The growing world of small heat shock proteins: from structure to functions

Small heat shock proteins (sHSPs) are present in all kingdoms of life and play fundamental roles in cell biology. sHSPs are key components of the cellular protein quality control system, acting as the first line of defense against conditions that affect protein homeostasis and proteome stability, from bacteria to plants to humans. sHSPs have the ability to bind to a large subset of substrates and to maintain them in a state competent for refolding or clearance with the assistance of the HSP70 machinery. sHSPs participate in a number of biological processes, from the cell cycle, to cell differentiation, from adaptation to stressful conditions, to apoptosis, and, even, to the transformation of a cell into a malignant state. As a consequence, sHSP malfunction has been implicated in abnormal placental development and preterm deliveries, in the prognosis of several types of cancer, and in the development of neurological diseases. Moreover, mutations in the genes encoding several mammalian sHSPs result in neurological, muscular, or cardiac age-related diseases in humans. Loss of protein homeostasis due to protein aggregation is typical of many age-related neurodegenerative and neuromuscular diseases. In light of the role of sHSPs in the clearance of un/misfolded aggregation-prone substrates, pharmacological modulation of sHSP expression or function and rescue of defective sHSPs represent possible routes to alleviate or cure protein conformation diseases. Here, we report the latest news and views on sHSPs discussed by many of the world’s experts in the sHSP field during a dedicated workshop organized in Italy (Bertinoro, CEUB, October 12–15, 2016).     

Ventromedial prefrontal cortex activation is associated with memory formation for predictable rewards

During reinforcement learning, dopamine release shifts from the moment of reward consumption to the time point when the reward can be predicted. Previous studies provide consistent evidence that reward-predicting cues enhance long-term memory (LTM) formation of these items via dopaminergic projections to the ventral striatum. However, it is less clear whether memory for items that do not precede a reward but are directly associated with reward consumption is also facilitated. Here, we investigated this question in an fMRI paradigm in which LTM for reward-predicting and neutral cues was compared to LTM for items presented during consumption of reliably predictable as compared to less predictable rewards. We observed activation of the ventral striatum and enhanced memory formation during reward anticipation. During processing of less predictable as compared to reliably predictable rewards, the ventral striatum was activated as well, but items associated with less predictable outcomes were remembered worse than items associated with reliably predictable outcomes. Processing of reliably predictable rewards activated the ventromedial prefrontal cortex (vmPFC), and vmPFC BOLD responses were associated with successful memory formation of these items. Taken together, these findings show that consumption of reliably predictable rewards facilitates LTM formation and is associated with activation of the vmPFC.     

Wavelet Domain Radiofrequency Pulse Design Applied to Magnetic Resonance Imaging

A new method for designing radiofrequency (RF) pulses with numerical optimization in the wavelet domain is presented. Numerical optimization may yield solutions that might otherwise have not been discovered with analytic techniques alone. Further, processing in the wavelet domain reduces the number of unknowns through compression properties inherent in wavelet transforms, providing a more tractable optimization problem. This algorithm is demonstrated with simultaneous multi-slice (SMS) spin echo refocusing pulses because reduced peak RF power is necessary for SMS diffusion imaging with high acceleration factors. An iterative, nonlinear, constrained numerical minimization algorithm was developed to generate an optimized RF pulse waveform. Wavelet domain coefficients were modulated while iteratively running a Bloch equation simulator to generate the intermediate slice profile of the net magnetization. The algorithm minimizes the L2-norm of the slice profile with additional terms to penalize rejection band ripple and maximize the net transverse magnetization across each slice. Simulations and human brain imaging were used to demonstrate a new RF pulse design that yields an optimized slice profile and reduced peak energy deposition when applied to a multiband single-shot echo planar diffusion acquisition. This method may be used to optimize factors such as magnitude and phase spectral profiles and peak RF pulse power for multiband simultaneous multi-slice (SMS) acquisitions. Wavelet-based RF pulse optimization provides a useful design method to achieve a pulse waveform with beneficial amplitude reduction while preserving appropriate magnetization response for magnetic resonance imaging.     

Heterogeneity of photosystem II reaction centers as influenced by heat treatment of barley leaves

Three functionally distinct populations of PSII reaction centers differing in the ability to keep the primary acceptors in a reduced state and to transfer electrons to PSI were estimated using chlorophyll fluorescence measurements in primary barley leaves exposed to elevated temperatures in the range of 37–51°C. The capacity of the PSII reaction centers to perform at least one light-induced charge separation was not affected by a 5-min heat treatment at temperatures up to 51°C. The first population containing Q_B-non-reducing centers corresponded to 15–20% of the total PSII activity up to 45°C. In a second population, PSII reaction centers maintained Q_A reduction under light in the presence of oxygen, but not in the presence of a strong artificial PSI electron acceptor, methyl viologen. In a third population that gradually increases from zero at 37°C to about 60% at 45°C, the PSII centers were not able to keep Q_A in the reduced state even in the presence of oxygen as the sole electron acceptor. Three electron transport pathways, the pseudocyclic one involving both PSII and PSI, the NAD(P)H-dependent pathway mediated by PSI alone after the loss of activity in some PSII centers, and the PSI-driven ferredoxin-dependent route enhanced by weakly efficient PSII centers that are able to provide only catalytic amounts of electrons, are suggested to create a proton gradient in chloroplasts of heat-stressed leaves thus protecting PSII reaction centers from photodamage.     

