways associated with murine pluripotent stem cells
Pluripotent cells exist in a fleeting manner within the mouse embryo, placing emphasis on the remarkable extension of their life in culture. Supporting chemicals or matrix are necessary for the maintenance of pluripotency in culture, as exemplified in the reliance on fibroblasts and serum in primary studies describing ES cells, EC cells and EG cells, suggesting a non-cell autonomous mechanism in self-renewal. Extrication of components that support pluripotency, in concert with our current understanding of developmental pathways, can lead to the improvement of growth parameters of pluripotent cells, and augment our knowledge on embryonic development.
Stemming from the discovery that medium conditioned by Buffalo rat liver cells was sufficient to retain pluripotency , the active component necessary for this phenomenon was narrowed down to leukemia inhibitory factor (LIF) [67, 68]. The importance of LIF has been portrayed by its obligatory need in the culture medium , acting through gp130 and the recruitment of JAK kinase and STAT3 [70, 71]. The ability of LIF to maintain pluripotency in culture is mirrored in a physiological context, where LIF and gp130 are expressed in early embryos and during diapause .
Although LIF/gp130 and their related pathways are pivotal in the maintenance of pluripotency, the use of chemically defined basal media supplemented with N2, B27 and LIF is unable to impede differentiation of ES cells into neuronal derivatives . This propensity to differentiate can be restrained by the addition of bone morphogenetic protein (BMP), an anti-neural factor in vertebrate development . Functioning through Inhibitor of differentiation (Id), BMP together with LIF are sufficient to drive ES cells into self-renewal without differentiation .
Interaction between LIF and gp130 triggers a conflicting response, where both the JAK/STAT and ERK1/2 pathways are activated [75, 76]. As the latter stimulates differentiation, ERK or FGF inhibitors were demonstrated to circumvent this impediment and support the maintenance of ES cells . Activation of the Wnt pathway through the inhibition of GSK3β also assists in the sustenance of an undifferentiated state. The effects of ERK and GSK3β inhibition (2i) are compounded when used in combination, and results in a homogenous population of primitive cells designated as ground state pluripotency . Mirroring this in vivo, addition of 2i to early mouse embryos in culture causes an expansion of the Nanog-expressing epiblast at the expense of the hypoblast and trophoectoderm compartments . Growth media containing 2i and LIF has also made it possible to derive ES cells from mouse strains, such as CBA and NOD, and rats, which have been recalcitrant to previous methods [77, 80–82].
The culture conditions of EpiSCs are distinct from ES cells. FGF and Activin are necessary to preserve EpiSCs [4, 9], whereas the addition of 2i and LIF generally results in cell differentiation or death . In contrast, addition of an Activin inhibitor led to widespread differentiation, suggesting reliance on Nodal/Activin signalling .
The disparities reflected by dissimilar developmental potential and growth conditions of mouse ES cells and EpiSCs has led to the notion of naïve and primed pluripotency (Nichols and Smith, 2009c). Originating from the pre-implantation epiblast, ES cells display complete pluripotent potential and are capable of germline contribution. In contrast, EpiSCs derived from the post-implantation epiblast are incapable of neither somatic nor germline contribution, exhibiting limited pluripotent potential.
Classification of naïve and primed pluripotency has been strengthened by the analysis of X-chromosome inactivation (XCI). XCI is a process where one X chromosome in female diploid cells is inactivated, resulting in the reduction of most X-linked transcripts to comparable levels between males and females (; reviewed by ). Apart from EpiSCs, mouse pluripotent cells (ES, EC, EG, iPS cells) display two copies of active X chromosomes [86–88]. This is reminiscent of pre-implantation epiblasts which possess two active X chromosomes and hold the capacity to derive complete organisms, exemplifying naïve pluripotency [89, 90]. In contrast, EpiSCs exhibit XCI  or primed pluripotency and represent post-implantation epiblasts where XCI begins and the capacity to form whole organisms is lost.
Establishment of ES cells from other species
After successful isolation and culture of mouse ES cells, there have been several attempts at engineering an equivalent in various species, including rodents such as hamsters and rats [80, 81, 91], non-rodents such as rabbits, minks, chickens, pigs and cows [92–98], and primates such as rhesus monkeys and the common marmosets [99, 100].
Heightened interest in the generation of an array of pluripotent stem cells can be attributed to its potential to differentiate into an array of cell types, representative of the three germ layers. Application of this technology to humans illuminates the possibility of regenerative medicine. To address this, human ES cells were derived from cleavage stage human embryos that were acquired from in vitro fertilization donors .
