Polycarnitine—a new biomaterial

The natural product l-carnitine is—due to its biotechnological accessibility and specific properties—on the way to becoming an attractive biobased bulk product. l-Carnitine is a natural betaine with vitamin properties. Carnitine is an essential part of the fatty acid metabolism of human beings and animals. Carnitine was first isolated in 1905 from meat extract and important recent developments include the biosyntheses of l-carnitine from l-lysine or -butyrobetaine. Our synthesis routes are designed to maintain the primary structure and specific properties of carnitine, such as hydrophilicity and stiffening effects for polymeric structures and applications. l-Carnitine is converted via lactonization or olefinization into polymerizable basic molecules. The properties and the applications of carnitine polymers are described.This revised version was published online in February 2005 with text corrections in the subsection Biotechnological production of L-carnitine of the Introduction section.     

Roflamycoin — a new channel-forming antibiotic

Ion permeability of lipid bilayers was studied in the presence of a new antifungal pentaene antibiotic, roflamycoin, the structure of which differs of which differs considerably from that of the well-known polyene channel-former amphotericin B. Both of them, however, show the property of increasing the membrane permeability only in the case of sterol-containing membrane when added on both its sides. The conductance is strongly dependent on the concentration of the antibiotic in the solutions and of sterol in the membrane. Unlike the amphotericin B channels, roflamycoin channels are potential-dependent and have short lifetime (approx. 1 s) and high conductance (approx. 100 ps in 1 M KCl), which increases linearly with the salt concentration and is not blocked by the familiar blockers of amphotericin B channels. The two antibiotics seem to have a common mechanism of channel formation, viz. the formation starts from two semi-pores assembled in the opposite monolayers from several molecules of the antibiotic and sterol. However, the inner diameter of the roflamycoin channel is larger because of the different antibiotic-to-sterol ratio in the channel aggregate. It is believed that the difference in the ratio is due to the presence of the methyl group in the polyene chain of roflamycoin, and the considerable difference in lifetimes of the two types of channels depends on the terminal groups of the antibiotics.     

Haematemesis: a new syndrome?

Three patients presented with symptoms suggesting a Mallory-Weiss tear. Endoscopy showed a localized, clearly demarcated area of bright red mucosa near the gastro-oesophageal junction; this was thought to have arisen by retrograde intussusception of the stomach during vomiting or retching and may have caused the haemorrhage.     

Intra-Golgi transport: a way to a new paradigm?

The morpho-functional principles of intra-Golgi transport are, surprisingly, still not clear, which is in marked contrast to our advanced knowledge of the underlying molecular machineries. Recently, the conceptual and technological hindrances that had delayed progress in this area have been disappearing, and a cluster of powerful morphological techniques has been revealing new glimpses of the organization of traffic in intact cells. Here, we discuss the new concepts around the present models of intra-Golgi transport.     

Secretin—a new stress hormone?

The plasma concentration of secretin was measured during a 5-day military training course comprising prolonged physical exercise (35% of max O₂ uptake), severe caloric deficiency (approx. 35700 kJ/24 h) and sleep deprivation (only 2 h of sleep as a total during 5 days). 24 subjects were divided into 3 groups, one group was compensated for the caloric deficiency and another group was partly compensated for the sleep deprivation. The results showed that the fasting plasma secretin increased 3–6-fold (from 1.8–3.7 to 13.3–19.1 pmol/l) during the course with small differences in increase between the groups. Ingestion of a mixed meal reduced the fasting plasma secretin by about 40% during the course, while oral glucose reduced the plasma secretin to the concentrations found in the control experiment.The study shows that plasma secretin is increased when man is exposed to prolonged multifactorial stress. Additional food or sleep appears to have small influence on the fasting plasma secretin, but after giving a meal or oral glucose solution the plasma secretin decreases rapidly.     

Accelerated nitrogen inputs — A new problem or a new perspective?