Ric-8A,a GEF,and a Chaperone for G Protein α-Subunits: Evidence for the Two-Faced Interface

Resistance to inhibitors of cholinesterase 8A (Ric-8A) is a prominent non-receptor GEF and a chaperone of G protein α-subunits (Gα). Recent studies shed light on the structure of Ric-8A, providing insights into the mechanisms underlying its interaction with Gα. Ric-8A is composed of a core armadillo-like domain and a flexible C-terminal tail. Interaction of a conserved concave surface of its core domain with the Gα C-terminus appears to mediate formation of the initial Ric-8A/GαGDP intermediate, followed by the formation of a stable nucleotide-free complex. The latter event involves a large-scale dislocation of the Gα α5-helix that produces an extensive primary interface and disrupts the nucleotide-binding site of Gα. The distal portion of the C-terminal tail of Ric-8A forms a smaller secondary interface, which ostensibly binds the switch II region of Gα, facilitating binding of GTP. The two-site Gα interface of Ric-8A is distinct from that of GPCRs, and might have evolved to support the chaperone function of Ric-8A.     

Cost-Effectiveness of Cetuximab for Advanced Esophageal Squamous Cell Carcinoma

BackgroundCostly biologicals in palliative oncology are emerging at a rapid pace. For example, in patients with advanced esophageal squamous cell carcinoma addition of cetuximab to a palliative chemotherapy regimen appears to improve survival. However, it simultaneously results in higher costs. We aimed to determine the incremental cost-effectiveness ratio of adding cetuximab to first-line chemotherapeutic treatment of patients with advanced esophageal squamous cell carcinoma, based on data from a randomized controlled phase II trial.MethodsA cost effectiveness analysis model was applied based on individual patient data. It included only direct medical costs from the health-care perspective. Quality-adjusted life-years and incremental cost-effectiveness ratios were calculated. Sensitivity analysis was performed by a Monte Carlo analysis.ResultsAdding cetuximab to a cisplatin-5-fluorouracil first-line regimen for advanced esophageal squamous cell carcinoma resulted in an the incremental cost-effectiveness ratio of €252,203 per quality-adjusted life-year. Sensitivity analysis shows that there is a chance of less than 0.001 that the incremental cost-effectiveness ratio will be less than a maximum willingness to pay threshold of €40,000 per quality-adjusted life-year, which is representative for the threshold used in The Netherlands and other developed countries.ConclusionsAddition of cetuximab to a cisplatin-5-fluorouracil first-line regimen for advanced esophageal squamous cell carcinoma is not cost-effective when appraised according to currently accepted criteria. Cost-effectiveness analyses using outcome data from early clinical trials (i.c. a phase II trial) enable pharmaceutical companies and policy makers to gain early insight into whether a new drug meets the current eligibility standards for reimbursement and thereby potential admittance for use in regular clinical practice.     

The parasitic polychaete known as Asetocalamyzas laonicola (Calamyzidae) is in fact the dwarf male of the spionid Scolelepis laonicola (comb. nov.)

Abstract. The morphology of the obligately ectoparasitic polychaete Asetocalamyzas laonicola was studied by light and electron microscopy, and its taxonomic position was determined using molecular methods. The parasite has an extensive coelomic cavity, complete septae, and well-developed segmental nephridia, circulatory, and digestive systems. The nervous system is rudimentary and without ganglia. The parasite's anterior region penetrates the tissues of the host, and opens into the host's body cavity. The epidermal tissues of the parasite and the host are highly integrated in the area of contact, and the parasite's cuticle is continuous with that of the host. Blood vessels of the parasite and the host may interlace in the fusion zone. The dorsal side of the parasite faces the dorsal side of the host. All parasites were males, but all hosts were females. In order to elucidate the uncertain systematic position of the parasite, molecular systematic studies were conducted. Parasite and host 18S rDNA sequences were virtually identical and revealed that both belong to the spionid cluster. These sequences differed from those of Scolelepis squamata and Scolelepis bonnieri by 2.7% and 0.9%, respectively. In addition, of seven partial sequences of the mitochondrial COI gene obtained from three parasites and four hosts, six were identical, and in one host–parasite pair, COI sequences differed by one substitution. Partial ITS2 sequences from one host–parasite pair were analyzed and also found to be similar but not identical, with two indels in a 645-bp alignment. We conclude that the parasite is in fact a dwarf male of its conspecific spionid female host. Consequently, A. laonicola is transferred to Scolelepis (Spionidae), forming the new combination Scolelepis laonicola.     

Biogeographical study of West Siberian hemiboreal forest associations with species range overlay methods

The geographical distributions of plant communities are usually inferred from mapping relevés. Here, we study another approach to map the ranges of associations and higher syntaxa: the joint distribution of the constant species of the associations, i.e. those species most frequently found in the relevés. We ask whether the joint distribution of the species reflects the distribution of the associations and higher syntaxa. Because of limited availability of plant distribution maps we consider species occurring in more than 40% of the relevés of four associations belonging to Western and Central Siberian hemiboreal forests of the class Brachypodio pinnati–Betuletea pendulae. Those species are the most informative for syntaxonomic considerations. The joint distribution is established by overlaying the distribution maps of the species and numerically compared with the mapped distribution of the vegetation communities using Cohen's Kappa. Most species occurring in the associations have a small to mid-sized range. The range size distribution of the contributing species approaches a normal distribution after logarithmic transformation of the range sizes. The geographical extents of the associations are well reflected by the overlays of all constant species. Removing sequentially the species beginning with those having the smallest distribution ranges from the overlay leads to progressive loss of similarity between mapped and modelled range of the associations. For the higher syntaxa (order and class) the similarity between mapped and modelled range increases first but drops at the end of the removal procedure. The less widespread species are particularly important for the recognition of a local plant community, i.e. the association. In contrast, more widespread species allow the definition of the ranges of higher syntaxa and reveal more large-scale geographic relationships of the vegetation. From our quantitative assessment of mapped and modelled maps of the distribution of plant communities, we conclude that the overlay method is useful to infer the geographical extent of plant communities.