With the successful establishment of human ES cells, much effort has been directed at understanding the pathways involved in maintaining the pluripotent cells in culture and modifications to growth conditions of human ES cells have since been implemented. Unlike mouse ES cells, LIF signalling is not sufficient to sustain undifferentiated human ES cells [102, 103]. In addition, BMP4 triggers trophectoderm differentiation in human ES cells [104, 105]. Instead, FGF and Nodal/Activin signalling pathways have been implicated in the self-renewal of human ES cells, reminiscent of EpiSCs [106–109]. Furthermore, comparison of gene expression patterns and XCI further supports the resemblance between human ES cells and EpiSCs .
Following the inception of transcription factor induced reprogramming, an array of human somatic cell types have been competently reprogrammed to derive human iPS cells [54, 55, 111, 112]. Human iPS cells represent an attractive source of patient-specific pluripotent cells and evade ethical concerns faced by the usage of human ES cells. Cultivated in a similar environment to human ES cells, human iPS cells display close resemblance when protein and epigenetic signatures are compared [57, 58], hence are also likened to EpiSCs.
Differences between human and mouse ES cells: naïve and primed pluripotency
The similarities between human pluripotent cells (human ES cells and iPS cells) and primed pluripotent mouse EpiSCs propose the possible existence of an unexplored naïve human pluripotent state reminiscent of mouse ES cells. Using human embryos, it has been recently demonstrated that introduction of inhibitors against FGF, ERK or GSK3 did not reduce the Nanog-expressing epiblast compartment, highlighting a stark contrast to conventional human pluripotent cells which readily differentiate in similar conditions [113, 114]. An additional study which traced the origin of human ES cells derived from human blastocysts noted that the establishment of human ES cell lines required the transition into a post-ICM intermediate displaying X-inactivation ().
Murine EpiSCs can be converted into ES cells with the ectopic expression of Klf2, Klf4, Nr5a2, or the addition of 2i and LIF ([83, 116], ). Likewise, human ES cells have been manipulated to phenotypically resemble mouse ES cells . Using iPS cell technology, similar cellular states have been achieved using chemical cocktails or various transgenic combinations [88, 118–120]. In some of these findings, both copies of X chromosomes are active, suggesting the possible attainment of naïve pluripotency. Strikingly, these novel pluripotent states rely on continuous transgenic expression, and only one study established human iPS cells that exhibited XCI reversion and transgene independence .
The study of pluripotency has amassed a wealth of information (Figure 1), from the discovery of nuclear reprogramming in the 1952, to the isolation of mouse ES cells and EpiSCs in 1981 and 2007 respectively. As the first vertebrate model organism used to study pluripotency, our understanding of the various stages during mouse embryonic development has thrived. Translating this knowledge to the developmental processes in other organisms may shed light on species-specific embryological properties, or offer refinements to the strategies employed for the study of development.
The identification of human pluripotent cells and their comparison to murine counterparts is one such example. Disparate chemical components within the growth media plays a critical role in the observed differences between primed human pluripotent cells and naïve mouse ES cells. The generation of mouse ES cells from the inner cell mass of the blastocyst involves the acquisition of new genetic profiles associated to self-renewal, epigenetic regulation and arrest of normal development , emphasising the influence of culture conditions on the establishment of cell lines. Furthermore, growth conditions can be manipulated to derive pluripotent cell lines from blastocysts which are distinct from mouse ES cells and EpiSCs , and EpiSC-like derivatives from fibroblasts using the conventional cocktail of reprogramming factors .
Although conventional human pluripotent stem cells resemble mouse EpiSCs closely, there exist differences between the two. EpiSCs express cell surface marker SSEA-1, whereas conventional human ES cells and iPS cells display SSEA3/4 (; reviewed by ). In addition, human ES cells, express pluripotency markers DPPA3, KLF4 and REX1, unlike EpiSCs [39, 110].
As the study of human pluripotency is in its infancy, parallel studies in mouse models can only serve as a guide and may not faithfully recapitulate the physiological events which occur during human development. However, recent pieces of evidence suggest the existence of a naïve state of pluripotency and may surmount difficulties met with FGF-dependent human ES cell and iPS cells. These include susceptibility to harsh dissociation, inability to survive in single cell suspension and genomic instability [125–130]. In conclusion, there remains much to be unearthed for the full elucidation of human embryonic development and further experiments are essential to uncover the proposed subset of naïve pluripotent stem cells.
This article highlights advancements in the study of pluripotency, evolving from primary embryological experiments, to the recapitulation of an array of pluripotent states in vitro. Murine ES cells were first reported in 1981  and represented an amenable and convenient platform to study developmental pathways and the sustenance of pluripotency. The identification of EG cells, EpiSCs and iPS cells led to the comprehension of various developmental stages. It was only in 1998 that success was met with human ES cells . Armed with 17 more years of research, mouse pluripotent states serve as a reference point when delineating human pluripotency. With the advent of iPS cells and sophisticated technical resources, knowledge garnered from the study of human ES cells and iPS cells will continue to amass exponentially, addressing our concerns on naïve pluripotency.
