From the endoplasmic reticulum to the plasma membrane: mechanisms of CFTR folding and trafficking

CFTR biogenesis starts with its co-translational insertion into the membrane of endoplasmic reticulum and folding of the cytosolic domains, towards the acquisition of a fully folded compact native structure. Efficiency of this process is assessed by the ER quality control system that allows the exit of folded proteins but targets unfolded/misfolded CFTR to degradation. If allowed to leave the ER, CFTR is modified at the Golgi and reaches the post-Golgi compartments to be delivered to the plasma membrane where it functions as a cAMP- and phosphorylation-regulated chloride/bicarbonate channel. CFTR residence at the membrane is a balance of membrane delivery, endocytosis, and recycling. Several adaptors, motor, and scaffold proteins contribute to the regulation of CFTR stability and are involved in continuously assessing its structure through peripheral quality control systems. Regulation of CFTR biogenesis and traffic (and its dysregulation by mutations, such as the most common F508del) determine its overall activity and thus contribute to the fine modulation of chloride secretion and hydration of epithelial surfaces. This review covers old and recent knowledge on CFTR folding and trafficking from its synthesis to the regulation of its stability at the plasma membrane and highlights how several of these steps can be modulated to promote the rescue of mutant CFTR.     

Connexins and pannexins in the skeleton: gap junctions,hemichannels and more

Regulation of bone homeostasis depends on the concerted actions of bone-forming osteoblasts and bone-resorbing osteoclasts, controlled by osteocytes, cells derived from osteoblasts surrounded by bone matrix. The control of differentiation, viability and function of bone cells relies on the presence of connexins. Connexin43 regulates the expression of genes required for osteoblast and osteoclast differentiation directly or by changing the levels of osteocytic genes, and connexin45 may oppose connexin43 actions in osteoblastic cells. Connexin37 is required for osteoclast differentiation and its deletion results in increased bone mass. Less is known on the role of connexins in cartilage, ligaments and tendons. Connexin43, connexin45, connexin32, connexin46 and connexin29 are expressed in chondrocytes, while connexin43 and connexin32 are expressed in ligaments and tendons. Similarly, although the expression of pannexin1, pannexin2 and pannexin3 has been demonstrated in bone and cartilage cells, their function in these tissues is not fully understood.     

General mechanisms of drought response and their application in drought resistance improvement in plants

Plants often encounter unfavorable environmental conditions because of their sessile lifestyle. These adverse factors greatly affect the geographic distribution of plants, as well as their growth and productivity. Drought stress is one of the premier limitations to global agricultural production due to the complexity of the water-limiting environment and changing climate. Plants have evolved a series of mechanisms at the morphological, physiological, biochemical, cellular, and molecular levels to overcome water deficit or drought stress conditions. The drought resistance of plants can be divided into four basic types-drought avoidance, drought tolerance, drought escape, and drought recovery. Various drought-related traits, including root traits, leaf traits, osmotic adjustment capabilities, water potential, ABA content, and stability of the cell membrane, have been used as indicators to evaluate the drought resistance of plants. In the last decade, scientists have investigated the genetic and molecular mechanisms of drought resistance to enhance the drought resistance of various crops, and significant progress has been made with regard to drought avoidance and drought tolerance. With increasing knowledge to comprehensively decipher the complicated mechanisms of drought resistance in model plants, it still remains an enormous challenge to develop water-saving and drought-resistant crops to cope with the water shortage and increasing demand for food production in the future.     

The expansion of GPCR transactivation-dependent signalling to include serine/threonine kinase receptors represents a new cell signalling frontier

G protein-coupled receptor (GPCR) signalling is mediated through transactivation-independent signalling pathways or the transactivation of protein tyrosine kinase receptors and the recently reported activation of the serine/threonine kinase receptors, most notably the transforming growth factor-β receptor family. Since the original observation of GPCR transactivation of protein tyrosine kinase receptors, there has been considerable work on the mechanism of transactivation and several pathways are prominent. These pathways include the “triple membrane bypass” pathway and the generation of reactive oxygen species. The recent recognition of GPCR transactivation of serine/threonine kinase receptors enormously broadens the GPCR signalling paradigm. It may be predicted that the transactivation of serine/threonine kinase receptors would have mechanistic similarities with transactivation of tyrosine kinase pathways; however, initial studies suggest that these two transactivation pathways are mechanistically distinct. Important questions are the relative importance of tyrosine and serine/threonine transactivation pathways, the contribution of transactivation to overall GPCR signalling, mechanisms of transactivation and the range of cell types in which this phenomenon occurs. The ultimate significance of transactivation-dependent signalling remains to be defined but it appears to be prominent and if so will represent a new cell signalling frontier.     

