Outreach, Screening, and Randomization of APOE ε4 Carriers into an Alzheimer's Prevention Trial: A global Perspective from the API Generation Program.

BACKGROUND: Alzheimer's disease (AD) prevention trials require a large outreach and screening funnel to identify cognitively unimpaired adults who meet the study's inclusion criteria, such as certain clinical or demographic criteria, genetic risk factors, and/or biomarker evidence of the disease. OBJECTIVES: Describe tactics and strategies to identify and enroll cognitively unimpaired adults with one (heterozygotes [HT]) or two (homozygotes [HM]) copies of the APOE ε4 allele, a genetic risk factor for dementia due to AD, into the Alzheimer's Prevention Initiative (API) Generation Program, the largest and only prevention trials for late onset AD using this enrichment technique. DESIGN AND SETTING: The Generation Program was comprised of two global, randomized, double-blind, placebo-controlled, parallel group adaptive design with variable treatment duration clinical trials. Generation Study 1 randomized participants into one of two cohorts: Cohort 1 which evaluated CAD106 vs. placebo or Cohort 2 which evaluated umibecestat vs placebo. Generation Study 2 randomized participants into two doses of umibecestat vs. placebo. The Generation Program was terminated early in 2019, while enrollment was still occurring. PARTICIPANTS: Both Generation Study 1 and Generation Study 2 enrolled cognitively unimpaired APOE ε4 HMs aged 60-75; Generation Study 2 also enrolled APOE ε4 HTs ages 60-75 with elevated brain amyloid. METHODS AND MEASUREMENTS: Describe results of the centralized and localized outreach, recruitment, screening strategies and tactics as well as characteristics of sites successful at enrolling genetically eligible participants, with a particular focus on APOE ε4 HMs given the 2-3% prevalence of this genotype. RESULTS: At the time the trial program was terminated, 35,333 individuals had consented to the optional prescreening ICF1a/ICFA and provided a sample of DNA for APOE genotyping, 1,138 APOE ε4 HMs consented to screening for Generation Study 1 (ICF1b), and 1,626 APOE ε4 carriers were randomized into either Generation Study 1 or Generation Study 2. Genetic testing registries, partnerships with genetic testing/counseling companies, and the optional prescreening ICF1a/ICFA were the most successful strategies for identifying genetically eligible participants for screening. CONCLUSIONS: It is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites.

[Fracture sequelae type 2 of the proximal humerus-clinical results after arthroplasty]. / Frakturfolge Typ 2 des proximalen Humerus ­ klinische Ergebnisse nach endoprothetischer Therapie.

Locked dislocations of the glenohumeral joint are rare but often painful and are associated with limited range of motion in the shoulder. In patients of advanced age, arthroplasty is increasingly indicated as a surgical treatment option. Preoperatively, the direction of dislocation, the presence and extent of a glenoid defect, and the soft tissue situation (rotator cuff status, joint capsule) should be analyzed in a differentiated manner. Based on the above factors, we recommend the subclassification of type 2 according to Boileau: posterior locked dislocation (2a), anterior locked dislocation without glenoid defect (2b), and anterior locked dislocation with glenoid defect (2c). In the case of dorsally locked dislocation, a good clinical result can be achieved by using an anatomical endoprosthesis. For ventrally locked dislocations, we recommend using an inverse total endoprosthesis with, if necessary, bony glenoid reconstruction and transfer of the pectoralis major muscle.Level of evidence: IV.

A Novel Approach for Non-Invasive Continuous In-Line Control of Perfusion Cell Cultivations by Raman Spectroscopy.

Continuous manufacturing is becoming more important in the biopharmaceutical industry. This processing strategy is favorable, as it is more efficient, flexible, and has the potential to produce higher and more consistent product quality. At the same time, it faces some challenges, especially in cell culture. As a steady state has to be maintained over a prolonged time, it is unavoidable to implement advanced process analytical technologies to control the relevant process parameters in a fast and precise manner. One such analytical technology is Raman spectroscopy, which has proven its advantages for process monitoring and control mostly in (fed-) batch cultivations. In this study, an in-line flow cell for Raman spectroscopy is included in the cell-free harvest stream of a perfusion process. Quantitative models for glucose and lactate were generated based on five cultivations originating from varying bioreactor scales. After successfully validating the glucose model (Root Mean Square Error of Prediction (RMSEP) of ∼0.2 g/L), it was employed for control of an external glucose feed in cultivation with a glucose-free perfusion medium. The generated model was successfully applied to perform process control at 4 g/L and 1.5 g/L glucose over several days, respectively, with variability of ±0.4 g/L. The results demonstrate the high potential of Raman spectroscopy for advanced process monitoring and control of a perfusion process with a bioreactor and scale-independent measurement method.

