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.     

An innovative lattice Boltzmann model for simulating Michaelis–Menten-based diffusion–advection kinetics and its application within a cartilage cell bioreactor

Lattice Boltzmann models (LBM) are rapidly showing their ability to simulate a lot of fluid dynamics problems that previously required very complex approaches. This study presents a LBM for simulating diffusion–advection transport of substrate in a 2-D laminar flow. The model considers the substrate influx into a set of active cells placed inside the flow field. A new innovative method was used to simulate the cells activity using the LBM by means of Michaelis–Menten kinetics. The model is validated with some numerical benchmark problems and proved highly accurate results. After validation the model was used to simulate the transport of oxygen substrates that diffuse in water to feed a set of active cartilage cells inside a new designed bioreactor.     

The polysaccharides of mango seeds (mangifera indica,var. bullock's heart)

Mangoes (Mangifera indica) are grown in many warm regions of the world; for example, in Australia, Brazil, India, South America, and the United States (California and Florida), and along the shores of the Mediterranean sea (Egypt, Italy, and Spain). In Egypt, many varieties yielding delicious fruits are grown in large quantities (50,000 tons annually). Mango kernels are used for feeding mammals and chickens. Starch has been isolated from mango and its physical properties studied.The aim of the present work was to study the polysaccharides present in mango kernels.     

The effect of sodium chlorate and nitrapyrin on the nitrification mediated nitrosation process in soils

Summary The influence of total nitrification to nitrate or partial nitrification to nitrite on the soil organic nitrogen status was examined. NH ₄ ⁺ –¹⁵N was added to the soil in the absence and the presence of NaClO₃, respectively nitrapyrin. The first chemical inhibits only nitrate formation, the second inhibits total nitrification. The accumulation of nitrite nitrogen in the soil at levels up to 5 mg kg^–1 increased the loss of nitrogen. Yet, it did not increase the binding of mineral nitrogen into soil organic matter, relative to the control soil. The data suggest that the biochemistry of the nitrite formation process, rather than the levels of nitrite ions formed, are of primary importance in the role of nitrification mediated nitrosation of soil organic matter.     

Modulation of the immune response by Middle East respiratory syndrome coronavirus

Coronavirus (CoV) infections are commonly associated with respiratory and enteric disease in humans and animals. In 2012, a new human disease called Middle East respiratory syndrome (MERS) emerged in the Middle East. MERS was caused by a virus that was originally called human coronavirus-Erasmus Medical Center/2012 but was later renamed as Middle East respiratory syndrome coronavirus (MERS-CoV). MERS-CoV causes high fever, cough, acute respiratory tract infection, and multiorgan dysfunction that may eventually lead to the death of the infected individuals. The exact origin of MERS-CoV remains unknown, but the transmission pattern and evidence from virological studies suggest that dromedary camels are the major reservoir host, from which human infections may sporadically occur through the zoonotic transmission. Human to human transmission also occurs in healthcare facilities and communities. Recent studies on Middle Eastern respiratory continue to highlight the need for further understanding the virus-host interactions that govern disease severity and infection outcome. In this review, we have highlighted the major mechanisms of immune evasion strategies of MERS-CoV. We have demonstrated that M, 4a, 4b proteins and Plppro of MERS-CoV inhibit the type I interferon (IFN) and nuclear factor-κB signaling pathways and therefore facilitate innate immune evasion. In addition, nonstructural protein 4a (NSP4a), NSP4b, and NSP15 inhibit double-stranded RNA sensors. Therefore, the mentioned proteins limit early induction of IFN and cause rapid apoptosis of macrophages. MERS-CoV strongly inhibits the activation of T cells with downregulation of antigen presentation. In addition, uncontrolled secretion of interferon ɣ-induced protein 10 and monocyte chemoattractant protein-1 can suppress proliferation of human myeloid progenitor cells.     

Coffee production in southern Saudi Arabian highlands: Current status and water conservation

Work aimed at assessing status and introducing water conservation regimes for coffee production in southern Saudi Arabian highlands. Data on farm locations, altitudes, areas, practices, irrigation, tree density, and annual coffee production were analyzed. Field experiment using chlorophyll fluorescence and different irrigation regimes was conducted to examine effects of reducing irrigation frequency on photosynthesis. Results indicated that Coffea arabica L. is commonly grown at altitudes of 1300–1400 m. Plants grown at 4–6 Trees m^?2 using 100 kg ha^?1 mineral fertilizer produce an average of 3 t ha^?1. High frequency 2-day-intervals irrigation regime practiced by farmers during the dry season presents ecological challenge to limited local artesian water resources. Changes in chlorophyll fluorescence under 14-day-intervals irrigation regime initiated water stress that markedly inhibited Photosystem II efficiency and quantum yield and increased non-photochemical energy dissipation. Applying a 7-day-intervals irrigation regime induced less inhibitory effects on Photosystem II. Results also indicated that shifting from 2-day-intervals irrigation regime to 7-day-intervals regime improves coffee agroecology and directs coffee production towards sustainability.     