This paper considers whether new problems are arising in forest ecosystems due to increased levels of inorganic N deposition from the atmosphere, or whether there are no new problems, just a change of perception. Deposition of N has indeed increased. Wet deposition rates are reasonably quantified, but the rates of dry deposition to forests are largely unknown. Current transport and deposition models are probably under-estimating N deposition to forests. Consideration of possible effects of enhanced N deposition reveals with varying degrees of certainty that there may be effects due to high N in biomass, high uptake rates, leaching of nitrate and consequent acidification, and an overall increase in N availability. Forest ecosystems are not well-enough understood to set a critical load for N deposition, but enough is known to define some upper limits.     

Towards a new politics of migration?

This paper reconsiders Stephen Castle’s classic paper Why Migration Policies Fail. Beginning with the so-called migration crisis of 2015 it considers the role of numbers is assessing success or failure. It argues that in the UK public debates about immigration changed with European Union (EU) Enlargement in 2004, when the emphasis shifted from concerns about asylum to concerns about EU mobility. Concerns were exacerbated by the government’s failure to meet its promise to reduce net migration. This policy is hampered by the general problem of definition of “migrant” and the gap between statistical measures and popular usage in which “migration” signifies problematic mobility. In fact, concern about migration has become a placeholder for concerns about globalization and democratic accountability. A new politics of migration must make connections between migrants and citizens, but also between migration and other global processes, particularly outsourcing and the exploitation of labour and resources in the global south.     

Hypoalbuminaemic hyponatraemia: a new syndrome?

Six patients with severe hyponatraemia had neurological features of hyponatraemia and pronounced hypoalbuminaemia. All had biochemical features typical of the syndrome of inappropriate secretion of antidiuretic hormone with low serum osmolality and an inappropriately high urinary osmolality. All were given infusions of whole plasma or albumin solution, or both, to restore their plasma albumin concentrations to normal, which led to a dramatic increase in plasma sodium concentrations and serum osmolality, with a concomitant fall in urinary osmolality in all patients. Neurological features were reversed in four patients. It is suggested that severe hypoalbuminaemia is an important cause of appreciable hyponatraemia; infusions of plasma and albumin in such patients may reverse the biochemical and clinical features and should form the basis of management.     

