Reflections on classic papers in Ethnic and Racial Studies

This paper provides an overview of this Special Issue celebrating the 40th anniversary of Ethnic and Racial Studies. We discuss some of the themes that are covered in this issue in the context of the wider history of the journal. We argue that the journal has worked over the years both to publish the highest quality original research and to feature scholarship in emerging subfields that have helped to broaden both our scope and reach across the globe. In addition we highlight some of the contribution that the journal has made to the development of both established and new areas of scholarship in its field throughout the world.     

Racial and Ethnic Disparities in Diabetes Clinical Care and Management: A Narrative Review

Diabetes affects nearly 37 million Americans, with disproportionately higher disease burden amongst those from minoritized communities. The result of this is greater rates of diabetic complications and mortality. To close this gap in care, it is important to assess the differences in both diagnosis and care between White and ethnic/racial minoritized persons with diabetes. The purpose of this narrative review is to explore this further by assessing the differences in diagnosis, management, diabetes education, and complications.     

尼可霉素(Nikkomycins)多组分结构及其生物合成相关基因的研究进展

尼可霉素是一种新的抗真菌抗生素,在分离到的20多种活性单组分中,X、Z、I、J为主要生物活性组分。本文介绍了尼可霉素的结构,结构与活性的关系及其生物合成途径中有关基因的研究进展。     

Statistical Comparison of Carcinogenic Effects and Dose–Response Relationships in Rats and Mice for 2,4-Toluene Diamine to those Ascribed to Toluene Diisocyanate

The U.S. National Toxicology Program (NTP) conducted 2-year bioassays of commercial grade toluene diisocyanate (TDI) (80% 2,4-TDI and 20% 2,6-TDI) and 2,4-toluene diamine (TDA) and concluded that both were carcinogenic in rodents. In the TDI study, there was an unproven but likely formation of TDA either because of flawed test-substance handling and storage conditions and/or the atypical exposure conditions employed. Although the carcinogenic responses in both studies were qualitatively similar, several statistical analyses were performed to substantiate this possibility more rigorously. Seven different statistical approaches combine to yield a robust and consistent conclusion that, if only a small fraction (approximately 5%) of the dose of TDI were hydrolyzed to TDA in the TDI study, then that would be sufficient to explain the observed carcinogenic responses in the TDI study.     

Response of nutrient dynamics of decomposing pine (Pinus massoniana) needles to simulated N deposition in a disturbed and a rehabilitated forest in tropical China

The effects of simulated N deposition on changes in mass, C, N and P of decomposing pine (Pinus massoniana) needles in a disturbed and a rehabilitated forest in tropical China were studied during a 24-month period. The objective of the study was to test the hypothesis that litter decomposition in a disturbed forest is more sensitive to N deposition rate than litter decomposition in a rehabilitated forest due to the relatively low nutrient status in the former as a result of constant human disturbance (harvesting understory and litter). The litterbag method and N treatments (control, no N addition; low-N, 5 g N m⁻² year⁻¹; medium-N, 10 g N m⁻² year⁻¹) were employed to evaluate decomposition. The results revealed that N addition increased (positive effect) mass loss rate and C release rate but suppressed (negative effect) the release rate of N and P from decomposing needles in both disturbed and rehabilitated forests. The enhanced needle decomposition rate by N addition was significantly related to the reduction in the C/N ratio in decomposing needles. However, N availability is not the sole factor limiting needle decomposition in both disturbed and rehabilitated forests. The positive effect was more sensitive to the N addition rate in the rehabilitated forest than in the disturbed forest, however the reverse was true for the negative effect. These results suggest that nutrient status could be one of the important factors in controlling the response of litter decomposition and its nutrient release to elevated N deposition in reforested ecosystems in the study region.     