An ultralow-noise superconducting radio-frequency ion trap for frequency metrology with highly charged ions.

We present a novel ultrastable superconducting radio-frequency (RF) ion trap realized as a combination of an RF cavity and a linear Paul trap. Its RF quadrupole mode at 34.52 MHz reaches a quality factor of Q ≈ 2.3 × 105 at a temperature of 4.1 K and is used to radially confine ions in an ultralow-noise pseudopotential. This concept is expected to strongly suppress motional heating rates and related frequency shifts that limit the ultimate accuracy achieved in advanced ion traps for frequency metrology. Running with its low-vibration cryogenic cooling system, electron-beam ion trap, and deceleration beamline supplying highly charged ions (HCIs), the superconducting trap offers ideal conditions for optical frequency metrology with ionic species. We report its proof-of-principle operation as a quadrupole-mass filter with HCIs and trapping of Doppler-cooled 9Be+ Coulomb crystals.

Evaluation of facial aesthetics by laypersons in patients undergoing intraoral quadrangular Le Fort II osteotomy compared with conventional Le Fort I osteotomy.

In this study we compared the aesthetic outcome of (1) Le Fort I (LFI) osteotomy and (2) intraoral quadrangular Le Fort II (IQLFII) osteotomy for surgical correction of skeletal class III dysgnathia involving midfacial deficiency. The aim was to investigate whether laypersons see differences in facial changes that occur due to variations of the osteotomy cuts. The patient collectives consisted of 23 patients in each group. Pre- and postoperative photographs were presented in a random sequence to 40 layperson raters. The rating procedure was conducted with a four-point Likert scale. Assessed characteristics were 'attractiveness' ('Attraktivität'), 'likeability' ('Sympathie'), 'intelligence' ('Intelligenz'), 'aggressiveness' ('Aggressivität') and 'dominance' ('Dominanz'). For preoperative photographs we found a significant difference for 'likeability' with lower ratings for the IQLFII group; all other criteria were rated similarly. For the IQLFII group we found a significantly larger shift from lower to higher ratings for 'attractiveness' and 'likeability' and a significantly larger shift from higher to lower ratings for 'aggressiveness' and 'dominance' than for the LF I group. Our study shows that lay raters detect significant differences between the two surgical groups. Thus, IQLFII osteotomy, when indicated, represents a favourable alternative to conventional LFI osteotomy, if patients desire the expectable change in recognition by their social circle.

Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy.

Frameshift mutations in the DMD gene, encoding dystrophin, cause Duchenne muscular dystrophy (DMD), leading to terminal muscle and heart failure in patients. Somatic gene editing by sequence-specific nucleases offers new options for restoring the DMD reading frame, resulting in expression of a shortened but largely functional dystrophin protein. Here, we validated this approach in a pig model of DMD lacking exon 52 of DMD (DMDΔ52), as well as in a corresponding patient-derived induced pluripotent stem cell model. In DMDΔ52 pigs1, intramuscular injection of adeno-associated viral vectors of serotype 9 carrying an intein-split Cas9 (ref. 2) and a pair of guide RNAs targeting sequences flanking exon 51 (AAV9-Cas9-gE51) induced expression of a shortened dystrophin (DMDΔ51-52) and improved skeletal muscle function. Moreover, systemic application of AAV9-Cas9-gE51 led to widespread dystrophin expression in muscle, including diaphragm and heart, prolonging survival and reducing arrhythmogenic vulnerability. Similarly, in induced pluripotent stem cell-derived myoblasts and cardiomyocytes of a patient lacking DMDΔ52, AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and amelioreate skeletal myotube formation as well as abnormal cardiomyocyte Ca2+ handling and arrhythmogenic susceptibility. The ability of Cas9-mediated exon excision to improve DMD pathology in these translational models paves the way for new treatment approaches in patients with this devastating disease.