- ES cells:
embryonic stem cells
- EC cells:
embryonic carcinoma cells
Epiblast stem cells
- EG cells:
embryonic germ cells
- iPS cells:
induced pluripotent stem cells
leukemia inhibitory factor
fibroblast growth factor
Bone morphogenetic protein
Primordial germ cell.
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Ooi, J., Liu, P. Pluripotency and its layers of complexity. Cell Regen 1, 7 (2012). https://doi.org/10.1186/2045-9769-1-7
- Naïve pluripotency
- Primed pluripotency
- Embryonic stem cells
- Induced pluripotent stem cells
- Epiblast stem cells

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International Scientific Forum on Alcohol Research Critique 136: Alcohol’s Effects on Cardiovascular Risk among Subjects with Diabetes Mellitus
By International Scientific Forum on Alcohol Research | 19 March 2014
The latest critique from The ISFAR looks at a study of around 11,000 diabetes sufferers from 20 countries
A paper by Blomster JI, to be published in Diabetes Care is based on the largest study on diabetes in the world.
It assesses the effects of alcohol use among participants in the 'Action in Diabetes and Vascular Disease' (ADVANCE) trial. It was based on more than 11,000 subjects with diabetes from 20 countries, including those in Eastern Europe, Asia and established market economies in Western Europe, North America, and the Pacific region.
The outcomes over five years of follow-up were cardiovascular disease (CVD) events (death from CVD, non-fatal myocardial infarction, non-fatal stroke), microvascular disease (renal disease, diabetic eye disease), and all-cause mortality.
A U- or J-shaped curve for the relation of alcohol consumption to CVD among diabetics has been shown in most prospective epidemiologic studies for many years, and CVD is the leading cause of death among diabetics. A variety of potential mechanisms of protection against CVD have been described, including beneficial effects of moderate drinking on lipids, inflammatory markers, and insulin resistance.
Key results of the analyses showed that, during follow-up, more than 1,000 subjects (about 10%) had a major CVD, with similar percentages experiencing a microvascular complication or dying.
The authors said: “Compared with abstainers, any alcohol use was associated with a 17% lower risk of cardiovascular events, a 15% lower risk of microvascular complications, and a 13% lower risk of all-cause mortality.”
While there were few heavy drinkers (<4% of subjects), their data indicated that there was no significant lowering of risk of the outcomes among such subjects. Subjects who consumed wine had lower estimates of cardiovascular disease outcomes and mortality than consumers of other beverages.
Forum reviewers considered this to be a well-done analysis based on a large cohort of subjects with diabetes mellitus, with an adequate number of non-drinkers to serve as a referent group. The results strongly support previous studies that have shown a lower risk of cardiovascular events and total mortality among diabetic subjects who consume alcohol moderately. The study also showed that the risks of microvascular complications (diabetic kidney disease, diabetic eye disease) were lower among moderate drinkers.
The Forum considers this to be an important message (to physicians and the public), as the vascular ravages of diabetes are very serious, and diabetes is such a common disease that is increasing throughout the world. Diabetic patients without contraindications to alcohol should be informed of the potential cardiovascular protection of moderate alcohol consumption.
To read the full critique, click here.
These critiques are published with the permission of The ISFAR.
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Functions as an extension of the outdoors — appropriate only for non-heated, non-air conditioned spaces.


Sheppey AD plant transformed in eight weeks
Transforming an underperforming anaerobic digestion (AD) plant and increasing production by 30% within eight weeks is all down to experience, according to Eco Verde Energy’s (EVE) Operations Director, Chris Brown.
Lying just off the Kent coast, The Isle of Sheppey is a 36 square-mile island renowned for seaside holidays, blue-flag beaches, fossils and nature reserves. The Sheppey Energy Limited anaerobic digestion (AD) plant was completed on the island in late 2019, boosting the island’s capacity for green energy production.
The plant generates 37,843MWh via combined heat and power (CHP) and 450 cubic metres of biomethane per hour from energy crops and plant waste. The plant offers a circular energy solution, powering more than 3,000 homes in the community using crops from an adjacent farm and waste sourced from fruit growers, and businesses in the local area. Digestate is also supplied back to the farm to be used as a nutritionally dense fertiliser for feedstock crops.
Eco Verde Energy (EVE), a specialist AD O&M (operations and management) green services provider, onboarded the Sheppey plant to optimise its output potential and profitability.
EVE delivers success by following a phased approach to onboard plants, allowing the team to observe key areas where time and resources are needed to achieve a plant’s full potential.
“A holistic approach allows us to gain a bird’s-eye view of plant operation,” explains Chris Brown, Operations Director (South) at EVE. “From here, we can identify key areas of optimisation that will benefit the client in terms of where we need to focus our time and resources. These can include compliance areas, such as safety and maintenance frameworks, right up to production,” he adds.
