Both of these groups of activities, carried out by stakeholders what we can call the ‘Inputters’ Vincristine datasheet and the ‘Extractors’, occur within the system being managed and so are regarded as Endogenic Managed Pressures, in which we need to control the causes and consequences. However, in the case of discharges to catchments (e.g. nutrients, persistent pollutants) outside the sea area being managed, these are also Exogenic Unmanaged Pressures in which we respond to the consequences without necessarily addressing the causes (Elliott 2011). Those

‘Inputters’ and ‘Extractors’ thus encompass the uses and users of the marine system. The third group of wider pressures such as global climate change will also be regarded as Exogenic Unmanaged Pressures, Belnacasan order i.e. the cause is not within the sea or ecoregion being managed but globally although marine management and the response to the consequences of climate change, such as building sea-defences to accommodate increased storminess

or water retention areas to accommodate relative sea-level rise, has to be within the management area. Marine management is required to deliver the Ecosystem Services which, following the input of complementary assets and human capital such as time, money, energy and skills, can then be translated into and deliver Societal Benefits (Atkins et al., 2011). For example, the marine system can maintain the ecological and hydrological processes to produce sediments, invertebrates and fish but society has to expend complementary assets (by building boats and infrastructure) to catch, process and consume those fish. GPX6 Hence the uses and users may affect another major group of stakeholders (‘Affectees’), for example by restricting the available area for other activities,

but provide the goods and benefits for the ‘Beneficiaries’) (Fig. 2). The actions of the users and the repercussions of the uses are then controlled by a system of governance (defined here as the politics, policies, administration and legislation of the system) and particularly by the ‘Regulators’ as a blanket-term for all stakeholders involved in that governance. Such a governance needs to operate at levels from the local to the national to the regional to the wider ecoregion and ultimately to global scales and thus constitute the Response in DPSIR to the problems created (Boyes and Elliott, 2014b). Hence we need vertical integration throughout those levels of governance across the geopolitical levels – for example, within Europe, global agreements such as those emanating from the UN Law of the Sea or the International Maritime Organisation, will filter through Regional Seas Conventions such as the OSPAR or HELCOM and the European Commission down to national legislatures and even to local bylaws and agreements (Boyes and Elliott, 2014b). The above indicates what we might consider elements of a generic typology of stakeholders to which we should also add the ‘Influencers’, i.e.

Nie udało się jednak wykazać pozytywnego efektu klinicznego przy zastosowaniu tego typu leczenia. U pacjenta z zespołem Zelwegera zastosowanie GTO obniżyło poziom VLCFA o ∼ 50%, nie wpłynęło to jednakże na stan kliniczny pacjenta [37]. Podobne wyniki uzyskano w przypadku stosowania kwasu dokozaheksenowego (docosahexaenoic acid DHA) [38]. Natomiast są doniesienia, ale niepotwierdzone przez inne badania, że zastosowanie DHA w noworodkowej adrenoleukodystrofii polepszyło stan neurologiczny pacjentów

[40]. Stosowanie oleju Lorenza (Lorenzo oil, LO) wraz z dietą ubogotłuszczową, będącego mieszaniną GTO i GTE (trójerukan glicerolu – grycerol trierucate) normalizuje w okresie ∼2 miesięcy poziom VLCFA w płynach ustrojowych [39]. W literaturze pojawiały się sprzeczne informacje na temat skuteczności tej formy learn more terapii. Niektórzy autorzy uważają, że prowadzenie pacjenta na LO w okresie bezobjawowym może opóźnić wystąpienie objawów neurologicznych choroby. W ostatnich latach donoszono o łagodzeniu objawów przez stosowanie leczenia przeciwzapalnego i immunosupresyjnego u chorych z zapalną postacią X-ALD [34]. Od kilku lat jest również stosowany przeszczep szpiku (hematopoietic cell transplantation – HCT). Na obecnym etapie doświadczeń uważa się, że przeszczep komórek macierzystych może być skuteczną metodą prowadzenia chorego z X-ALD/AMN

tylko w najwcześniejszej fazie choroby, przed wystąpieniem objawów neurologicznych lub przy minimalnych zmianach demielinizacyjnych w AMN. Angiogenesis inhibitor W czystej formie AMN stosowanie HCT jest niewskazane [40]. Ze względu na różnorodność fenotypów oraz dużą labilność czasową występowania pierwszych objawów są trudności