The association of pre-operative anaemia with survival after orthotopic liver transplantation.

Anaemia is common in patients with end-stage liver disease. Pre-operative anaemia is associated with greater mortality after major surgery. We analysed the association of pre-operative anaemia (World Health Organization classification) with survival and complications after orthotopic liver transplantation using Cox and logistic regression models. We included patients undergoing their first orthotopic liver transplantation between 2004 and 2016. Out of 599 included patients, 455 (76%) were anaemic before transplantation. Pre-operative anaemia was not associated with the survival of 485/599 (81%) patients to 1 year after liver transplantation, OR (95%CI) 1.04 (0.64-1.68), p = 0.88. Pre-operative anaemia was associated with higher rates of intra-operative blood transfusions and acute postoperative kidney injury on multivariable analysis, OR (95%CI) 1.70 (0.82-2.59) and 1.72 (1.11-2.67), respectively, p < 0.001 for both. Postoperative renal replacement therapy was associated with pre-operative anaemia on univariate analysis, OR (95%CI) 1.87 (1.11-3.15), p = 0.018.

Superlocalization of Excitons in Carbon Nanotubes at Cryogenic Temperature.

At cryogenic temperature and at the single emitter level, the optical properties of single-wall carbon nanotubes depart drastically from that of a one-dimensional (1D) object. In fact, the (usually unintentional) localization of excitons in local potential wells leads to nearly 0D behaviors such as photon antibunching, spectral diffusion, inhomogeneous broadening, etc. Here, we present a hyperspectral imaging of this spontaneous exciton localization effect at the single nanotube level using a super-resolved optical microscopy approach. We report on the statistical distribution of the trap localization, depth, and width. We use a quasi-resonant photoluminescence excitation approach to probe the confined quantum states. Numerical simulations of the quantum states and exciton diffusion show that the excitonic states are deeply modified by the interface disorder inducing a remarkable discretization of the excitonic absorption spectrum and a quenching of the free 1D exciton absorption.

Assessment of Clinical Meaningfulness of Endpoints in the Generation Program by the Insights to Model Alzheimer's Progression in Real Life (iMAP) Study.

We are launching the Insights to Model Alzheimer's Progression in Real Life study in parallel with the Alzheimer Prevention Initiative Generation Program. This is a 5-year, multinational, prospective, longitudinal, non-interventional cohort study that will collect data across the spectrum of Alzheimer's disease. The primary objective is to assess the ability of the Alzheimer's Prevention Initiative Cognitive Composite Test Score and Repeatable Battery for the Assessment of Neuropsychological Status to predict clinically meaningful outcomes such as diagnosis of mild cognitive impairment or dementia due to Alzheimer's disease, and change in Clinical Dementia Rating - Global Score. This study is the first large-scale, prospective effort to establish the clinical meaningfulness of cognitive test scores that track longitudinal decline in preclinical Alzheimer's disease. This study is also expected to contribute to our understanding of the relationships among outcomes in different stages of Alzheimer's disease as well as models of individual trajectories during the course of the disease.

Analysis of pre-test failures and bond-strengths of seven adhesive systems to bovine dentine: A nine-year novice/beginner operator study.

