Search

Aims/hypothesis Distal diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes with many patients showing a reduction of intraepidermal nerve fibre density (IENFD) from skin biopsy, a validated and sensitive diagnostic tool for the assessment of DSP. Axonal swelling ratio is a morphological quantification altered in DSP. It is, however, unclear if axonal swellings are related to diabetes or DSP. The aim of this study was to investigate how axonal swellings in cutaneous nerve fibres are related to type 2 diabetes mellitus, DSP and neuropathic pain in a well-defined cohort of patients diagnosed with type 2 diabetes. Methods A total of 249 participants, from the Pain in Neuropathy Study (UK) and the International Diabetic Neuropathy Consortium (Denmark), underwent a structured neurological examination, nerve conduction studies, quantitative sensory testing and skin biopsy. The study included four groups: healthy control study participants without diabetes (n = 45); participants with type 2 diabetes without DSP (DSP−; n = 31); and participants with evidence of DSP (DSP+; n = 173); the last were further separated into painless DSP+ (n = 74) and painful DSP+ (n = 99). Axonal swellings were defined as enlargements on epidermal-penetrating fibres exceeding 1.5 μm in diameter. Axonal swelling ratio is calculated by dividing the number of axonal swellings by the number of intraepidermal nerve fibres. Results Median (IQR) IENFD (fibres/mm) was: 6.7 (5.2–9.2) for healthy control participants; 6.2 (4.4–7.3) for DSP−; 1.3 (0.5–2.2) for painless DSP+; and 0.84 (0.4–1.6) for painful DSP+. Swelling ratios were calculated for all participants and those with IENFD > 1.0 fibre/mm. When only those participants with IENFD > 1.0 fibre/mm were included, the axonal swelling ratio was higher in participants with type 2 diabetes when compared with healthy control participants (p 1c (r = 0.16, p = 0.04), but did not correlate with the Toronto Clinical Scoring System (surrogate measure of DSP severity), BMI or type 2 diabetes duration. Conclusions/interpretation In individuals with type 2 diabetes where IENFD is >1.0 fibre/mm, axonal swelling ratio is related to type 2 diabetes but is not related to DSP or painful DSP. Axonal swellings may be an early marker of sensory nerve injury in type 2 diabetes. Graphical abstract