东南景天对锌、镉复合污染的反应及其对锌、镉的吸收和积累特性

东南景天(Sedum alfredii Hance)已被鉴定为一种中国原生的新的锌超积累植物。 本文主要研究了锌(Zn)、镉(Cd)复合处理水平对东南景天的生长及其对锌、镉的吸收积累特性的影响。 结果表明,在Zn/Cd复合水平为500/100 祄ol/L时,植物生长最佳。Zn/Cd在东南景天叶片、茎部和根系中含量随着Zn/Cd处理水平的提高而增高。在Zn/Cd 复合水平为50/400 祄ol/L时茎叶中Cd含量达最高,其中叶片Cd含量达12.1 g/kg;在Zn/Cd 复合水平为1 000/50 祄ol/L时茎叶中Zn含量达最高, 其中茎中Zn含量达 23.2 g/kg。 植株各部位Cd含量的分布为:叶片>茎>>根系,而Zn在体内的分布为: 茎>叶片>>根系。 Zn、Cd在地上部和根部的积累量也随着处理水平的提高而增加,分别在Zn/Cd复合水平为250/400和500/100 祄ol/L下达高峰值。 东南景天地上部积累最高Zn和Cd的量分别达11和5 g/plant, 其比根系的积累量分别大10和25余倍。 Zn、Cd对东南景天的生长、吸收积累的相互作用依赖于Zn/Cd复合水平和植物部位。 在适宜Zn/Cd 处理水平范围内,Zn和Cd的吸收和积累具有相互促进作用。 高Zn或高Cd处理均抑制了植物对Zn和Cd的吸收和积累。 本研究结果表明,东南景天不仅具有忍耐高Zn/Cd复合污染,而且具有超量积累Zn和Cd的特异能力。 它为进一步研究植物Zn、Cd     

Studies on the possible biological effects of 50 Hz electric and/or magnetic fields: Evaluation of some glycolytic enzymes,glycolytic flux,energy and oxido-reductive potentials in human erythrocytes exposed in vitro to power frequency fields

An attempt has been made to understand whether 50 Hz electric and magnetic fields (EMFs) are involved in producing bioeffects by exposing human erythrocytes in vitro. The study evaluated some key glycolytic enzymes, glucose consumption, lactate production, energy charge, 2,3-diphosphoglycerate, and reduced glutathione levels. all of which are biochemical parameters significant to erythrocyte function. Cells exposed to individual or superimposed EMFs have not shown any significant difference compared with the controls. © 1993 Wiley-Liss. Inc.     

The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage

The non-receptor tyrosine kinase c-Abl is activated in response to DNA damage and induces p73-dependent apoptosis. Here, we investigated c-Abl regulation of the homeodomain-interacting protein kinase 2 (HIPK2), an important regulator of p53-dependent apoptosis. c-Abl phosphorylated HIPK2 at several sites, and phosphorylation by c-Abl protected HIPK2 from degradation mediated by the ubiquitin E3 ligase Siah-1. c-Abl and HIPK2 synergized in activating p53 on apoptotic promoters in a reporter assay, and c-Abl was required for endogenous HIPK2 accumulation and phosphorylation of p53 at Ser⁴⁶ in response to DNA damage by γ- and UV radiation. Accumulation of HIPK2 in nuclear speckles and association with promyelocytic leukemia protein (PML) in response to DNA damage were also dependent on c-Abl activity. At high cell density, the Hippo pathway inhibits DNA damage-induced c-Abl activation. Under this condition, DNA damage-induced HIPK2 accumulation, phosphorylation of p53 at Ser⁴⁶, and apoptosis were attenuated. These data demonstrate a new mechanism for the induction of DNA damage-induced apoptosis by c-Abl and illustrate network interactions between serine/threonine and tyrosine kinases that dictate cell fate.     

Mass Spectrometry-based Structural Analysis and Systems Immunoproteomics Strategies for Deciphering the Host Response to Endotoxin

One cause of sepsis is systemic maladaptive immune response of the host to bacteria and specifically, to Gram-negative bacterial outer-membrane glycolipid lipopolysaccharide (LPS). On the host myeloid cell surface, proinflammatory LPS activates the innate immune system via Toll-like receptor-4/myeloid differentiation factor-2 complex. Intracellularly, LPS is also sensed by the noncanonical inflammasome through caspase-11 in mice and 4/5 in humans. The minimal functional determinant for innate immune activation is the membrane anchor of LPS called lipid A. Even subtle modifications to the lipid A scaffold can enable, diminish, or abolish immune activation. Bacteria are known to modify their LPS structure during environmental stress and infection of hosts to alter cellular immune phenotypes. In this review, we describe how mass spectrometry-based structural analysis of endotoxin helped uncover major determinations of molecular pathogenesis. Through characterization of LPS modifications, we now better understand resistance to antibiotics and cationic antimicrobial peptides, as well as how the environment impacts overall endotoxin structure. In addition, mass spectrometry-based systems immunoproteomics approaches can assist in elucidating the immune response against LPS. Many regulatory proteins have been characterized through proteomics and global/targeted analysis of protein modifications, enabling the discovery and characterization of novel endotoxin-mediated protein translational modifications.     