People are the driving force of change
A strong team is critical to the success of any business, so one of the first tasks for EVE is to ensure employees at their sites have a unified sense of direction, stability and purpose to achieve a common goal.
While change can be unsettling for staff, the process is easier when the company coming on board has years of experience within the sector and all stakeholders involved have shared objectives. This gives a solid base to address wider operational factors, explains Mr Brown.
“Getting the staff on the ground to work as a cohesive team and identifying areas for training is crucial to help bring everyone together on the improvement journey. It also gives existing employees a renewed sense of security within their role,” he says.
“Once we’ve brought the team up to speed with new processes, we can turn attention to addressing other areas of the businesses such as quality control, equipment maintenance schedules or feedstock consistency,” adds Mr Brown.
EVE’s extensive specialist knowledge and expertise means they are able to conduct a gap analysis: an on-site fact-finding mission to help identify and resolve issues to improve compliance and efficiency levels.
At the Sheppey facility, the team found difficulty with the oxygen dosing system, a process that injects pure oxygen into the digestor to combat the build-up of hydrogen sulfide (H2S). The system did not have the correct maintenance programme in place and was injecting nitrogen into the digestor, causing the gas to be out of specification and tripping the gas-to-grid unit. After discovering the root cause of this issue, which was limiting production at the facility, the team implemented a planned maintenance schedule, allocating specialist contractors to conduct work, and confirmed key revenue-generating activity with gas-to-grid and CHP agreements.
Optimising feedstock to support plant output
Maintaining a consistent supply of feedstock is another hurdle to AD plants achieving maximum output, Mr Brown explains.
“Forward planning is a crucial aspect of keeping a plant running at the optimum output. Without a quality management system in place to control the incoming feedstock, the plant will use more of the crop than expected to maintain productivity.”
The team has conducted research into feedstocks to identify the best combination, with a focus on quality and reliability of supply.
“Understanding the mass balance of a plant and the potential of what the plant can actually deliver and process in terms of feedstocks is critical. A lack of planning can cause fluctuations in output, so at Sheppey, we’ve put a new management system in place to ensure that the plant will receive a regular supply of high-quality feedstocks on time,” he says.
As a result of implementing these initial changes, overall production at the site has increased by 30%, but according to Mr Brown, creating a successful AD plant takes more than fixing singular issues.
“You can’t look at a plant in isolation to assess its performance, there’s a multitude of factors that contribute to an efficient, safe and profitable plant. It’s not just about production and output, it’s also about compliance, health and safety and building a supportive team environment,” he explains.
“We’ve standardised our audit processes, which has enabled us to set our internal benchmarks towards achieving a compliance target of 90% for health and safety, so it’s fantastic to see that the plant is reaching the high standards we strive for,” adds Mr Brown
The team is looking to the future at Sheppey and is optimising the plant, putting measures in place to secure the site’s long-term viability. They are exploring plans to install equipment that will clean the biogas, by removing the carbon dioxide, which can be captured and sold for industrial and manufacturing processes, improving the profitability and diversifying income streams for the plant.
Mr Brown is clear that he considers the experience of the EVE team as being critical to the success of turning plants such as Sheppey to high levels of compliance and output.
“In my opinion, it’s the people and the culture that enable us to deliver results. By nurturing a strong team, we’re able to troubleshoot problematic AD plants effectively and achieve maximum output for our clients while maintaining sustainability,” he says.


Defeats Davis Riley in thrilling final match
NORTHFIELD, IL - Cole Hammer, of Houston, Texas, never doubted Saturday he would win the 116th Western Amateur at Sunset Ridge Country Club.
Neither did Davis Riley, of Hattiesburg, Mississippi.
The difference was Hammer, the tournament co-medalist, was the frontrunner nearly the entire championship match and was able to hold off Riley’s late charge to hoist the George R. Thorne Trophy. He’s the sixth 18-year-old champion, joining a group that includes 14-time major champion Tiger Woods and last year’s winner Norman Xiong.
“Surreal,” said Hammer, whose mother, Allison, served as his caddie all week. “Biggest day in my golf career, no question.”
A freshman at Texas, Hammer took the lead with a birdie at No. 3 and carried a 4-up advantage into the second nine. Riley won his first hole at No. 11 with a par, and then he went on a run. He trailed 1 down after his fourth birdie on the back nine on No. 16.
On the par-3 17th, Riley went first and hit it to 10 feet. Hammer also hit the green, but he was farther away. After Hammer missed his birdie putt, Riley’s match-tying effort slid past the hole.
The match ended when the two tied with pars on No. 18.
Even as Hammer’s lead shrunk, he remained confident in his chances. He called his 12-foot birdie putt on No. 13 that kept him 2 up a “huge momentum putt.”