Montelukast Sodium z oceną skuteczności stosowanych metod terapeutycznych. Bardzo duża heterogenność ekspresji klinicznej w X-ALD, brak możliwości przewidzenia u osób bezobjawowych rozwoju ewentualnej postaci i przebiegu choroby, czyni niemal niemożliwym wiarygodną ocenę skuteczności, określonej formy terapii. Autorka pracy nie zgłasza konfliktu interesów. “
“Gruźlica jest wciąż aktualnym problemem. Występuje rzadziej niż przed erą antybiotyków oraz szczepień niemniej w ostatnich latach obserwuje się ponownie wzrost zachorowań [1]. Jak wynika z danych epidemiologicznych w Polsce w pierwszych latach powojennych gruźlica w całej populacji, w tym również u dzieci i młodzieży, była poważnym problemem zdrowotnym. W 1957 r. zanotowano 16 402 nowe zachorowania wśród dzieci do 14 r.ż. i 5757 zachorowań wśród młodzieży [2]. W 2007 r. zachorowało w Polsce 74 dzieci, w tym 17 przypadków dotyczyło dzieci do 4 r. ż. Obserwuje się zwiększoną zachorowalność wśród dzieci mieszkających w mieście – 74% [3]. Zakażenie następuje drogą kropelkową a czynnikiem etiologicznym jest Mycobacterium tuberculosis (99%) oraz zdecydowanie rzadziej Mycobacterum bovis (1%) [4].

Our results suggest that PINA and PINB act redundantly to remove auxin from the apex and initiating leaves, allowing normal development to proceed. As shoot development is strongly affected in pinA single mutants treated with 100 nM NAA, but not in pinB mutants, we postulate that MK-1775 order PINA plays the dominant role ( Figure S4B). These data support the hypothesis that the apical auxin distribution in Physcomitrella regulates gametophore architecture and is modulated by PIN proteins. To further test the hypothesis that PIN proteins modulate the auxin distribution in Physcomitrella, we analyzed

the staining distribution pattern of the GH3:GUS reporter [ 50] in WT and mutant plants ( Figure 5A). In pinA and pinB

single mutant shoots, staining was slightly stronger than in WT and displaced up the stem. In contrast, the staining intensity in pinA pinB mutants was strongly reduced with respect to WT and single mutants and, where present, was localized to the middle Selleck Torin 1 portion of the stem. Gametophores with the most-severe leaf phenotypes had the least signal and very few rhizoids initiated; no basal zone of rhizoid emergence was apparent ( Figures 5A–5C). Transverse sections taken through the base and midstem region confirmed this inference, indicating a difference in the apical-basal auxin level and distribution as the main defect ( Figures 5B and 5C). To test whether auxin-inducible phenotypic alterations to shoot development ( Figure 3A) corresponded to an altered auxin response distribution, plants were grown on 100 nM NAA before staining. Whereas gametophores with a class I–III response showed only an upregulation in signal intensity, pinA and pinA pinB mutants with class IV and V phenotypes accumulated staining toward or at the apex ( Figure 5A). These data support the hypothesis that PIN proteins modulate the auxin distribution in gametophores. In angiosperms, PIN-mediated polar auxin transport drives phototropic and gravitropic responses in shoots and roots [58 and 59]. Physcomitrella

filaments and gametophores have strong negative gravitropism when grown in the dark [ 60]. Interestingly, moss mutants defective in filament gravitropism are not defective in shoot gravitropism, suggesting that two distinct Adenosine triphosphate tropism pathways may operate [ 60]. To assess a putative role for PIN-mediated auxin transport in gravitropism, we grew WT, single and double pin mutants for 2 weeks in the light and then grew them vertically in the dark on sucrose supplemented medium (0.5% w/v) for a further 2 weeks. In WT plants, this treatment induced a strong negative gravitropic response in both filaments and gametophores ( Figures 6A–6C). Whereas pinA and pinB single mutants showed a normal gravitropic response, the pinA pinB double mutant had agravitropic gametophores. This result was phenocopied by treatment with 2,4-D (data not shown).