Synapse reorganization—a new partnership revealed

Changes in synaptic function require both qualitative and quantitative reorganization of the synaptic components. Ca²⁺ plays a central role in this process, but the mechanism has not been fully elucidated. Zhang et al report a novel mechanism whereby Ca²⁺/calmodulin (CaM) regulates the stability of the postsynaptic scaffold. Ca²⁺/CaM interacts with PSD-95, a core protein in the postsynaptic density (PSD) that supports synaptic signaling and structural components. Ca²⁺/CaM interferes with the palmitoylation of PSD-95, resulting in the dissociation of PSD-95 from the postsynaptic membrane. This process may explain the reduction of surface glutamate receptor observed during synaptic depression and homeostatic regulation of the synaptic response after prolonged neuronal activity.The adaptation of synaptic strength is a fundamental process for learning and memory. This form of synaptic plasticity is triggered by influx of Ca²⁺ from NMDA-type glutamate receptor (NMDAR), leading to the synaptic insertion or removal of AMPA-type glutamate receptor (AMPAR) and determines the strength of synaptic transmission. This process is mediated by the gross reorganization of the postsynaptic composition in a qualitative and quantitative fashion (Bosch et al, 2014). Importantly, the number of synaptic AMPAR is regulated by the number and affinity of postsynaptic ‘slots’, a hypothetical receptor binding site within a synapse, which is regulated during synaptic plasticity processes.PSD-95, a scaffolding protein at excitatory synapses, has been considered as a major candidate for the slot. It interacts with AMPAR through the TARP/stargazin protein family and modulates the synaptic localization of the receptor as well as the strength of synaptic transmission (El-Husseini et al, 2000). In turn, the localization of PSD-95 at the synapse is regulated by a constant cycle of palmitoylation by protein palmitoyl acyltransferases (PAT) at cysteines 3 and 5, which is required for efficient synaptic targeting of the protein, and depalmitoylation by palmitoyl protein thioesterases (PPT) (El-Husseini et al, 2002; Noritake et al, 2009). Activation of glutamate receptors increases depalmitoylated PSD-95 and releases it from the postsynaptic site (El-Husseini et al, 2002; Sturgill et al, 2009), whereas blockage of neuronal activity by TTX increases palmitoylated PSD-95 and targets it to the synapse (Noritake et al, 2009). However, it remains unclear how neuronal activity controls the palmitoylation/depalmitoylation cycle and the subsequent trafficking of PSD-95 to and from the synapse.In this issue of The EMBO Journal, using a combination of structural biological, biochemical, and cell biological approaches, Zhang et al (2014) revealed a novel mechanism by which Ca²⁺ regulates the synaptic localization of PSD-95. The authors found that Ca²⁺ complexed to CaM can bind PSD-95 within the first 13 residues—the exact location where palmitoylation takes place. Ca²⁺/CaM binds preferentially to unmodified PSD-95, thereby blocking the accessibility of the PAT to the palmitoylation sites. In contrast, Ca²⁺/CaM does not bind to palmitoylated PSD-95, and therefore, palmitoylated PSD-95 is subject to depalymitoylation by PPT. Overall, the net effect of Ca²⁺/CaM is a reduction of PSD-95 bound to the synaptic membrane (Fig​(Fig1).1). Consistent with this, a PSD-95 mutant that was unable to bind Ca²⁺/CaM does not leave the synapse following glutamate/glycine treatment. Furthermore, the mutant PSD-95 showed an increased in synaptic accumulation, indicating that the treatment also increases palmitoylation activity but it is normally dominated by the depalmitoylating action of Ca²⁺/CaM binding (Noritake et al, 2009).Open in a separate windowFigure 1Calcium influx-induced release of PSD-95 and glutamate receptor from the synapseAt a synapse, cysteine residues of PSD-95 (C3 and C5) are under a continuous cycle of palmitoylation by protein palmitoyl acyltransferase (PAT), and depalmitoylation by palmitoyl protein thioesterase (PPT). A. Palmitoylated PSD-95 associates with the synaptic membrane and CDKL5 and serves as a ‘slot’ for AMPAR at the synapse through the interaction with TARP/stargazin. B. Upon glutamate stimulation, Ca²⁺ influx through NMDARs induces binding of Ca²⁺/CaM to PSD-95. Ca²⁺/CaM blocks the accessibility of PAT, thereby facilitating the depalmitoylation of PSD-95, which subsequently allows PSD-95 to dissociate from the synaptic membrane and CDKL5. C. The dissociation of PSD-95 from the synaptic membrane reduces the number of available ‘slots’ for AMPAR on the postsynaptic membrane, leading to a reduction of AMPAR-mediated synaptic transmission.The beauty of the work by Zhang et al (2014) is that the structure fully explains the biology. However, several important questions remain. Above all, it is still unclear when this mechanism would operate. Generally, the palmitoylation/depalmitoylation cycle is considered to be in the order of minutes. Therefore, for Ca²⁺/CaM to effectively reduce the palmitoylation of PSD-95, a prolonged influx of Ca²⁺ is required. In contrast, the rise in intracellular Ca²⁺ induced by a single excitatory postsynaptic current (EPSC) or dendritic action potential is in the order of milliseconds to seconds. A slow repetitive stimulation protocol, such as that used to induce long-term depression (LTD) (1 Hz, 15 min), may be effective in increasing Ca²⁺/CaM for a sufficiently long period of time. Homeostatic scaling induced by a prolonged increase in network activity (for example, via the pharmacological blockade of inhibitory synaptic transmission) may also be a possible mechanism for the Ca²⁺/CaM-mediated removal of synaptic PSD-95. In contrast, stimulation used to induce long-term potentiation (LTP) (a brief high-frequency stimulation such as 100 Hz, 1 s) may not be effective. Indeed, Bosch et al (2014) found that the induction of LTP at single dendritic spines in hippocampal CA1 pyramidal neurons does not decrease or increase PSD-95 during the first hour after induction even if the dendritic spine enlarges during this period.In this context, it is important to understand what impact Ca²⁺/CaM-mediated removal of synaptic PSD-95 has on synaptic transmission. If PSD-95 is indeed the slot for AMPAR, the Ca²⁺/CaM-mediated removal of synaptic PSD-95 is expected to reduce the synaptic transmission. The stimulation protocol used here by Zhang et al (bath application of glutamate/glycine) is similar to previously reported approaches to induce ‘chemical’ LTD and hence can provide an explanation for the decrease in PSD-95 from the synapse for 10–15 min after stimulation. The PSD-95 mutant that is unable to bind Ca²⁺/CaM will be useful to further analyze the link between the observed PSD-95-Ca²⁺/CaM interaction and synaptic plasticity.PSD-95 is also known to interact with the cyclin-dependent protein kinase-like kinase 5 (CDKL5) at the first 19 residues in a palmitoylation-dependent manner (Zhu et al, 2013). As expected, Ca²⁺/CaM binding also regulates CDKL5 association with PSD-95. The treatment of neurons with NMDA reduces the palmitoylation of PSD-95 and, concomitantly, the association with CDKL5. Mutations of CDKL5 and netrin-G1 gene have been reported in patients with an atypical form of Rett syndrome. Netrin-G1 ligand (NGL1) has been identified as an interaction partner and substrate of CDKL5 (Ricciardi et al, 2012). CDKL5 phosphorylates NGL1, and this phosphorylation stabilizes the interaction of NGL1 with PSD-95. Given that the Ca²⁺ signal only lasts a few milliseconds to seconds, it is important to investigate the spatiotemporal interaction between CaM, PSD-95, CDKL5, and NGL1 in dendritic spines during physiological and pathological conditions. In addition, CDKL5 can function as an upstream modulator of Rac signaling during development (Chen et al, 2010). Together with the fact that Rac also plays an important role in long-term potentiation, the PSD-95/CDKL5 complex might regulate Rac activity in the vicinity of the PSD.Other neuronal proteins including AMPAR subunit GluR1/2, glutamate receptor interacting protein (GRIP), G-protein-coupled receptors, δ-catenin, and small and trimeric G-proteins can also undergo palmitoylation, suggesting that this process plays an essential role in subcellular targeting and that these proteins can be regulated by activity (Kang et al, 2008). The question of whether Ca²⁺/CaM can regulate the palmitoylation of these proteins remains. Interestingly, the Ca²⁺/CaM interaction site of PSD-95 does not conform to a canonical IQ-motif, a CaM binding motif found in many other proteins (Zhang et al, 2014). Therefore, a bioinformatic approach is not possible at this point in time. This opens further directions of research.     