“It gave me a big enough cushion, barely, to get it done,” he said.
Despite being down by as many as four holes on the first nine and three with four to play, Riley, a senior at Alabama, never counted himself out Saturday.
“I had faith in what I was doing,” he said. “I stayed patient, and I was good enough to make a charge. I knew I could do it. I hit some good shots and made some birdies.”
According to Riley, the momentum was on his side after his tee shot on No. 17, even though he was 1 down after 16 holes.
“I hit that shot, and anybody would get a little nervous,” he said. “If I could have made that putt, I was going to win it.”
Hammer’s 76 holes in four rounds of match play tied the record with Justin Leonard (1992) and David Chung (2010) for most holes played. He becomes the second consecutive player to earn medalist honors and win the overall title. Sam Stevens, of Wichita, Kansas, tied Hammer for medalist honors to qualify for the Sweet 16 before losing in the first round.
Five other Texas Longhorns have won the Western Amateur, including major champions Ben Crenshaw and Leonard. Beau Hossler was the most recent, winning the title in 2014 at Beverly Country Club in Chicago, Illinois. Doug Ghim, another Longhorn, was the medalist that year.
“It was a really special week from start to finish,” Hammer said.
Both Hammer and Riley will compete in the U.S. Amateur at Pebble Beach Golf Links in Pebble Beach, California, on Aug. 13-19.


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California is a must-visit state for any car enthusiasts, with no shortage of remarkable events.
California is often criticized for its overabundance of Starbucks and Chipotle franchises.
On the other hand, California is often praised for its stunning scenery, beautiful beaches, and excellent weather.
Cali is home to some of the world's best driving roads, with beautiful scenery and long, winding roads. Here are the three best backroads to drive in the beautiful state of California.
3. Angeles Crest Highway
The Angeles Crest Highway is a 66-mile stretch of road that is home to stunning mountain and forest views. This road is stretched between Los Angeles County and San Bernadino County.
The road is littered with plenty of straights, twists, and turns, the ideal haven for any car or bike enthusiast.
2. Mulholland Drive
Mulholland Drive is a 21-mile stretch of road nestled in the Santa Monica Mountains of Southern California. This road takes you right along the Hollywood Hills and gives you excellent views of Los Angeles.
While this route is well-known for its beautiful scenery and neat twists and turns, it tends to be relatively light on traffic, making Mulholland Drive a must-visit for anybody whose veins are filled with 100 octane fuel.
1. Palos Verdes Drive
Palos Verdes Drive is home to some of the best scenery California has to offer. This stretch of road offers brilliant views of the ocean while keeping any driver occupied through twisty, windy roads with sharp hairpin turns. The Palos Verdes area is arguably the most beautiful region of SoCal, if not California as a whole, making it a must-visit for anybody in the area.

domain: geography


Catching passes from Matthew Stafford was something that Marvin Jones got acclimated to in the past five seasons during his time with the Detroit Lions. Could Jones be one of the players from the Lions who reunites with Stafford on the Los Angeles Rams this offseason?
With the stellar acquisition of Stafford, the Rams could very well be in the market for a wide receiver that can create plays down the field. Josh Reynolds is an impending free agent and Los Angeles isn’t expected to make an effort to retain him this offseason.
When free agency gets underway, I fully expect the Rams to be a team who is seeking a bargain option at the wide receiver position. I’ve already done a free-agent profile for John Ross, who could also be a target for Los Angeles once the free agency period begins.
By looking at their current cap situation, Los Angeles isn’t going to be able to afford any of the elite wide receivers on the open market. But with Jones likely being a feasible addition, I’ll be taking a quick look at how he’s fared thus far in his career, if he’d be an ideal fit on the Rams, and what his free-agency market could look like.
Back in 2012, Jones jumpstarted his career in the NFL as a fifth-round selection of the Cincinnati Bengals out of Cal. Jones had a somewhat quiet rookie season in 2012 as he tallied only 18 receptions for 201 yards and one touchdown in 11 games of action.
However, in his sophomore campaign, Jones exploded for 51 catches, 712 yards, and 10 touchdowns as the No. 2 option alongside A.J. Green. While Jones missed the 2014 season due to an ankle injury, he would compile another productive year with the Bengals in 2015 before joining the Lions ahead of the 2016 season.
|5 yr||5 yr||DET||69||67||478||289||4296||14.9||36||205||73||4.2||62.3||60.5%||9.0|
|3 yr||3 yr||CIN||43||21||215||134||1729||12.9||15||81||47||3.1||40.2||62.3%||8.0|
How would Marvin Jones fit with the Rams?
Seeing that Jones doesn’t possess the same speed he came into the league with, he may not be the every-down, vertical threat that the Rams need. With that being said, he is more than capable of putting pressure on the defense vertically. Just this past season, Jones averaged an aDOT of 12.7 yards, which was the 18th most among wide receivers who saw 50+ targets.