OBJECTIVE: The aims were to evaluate, via multi-year student cohorts: (i) the incidence of pre-test failures and (ii) shear bond strengths of single- and multi-step adhesives to bovine dentin. METHODS: The experiments were performed by cohorts of dental students (2008-2016). Each year the bond strengths of three dental adhesives to bovine dentin were tested. Four self-etching adhesives (Optibond-All-in-One, [OBAIO]; Optibond XTR [OBXTR]); Xeno V [XV]; Xeno V+ [XV+]; a three-step etch-and-rinse-system (Optibond FL, [OBFL]), a self-etch universal adhesive (Scotchbond Universal [SBU]) and a self-etch/etch-and-rinse adhesive (Xeno Select, [XS]) were included in the study. Composite-cylinders were bonded perpendicularly to prepared bovine dentin surfaces. Shear-tests were performed with a universal-testing-machine. RESULTS: Both overall, and within years, XV and XV+ showed significantly (p<0.01) higher percentages of pre-test failures versus other adhesive systems tested in the period 2008-2014 (OAIO, OBFL, OBXTR). Fewest pre-test failures were observed for OBFL, OBXTR and SBU. Trends in mean bond strengths and Weibull distributions were noted, per adhesive, with trends in the incidence of pre-test failures. Pre-test-failures and bond strengths depended on the air-drying technique. The adhesive systems showed variable technique sensitivity. Multistep bonding systems (Optibond FL and Optibond XTR) showed minimal pre-test failures and high bond strength applied by relatively inexperienced operators and irrespective of the applied air-drying technique. However, two single-step adhesives (OAIO and SBU) showed comparable results to the multi-step systems. SIGNIFICANCE: The clinical need for rapid application dentine adhesives can result in varied outcomes with relatively inexperienced operators. These outcomes include both the incidence of pre-test failures as well as the distributions of shear bond strengths achieved, although these measures appear to be related. However, both outcomes are dependent upon the adhesive products utilised and especially upon the applied air pressure (flow rate). Some rapid application systems appear to perform comparably with well-established multi-step adhesives.

Nonthermal Plasma Jet Treatment Negatively Affects the Viability and Structure of Candida albicans SC5314 Biofilms.

Microorganisms are predominantly organized in biofilms, where cells live in dense communities and are more resistant to external stresses than are their planktonic counterparts. With in vitro experiments, the susceptibility of Candida albicans biofilms to a nonthermal plasma treatment (plasma source, kINPen09) in terms of growth, survival, and cell viability was investigated. C. albicans strain SC5314 (ATCC MYA-2876) was plasma treated for different time periods (30 s, 60 s, 120 s, 180 s, 300 s). The results of the experiments, encompassing CFU, fluorescence Live/Dead, and 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide salt (XTT) assays, revealed a negative influence of the plasma treatment on the proliferation ability, vitality, and metabolism of C. albicans biofilms, respectively. Morphological analysis of plasma-treated biofilms using atomic force microscopy supported the indications for lethal plasma effects concomitant with membrane disruptions and the loss of intracellular fluid. Yielding controversial results compared to those of other publications, fluorescence and confocal laser scanning microscopic inspection of plasma-treated biofilms indicated that an inactivation of cells appeared mainly on the bottom of the biofilms. If this inactivation leads to a detachment of the biofilms from the overgrown surface, it might offer completely new approaches in the plasma treatment of biofilms. Because of plasma's biochemical-mechanical mode of action, resistance of microbial cells against plasma is unknown at this state of research.IMPORTANCE Microbial communities are an increasing problem in medicine but also in industry. Thus, an efficient and rapid removal of biofilms is becoming increasingly important. With the aid of the kINPen09, a radiofrequency plasma jet (RFPJ) instrument, decisive new findings on the effects of plasma on C. albicans biofilms were obtained. This work showed that the inactivation of biofilms takes place mainly on the bottom, which in turn offers new possibilities for the removal of biofilms by other strategies, e.g., mechanical treatment. This result demonstrated that nonthermal atmospheric pressure plasma is well suited for biofilm decontamination.

The Alzheimer's Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer's Disease.

Alzheimer's disease pathology begins decades before the onset of clinical symptoms. This provides an opportunity for interventional clinical trials to potentially delay or prevent the onset of cognitive impairment or dementia. CNP520 (a beta-site-amyloid precursor protein-cleaving enzyme inhibitor) is in clinical development for the treatment of preclinical Alzheimer's disease under the Alzheimer's Prevention Initiative Generation Program. The Alzheimer's Prevention Initiative is a public-private partnership intended to accelerate the evaluation of Alzheimer's disease prevention therapies. The Generation Program comprises two pivotal phase II/III studies with similar designs to assess the efficacy and safety of investigational treatments in a cognitively unimpaired population at increased risk for developing Alzheimer's disease based on age and apolipoprotein E (APOE) genotype (i.e., presence of the APOE ε4 allele). The program has been designed to maximize benefit to Alzheimer's disease research. Generation Study 1 (NCT02565511) and Generation Study 2 (NCT03131453) are currently enrolling; their key features are presented here.

Analysis of Free Amino Acids in Mammalian Brain Extracts.