Serum infliximab concentrations and efficacy outcomes at week 8 (time for induction efficacy end points for both ACT-1 and ACT-2), week 30 (time for maintenance end points for both ACT-1 and ACT-2), and week 54 (additional time for maintenance end points for only ACT-1) were the primary focus of these analyses. The prognostic value of earlier PCI-32765 order infliximab concentrations on

subsequent efficacy outcomes also was evaluated. Patient characteristics and serum infliximab concentration data were summarized using descriptive statistics. The correlation between serum infliximab concentrations at different time points was assessed using the Pearson correlation coefficient. Serum infliximab concentration data were compared between patients with and without the specified efficacy outcomes using a 2-sided Wilcoxon–Mann–Whitney, 2-sample, rank-sum test. Serum infliximab concentrations also were categorized into quartiles, and the trend of the proportion of patients with clinical outcomes across the quartiles was evaluated using the 1-sided Cochrane–Armitage trend test. Comparison of the

proportions of patients with a given efficacy outcome across serum infliximab concentration quartiles or across a given categoric variable was performed using the Fisher exact test, and the Kruskal–Wallis Apitolisib test was used to compare continuous variables across quartile groups. The association between serum infliximab concentration (log-transformed) and clinical outcomes was evaluated further by multivariable logistic regression modeling. The effects of covariates (body weight, age, albumin, C-reactive protein level, Mayo score, sex, ATI status, and the use of immunosuppressive agents and corticosteroids) were assessed by logistic regression analyses. A backward elimination approach using a significance level of .05 for a covariate as a requirement for continued inclusion PAK6 in the model was adopted. Receiver operating characteristic

(ROC) curve analysis was used to identify infliximab concentration thresholds associated with efficacy during induction and maintenance. Optimal thresholds were chosen using the Youden17 index, which maximizes the sum of the specificity and sensitivity of the ROC curve. All authors had access to the study data and reviewed and approved the final manuscript. The baseline characteristics of patients who participated in ACT-1 and ACT-2 have been detailed.2 A summary of characteristics for patients who were randomized to infliximab treatment in both studies is provided in Supplementary Table 1. The distribution of serum infliximab concentrations observed at each visit through week 30 in patients receiving infliximab 5 or 10 mg/kg is shown in Supplementary Figure 2. When assessed by clinical response status (using total Mayo score) at week 8, serum infliximab concentrations over time were higher among patients with clinical response than among patients without response, as illustrated for both dose regimens in Figure 2.

It has also been suggested that because the vestibular system plays a role in controlling autonomic functions (e.g. heart rate, blood pressure) (Yates and Miller, 1998), alterations to these autonomic functions may also trigger a range of changes in cognition, emotion and personality. There are

several reports that suggest patients with vestibular disturbance experience symptoms of depression, anxiety and agoraphobia at higher rates than the general population (Eagger et al., 1992, Gazzola et al., 2009 and Guidetti et al., 2008). In a study of 93 patients with objective evidence of peripheral vestibular disorder two thirds of the patients reported symptoms of depression and/or anxiety since the onset of the vestibular symptoms. Fifty-four of these patients were

seen 3 to 5 years after their original referral and more than half the group (37 out of 54) were rated above the cut off point for selleck chemicals significant psychiatric disturbance when interviewed. Panic disorder with or without agoraphobia and major depression were the commonest psychiatric diagnoses. There is some evidence to suggest that these symptoms are more than a reaction to the symptoms of vestibular dysfunction (e.g. vertigo or dizziness). For example, Guidetti et al., (2008) reported significantly higher Oligomycin A price levels of anxiety and depression in 50 patients with well compensated (no vertigo symptoms) unilateral labyrinthine hypofunction as a consequence of previous vestibular neuritis

as compared to 50 age- and sex-matched healthy controls. Somewhat contrasting these findings is a recent prospective study that looked at predictors of anxiety (STAI) and depression (BDI) in 407 patients who presented with dizziness and vestibular disease (194 patients were diagnosed with BPPV, 75 with vestibular neuritis, 63 with Ménière′s disease, 58 with migrainous vertigo, and AMP deaminase 17 with presbystasis). Results suggested that rather than the type of vestibular disease, the best predictor of depression and anxiety was the patient′s level of distress associated with symptoms of dizziness or vertigo (dizziness handicap inventory scores) (Hong et al., 2013). A series of prospective, interdisciplinary studies were conducted to explore the relationship between comorbid psychiatric disorders and symptoms in patients with various organic vertigo syndromes (Best et al., 2006 and Eckhardt-Henn et al., 2008). Patients with organic vertigo syndromes (benign paroxysmal positioning vertigo—BPPV; vestibular neuritis; Menière′s disease; vestibular migraine), and healthy volunteers were assessed on the Symptom-Check List 90 (a standardised, self-reporting instrument that measures psychological strain) and The structural clinical interview for DSM-IV Axis I (SCID-I). Results of the initial study (Best et al.