Laccases of prokaryotic origin: enzymes at the interface of protein science and protein technology

The ubiquitous members of the multicopper oxidase family of enzymes oxidize a range of aromatic substrates such as polyphenols, methoxy-substituted phenols, amines and inorganic compounds, concomitantly with the reduction of molecular dioxygen to water. This family of enzymes can be broadly divided into two functional classes: metalloxidases and laccases. Several prokaryotic metalloxidases have been described in the last decade showing a robust activity towards metals, such as Cu(I), Fe(II) or Mn(II) and have been implicated in the metal metabolism of the corresponding microorganisms. Many laccases, with a superior efficiency for oxidation of organic compounds when compared with metals, have also been identified and characterized from prokaryotes, playing roles that more closely conform to those of intermediary metabolism. This review aims to present an update of current knowledge on prokaryotic multicopper oxidases, with a special emphasis on laccases, anticipating their enormous potential for industrial and environmental applications.     

Euler’s beta integral in Pietro Mengoli’s works

Beta integrals for several non-integer values of the exponents were calculated by Leonhard Euler in 1730, when he was trying to find the general term for the factorial function by means of an algebraic expression. Nevertheless, 70 years before, Pietro Mengoli (1626–1686) had computed such integrals for natural and half-integer exponents in his Geometriae Speciosae Elementa (1659) and Circolo(1672) and displayed the results in triangular tables. In particular, his new arithmetic–algebraic method allowed him to compute the quadrature of the circle. The aim of this article is to show how Mengoli calculated the values of these integrals as well as how he analysed the relation between these values and the exponents inside the integrals. This analysis provides new insights into Mengoli’s view of his algorithmic computation of quadratures.     

Giulio Racah and theoretical physics in Jerusalem

The present article considers Giulio Racah’s contributions to general physical theory and his establishment of theoretical physics as a discipline in Israel. Racah developed mathematical methods that are based on tensor operators and continuous groups. These methods revolutionized spectroscopy. Currently, these are essential research tools in atomic, nuclear and elementary particle physics. He himself applied them to modernizing theoretical atomic spectroscopy. Racah laid the foundations of theoretical physics in Israel. He educated several generations of Israeli physicists, and put Israel on the world map of physics.     

Mean Motions in Ptolemy’s <Emphasis Type="Italic">Planetary Hypotheses</Emphasis>

In the Planetary Hypotheses, Ptolemy summarizes the planetary models that he discusses in great detail in the Almagest, but he changes the mean motions to account for more prolonged comparison of observations. He gives the mean motions in two different forms: first, in terms of ‘simple, unmixed’ periods and next, in terms of ‘particular, complex’ periods, which are approximations to linear combinations of the simple periods. As a consequence, all of the epoch values for the Moon and the planets are different at era Philip. This is in part a consequence of the changes in the mean motions and in part due to changes in Ptolemy’s time in the anomaly, but not the longitude or latitude, of the Moon, the mean longitude of Saturn and Jupiter, but not Mars, and the anomaly of Venus and Mercury, the former a large change, the latter a small one. The pattern of parameter changes we see suggests that the analyses that yielded the Planetary Hypotheses parameters were not the elegant trio analyses of the Almagest but some sort of serial determinations of the parameters based on sequences of independent observations.     

Letters from William Burnside to Robert Fricke: automorphic functions,and the emergence of the Burnside Problem

Two letters from William Burnside have recently been found in the Nachlass of Robert Fricke that contain instances of the Burnside Problem prior to its first publication. We present these letters as a whole to the public for the first time. We draw a picture of these two mathematicians and describe their activities leading to their correspondence. We thus gain an insight into their respective motivations, reactions, and attitudes, which may sharpen the current understanding of professional and social interactions of the mathematical community at the turn of the twentieth century. Dedicated to Heiko Harborth on the occasion of his seventieth birthday.