Motif inference reveals optimal CTL epitopes presented by HLA class I alleles highly prevalent in southern Africa

HIV-specific CTL play a central role in immune control of HIV. The basis for understanding the success or failure of this immune response requires identification of the specific epitopes targeted by CTL. However, in populations most severely affected by the global epidemic, this fundamental knowledge is hindered by the lack of characterization of many of the HLA class I alleles highly prevalent in such populations. Overall, the peptide-binding motif has been determined for a small minority (9%) of HLA class I alleles, with a strong bias toward those alleles prevalent in Caucasoid populations. These studies therefore set out to define, in a South African Zulu/Xhosa population at the epicenter of the epidemic, the epitopes presented by alleles highly prevalent, but for which the peptide-binding motif had not been characterized. Using a method of motif inference, epitopes presented by four such alleles prevalent in the Zulu/Xhosa population of Durban, South Africa, namely, B*3910, B*4201, B*8101, and Cw*1801, are described. Importantly, this approach may additionally facilitate optimization of epitopes in certain instances where conflicting reports in the literature exist regarding the peptide-binding motif, such as for HLA-A*2902, also highly prevalent in southern African populations. These data indicate that the previously anomalous position of HLA-A*2902 among HLA-A alleles, outside any recognized HLA-A supertype, is artifactual, and the true position of the A*2902 motif overlaps those of the A1 and A24 supertypes.     

The polymorphisms of IL-4, IL-4R and IL-13 genes and bladder cancer risk in a Chinese population: a case-control study

Accumulating evidence suggests that inflammatory process may play a role in bladder carcinogenesis. However, the exact mechanisms of how the inflammatory factors associate with bladder cancer risk are still unknown. In this study, we explored whether polymorphisms (i.e. IL-4 C-590T, IL-4R Ile50Val, IL-4R Ser478Pro, IL-4R Gln551Arg, IL-13 C-1055T and IL-13 Arg130Gln) of IL-4, IL-4R and IL-13 genes predicted Chinese bladder cancer risk in 817 bladder cancer and 1,141 controls. Genotyping was performed by using the TaqMan method. We did not find any overall association between these single nucleotide polymorphisms (SNPs) and bladder cancer susceptibility in a Chinese population. However, in the classification and regression tree (CART) analysis, we found that carriers of IL-13 C-1055T variant genotype in smokers had a 2.57-fold increased bladder cancer risk with a 55% patient rate (OR = 2.57; 95% CI = 1.93-3.43), comparing with non-smokers. Similar result was also observed in combination of IL-13 C-1055T and IL-13 Arg130Gln in smokers. By multifactor dimensionality reduction (MDR) analysis, the best interaction model was the two-factor model that smokers with the IL-13 C-1055T genotypes were the subgroup to predict bladder cancer risk. The results suggested that the genetic variants in IL-4, IL-4R and IL-13 genes might modulate the bladder cancer risk in a Chinese population.     

Microscopic Delineation of Medulloblastoma Margins in a Transgenic Mouse Model Using a Topically Applied VEGFR-1 Probe

The unambiguous demarcation of tumor margins is critical at the final stages in the surgical treatment of brain tumors because patient outcomes have been shown to correlate with the extent of resection. Real-time high-resolution imaging with the aid of a tumor-targeting fluorescent contrast agent has the potential to enable intraoperative differentiation of tumor versus normal tissues with accuracy approaching the current gold standard of histopathology. In this study, a monoclonal antibody targeting the vascular endothelial growth factor receptor 1 (VEGFR-1) was conjugated to fluorophores and evaluated as a tumor contrast agent in a transgenic mouse model of medulloblastoma. The probe was administered topically, and its efficacy as an imaging agent was evaluated in vitro using flow cytometry, as well as ex vivo on fixed and fresh tissues through immunohistochemistry and dual-axis confocal microscopy, respectively. Results show a preferential binding to tumor versus normal tissue, suggesting that a topically applied VEGFR-1 probe can potentially be used with real-time intraoperative optical sectioning microscopy to guide brain tumor resections.     

