Divalent metals play important roles in maintaining metabolism and cellular growth of both eukaryotic hosts and invading microbes. Both metal deficiency and overload can result in abnormal cellular ...function or damage. Given its central role in host–pathogen interactions, subtle alterations of divalent metal homeostasis can occur in the course of infectious diseases which aim, from the host perspective, either to reduce the availability of respective metals to microbes or to use toxic metal accumulation to eliminate pathogens.
To provide the reader with background information and clinical data on divalent metal homeostasis in host–pathogen interactions, how this affects the course of infectious disease and whether correction of metal disturbances has shown benefit in infections.
An in-depth analysis of PubMed articles related to the topic of this review published in English between 1970 and 2016 was performed.
From the microbial perspective, divalent metals are essential for growth and pathogenicity and to mount effective protection against antimicrobial host responses, including toxic radical formation. Microbes have evolved multiple strategies to control their access to divalent metals. From the clinical perspective, alterations of divalent metal levels may result in increased or decreased susceptibility to infection and often occur in response to infections. However, keeping in mind the strategies underlying such alterations, for which the term ‘nutritional immunity’ was coined, the uncritical correction of such divalent metal imbalances may cause harm to patients. This review addresses the role of the divalent metals iron, selenium, zinc, manganese and copper in infectious diseases from a mechanistic and clinical perspective.
We point out areas of research needed to expand our limited knowledge, hoping to improve the clinical management of patients with infections and to identify promising new targets for treatment by modulation of host or microbe divalent metal metabolism.
Mammalian small heat-shock proteins (sHSPs) are molecular chaperones that form polydisperse and dynamic complexes with target proteins, serving as a first line of defense in preventing their ...aggregation into either amorphous deposits or amyloid fibrils. Their apparently broad target specificity makes sHSPs attractive for investigating ways to tackle disorders of protein aggregation. The two most abundant sHSPs in human tissue are αB-crystallin (ABC) and HSP27; here we present high-resolution structures of their core domains (cABC, cHSP27), each in complex with a segment of their respective C-terminal regions. We find that both truncated proteins dimerize, and although this interface is labile in the case of cABC, in cHSP27 the dimer can be cross-linked by an intermonomer disulfide linkage. Using cHSP27 as a template, we have designed an equivalently locked cABC to enable us to investigate the functional role played by oligomerization, disordered N and C termini, subunit exchange, and variable dimer interfaces in ABC. We have assayed the ability of the different forms of ABC to prevent protein aggregation in vitro. Remarkably, we find that cABC has chaperone activity comparable to that of the full-length protein, even when monomer dissociation is restricted through disulfide linkage. Furthermore, cABC is a potent inhibitor of amyloid fibril formation and, by slowing the rate of its aggregation, effectively reduces the toxicity of amyloid-β peptide to cells. Overall we present a small chaperone unit together with its atomic coordinates that potentially enables the rational design of more effective chaperones and amyloid inhibitors.
Background. During the past decade, Candida glabrata has emerged as an important cause of fungemia. We reviewed demographic data, risk factors, treatment, and outcomes associated with C. glabrata ...fungemia from 1995–2002 and performed susceptibility testing of isolates. Methods. Data on all episodes of fungemia were prospectively recorded, and the associated isolates were saved. Medical records were reviewed retrospectively. Susceptibility testing was performed for fluconazole, itraconazole, and voriconazole. Results. C. glabrata caused 103 (17%) of 609 fungemic episodes during the 8-year period that we studied. Medical records and isolates were available for 94 episodes that occurred in 91 patients. The patients included 42 men and 49 women. The mean age was 51 years. Thirty-four episodes (36%) occurred in patients >60 years old; only 3 episodes occurred in patients <1 year old. The most common predisposing factors were use of broad-spectrum antibiotics (in 86% of episodes), use of central venous catheters (77%), stay in an intensive care unit (48%), renal failure (46%), and receipt of parenteral nutrition (45%). Of the 94 episodes, 83 were treated with antifungal agents. The overall mortality rate at day 30 was 29%. For the 11 episodes that were not treated, the mortality rate was 64% (7 of 11 episodes). Outcome appeared to be unrelated to whether fluconazole or amphotericin B was administered. In vitro, 60% of isolates were resistant to fluconazole, 83% to itraconazole, and 44% to voriconazole. Susceptibility to these azoles did not change over the 8 years of the study. Conclusion. C. glabrata fungemia was most often seen in older adults and was associated with a mortality rate of 29%. Outcomes appeared to be unrelated to in vitro susceptibility results and to the antifungal agent used.