An optimized method for analysis of free amino acids using a modified lithium-citrate buffer system with a Hitachi L-8800 amino acid analyzer is described. It demonstrates clear advantages over the sodium-citrate buffer system commonly used for the analysis of protein hydrolysates. A sample pretreatment technique for amino acid analysis of brain extracts is also discussed. The focus has been placed on the possibility of quantitative determination of the reduced form of glutathione (GSH) with simultaneous analysis of all other amino acids in brain extracts. The method was validated and calibration coefficient (KGSH) was determined. Examples of chromatographic separation of free amino acids in extracts derived from different parts of the brain are presented.

Effect of Chronic Administration of Obestatin and Its Fragment FNAP-NH2 on Behavioral Activity and Nociceptive Threshold in Rats with Normal and Excess Body Weight.

The effects of chronic intranasal administration of 300 nmol/kg obestatin and its fragment FNAP-NH2 on behavioral activity and nociceptive threshold were examined in male Wistar rats with normal body weight or alimentary obesity. In normal rats, obestatin produced no effect on behavior and nociception, whereas FNAP-NH2 fragment enhanced risk-taking behavior. Rats with excess body weight demonstrated less pronounced risk-taking behavior and elevated nociceptive threshold in comparison with normal animals, but these differences were abolished by chronic administration of FNAP-NH2.

Thiamine Induces Long-Term Changes in Amino Acid Profiles and Activities of 2-Oxoglutarate and 2-Oxoadipate Dehydrogenases in Rat Brain.

Molecular mechanisms of long-term changes in brain metabolism after thiamine administration (single i.p. injection, 400 mg/kg) were investigated. Protocols for discrimination of the activities of the thiamine diphosphate (ThDP)-dependent 2-oxoglutarate and 2-oxoadipate dehydrogenases were developed to characterize specific regulation of the multienzyme complexes of the 2-oxoglutarate (OGDHC) and 2-oxoadipate (OADHC) dehydrogenases by thiamine. The thiamine-induced changes depended on the brain-region-specific expression of the ThDP-dependent dehydrogenases. In the cerebral cortex, the original levels of OGDHC and OADHC were relatively high and not increased by thiamine, whereas in the cerebellum thiamine upregulated the OGDHC and OADHC activities, whose original levels were relatively low. The effects of thiamine on each of the complexes were different and associated with metabolic rearrangements, which included (i) the brain-region-specific alterations of glutamine synthase and/or glutamate dehydrogenase and NADP+-dependent malic enzyme, (ii) the brain-region-specific changes of the amino acid profiles, and (iii) decreased levels of a number of amino acids in blood plasma. Along with the assays of enzymatic activities and average levels of amino acids in the blood and brain, the thiamine-induced metabolic rearrangements were assessed by analysis of correlations between the levels of amino acids. The set and parameters of the correlations were tissue-specific, and their responses to the thiamine treatment provided additional information on metabolic changes, compared to that gained from the average levels of amino acids. Taken together, the data suggest that thiamine decreases catabolism of amino acids by means of a complex and long-term regulation of metabolic flux through the tricarboxylic acid cycle, which includes coupled changes in activities of the ThDP-dependent dehydrogenases of 2-oxoglutarate and 2-oxoadipate and adjacent enzymes.

Cellular thiamine status is coupled to function of mitochondrial 2-oxoglutarate dehydrogenase.

Decreased thiamine and reduced activity of thiamine diphosphate (ThDP)-dependent 2-oxoglutarate dehydrogenase (OGDH) cause neurodegeneration. We hypothesized on concerted cell-specific regulation of the thiamine metabolism and ThDP-dependent reactions. We identified a smaller thiamine pool, a lower expression of the mitochondrial ThDP transporter, and a higher expression of OGDH in rat astrocytes versus neuroblastoma N2A. According to the data, the astrocytic OGDH may be up-regulated by an increase in intracellular ThDP, while the neuroblastomal OGDH functions at full ThDP saturation. Indeed, in rat astrocytes and brain cortex, OGDH inhibition by succinyl phosphonate (SP) enlarged the pool of thiamine compounds. Increased ThDP level in response to the OGDH inhibition presumably up-regulated the enzyme to compensate for a decrease in reducing power which occurred in SP-treated astrocytes. Under the same SP treatment of N2A cells, their thiamine pool and reducing power were unchanged, although SP action was evident from accumulation of glutamate. The presented data indicate that functional interplay between OGDH, other proteins of the tricarbocylic acid cycle and proteins of thiamine metabolism is an important determinant of physiology-specific networks and their homeostatic mechanisms.