His aDOT of 12.7 yards was also 2.3 yards more than the highest aDOT on the Rams, with Reynolds logging an aDOT of 10.4 yards for Los Angeles in 2020. Provided that Stafford loves to push the ball down the field — and did so by targeting Jones on the Lions — Jones would be a welcomed addition to McVay’s offense.
What Jones lacks in speed nowadays — he’s still pretty quick — he more than makes up for it with his contested-catch ability and his ability to create after the catch. While Kenny Golladay was sidelined for 11 games for Detroit in 2020, Jones logged an impressive 72.7 percent contested catch rate (fifth-best among wide receivers).
Given his previous experience with Stafford, Jones wouldn’t need much time to get on the same page as the gunslinging signal-caller. Also, the idea of pairing Jones with Cooper Kupp, Robert Woods, and Van Jefferson is something that could cause McVay to get even younger (if that is even possible).
Marvin Jones Free agency outlook
Heading into free agency, there is a large group of talented wide receivers that could be playing elsewhere in 2021. Besides Jones, Golladay, Allen Robinson, Chris Godwin, Will Fuller, JuJu Smith-Schuster, Corey Davis, Curtis Samuel, and even more are all set to hit free agency.
With the wide receiver market increasing exponentially in recent seasons, it’s fair to assume that a majority of these guys could garner lucrative contracts or get the franchise tag. As for Jones, being that he turns 31 years old on March 12, his price could be on the more affordable side, which bodes well for the Rams.
According to Spotrac’s Market Value Jones could be set to make $10.5 million annually. Though, with the lowered salary cap for teams this offseason, it remains to be seen if a team is willing to offer $10 million or more for Jones
Jones was born in Los Angeles, and he is reportedly among the players from the Lions who are interested in reuniting with Stafford. Being able to play for a contending team for the first time in his career — while playing near home — could be a breath of fresh air for the veteran wideout.
Even though he doesn’t have the accolades of the other wide receivers on the market, Jones should still see interest from other teams. But the pros of playing for the Rams could be enough to convince the heavily underrated wide receiver to sport horns on his helmet.


Dermot Murnaghan is a well-known British journalist, broadcaster, reporter, and personality in the television media. He also presents the news on television. He became well-known for his work as a presenter for Sky News, which contributed to his rise to prominence. He began hosting news programmes shortly after beginning his tenure at Sky News in the year 2007.
Murnaghan is a newscaster for several outlets, including BBC News, CNBC Europe, Sky News, and Independent television. He began his career at Channel 4 as a researcher, and then, in the early 1990s, he made the shift to reporting for the business round-up on that station. After that, he moved on to ITV to become the host of the News at Ten, where Dermot was in charge of handling breaking news for the UK.
Among his hosting duties at ITV, he was responsible for News at Ten and ITV Lunchtime News. Between the years 1993 and 1997, he served as the host of approximately one hundred episodes of the news show The Big Story. Murnaghan broke the news to viewers of ITV in 1997 that Diana, Princess of Wales, had passed away while she was working for ITN as a newscaster. The coverage of the general election in 2001 that was shown on ITV also included contributions from a television presenter.
In addition to that, he was the anchor of the programme Murnaghan on Sky News, which aired on Sunday mornings from ten in the morning until twelve in the afternoon from January 2011 until December 2016 inclusive. Since September 2016, he has been the host of Sky News Tonight from Monday through Thursday of each week.
What Can You Tell Me About Maria Keegan, Dermot Murnaghan’s Wife?
Maria Keegan, who is married to Dermot Murnaghan, has established herself as a prominent journalist.
Maria is responsible for handling both the household budget and Dermot’s business office in addition to her other responsibilities. In August of 1989, the couple married and the ceremony took place in Camden. Both of them had attended Sussex University, and it was at that institution that they made their initial acquaintance. In a past interview, he lauded his wife for the way she handled the responsibilities of running the household.
During an interview held four years ago, a journalist claimed, “I receive my happiness mostly from my wife and family, and the satisfaction I get from my job comes in second place.”
The couple has been together for some time and currently makes their home in North London. They are parents to four children. Both of the partners in the marriage are quite successful in their own fields of work. Because they are both so driven to be successful in their own careers, they each exude an exceptional amount of charm and have developed their own individual personas. They have proven their worth in the field of journalism by establishing a name for themselves and displaying their abilities.
Sky News Presenter Dermot Murnaghan, who is in charge of the Children and Family segment
The presenter of Sky News, Dermot Murnaghan, and his wife, Maria Keegan, have raised four children together. He has not disclosed any of his private information to the press despite the fact that he is widely considered to be one of the most respected journalists covering the news.