Heterogeneity in small heat shock proteins (sHsps) spans multiple spatiotemporal regimes—from fast fluctuations of part of the protein, to conformational variability of tertiary structure, plasticity ...of the interfaces, and polydispersity of the inter-converting, and co-assembling oligomers. This heterogeneity and dynamic nature of sHsps has significantly hindered their structural characterization. Atomic coordinates are particularly lacking for vertebrate sHsps, where most available structures are of extensively truncated homomers. sHsps play important roles in maintaining protein levels in the cell and therefore in organismal health and disease. HspB2 and HspB3 are vertebrate sHsps that are found co-assembled in neuromuscular cells, and variants thereof are associated with disease. Here, we present the structure of human HspB2/B3, which crystallized as a hetero-tetramer in a 3:1 ratio. In the HspB2/B3 tetramer, the four α-crystallin domains (ACDs) assemble into a flattened tetrahedron which is pierced by two non-intersecting approximate dyads. Assembly is mediated by flexible “nuts and bolts” involving IXI/V motifs from terminal regions filling ACD pockets. Parts of the N-terminal region bind in an unfolded conformation into the anti-parallel shared ACD dimer grooves. Tracts of the terminal regions are not resolved, most likely due to their disorder in the crystal lattice. This first structure of a full-length human sHsp heteromer reveals the heterogeneous interactions of the terminal regions and suggests a plasticity that is important for the cytoprotective functions of sHsps.
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•Dynamic behavior of heteromeric sHsps hinders structural biology of cytoprotection.•Full-length human HspB2/B3 in 3:1 ratio was crystallized and solved at 3.9-Å resolution.•Assembly is by flexible “nuts and bolts” from terminal regions filling domain pockets.•N-terminal regions bind in an unfolded conformation into shared dimer grooves.•IXI/V motifs from unstructured proteins may be sequestered by sHsps during disease.
Small Heat Shock Proteins (sHSPs) evolved early in the history of life; they are present in archaea, bacteria, and eukaryota. sHSPs belong to the superfamily of molecular chaperones: they are ...components of the cellular protein quality control machinery and are thought to act as the first line of defense against conditions that endanger the cellular proteome. In plants, sHSPs protect cells against abiotic stresses, providing innovative targets for sustainable agricultural production. In humans, sHSPs (also known as HSPBs) are associated with the development of several neurological diseases. Thus, manipulation of sHSP expression may represent an attractive therapeutic strategy for disease treatment. Experimental evidence demonstrates that enhancing the chaperone function of sHSPs protects against age-related protein conformation diseases, which are characterized by protein aggregation. Moreover, sHSPs can promote longevity and healthy aging in vivo. In addition, sHSPs have been implicated in the prognosis of several types of cancer. Here, sHSP upregulation, by enhancing cellular health, could promote cancer development; on the other hand, their downregulation, by sensitizing cells to external Stressors and chemotherapeutics, may have beneficial outcomes. The complexity and diversity of sHSP function and properties and the need to identify their specific clients, as well as their implication in human disease, have been discussed by many of the world's experts in the sHSP field during a dedicated workshop in Québec City, Canada, on 26-29 August 2018.
The authors tested effects of a 10-week group cognitive-behavioral stress management intervention among 100 women newly treated for Stage 0-II breast cancer. The intervention reduced prevalence of ...moderate depression (which remained relatively stable in the control condition) but did not affect other measures of emotional distress. The intervention also increased participants' reports that having breast cancer had made positive contributions to their lives, and it increased generalized optimism. Both remained significantly elevated at a 3-month follow-up of the intervention. Further analysis revealed that the intervention had its greatest impact on these 2 variables among women who were lowest in optimism at baseline. Discussion centers on the importance of examining positive responses to traumatic events-growth, appreciation of life, shift in priorities, and positive affect-as well as negative responses.
αB-crystallin is a member of the sHsp (small heat-shock protein) family that prevents misfolded target proteins from aggregating and precipitating. Phosphorylation at three serine residues (Ser19, ...Ser45 and Ser59) is a major post-translational modification that occurs to αB-crystallin. In the present study, we produced recombi-nant proteins designed to mimic phosphorylation of αB-crystallin by incorporating a negative charge at these sites. We employed these mimics to undertake a mechanistic and structural invest-igation of the effect of phosphorylation on the chaperone activity of αB-crystallin to protect against two types of protein misfolding, i.e. amorphous aggregation and amyloid fibril assembly. We show that mimicking phosphorylation of αB-crystallin results in more efficient chaperone activity against both heat-induced and reduc-tion-induced amorphous aggregation of target proteins. Mimick-ing phosphorylation increased the chaperone activity of αB-crystallin against one amyloid-forming target protein (κ-casein), but decreased it against another (ccβ-Trp peptide). We observed that both target protein identity and solution (buffer) conditions are critical factors in determining the relative chaperone ability of wild-type and phosphorylated αB-crystallins. The present study provides evidence for the regulation of the chaperone activity of αB-crystallin by phosphorylation and indicates that this may play an important role in alleviating the pathogenic effects associated with protein conformational diseases.
The quark structure of the f_{2}(1270) meson has, for many years, been assumed to be a pure quark-antiquark (qqover ¯) resonance with quantum numbers J^{PC}=2^{++}. Recently, it was proposed that the ...f_{2}(1270) is a molecular state made from the attractive interaction of two ρ mesons. Such a state would be expected to decay strongly to final states with charged pions due to the dominant decay ρ→π^{+}π^{-}, whereas decay to two neutral pions would likely be suppressed. Here, we measure for the first time the reaction γp→π^{0}π^{0}p, using the CEBAF Large Acceptance Spectrometer detector at Jefferson Lab for incident beam energies between 3.6 and 5.4 GeV. Differential cross sections, dσ/dt, for f_{2}(1270) photoproduction are extracted with good precision due to low backgrounds and are compared to theoretical calculations.
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