Changes in Behavior and Blood Corticosterone Level in Male and Female Rats after Single Administration of Obestatin Fragment 1-4.

Single administration of the obestatin fragment 1-4 (300 nmol/kg) to male Wistar rats produced a significant weight loss in male rats on observation days 5-8, while in female rats only on day 8. In addition, males demonstrated decreased risk factor in the elevated plus-maze test, but no effect of the preparation on behavior of female rats was revealed. Obestatin fragment 1-4 had no effect on corticosterone level 1 week after single administration in both females and male rats.

Long-term significance of urinary neopterin in ovarian cancer: a study by the Austrian Association for Gynecologic Oncology (AGO).

BACKGROUND: Neopterin is produced by activated macrophages upon stimulation with interferon-γ (IFN-γ) and thus, elevated neopterin concentrations in patients indicate cellular inate immune response. Most studies in patients with malignant diseases found an association between higher neopterin concentrations and reduced survival and impaired prognosis. Nevertheless, neopterin is not a classical tumor marker since it is not produced by the cancer cells themselves. PATIENTS AND METHODS: In a study conducted by the Austrian Gynecologic Oncology Group (AGO) in 114 patients with ovarian cystadenomas and 223 patients with invasive ovarian cancer, patients' urinary neopterin was determined before and after primary therapy. The relevance of neopterin in long-term median follow-up was assessed. RESULTS: Elevated levels (cut-off 250 µmol/mol creatinine) were found less frequently in women with benign ovarian cystadenomas (24%) than in patients with malignant disease (58%). After 10 years, only 57% of ovarian cancer patients with elevated urinary neopterin levels survived without disease progression following primary therapy when compared with 86% of women with normal levels (P < 0.001). Along with residual tumor, FIGO stage, age and histological type, neopterin was significantly associated with overall survival (OS) and progression-free survival (PFS). The median PFS was 52 and 12 months and the median OS was 81 and 24 months for patients with normal and elevated neopterin, respectively, P < 0.001. In a multivariate Cox regression analysis, only residual tumor, neopterin and age were independently associated with OS, while only residual tumor was predictive for PFS. Thirty patients with early-stage invasive ovarian cancer (FIGO I and II) were analyzed separately. Of 3 patients with elevated neopterin, 2 died of disease in contrast to 2 out of 27 patients with normal neopterin (P = 0.004). CONCLUSION: In ovarian cancer, the negative impact of elevated urinary neopterin levels indicates a detrimental effect of cancer-associated inflammatory reaction.

Directed Regulation of Multienzyme Complexes of 2-Oxo Acid Dehydrogenases Using Phosphonate and Phosphinate Analogs of 2-Oxo Acids.

2-Oxo acid dehydrogenase complexes are important metabolic checkpoints functioning at the intercept of sugar and amino acid degradation. This review presents a short summary of architectural, catalytic, and regulatory principles of the complexes structure and function, based on recent advances in studies of well-characterized family members. Special attention is given to use of synthetic phosphonate and phosphinate analogs of 2-oxo acids as selective and efficient inhibitors of the cognate complexes in biological systems of bacterial, plant, and animal origin. We summarize our own results concerning the application of synthetic analogs of 2-oxo acids in situ and in vivo to reveal functional interactions between 2-oxo acid dehydrogenase complexes and other components of metabolic networks specific to different cells and tissues. Based on our study of glutamate excitotoxicity in cultured neurons, we show how a modulation of metabolism by specific inhibition of its key reaction may be employed to correct pathologies. This approach is further developed in our study on the action of the phosphonate analog of 2-oxoglutarate in animals. The study revealed that upregulation of 2-oxoglutarate dehydrogenase complex is involved in animal stress response and may provide increased resistance to damaging effects, underlying so-called preconditioning. The presented analysis of published data suggests synthetic inhibitors of metabolic checkpoints as promising tools to solve modern challenges of systems biology, metabolic engineering, and medicine.