Multiomic Metabolic Enrichment Network Analysis Reveals Metabolite–Protein Physical Interaction Subnetworks Altered in Cancer

Metabolism is recognized as an important driver of cancer progression and other complex diseases, but global metabolite profiling remains a challenge. Protein expression profiling is often a poor proxy since existing pathway enrichment models provide an incomplete mapping between the proteome and metabolism. To overcome these gaps, we introduce multiomic metabolic enrichment network analysis (MOMENTA), an integrative multiomic data analysis framework for more accurately deducing metabolic pathway changes from proteomics data alone in a gene set analysis context by leveraging protein interaction networks to extend annotated metabolic models. We apply MOMENTA to proteomic data from diverse cancer cell lines and human tumors to demonstrate its utility at revealing variation in metabolic pathway activity across cancer types, which we verify using independent metabolomics measurements. The novel metabolic networks we uncover in breast cancer and other tumors are linked to clinical outcomes, underscoring the pathophysiological relevance of the findings.     

Targeting age‐specific changes in CD4+ T cell metabolism ameliorates alloimmune responses and prolongs graft survival

Age impacts alloimmunity. Effects of aging on T‐cell metabolism and the potential to interfere with immunosuppressants have not been explored yet. Here, we dissected metabolic pathways of CD4⁺ and CD8⁺ T cells in aging and offer novel immunosuppressive targets. Upon activation, CD4⁺ T cells from old mice failed to exhibit adequate metabolic reprogramming resulting into compromised metabolic pathways, including oxidative phosphorylation (OXPHOS) and glycolysis. Comparable results were also observed in elderly human patients. Although glutaminolysis remained the dominant and age‐independent source of mitochondria for activated CD4⁺ T cells, old but not young CD4⁺ T cells relied heavily on glutaminolysis. Treating young and old murine and human CD4⁺ T cells with 6‐diazo‐5‐oxo‐l‐norleucine (DON), a glutaminolysis inhibitor resulted in significantly reduced IFN‐γ production and compromised proliferative capacities specifically of old CD4⁺ T cells. Of translational relevance, old and young mice that had been transplanted with fully mismatched skin grafts and treated with DON demonstrated dampened Th1‐ and Th17‐driven alloimmune responses. Moreover, DON diminished cytokine production and proliferation of old CD4⁺ T cells in vivo leading to a significantly prolonged allograft survival specifically in old recipients. Graft prolongation in young animals, in contrast, was only achieved when DON was applied in combination with an inhibition of glycolysis (2‐deoxy‐d‐glucose, 2‐DG) and OXPHOS (metformin), two alternative metabolic pathways. Notably, metabolic treatment had not been linked to toxicities. Remarkably, immunosuppressive capacities of DON were specific to CD4⁺ T cells as adoptively transferred young CD4⁺ T cells prevented immunosuppressive capacities of DON on allograft survival in old recipients. Depletion of CD8⁺ T cells did not alter transplant outcomes in either young or old recipients. Taken together, our data introduce an age‐specific metabolic reprogramming of CD4⁺ T cells. Targeting those pathways offers novel and age‐specific approaches for immunosuppression.     

Effect of natural exogenous antioxidants on aging and on neurodegenerative diseases

Abstract

Aging and neurodegenerative diseases share oxidative stress cell damage and depletion of endogenous antioxidants as mechanisms of injury, phenomena that are occurring at different rates in each process. Nevertheless, as the central nervous system (CNS) consists largely of lipids and has a poor catalase activity, a low amount of superoxide dismutase and is rich in iron, its cellular components are damaged easily by overproduction of free radicals in any of these physiological or pathological conditions. Thus, antioxidants are needed to prevent the formation and to oppose the free radicals damage to DNA, lipids, proteins, and other biomolecules. Due to endogenous antioxidant defenses are inadequate to prevent damage completely, different efforts have been undertaken in order to increase the use of natural antioxidants and to develop antioxidants that might ameliorate neural injury by oxidative stress. In this context, natural antioxidants like flavonoids (quercetin, curcumin, luteolin and catechins), magnolol and honokiol are showing to be the efficient inhibitors of the oxidative process and seem to be a better therapeutic option than the traditional ones (vitamins C and E, and β-carotene) in various models of aging and injury in vitro and in vivo conditions. Thus, the goal of the present review is to discuss the molecular basis, mechanisms of action, functions, and targets of flavonoids, magnolol, honokiol and traditional antioxidants with the aim of obtaining better results when they are prescribed on aging and neurodegenerative diseases.     

Cryptic species in Diacyclops bicuspidatus (Copepoda:Cyclopoida): evidence from crossbreeding studies

The problem of cryptic species in Diacyclops bicuspidatus was examined using interpopulation crosses of four populations collected from a: (1) permanent flood lake in Kiev, Ukraine, (2) temporary pool in Kiev, (3) permanent pond in St. Petersburg, Russia (1200 km to north from Kiev) and (4) lake in Crimea (1100 km south of Kiev). The only interpopulation crosses to exhibit fertility were those between the St. Petersburg population and each of the two Kiev populations. The crosses between the Kiev and Crimea populations, between the St. Petersburg and Crimea populations, and between the two Kiev populations were sterile, as evidenced by either nonviable eggs, empty egg membranes or incomplete copulations. The F₁ hybrids resulting from the St. Petersburg permanent pond X Kiev flood lake cross were fertile and produced mature F₂ offspring. Some data on development times of parental and hybrid lines are presented. The St. Petersburg parental line showed development times almost twice as long as those of the Kiev flood lake population when reared at 10 °C and 20 °C in the laboratory. The F₁ offspring of the cross between St. Petersburg females and Kiev floodlake males showed similar development times to females of the St. Petersburg parental lines at both temperatures. The F₂ hybrids also showed development times that approximated those of the St. Petersburg parental line. These crossbreeding studies suggest the presence of cryptic species in the D. bicuspidatus inhabiting ecologically different populations in many parts of its large holarctic range.     