Neurosteroids: a new brain function?

The biosynthesis of neurosteroids proceeds through cholesterol side-chain cleavage, and gives rise to pregnenolone (P) and dehydroepiandrosterone (D). These steroids accumulate in the rat brain independently of the supply by peripheral endocrine glands. This led to the discovery of a steroid biosynthesis pathway in rat brain oligodendrocytes based on enzyme immunocytochemistry and conversion of radioactive precursors to C-21 steroids. Several biological functions have been proposed for P and D. They may serve as precursors of other steroids (such as progesterone and testosterone and their metabolites). They are implicated in the control of some behavioural activities. They have excitatory effects on neurons, and they modulate the function of GABAA-receptors. These observations may apply to all mammalian species including the human, and the physiological significance of neurosteroid synthesis needs further investigation. The relationship between steroids and cerebral function may be reconsidered in the light of a new fact: the existence of a biosynthetic pathway of these compounds from cholesterol, assured in the brain by the oligodendrocytes, glial cells which synthesize myelin.     

Hb Sinai,a new α chain mutant a 47 His

Summary A new chain mutant Hb-Sinai ₄₇ ^His is described. The aminoacid composition of all tryptic peptides has been determined, with the exception of the insoluble core. In the fingerprint peptide T 6 which normally migrates between T 3 and T 1, moves now between T 3 and T 7. The aminoacid composition of peptide T 6 indicates a change in the aminoacid composition from Asp- to His⁺ in position 47.This work was supported by Grant No. GM 13714 U.S.P.H.S.     

Pinguicula rotundiflora—a new species from Mexico

Pinguicula rotundiflora (Lentibulariaceae), a new species from southern Mexico related toP. parvifolia Robinson is described and illustrated.     

‘Kumanasamuha’ a new genus of dematiaceae

Summary Kumanasamuha a new genus of Dematiaceae is described, collected growing as saprophyte on unidentified wood, from Pakhal forest, withK. sundara as type.