International audience; The iron(II) [2´2] grid complex Fe-8H has been synthesized and characterized. It undergoes spin-crossover (SCO) upon deprotonation of the hydrazine-based terpyridine-like ligand. The deprotonation patterns have been determined by X-ray crystallography and 1H NMR spectroscopy and discussed in relation to the spin state of the iron(II) centers which influences greatly the pKa of the ligand. The synthesis of the magnetically-silent zinc(II) analogue is also reported and its (de)protonation behavior has been characterized to serve as reference for the study of the Fe II grid complexes. DFT computations have also been performed in order to investigate how the successive deproto-nation of the bridging ligands affects the SCO behavior within the grid. n INTRODUCTION The search for materials having tunable properties is a very active research area. 1 In this context, special attention has been given to the modulation of magnetic properties by physical means such as temperature, 2 pressure and light, 2,3 or through chemical processes affecting the ligand field in complexes. 4 Spin crossover (SCO) complexes are interesting candidates, particularly iron(II) complexes, which exhibit a switching process between a paramagnetic high spin state (HS, S = 2) and a dia-magnetic low spin state (LS, S = 0). 5 Polymetallic [2´2] grid-like complexes 6 with modulable properties can be seen as molecular precursors of metallosupramolecular architectures or materials due to their ability to generate ordered arrangements of multiple grid entities by self-assembly at the air-water interface, 7 through hydrogen-bond formation in the solid array 8 and on adsorption onto a graphite surface. 9 It has been shown that tetranuclear iron(II) [2´2] grids undergo multiple spin state switching under the action of three physical triggers, temperature, pressure and light. 2,10 The influence of hydrogen-bond donors, 11 as well as that of counterions and solvent, 12 have also been shown to allow the modulation of the magnetism of these architectures. On the other hand, [2´2] grids presenting ionizable N-H sites undergo reversible protonic modulation of optical and redox properties. 13 One thus expects that the magnetic properties of such entities may also be modulated by reversible ligand deprotonation without destruction of the initial complex. 2,13 The hydrazine-based ditopic isomeric ligand H2L (Scheme 1) offers the opportunity to both generate [2´2] grid architectures by self-assembly and to study the protonic modulation of their physico-chemical properties, due to their ionizable N-H sites. The final step of the synthesis of such a ditopic ligand consists in the condensation reaction of one equivalent of 4,6-bis(hydrazino)-2-phenyl-pyrimidine with two equivalents of 2-pyri-dine-carboxaldehyde to yield ligand H2L. This ligand contains two com-plexation subunits of terpyridine (terpy) type, where the hydrazone function acts as an ionizable group whose acidity is greatly enhanced on complexation, as compared to the free ligands. Scheme 1. Synthesis of the ditopic ionizable hydrazine-based ligand H2L and its self-assembly into the corresponding tetranu-clear [Fe4(H2L)4] 8+ [2´2] grid complex by coordination with Fe II cations. Red spheres represent Fe metal ions. Hydrogen atoms that are colored in blue emphasize the deprotonation sites on the [2´2] grid. ABSTRACT: When immersed in solutions containing Cu(II) cations, the microporous metal−organic material P11 ([Cd 4 (BPT) 4 ]·[Cd(C 44 H 36 N 8)(S)]·[S], BPT = bi-phenyl-3,4′,5-tricarboxylate) undergoes a transformation of its [Cd 2 (COO) 6 ] 2− molecular building blocks (MBBs) into novel tetranuclear [Cu 4 X 2 (COO) 6 (S) 2 ] MBBs to form P11-Cu. The transformation occurs in single-crystal to single-crystal fashion, and its stepwise mechanism was studied by varying the Cd 2+ /Cu 2+ ratio of the solution in which crystals of P11 were immersed. P11-16/1 (Cd in framework retained, Cd in encapsulated porphyrins exchanged) and other intermediate phases were thereby isolated and structurally characterized. P11-16/1 and P11-Cu retain the microporosity of P11, and the relatively larger MBBs in P11-Cu permit a 20% unit cell expansion and afford a higher surface area and a larger pore size. P orous metal−organic materials (MOMs) that incorporate

PMC5479146; Molecular dynamics (MD) simulations and far-infrared (far-IR) spectroscopy were combined to study peptide binding by the second PDZ domain (PDZ1) of MAGI1, which has been identified as an important target for the Human Papilloma Virus. PDZ1 recognizes and binds to the C-terminal end of the E6 protein from high-risk Human Papilloma Virus. The far-IR spectra of two forms of the protein, an unbound APO form and a HOLO form (where the PDZ1 is bound to an 11-residue peptide derived from the C terminus of HPV16 E6), were obtained. MD simulations were used to determine the most representative structure of each form and these were used to compute their respective IR spectra by normal mode analysis. Far-UV circular dichroism spectroscopy was used to confirm the secondary structure content and the stability through temperature-dependent studies. Both the experimental and calculated far-IR spectra showed a red shift of the low-frequency peaks upon peptide binding. The calculations show that this is coincident with an increased number of hydrogen bonds formed as the peptide augments the protein beta-sheet. We further identified the contribution of surface-bound water molecules to bands in the far-IR and, through the calculations, identified potential pathways for allosteric communication. Together, these results demonstrate the utility of combining far-IR experiments and MD studies to study peptide binding by proteins.

Key Clinical Message Heparin‐induced thrombocytopenia (HIT) is a prothrombotic state that can affect patients with chronic kidney disease (CKD) on hemodialysis (HD). This case highlights the potential usefulness of apixaban therapy for patients with HIT and CKD on HD.