In addition to this, he has made the decision to protect his children from the attention of the media, possibly in an effort to provide them with a normal life away from the limelight.
When discussing Dormot’s professional life, it is important to note that he was born in Barnstaple, Devon, England, on December 26, 1957, to parents who cared deeply about their children. After some time, he and his family moved to Northern Ireland, initially settling in Holywood and later relocating to Newry, which is located in County Down.
The journalist had his primary education at St. Malachy’s Primary School, located in Armagh City, and his secondary education at Sullivan Upper School, a grammar school located in Northern Ireland. After that, the TV presenter continued his education at the University of Sussex in England, where he received a master’s degree in history in the year 1980. Later on, he graduated with a master’s degree in journalism from City University London.
How much money does Dermot Murnaghan make per year? What is his estimated net worth for 2022?
According to the website celebworth, Dermot Murnaghan is reported to have a net worth of $5 million, and he earns $800,000 every year.
Dermot is one of the most well-known and successful journalists in the world. He is also quite wealthy. He invested a considerable amount of his life into this sector, working for some of the most prestigious and well-known companies in the world.
Throughout the course of his career, the news presenter has garnered increasing levels of both recognition and notoriety. After being elected president of the Television and Radio Industries Club (TRIC) in 2006, he was the host of the TRIC Awards the following year in 2007. His work as a British journalist, broadcaster, reporter, TV media personality, and news presenter has been the principal source of his income throughout his career, and as a result, he has earned a considerable wealth up to this time.
Because he has so many different avenues of financial support, he has been able to build a substantial fortune and can now afford to live an extravagant lifestyle.
Intimate Relationship Between Dermot Murnaghan and Camilla Tew
Dermot Murnaghan is involved in a number of different romantic relationships at once. In 2012, Dermot, a married broadcaster, was caught kissing Camilla, his makeup artist, when they were on a secret date in the park. The two of them had been seeing each other for some time.
Dermot Murnaghan and Camilla Tew are seen sitting next to one another, possibly feeling self-conscious about the presence of other people in the room.
Camilla has worked as a makeup artist for Sky News, as well as for the BBC’s Spooks series and the film The Pinocchio Effect. She has also contributed to both of these projects.
They sat on a blanket that they had laid out at the banks of the Serpentine lake, which is a popular tourist destination, and they embraced and kissed in the bright sunlight in front of a large number of people. But once the two were seen kissing and cuddling, Murnaghan was not going to look good no matter how much gloss was applied to her face.
At one time, Murnaghan was observed fumbling with a zip that was located down the front of Miss Tew’s red dress. Someone who was seeing them from a distance noted that they could have been any other recently married couple. In addition to this, it seemed as though they were at comfortable with one another and that neither of them had any concerns about the outside world. Aside from this one instance, there is no more evidence to support the allegations or affairs around Murnaghan.
Dermot Murnaghan Career
Before joining Channel 4 initially as a researcher and then as a reporter for The Business Programme, Murnaghan gained experience in the field of journalism by working as an intern for a number of local newspapers.
Before being recalled by ITN to broadcast the World News on The Channel 4 Daily between 1991 and 1992 after the departure of the original anchor Carol Barnes, Murnaghan hosted the European Business Channel in Switzerland. This was during the time period between 1991 and 1992.
Murnaghan was the host of a number of shows on ITV, including “News at Ten” and “ITV Lunchtime News.” Approximately one hundred episodes of the current affairs show The Big Story were fronted by him during the years 1993 and 1997. Murnaghan was working as a news presenter for ITN in 1997 when he was the one who informed ITV viewers of the passing of Diana, Princess of Wales. After thereafter, he became the host of the ITV Evening News and the ITV Nightly News during the network’s 1999 relaunch of their news programming. In addition, he was a contributor to ITV’s coverage of the general election in 2001.
Murnaghan took over the role of main presenter of BBC Breakfast from Jeremy Bowen in September 2002 and remained there until December 2007. Alongside Sophie Raworth, Natasha Kaplinsky, Kate Silverton, and Susanna Reid, he was one of the show’s presenters. Additionally, he was a regular stand-in on the BBC Six O’Clock News and the BBC Ten O’Clock News. Additionally, he co-presented the BBC News at Six on Fridays alongside Sian Williams from September 2003 until the summer of 2007. In the impersonation sketch show Dead Ringers, hosted by Jon Culshaw, his presenting style was made fun of by mocking his widely separated legs on the presenting couch with the slogan “I’m Dermot Murnaghan, watch my crotch follow you round the room.”
While he was working for the BBC, he and Suzi Perry co-presented Treasure Hunt on BBC Two (2002–2003). This show was a resurrection of an older format that had originally shown on Channel 4. In addition to routinely hosting the national BBC news bulletins up until December 2007, he was a co-host of the BBC Breakfast show Monday through Thursday.