Estimating cladoceran birth rate: use of the egg age distribution to estimate mortality of ovigerous females and eggs

The birth rate of natural cladoceran populations can change rapidly (during 2–3 days), reflecting rapid changes in their environment. If the egg ratio is calculated on the basis of egg age distribution, the birth rate can be estimated at short sampling intervals (shorter than egg stage duration) by modified Paloheimo's (1974) formula. When female size structure and age of eggs in clutches at the beginning and the end of a sampling interval are known, death rates of ovigerous females and eggs in separate size classes can be determined and incorporated in birth rate estimates. All these methods have been employed using the data on the population of Diaphanosoma brahyurum from the lake Obsterno (North-Western Belarus) in July–August, 1992. The birth rate values computed by the proposed methods and Poloheimo's formula differed significantly in many cases. The accuracy of birth rate estimations from various calculation methods was tested using a computer simulation. The model contains the essential features of cladoceran life history: distinct egg, juvenile and adult stages, development of eggs and reproduction. The population was divided into 25 age classes, each of 1 day duration. Durations of the egg, juvenile and adult stages were set at 3, 6 and 20 days, respectively. The embryogenesis was divided into three egg stages, each of 1 day duration. Survivorship was set from 0.2 up to 1.0 for each age class. The survivorship and brood size were changed through each of five time intervals (days) that allowed to simulate an increase or reduction of population density. Fecundity, survivorship and egg stage duration remained constant during each of 5 days that assumed stability of an environment (this does not occur in nature). Nevertheless, the egg ratio, proportion of juveniles and birth rates were variable even under these circumstances. Computer simulations showed that Poloheimo's formula evaluates birth rate with the relative error of 62% and usually overestimates its values. We propose methods to decrease errors of birth rate estimations by 3.5–5.5 times.     

Distribution of Fusarium wilt of Bambara nut (Vigna subterranea (L.) Verdc.) in farmers’ fields’ of Busia County in Western Kenya and its management using farmyard manure

A study was carried out to determine Fusarium wilt distribution in Bambara nut farmers’ fields and its management using farm yard manure (FYM). Four villages in Busia County were purposively sampled for the study. The data generated were subjected to analysis of variance and treatment means separated by least significant difference test. Fusarium wilt incidence in the fields ranged from 14.63 to 43.56%. In the greenhouse, FYM reduced the disease incidence by 10.2% and severity by 9.5% on the black landrace and 1.9 and 12.8%, respectively, on the red landrace. In the field, FYM reduced disease incidence by 9.1% and severity by 6.9% on the black landrace and 10.4 and 10.4%, respectively, on the red landrace. Farm yard manure had the lowest area under disease progress curve irrespective of the landrace. The study confirmed the presence of the pathogen in the fields and the ability to manage the disease using FYM.     

Synthesis of novel chromenones linked to 1,2,3-triazole ring system: Investigation of biological activities against Alzheimer’s disease

In this work, novel chromenones linked to 1,2,3-triazole ring system were synthesized and evaluated for their anti-ChE activity. Among them, N-((1-(2-chlorobenzyl)-1H-1,2,3-triazol-5-yl)methyl)-8-methoxy-2-oxo-2H-chromene-3-carboxamide (6m) showed good anti-acetylcholinesterase activity (IC₅₀ = 15.42 μM). Also, compound 6m demonstrated neuroprotective effect against H₂O₂-induced cell death in PC12 neurons, however, it showed no beta-secretase (BACE1) inhibitory activity. Docking and kinetic studies separately confirmed dual binding activity of compound 6m since it targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.     

Mortality incidence estimation using federal death certificate and natality data with an application to Tay–Sachs disease

For confidentiality reasons, US federal death certificate data are incomplete with regards to the dates of birth and death for the decedents, making calculation of total lifetime of a decedent impossible and thus estimation of mortality incidence difficult. This paper proposes the use of natality data and an imputation‐based method to estimate age‐specific mortality incidence rates in the face of this missing information. By utilizing previously determined probabilities of birth, a birth date and death date are imputed for every decedent in the dataset. Thus, the birth cohort of each individual is imputed, and the total on‐study time can be calculated. This idea is implemented in two approaches for estimation of mortality incidence rates. The first is an extension of a person‐time approach, while the second is an extension of a life table approach. Monte Carlo simulations showed that both approaches perform well in comparison to the ideal complete data methods, but that the person‐time method is preferred. An application to Tay–Sachs disease is demonstrated. It is concluded that the imputation methods proposed provide valid estimates of the incidence of death from death certificate data without the need for additional assumptions under which usual mortality rates provide valid estimates.