Heart receptors for VIP, PHI and secretin are able to activate adenylate cyclase and to mediate inotropic and chronotropic effects. Species variations and physiopathology

We have assessed the presence of VIP/PHI/secretin receptors in heart by: (1) testing the ability of the corresponding peptides to activate adenylate cyclase in cardiac membranes from rat, dog, Cynomolgus monkey and man, and (2) examining the ability of the same peptides to exert inotropic and chronotropic effects on heart preparations from rat and Cynomolgus monkey in vitro. Based on their affinity for natural peptides and synthetic analogs, two types of VIP/PHI/secretin receptors were characterized: the relatively nonspecific "secretin/VIP receptor" of rat heart (that is "secretin-preferring" only in that secretin was more efficient than VIP in stimulating adenylate cyclase), and the "VIP/PHI-preferring" receptor of man, monkey and dog heart. Four physiopathological situations affecting secretin/VIP receptors in rat heart were explored: In male rats from the Okamoto strain and the Lyon strain, two strains presenting spontaneous hypertension, heart membranes exhibited a markedly decreased response of adenylate cyclase to secretin/VIP, with lesser alterations in the responses to isoproterenol and glucagon. This impairment developed in parallel with the occurrence of hypertension and was reproduced in normotensive rats submitted to chronic isoproterenol treatment (but not in Goldblatt hypertensive rats). These findings are consistent with a hyperactivity of norepinephrine pathways in spontaneously hypertensive rats, leading to a reduced number of cardiac post-junctional secretin/VIP receptors bound to adenylate cyclase. Heart membranes from genetically obese (fa/fa) Zucker rats also exhibited severely decreased responses to secretin/VIP with lesser alterations in the responses to glucagon and isoproterenol. These anomalies were specific for the heart, and developed in concomitance with obesity. The first anomaly could not be corrected by severe food restriction. Secretin stimulation of heart adenylate cyclase was also selectively altered in streptozotocin-diabetic rats. Thus, two types of diabetic cardiomyopathy were characterized by a severe local alteration of secretin/VIP receptors coupled to adenylate cyclase. Hypothyroidism, provoked in rat by thyroidectomy or propylthiouracil treatment, again induced a marked decrease in secretin-stimulated cardiac adenylate cyclase activity. In rat papillary muscle electrically stimulated in vitro, secretin exerted a positive inotropic effect. This effect was reduced in obese (fa/fa) Zucker rats. In rat right atrium, secretin also exerted a positive chronotropic effects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Binding of a fluorescent lipid amphiphile to albumin and its transfer to lipid bilayer membranes

Kinetics and thermodynamics of the binding of a fluorescent lipid amphiphile, Rhodamine Green(TM)-tetradecylamide (RG-C(14:0)), to bovine serum albumin were characterized in an equilibrium titration and by stopped-flow fluorimetry. The binding equilibrium of RG-C(14:0) to albumin was then used to reduce its concentration in the aqueous phase to a value below its critical micelle concentration. Under these conditions, the only two species of RG-C(14:0) in the system were the monomer in aqueous solution in equilibrium with the protein-bound species. After previous determination of the kinetic and thermodynamic parameters for association of RG-C(14:0) with albumin, the kinetics of insertion of the amphiphile into and desorption off lipid bilayer membranes in different phases (solid, liquid-ordered, and liquid-disordered phases, presented as large unilamellar vesicles) were studied by stopped-flow fluorimetry at 30 degrees C. Insertion and desorption rate constants for association of the RG-C(14:0) monomer with the lipid bilayers were used to obtain lipid/water equilibrium partition coefficients for this fluorescent amphiphile. The direct measurement of these partition coefficients is shown to provide a new method for the indirect determination of the equilibrium partition coefficient of similar molecules between two defined lipid phases if they coexist in the same membrane.     

The xanthophyll cycle and antioxidative defense system are enhanced in the wheat hybrid subjected to high light stress

Although the wheat hybrids have often shown higher grain yields, the physiological basis of the higher yields remains unknown. Previous studies suggest that tolerance to photoinhibition in the hybrid may be one of the physiological bases (Yang et al., 2006, Plant Sci 171:389-97). The objective of this study was to further investigate the possible mechanism responsible for tolerance to photoinhibition in the hybrid. Photosystem II (PSII) photochemistry, the xanthophyll cycle, and antioxidative defense system were compared between the hybrid and its parents subjected to high light stress (1500 μmol m⁻² s⁻¹). The analyses of oxygen-evolving activity, chlorophyll fluorescence, and protein blotting demonstrated that the higher tolerance in the hybrid than in its parents was associated with its higher tolerance of PSII to photoinhibition. High light induced an increase in non-photochemical quenching, and this increase was greater in the hybrid than in its parents. There were no differences in the pool size of the xanthophyll cycle between the hybrid and its parents. The content of violaxanthin decreased significantly, whereas the content of zeaxanthin + antherxanthin increased considerably during high light treatments. However, the decrease in violaxanthin content and the increase in zeaxanthin + antherxanthin content were greater in the hybrid than in its parents. High light resulted in a significant accumulation of H₂O₂, O₂⁻ and catalytic Fe, and this accumulation was less in the hybrid than in its parents. High light induced a significant increase in the activities of superoxide dismutase, catalase, ascorbate peroxidase, glutathione reductase, dehydroascorbate reductase, and monodehydroascorbate reductase, and these increases were greater in the hybrid than its parents. These results suggest that the higher tolerance to photoinhibition in the hybrid may be associated with its higher capacity for antioxidative defense metabolism and the xanthophyll cycle.     