It was revealed in October 2007 that Murnaghan will be departing from his position at the BBC to take up a position at Sky News. In the same month that Murnaghan departed the organisation, Natasha Kaplinsky also left to join Five News, which is produced by Sky. Murnaghan became the second news presenter to leave the corporation. The morning of December 20, 2007, was the last time he hosted Breakfast.
Eggheads was a daytime show broadcast on BBC Two from 2003 to 2014, and Murnaghan was the host of both Eggheads and its spin-off series, Are You an Egghead?, which aired for just two seasons in 2008 and 2009. Following his shift to Sky News, he worked in this capacity alongside Jeremy Vine, who eventually took over as the program’s sole presenter beginning with series 16. Murnaghan has been as a guest presenter on a variety of travel series, including ITV’s Wish You Were Here…? and the competing programme Holiday on BBC One. Cameos as a newsreader can be found in the films Wimbledon (2004), Absolute Power, and Midnight Man, all of which he appeared in.
Murnaghan hosted his own show, titled “Murnaghan on Sky News,” beginning in January 2011 and continuing all the way through December 2016, when it was shown on Sunday mornings from 10:00 am to 12:00 pm. Since September of 2016, he has been hosting the Monday through Thursday edition of Sky News Tonight. Murnaghan acted as the host of the overnight coverage of Sky News’ election coverage for the 2019 general election, which was branded The Brexit Election.


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March Zuma Online Game
March Zuma Game DescriptionA great and funny version of the classic Zuma. People are lining up for great circus acts. Prevent the line from becomming to long by placing other people of the same colors in the lines and removing pairs of 3. Or place 3 of the same types of people together, like sunglasses and blond girls. When you removed enough people you will move on to the next level.
This game is played with mouse only.
March Zuma Game Instructions
Puzzle Online Game info
|Hot or not:|
|Category:||Puzzle games » Bubble Shooter games|
More Bubble Shooter games
Put the bubbles in the right container and then push the correct button. Sort all... Play game »
Destroy the fish balls by shooting them into groups of 3. You must clear all the f... Play game »
|Willy Wonka's Bubble Trouble
Keep Violet's bubble from bursting as she floats trough the factory! Play Bubble T... Play game »
Your objective in this arcade game is to control a bubble cannon placed in the mid... Play game »

domain: entertainment


text:
News - 7 Apr 2021
A new type of battery designed by scientists from St Petersburg University can charge 10 times faster than a regular lithium-ion battery.
Image Credit: Hryshchyshen...
News - 6 Apr 2021
Organic solar cell (OSC) is one of the most important green energy technologies. The photovoltaic efficiencies of OSCs are closely related to the photoactive layers, which are prepared by blending...
News - 30 Mar 2021
This could be where the rubber truly hits the road. Rice University scientists have optimized a process to convert waste from rubber tires into graphene that can, in turn, be used to strengthen...
News - 30 Mar 2021
ESPOO, Finland, 30th of March 2021 – Picosun Group reports strong growth and a positive operating profit from its fiscal year 1.1.2020-31.12.2020.
Fiscal year 2020 in...
News - 24 Mar 2021
Materials that interface with the human body, plastics to sequester carbon dioxide and other innovative and sustainable polymers will be explored in the opening session of the spring meeting of the...
News - 19 Mar 2021
A new, simpler solution process for fabricating stable perovskite solar cells overcomes the key bottleneck to large-scale production and commercialization of this promising renewable-energy...
News - 22 Feb 2021
A chemist from RUDN University, working with a group of colleagues, synthesized three new chalcogenides (compounds that contain metals and elements from group 16 of the periodic table). The team...
News - 19 Feb 2021
Applied Rigaku Technologies, Inc. Exhibiting Virtually at the 2021 Pittcon Exposition on Analytical Chemistry and Scientific Instrumentation
AUSTIN, Texas, February 16, 2021 – Applied Rigaku...
News - 17 Feb 2021
Research into 3D bioprinting has grown rapidly in recent years as scientists seek to re-create the structure and function of complex biological systems from human tissues to entire organs.
News - 16 Feb 2021
Dublin, Ireland, 16 February 2021 – Tibidabo Scientific Industries Ltd (“Tibidabo Scientific”), a global leader and supplier of highly differentiated technology for scientific...

domain: chemistry


text:
Red Rocket Pizza
Red Rocket Pizza specializes in ready-to-eat, wood-fired pizzas. Each pizza is made to order, using high-quality ingredients such as pre-cooked meats, fresh produce, and delicious cheeses. What sets Red Rocket Pizza apart is they combine traditional pizza-making techniques from Italy with the bold and unique flavors of New York, resulting in a pizza that's both classic and contemporary. Each pizza is cooked in a wood-fired oven, giving it that perfect crispy crust and smoky flavor!

domain: food