Consequences of warming up a hotspot: species range shifts within a centre of bee diversity

Aim Bees are the most important pollinators of flowering plants and essential ecological keystone species contributing to the integrity of most terrestrial ecosystems. Here, we examine the potential impact of climate change on bees’ geographic range in a global biodiversity hotspot. Location South Africa with a focus on the Cape Floristic Region (CFR) diversity hotspot. Methods  Geographic ranges of 12 South African bee species representing dominant distribution types were studied, and the climate change impacts upon bees were examined with A2 and B2 climate scenarios of HadCM3 model, using MaxEnt for species distribution modelling. Results The predicted levels of climate change‐induced impacts on species ranges varied from little shifts and range expansion of 5–50% for two species to substantial range contractions between 32% and 99% in another six species. Four species show considerable range shifts. Bees of the winter rainfall area in the west of South Africa generally have smaller range sizes than in the summer rainfall area and generally show eastward range contractions toward the dry interior. Bee species prevalent in summer rainfall regions show a tendency for a south‐easterly shift in geographic range. Main conclusions The bee fauna of the CFR is identified as the most vulnerable to climate change due to the high level of endemism, the small range sizes and the island‐like isolation of the Mediterranean‐type climate region at the SW tip of Africa. For monitoring climate change impact on bees, we suggest to establish observatories in the coastal plains of the west coast that are predicted to be worst affected and areas where persistence of populations is most likely. Likely impacts of climate change on life history traits of bees (phenology, sociality, bee‐host plant synchronization) are discussed but require further investigation.     

Change of liver metabolism of 1,2-dibromoethane during simultaneous treatment with carbon tetrachloride

The combination of carbon tetrachloride (CCl₄) and 1,2-dibromoethane (DBE) in isolated rat hepatocytes led to a significant potentiation of both lipid peroxidation and of plasma membrane damage observed after a single treatment with CCl₄. Such a synergistic effect appeared to be related to the CCl₄-induced shift of DBE metabolism from the cytosolic conjugation with glutathione towards the microsomal transformation into toxic intermediates. In fact, CCl₄ significantly inactivated hepatocyte total GSH-transferase, i.e. the DBE detoxification pathway. Furthermore, while the microsomal metabolism of CCl₄ was not affected by the simultaneous presence of DBE, the amount of DBE reactive metabolities covalently bound to hepatocyte protein was significantly enhanced in the presence of CCl₄.     

Disease-associated mutations in a bifunctional aminoacyl-tRNA synthetase gene elicit the integrated stress response

Aminoacyl-tRNA synthetases (ARSs) catalyze the charging of specific amino acids onto cognate tRNAs, an essential process for protein synthesis. Mutations in ARSs are frequently associated with a variety of human diseases. The human EPRS1 gene encodes a bifunctional glutamyl-prolyl-tRNA synthetase (EPRS) with two catalytic cores and appended domains that contribute to nontranslational functions. In this study, we report compound heterozygous mutations in EPRS1, which lead to amino acid substitutions P14R and E205G in two patients with diabetes and bone diseases. While neither mutation affects tRNA binding or association of EPRS with the multisynthetase complex, E205G in the glutamyl-tRNA synthetase (ERS) region of EPRS is defective in amino acid activation and tRNA^Glu charging. The P14R mutation induces a conformational change and altered tRNA charging kinetics in vitro. We propose that the altered catalytic activity and conformational changes in the EPRS variants sensitize patient cells to stress, triggering an increased integrated stress response (ISR) that diminishes cell viability. Indeed, patient-derived cells expressing the compound heterozygous EPRS show heightened induction of the ISR, suggestive of disruptions in protein homeostasis. These results have important implications for understanding ARS-associated human disease mechanisms and development of new therapeutics.     