Direct electron transfer from graphite and functionalized gold electrodes to T1 and T2/T3 copper centers of bilirubin oxidase

Direct electron transfer (DET) from bare spectrographic graphite (SPGE) or 3-mercaptopropionic acid-modified gold (MPA-gold) electrodes to Trachyderma tsunodae bilirubin oxidase (BOD) was studied under anaerobic and aerobic conditions by cyclic voltammetry and chronoamperometry. On cyclic voltammograms nonturnover Faradaic signals with midpoint potentials of about 700 mV and 400 mV were clearly observed corresponding to redox transformations of the T1 site and the T2/T3 cluster of the enzyme, respectively. The immobilized BOD was differently oriented on the two electrodes and its catalysis of O₂-electroreduction was also massively different. On SPGE, where most of the enzyme was oriented with the T1 copper site proximal to the carbon with a quite slow ET process, well-pronounced DET-bioelectroreduction of O₂ was observed, starting already at > 700 mV vs. NHE. In contrast, on MPA-gold most of the enzyme was oriented with its T2/T3 copper cluster proximal to the metal. Indeed, there was little DET-based catalysis of O₂-electroreduction, even though the ET between the MPA-gold and the T2/T3 copper cluster of BOD was similar to that observed for the T1 site at SPGE. When BOD actively catalyzes the O₂-electroreduction, the redox potential of its T1 site is 690 mV vs. NHE and that of one of its T2/T3 copper centers is 390 mV vs. NHE. The redox potential of the T2/T3 copper cluster of a resting form of BOD is suggested to be about 360 mV vs. NHE. These values, combined with the observed biocatalytic behavior, strongly suggest an uphill intra-molecular electron transfer from the T1 site to the T2/T3 cluster during the catalytic turnover of the enzyme.     

Independent tyrosyl contributions to the CD of Ff gene 5 protein and the distinctive effects of Y41H and Y41F mutants on protein-protein cooperative interactions

The gene 5 protein (g5p) of the Ff virus contains five Tyr, individual mutants of which have now all been characterized by CD spectroscopy. The protein has a dominant tyrosyl 229-nm L(a) CD band that is shown to be approximately the sum of the five individual Tyr contributions. Tyr41 is particularly important in contributing to the high cooperativity with which the g5p binds to ssDNA, and Y41F and Y41H mutants are known to differ in dimer-dimer packing interactions in crystal structures. We compared the solution structures and binding properties of the Y41F and Y41H mutants using CD spectroscopy. Secondary structures of the mutants were similar by CD analyses and close to those derived from the crystal structures. However, there were significant differences in the binding properties of the two mutant proteins. The Y41H protein had an especially low binding affinity and perturbed the spectrum of poly[d(A)] in 2 mM Na(+) much less than did Y41F and the wild-type gene 5 proteins. Moreover, a change in the Tyr 229 nm band, assigned to the perturbation of Tyr34 at the dimer-dimer interface, was absent in titrations with the Y41H mutant under low salt conditions. In contrast, titrations with the Y41H mutant in 50 mM Na(+) exhibited typical CD changes of both the nucleic acid and the Tyr 229-nm band. Thus, protein-protein and g5p-ssDNA interactions appeared to be mutually influenced by ionic strength, indicative of correlated changes in the ssDNA binding and cooperativity loops of the protein or of indirect structural constraints.     