Conversely, the constant activation of p53 consecutive to ribosomal stress induced by RPS20 mutation could favor, in the long run, the selection of cells that escape regulation by p53. In summary, we

show that inactivating germline mutation of RPS20 is associated with a dominant predisposition to colorectal cancer. This report links germline mutation of RPS20 to human disease. Future investigations are necessary to establish the prevalence of RPS20 mutations in FCCX families worldwide as well as the exact tumorigenic mechanisms Selleck PI3K inhibitor and the basis of apparent tumor-type specificity. Finally, our study encourages investigations into the possible involvement of other ribosomal protein genes in colon cancer susceptibility. The authors thank Saila Saarinen for expert technical assistance and Tuula Lehtinen and Kirsi Pylvänäinen for help in collecting clinical data. The authors also thank Dr Hanna Gazda for helpful discussions. “
“Podcast interview: www.gastro.org/gastropodcast.

Also available on iTunes. Current therapies for Crohn’s disease (CD), a chronic inflammatory disorder of the alimentary tract,1 include corticosteroids; immunosuppressives (eg, azathioprine, 6-mercaptopurine, methotrexate); the tumor necrosis factor (TNF) antagonists infliximab, adalimumab, and certolizumab; and the anti–α4 integrin Doxacurium chloride monoclonal antibody natalizumab.1, 2, 3, 4, 5 and 6 Treatment with TNF antagonists substantially has improved

the care of RG7420 manufacturer patients with CD that is refractory to other treatments by inducing and maintaining remission and decreasing the need for hospitalization and surgery.7 and 8 However, in controlled trials, approximately two thirds of patients did not attain or maintain remission at 1 year after TNF antagonist initiation.9, 10 and 11 In addition, patients in whom 1 TNF antagonist has failed have a substantially decreased response rate when treated with a second TNF antagonist.12 and 13 Important safety concerns are associated with the immunosuppressive effects of TNF antagonists, including an increased risk of serious infections (eg, tuberculosis).14, 15 and 16 Natalizumab, another option for patients with CD, binds to α4β1 and α4β7 integrins, inhibiting T-lymphocyte adhesion to vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Natalizumab is approved for multiple sclerosis in many countries and for moderate to severe CD in the United States.3, 5 and 6 However, an increased risk of progressive multifocal leukoencephalopathy (PML), a rare, serious infection of the central nervous system (CNS), has limited natalizumab use in patients with CD.

Obtaining knowledge to identify proteins associated with a particular physiological or pathological state, has a great significance in understanding disease states and to develop new diagnostic and prognostic assays [19] and [20]. Neuroproteomics include comparative analysis of protein expression in normal and diseased states to study the dynamic

properties associated with neuropeptide processing in biological system of diseases [21]. This review will discuss several key neuroproteomic areas that not only address CNS injury research but also will address the translational potential from animal studies to clinical practice. We will cover three major neuroproteomic platforms: differential neuroproteomics, quantitative proteomics, and imaging mass spectrometry (IMS) approach.

Differential Tacrolimus nmr proteomic approach is ideally suited to discover protein biomarkers that might be differentially expressed or altered by contrasting two or more biological samples (Fig. 1). The complexity, immense size, variability of the neuroproteome, extensive protein–protein and protein–lipid interactions, proteins in the CNS tissues are extraordinarily resistant to isolation Buparlisib [10] and [22]. Therefore, high resolving protein/peptide separation methods are essential for the separation and identification. The development of modern separation techniques coupled online with accurate and high resolving mass spectrometric tools have emerged as preferred components for diagnostic,