Background: \ud \ud Epidemiological studies in patients with neuropathic pain demonstrate a strong association with psychiatric conditions such as anxiety; however, the precipitating pathology between these symptoms remains unclear. To investigate this, we studied the effects of lifelong stress on levels of neuropathic pain–like behavior and conversely, the effects of chronic neuropathic injury on anxiety-like status in male and female mice. In addition, we assayed this link in painful and painless diabetic peripheral neuropathy patients.\ud \ud \ud Methods: \ud \ud Male and female mice were subject to ongoing life-stress or control living conditions. Baseline sensitivity and anxiety tests were measured followed by spared nerve injury (SNI) to the sciatic nerve. Subsequent sensory testing occurred until 3 weeks after SNI followed by anxiety tests between 4 and 6 weeks after SNI.\ud \ud \ud Results: \ud \ud Levels of tactile or cold allodynia did not differ between adult mice subject to lifelong chronic stress, relative to nonstressed controls, for at least 3 weeks after SNI. By contrast, longer-term neuropathic mice of both sexes displayed pronounced anxiety-like behavior, regardless of exposure to stress. If sex differences were present, females usually exhibited more pronounced anxiety-like behavior. These ongoing anxiety behaviors were corroborated with plasma corticosterone levels in distinct animal groups. In addition, data from patients with painful and nonpainful diabetic neuropathy showed a clear relationship between ongoing pain and anxiety, with females generally more affected than males.\ud \ud \ud Discussion: \ud \ud Taken together, these data demonstrate a strong link between chronic neuropathic pain and chronic anxiety, with the driver of this comorbidity being neuropathic pain as opposed to on-going stress.

Power converter topologies with series-connected devices must maintain repeatable blocking voltages across the devices to ensure reliability. Effective voltage sharing requires consistent diode reverse recovery charges, which is not guaranteed with commercially produced devices. To evaluate this effect, this paper measures and statistically quantifies the variation in reverse recovery characteristics of diodes from one manufacturer. Statistics are provided for various groupings by date code, shipment tube, and back-and front-end epitaxy processes. The devices are then matched for reverse recovery charge and series-connected in a medium-voltage five-level power converter. Voltage sharing is significantly better than a similar test with devices chosen at random. However, the device voltage mismatch exceeds predictions based solely on charge mismatch.

In order to properly address the issues of today’s global world, the importance of engineering students acquiring leadership and professional skills has increased tremendously. In fact, leadership is one of the basic pillars for global economic development. By immersing oneself in an engineering organization or honor society, one learns to cultivate a team-work mentality that will be invaluable in the future society. Global engineering organizations, such as the Institute of Electrical and Electronic Engineers, the Society of Hispanic Professional Engineers, and Tau Beta Pi Honor Society, have student chapters that offer opportunities to develop those critical leadership skills needed to become an essential asset in the problem solving required to keep the world progressing to its full potential. Throughout this paper, engineering students give the first-person accounts of how becoming a leader within their respective organizations has transformed their undergraduate degree experience. These students have gone on to establish other organizations at Florida Atlantic University that have also enhanced the educational experience of other students and illustrate the importance of emphasizing leadership skills in the Science, Technology, Engineering, Art, and Mathematics fields.

PDZ domains are highly abundant protein-protein interaction modules commonly found in multidomain scaffold proteins. The PDZ1 domain of MAGI-1, a protein present at cellular tight junctions that contains six PDZ domains, is targeted by the E6 oncoprotein of the high-risk human papilloma virus. Thermodynamic and dynamic studies using complementary isothermal titration calorimetry and nuclear magnetic resonance (NMR) (15)N heteronuclear relaxation measurements were conducted at different temperatures to decipher the molecular mechanism of this interaction. Binding of E6 peptides to the MAGI-1 PDZ1 domain is accompanied by an unusually large and negative change in heat capacity (ΔC(p)) that is attributed to a disorder-to-order transition of the C-terminal extension of the PDZ1 domain upon E6 binding. Analysis of temperature-dependent thermodynamic parameters and (15)N NMR relaxation data of a PDZ1 mutant in which this disorder-to-order transition was abolished allows the unusual thermodynamic signature of E6 binding to be correlated to local folding of the PDZ1 C-terminal extension. Comparison of the exchange contributions observed for wild-type and mutant proteins explains how variation in the solvent-exposed area may compensate for the loss of conformational entropy and further designates a distinct set of a few residues that mediate this local folding phenomena.