Structural alteration of glycosaminoglycan side chains and spatial disorganization of collagen networks in the skin of patients with mcEDS-CHST14

Musculocontractural Ehlers-Danlos syndrome (mcEDS) due to CHST14/D4ST1 deficiency (mcEDS-CHST14) is a recently delineated type of EDS caused by biallelic loss-of-function mutations in CHST14, which results in the depletion of dermatan sulfate (DS). Clinical characteristics of mcEDS-CHST14 consist of multiple malformations and progressive fragility-related manifestations, including skin hyperextensibility and fragility. Skin fragility is suspected to result from the impaired assembly of collagen fibrils caused by alteration of the glycosaminoglycan (GAG) chain of decorin-proteoglycan (PG) from DS to chondroitin sulfate (CS). This systematic investigation of the skin pathology of patients with mcEDS-CHST14 comprised both immunostaining of decorin and transmission electron microscopy-based cupromeronic blue staining to visualize GAG chains. Collagen fibrils were dispersed in the affected papillary to reticular dermis; in contrast, they were regularly and tightly assembled in controls. Moreover, the fibrils exhibited a perpendicular arrangement to the affected epidermis, whereas fibrils were parallel to control epidermis. Affected GAG chains were linear, stretching from the outer surface of collagen fibrils to adjacent fibrils; in contrast, those of controls were curved, maintaining close contact with attached collagen fibrils. This is the first observation of compositional alteration, from DS to CS, of GAG side chains, which caused structural alteration of GAG side chains and resulted in spatial disorganization of collagen networks; this presumably disrupted the ring-mesh structure of GAG side chains surrounding collagen fibrils. McEDS-CHST14 provides a critical example of the importance of DS in GAG side chains of decorin-PG during assembly of collagen fibrils in maintenance of connective tissues.     

Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery

The epithelial and endothelial barriers of the human body are major obstacles for drug delivery to the systemic circulation and to organs with unique environment and homeostasis, like the central nervous system. Several transport routes exist in these barriers, which potentially can be exploited for enhancing drug permeability. Beside the transcellular pathways via transporters, adsorptive and receptor-mediated transcytosis, the paracellular flux for cells and molecules is very limited. While lipophilic molecules can diffuse across the cellular plasma membranes, the junctional complexes restrict or completely block the free passage of hydrophilic molecules through the paracellular clefts. Absorption or permeability enhancers developed in the last 40 years for modifying intercellular junctions and paracellular permeability have unspecific mode of action and the effective and toxic doses are very close. Recent advances in barrier research led to the discovery of an increasing number of integral membrane, adaptor, regulator and signalling proteins in tight and adherens junctions. New tight junction modulators are under development, which can directly target tight or adherens junction proteins, the signalling pathways regulating junctional function, or tight junction associated lipid raft microdomains. Modulators acting directly on tight junctions include peptides derived from zonula occludens toxin, or Clostridium perfringens enterotoxin, peptides selected by phage display that bind to integral membrane tight junction proteins, and lipid modulators. They can reversibly increase paracellular transport and drug delivery with less toxicity than previous absorption enhancers, and have a potential to be used as pharmaceutical excipients to improve drug delivery across epithelial barriers and the blood-brain barrier.     

Evaluation of blood-brain barrier penetration and examination of binding to human serum albumin of 7-O-arylpiperazinylcoumarins as potential antipsychotic agents

The delivery of drugs to the brain is complicated by the multiple factors including low blood–brain barrier (BBB) passive permeability, active BBB efflux systems, and plasma protein binding. Thus, a detailed understanding of the transport of the new potent substances through the membranes is vitally important and their physico-chemical characteristics should be analyzed at first. This work presents an evaluation of drug likeness of eight 7-O-arylpiperazinylcoumarin derivatives with high affinity towards serotoninergic receptors 5-HT_1A and 5-HT_2A with particular analysis of the requirements for the CNS chemotherapeutics. The binding constants to human serum albumin (HSA) were determined at physiological pH using fluorescence spectroscopy, and then their mode of action was explained by analysis of theoretical HSA complexes. Dynamic simulation of systems allowed for reliable evaluation of the interaction strength. The analyzed coumarins were able to pass BBB, and they present good drug likeness properties. They showed high affinities to HSA (log K_Q = 5.3–6.0 which corresponds to −8.12 to −7.15 kcalmol⁻¹ of Gibbs free energy). The changes of the emission intensity upon binding to HSA were scrutinized showing the different mode of action for 4-phenylpiperazinylcoumarins. The values of computed Gibbs free energy and determined on the basis of experimentally obtained binding constants log K_Q coincide suggesting a good quality of the theoretical model. Overall the 8-acetyl-7-O-arylpiperazinyl-4-methylcoumarin derivatives represent valuable lead compounds to be further tested in various preclinical assays as a possible chemotherapeutics against CNS diseases. Studied coumarins can be metabolized by cytochrome P450 to aldehydes and hydroxy derivatives. The existence of other binding sites inside HSA than Sudlow’s site 1 was postulated. The longer aliphatic linker between coumarin and piperazine moieties favored binding to HSA in other than Sudlow site 1 pocket.