The congenital cataract-causing mutations P20R and A171T are associated with important changes in the amyloidogenic feature,structure and chaperone-like activity of human αB-crystallin

Cataract is the major reason for human blindness worldwide. α-Crystallin, as a key chaperone of eye lenses, keeps the lenticular tissues in its transparent state over time. In this study, cataract-causing familial mutations, P20R and A171T, were introduced in CRYАB gene. After successful expression in Escherichia coli and subsequent purification, the recombinant proteins were subjected to extensive structural and functional analyses using various spectroscopic techniques, gel electrophoresis, and electron microscopy. The results of fluorescence and Raman assessments suggest important but discreet conformational changes in human αB-Cry upon these cataractogenic mutations. Furthermore, the mutant proteins exhibited significant secondary structural alteration as revealed by FTIR and Raman spectroscopy. An increase in conformational stability was seen in the human αB-Cry bearing these congenital cataractogenic mutations. The oligomeric size distribution and chaperone-like activity of human αB-Cry were significantly altered by these mutations. The P20R mutant protein was observed to loose most of the chaperone-like activity. Finally, these cataractogenic mutant proteins exhibited an increased propensity to form the amyloid fibrils when incubated under environmental stress. Overall, the structural and functional changes in mutated human αB-Cry proteins can shed light on the pathogenic development of congenital cataracts.     

The recovery of ovarian function during breast-feeding

The pattern of breast-feeding was daily recorded and the serum concentrations of prolactin (PRL), FSH, LH, estradiol (E2) and progesterone (prog) were measured at weekly intervals in 26 breast-feeding mothers from the time of delivery and up to the resumption of regular ovulation or to the end of the first postpartum year. Twelve postpartum non-breast-feeding women were similarly studied as controls. An algorithm was used to characterize ovulatory events into three types: the first, with evidence highly suggestive of normal ovulation (EHSO), the second, with evidence of probable ovulation (EPO) and the third with evidence indicating questionable ovulation or deficient corpus luteum function (QO/DCT). Pregnancy preceded the first menstruation in one woman in each of the breast-feeding and control groups. Of the 19 breast-feeding women who started to menstruate during the first postpartum year, five had EHSO, one had EPO, 5 had EQO/DCL and 7 had anovulatory (AO) menstruation. The corresponding figures in the 11 controls were 6, 2, 3 and 0. Pregnancy occurred before a second menstruation in one woman in both the study group and the controls. In 18 breast-feeding women observed, the second menstruation was preceded by EHSO in 7, by EPO in 3, by EQO/DCL in one and AO in 7. In 10 controls the corresponding figures were 7, 3, 0 and 0. Out of a total of 79 menstruations observed during breast-feeding the incidence of AO was 30% and of QO/DCL was 15%. In actively breast-feeding mothers, hyperprolactinemia persisted for more than 1 yr. However, menstruation and ovulation occasionally occurred before the drop of PRL to concentrations seen during the normal menstrual cycle. In the majority of women, low E2 levels were present during lactational amenorrhea, but with occasional spikes in some. A few women maintained somewhat high values of E2 for several weeks before the resumption of menstruation. The implications of these hormonal findings to the attempts to improve on the contraceptive effect of breast-feeding are discussed.     

Nitrification and organic nitrogen formation in soils

Summary The formation of mineral nitrogen species and of organic nitrogen was studied in three different types of soils in relation to the application of the nitrification inhibitor nitrapyrin. The results indicate that nitrification brings about a deficit in total mineral nitrogen and a concomitant surplus in non biomass organic nitrogen. This phenomenon increases with increasing levels of applied ammonium nitrogen and soil organic matter. The phenomenon is considered to be due to the reaction of the transient nitrite formed with soil phenolic compounds and appears to be of significance in all soils in which nitrification occurs, even neutral to alkaline and low carbon soils.     

Lineage-specific expression of c-fos and c-fms in human hematopoietic cells: Discrepancies with the in vitro differentiation of leukemia cells

In vitro differentiation studies using the bipotential human leukemia cell line, HL60, have indicated that high levels of expression of two proto-oncogenes, c-fos and c-fms, are restricted to the myelomonocytic lineage. No such expression has been detected in induced granulocytic cells. In striking contrast to these observations, we found that c-fos mRNA levels are very high in purified human granulocytes, but barely detectable in blood monocytes and tissue macrophages. Human granulocytes contain, however, relatively low levels of c-fos protein, indicating that c-fos mRNA is inefficiently translated or that the protein is rapidly degraded in these cells. In closer agreement with the in vitro results, the level of the expression of c-fms is high in purified blood monocytes and undetectable in granulocytes. We found, however, that the evolution of monocytes into tissue macrophages is accompanied by a significant decrease in c-fms expression, suggesting that the function of c-fms is restricted to specific stages of monocytic differentiation. Our observations also show that results obtained using in vitro differentiation systems have to be regarded with caution, since they may not reflect the in vivo situation.