prognostic and therapeutic protein biomarkers discovery that expands the scope of protein identification, quantitation C-X-C chemokine receptor type 7 (CXCR-7) and characterization. Proteomics has two major approaches. The bottom-up (or shotgun) approach involves direct digestion of a biological sample using a proteolytic enzyme (such as trypsin) that cleaves at well-defined sites to create a complex peptide mixture. The digested samples can then be analyzed by liquid chromatography (single or multi-dimensional) prior to tandem mass spectrometry (LC–MS/MS) [23]. The second approach is top-down that involves separating intact proteins from complex biological samples using separation techniques such as liquid chromatography or 2-D gel electrophoresis (isoelectofocusing + SDS-gel electrophoresis – separation by relative molecular weight) followed by differential expression analysis using spectrum analysis or gel imaging platforms. This is sometimes assisted by differential dye-labeling of two samples (e.g. with Cy-3, Cy-5 dye) and equal amount of the labeled samples are mixed and resolved by 2-D gel, creating a differential gel map or differential gel electrophoresis (DIGE) where differentially expressed proteins (up- or down-regulated proteins) can be identified by fluorescence scanning and band cut out for protein identification [24].

In this study, we focus on S. horneri which is very important species from viewpoints of fisheries and biodiversity,

and aim to estimate change in geographical distribution of S. horneri in the northwestern Pacific according to global warming. We also discuss on its influences on fishes depending R428 cell line on floating S. horneri rafts. It is necessary to know spatial distribution of S. horneri in the northwestern Pacific for estimating the present and future geographical distributions of S. horneri. Umezaki (1984) collected information of geographical distribution of S. horneri in this zone. The distribution of S. horneri extends along the coast from north of Kyushu Island to west of Hokkaido facing East China Sea and the Sea of Japan and also along the coast from south of central Honshu Island to east of Hokkaido Island facing the Pacific Ocean ( Fig. 1). More precisely, the northern and southern limits facing the Sea of Japan are Teuri Island and Nagasaki, and those along the Pacific Ocean are Kunashiri Island and Mie Prefecture in Kii Peninsula, respectively. Tseng (2000) classified seaweeds

in China and described that S. horneri was distributed in Dalian and the east coast of Jinxian in Liaoning Province, Zhongjieshan Islands and Shengshi Islands in Zhejiang Province, Pingtan, Nanri Island of Putian, Xiamen, Zhangpu and Dongshan Island in Fujian click here Province, and Huilai, Nanao and Haifeng in Guangdong Province ( Fig. 2). Hu et al. (2011) added southmost locality, Naozhou Island, near Hainan Island, China. Wang (2003) studied intertidal flora in Zhejiang Province and reported S. horneri has been found in Shengshan, Zhongjieshan, Putuoshan and Nanji Glycogen branching enzyme Islands. Although distribution in Korean Peninsula has been reported (e.g. Yoshida, 1989), precise localities are not indicated. To examine influence of global warming on subtropical Sargassum species, we studied geographical change of Sargassum tenuifolium Yamada between 2000 and 2100 because its localities and water temperature ranges in February and in August were also described by Umezaki (1984). Umezaki (1984)

examined the lowest and highest surface water temperatures at the localities of S. horneri in Japan in a year. He used monthly mean surface water temperatures in February and in August as the minimum and maximum surface water temperatures in a year, respectively. Along the Japanese coast facing the Sea of Japan, the surface water temperatures at the southern and northern limits of S. horneri distribution in August were 28 °C and 20 °C, respectively. The surface water temperatures at the southern and northern limits of S. horneri distribution in February were 18 °C and 4 °C, respectively. Along the Japanese coast facing the Pacific Ocean, the surface water temperatures at the southern and northern limits of S. horneri distribution in August were 28 °C and 14 °C, respectively.

, 2008), were used as negative controls in LAMP assays. For a comparative qPCR testing of Las from the psyllids, extractions were

conducted using a Qiagen® Magmax kit (Qiagen Inc. CA). The qPCR reactions were conducted with primers and TaqMan™ probes for the psyllid internal control gene ‘wingless’ and the 16S rDNA fragment from Las ( Manjunath et al., 2008). Plant samples were obtained from field trees of many cultivars of citrus and close relatives from a severely HLB affected area in Florida. Plant DNA extracted using Plant DNeasy kit from Qiagen® was used for LAMP assay, mainly to validate the LAMP protocol and to compare the results with qPCR assays conducted from the same extractions. We have selected a 177 bp DNA fragment of Las encompassing a phage related genomic region (Tomimura et al., 2009). The target region consisted of 111 bp from the 3′ terminus of CLIBASIA_00025 (annotated Alectinib supplier as ABC-type dipeptide transport system, periplasmic component), 3 nucleotides from the intergenic region and 63 bp from the 5′ terminus of an adjacent gene, CLIBASIA_00030 (putative DNA polymerase of bacteriophage