Oxygen free radical scavenger properties of dehydroepiandrosterone

The microsomes from dehydroepiandrosterone (DHEA)-supplemented animals are good hydroxyl radical scavengers, as demonstrated through electron spin resonance and deoxyribose degradation. The ability of DHEA-supplemented microsomes to react with superoxide radical was also demonstrated through the inhibition of nitro-blue tetrazolium reduction determined by superoxide radicals produced in a hypoxanthine–xanthine oxidase system. DHEA-enriched microsomes, obtained from acutely DHEA-treated rats, become resistant to iron-dependent lipid peroxidation triggered by H₂O₂/FeSO₄ and ascorbate/FeSO₄. The direct addition of DHEA to microsomes from untreated rats failed to prevent iron-dependent lipid peroxidation, even if the microsomes were preincubated with DHEA for up to 15 min, indicating that in vivo transformation is required before antioxidant action can be exerted. © 1998 John Wiley & Sons, Ltd.     

Immune and nonimmune mechanisms mediate the mental stress-induced tumor growth in a xenograft model of breast cancer

Excess mental stress may harm health, and even accelerate cancer initiation and progression. One fourth of breast cancer patients suffer mental stress including anxiety, sadness, or depression, which negatively affect prognosis and survival. However, the regulatory mechanism is yet to be determined. Herein, we applied unpredictable stress stimuli to the breast tumor-bearing mice to establish a xenograft model of breast cancer suffering mental stress, followed by behavioral tests, tumor growth tracking, immune analysis, miRNA screening, and tumor cell proliferation analysis as well. As a result, increased stress hormone levels in serum, decreased percentage of T and NK cells in both blood and tumor samples and accelerated tumor growth in vivo were observed in the mice exposed to mental stress. Promoted cell proliferation was observed in both primary tumor cells derived from the stressed mice and 4T1 breast cancer cells treated with stress hormone corticosterone. In addition, a subset of miRNAs including miR-326, 346, 493, 595, 615, and 665 were identified through a miRNA screening with downregulation in tumors of the stressed mice. CCND1 was identified as a common target gene of miR-346 and miR-493, the top two most significantly downregulated miRNAs by stress exposure. The stress-miRNA-CCND1 signaling regulation of the tumor cell proliferation was further validated in 4T1 cells treated with corticosterone in vitro. GO terms and KEGG pathways analyses on the target genes of miR-346 and miR-493 revealed their involvement in the regulation of human cancer and neuron system, indicating the importance of non-coding genome in mediating the mental stress-induced cancer regulation. In conclusion, this study not only explored immune and nonimmune mechanisms through which mental stress exposure contributes to tumor growth in breast cancer, but also suggested a new therapeutic strategy for cancer patients suffering mental stress.Subject terms: Breast cancer, Disease model, miRNAs     

Enhanced Electrocatalysis for Energy‐Efficient Hydrogen Production over CoP Catalyst with Nonelectroactive Zn as a Promoter

As a non‐toxic species, Zn fulfills a multitude of biological roles, but its promoting effect on electrocatalysis has been rarely explored. Herein, the theoretic predications and experimental investigations that nonelectroactive Zn behaves as an effective promoter for CoP‐catalyzed hydrogen evolution reaction (HER) in both acidic and alkaline media is reported. Density function theory calculations reveal that Zn doing leads to more thermal‐neutral hydrogen adsorption free energy and thus enhanced HER activity for CoP catalyst. Electrochemical tests show that a Zn_0.08Co_0.92P nanowall array on titanium mesh (Zn_0.08Co_0.92P/TM) needs overpotentials of only 39 and 67 mV to drive a geometrical catalytic current of 10 mA cm^‐2 in 0.5 m H₂SO₄ and 1.0 m KOH, respectively. This Zn_0.08Co_0.92P/TM is also superior in activity over CoP/TM for urea oxidation reaction (UOR), driving 115 mA cm^‐2 at 0.6 V in 1.0 m KOH with 0.5 m urea. The high HER and UOR activity of this bifunctional electrode enables a Zn_0.08Co_0.92P/TM‐based two‐electrode electrolyzer for energy‐saving hydrogen production, offering 10 mA cm^‐2 at a low voltage of 1.38 V with strong long‐term electrochemical stability.