origin). This 177 bp sequence is conserved in many isolates of Las described from Southeast Asia (Tomimura et al., 2009). All the publicly available Las sequences for the 177 bp target region were aligned and confirmed to be highly conserved in Las strains from different geographical regions. The primers F3, B3, F1P Selleck Cyclopamine and B1P required for LAMP were designed using Primer explorer version 3 software (http://primerexplorer.jp/e/). The loop primers LF and LB were designed manually (Table 1, Supplementary Fig. 1). Primers were synthesized by Integrated DNA technologies, Coralville, IA, USA and the two double-domain primers, F1P and B1P, were HPLC purified. ALOX15 The specificity of the primers was checked in silico against all available sequences in the Genbank. We have used the Smart-DART™ tool from Diagenetix Inc.™ for

our experiments. The platform includes a custom device that can analyze 8 samples simultaneously, running at a programmable temperature, and periodically measuring fluorescence. The Smart-DART™ device interfaces wirelessly (by Bluetooth®) to an Android device through a custom application, which allows the user to control the reaction settings and view data graphically in real time (Fig. 1). Fluorescence readings were recorded using the channel optimized for fluorescein. Reactions were conducted in strips of 8 optically clear tubes that can be individually capped with a seal and lock mechanism to avoid cross contamination. The Smart-DART™ platform was used for psyllid DNA extraction (at 85 °C for 10 min) as well as for the LAMP reaction for detection (at 65 °C for 20 min). The results can be saved to view later, or e-mailed from the Android device. The platform functions as a closed amplification and detection system which limits the risk of amplicon contamination of the work area.

Papers of particular interest, published within Forskolin the period of review, have been highlighted as: • of special interest The support of the Momentum program (LP2012-41) of the Hungarian Academy of Sciences is gratefully acknowledged (MF). We also thank the Debrecen High Performance Computing within the TÁMOP-4.2.2.C-11/1/KONV-2012-0010 framework for computer time. “
“Current Opinion in Chemical Biology 2014,

21:63–72 This review comes from a themed issue on Mechanisms Edited by AnnMarie C O’Donoghue and Shina CL Kamerlin For a complete overview see the Issue and the Editorial Available online 27th May 2014 http://dx.doi.org/10.1016/j.cbpa.2014.05.001 1367-5931/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). The mechanisms of phosphoryl transfer between nucleophilic centres have been investigated intensely over the last half-century, with many generalisations of enzyme catalytic strategies becoming evident [1•]. Newly discovered enzymes that foster phosphoryl transfer have also regularly presented themselves, and offer fresh ground for research CFTR activator alongside

historically challenging systems. The catalysis of phosphoryl transfer is particularly intriguing given the manifest stability of diesters, and monoester dianion systems. The delineation of the strategies employed by enzymes to provide accelerations of up to 1021-fold, gives enzymologists true insight into some of Nature’s most efficient catalysts [2•]. Visualisation and parameterisation of the highly dynamic interactions between enzyme and substrate as they pass through to products via heavily stabilised

transition states represents the long-standing challenge in this field. This opinion brings together several recent examples of phosphate ester analogues and their use in deciphering the secrets of some of Nature’s most enticingly efficient biocatalysts, in the context of ubiquitous phosphoryl transfer processes ( Scheme Tyrosine-protein kinase BLK 1). Approaches towards understanding transfers from phosphate monoesters, diesters and phosphoanhydride systems will be included in this opinion. Both labile (reactive) and stable (inhibitory) analogues are covered, where the former usually, but not exclusively, tend to offer insight into the dynamic processes that occur during bond making and breaking between phosphorus and other nucleophilic groups. In many cases, multi-pronged strategies are adopted where parameterisations and inferences from one mechanistic tool can be supported and enhanced by others. The following three sections cover examples of phosphate monester, diester and anhydride analogues. Initially, each section focuses on examples where the nature of the transition state and factors that stabilise it can be extracted.