The Alsatian city Mulhouse, Alfred Werner’s birthplace, has a fascinating chemical history and has hosted numerous chemical personalities who are briefly presented in this paper.

Summary The spatial resolution of sensory systems is not homogeneous across their receptive surfaces. For example, tactile acuity is greatest on the fingertips, reflecting the high innervation density and small mechanoreceptive fields in this area [1, 2]. In contrast, pain is considered to lack any equivalent to the tactile fovea on the fingertips, where the density of nociceptive fibers is remarkably low [3]. Here, by combining psychophysics with histology, we show that this established notion is incorrect. By delivering small-diameter nociceptive-specific laser pulses to human volunteers, we discovered that (1) the spatial acuity for pain is higher on the fingertips than on proximal skin regions such as the hand dorsum, and (2) this distal-proximal gradient for pain is comparable to that for touch. In contrast, skin biopsies in the same participants showed that the intraepidermal nerve fiber density is lower in the fingertips than in the hand dorsum. The increased spatial acuity for pain on the fingertips therefore cannot be explained simply by peripheral innervation density. This finding is, however, consistent with the existence of fine-grained maps of nociceptive input to individual digits in the human primary somatosensory cortex [4]. Video Abstract, Highlights ► The spatial acuity for pain is higher on the fingertips than on the hand dorsum ► The density of nociceptive fibers is lower on the fingertips than on the dorsum ► The fovea at the fingertips is not explained by nociceptive innervation density

TOC summary Inherited neuropathies present with striking variety in their phenotype. We present a family with a myelin protein zero mutation and disabling neuropathic pain., We report an English kindred affected across 4 generations with a hereditary neuropathy associated with debilitating neuropathic pain as the main clinical feature. The principal finding on clinical examination was sensory loss, and there was variable motor dysfunction. Electrophysiological studies revealed mild features of demyelination with median conduction velocity in the intermediate range. There was an autosomal-dominant pattern of inheritance, and genetic testing revealed a novel heterozygous Trp101X mutation in exon 3 coding for a portion of the extracellular domain of myelin protein zero. This is predicted to lead to premature termination of translation. Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity. Chronic pain is an increasingly recognised sequela of certain hereditary neuropathies and may be musculoskeletal or neuropathic in origin. In this kindred, the neuropathy was relatively mild in severity, however, neuropathic pain was an important and disabling outcome.

Summary Human monogenic pain syndromes have provided important insights into the molecular mechanisms that underlie normal and pathological pain states. We describe an autosomal-dominant familial episodic pain syndrome characterized by episodes of debilitating upper body pain, triggered by fasting and physical stress. Linkage and haplotype analysis mapped this phenotype to a 25 cM region on chromosome 8q12–8q13. Candidate gene sequencing identified a point mutation (N855S) in the S4 transmembrane segment of TRPA1, a key sensor for environmental irritants. The mutant channel showed a normal pharmacological profile but altered biophysical properties, with a 5-fold increase in inward current on activation at normal resting potentials. Quantitative sensory testing demonstrated normal baseline sensory thresholds but an enhanced secondary hyperalgesia to punctate stimuli on treatment with mustard oil. TRPA1 antagonists inhibit the mutant channel, promising a useful therapy for this disorder. Our findings provide evidence that variation in the TRPA1 gene can alter pain perception in humans. Video Abstract, Highlights ► We describe a novel human autosomal-dominant pain syndrome (FEPS) ► We demonstrate linkage of FEPS to a TRPA1 N855S point mutation ► FEPS patients show debilitating pain on fasting and physical stress ► N855S TRPA1 channels show enhanced inward currents but unaltered pharmacology

The crystallographic structural features of the ditopic ligand pyrazine-2,5-dicarbaldehyde-bis(propionyl-N-methylhydrazone) 1, as well as their comparison with related ligands are herein reported. CH…O short contacts (2.46 and 2.55 A) supporting network formation were observed. The amplitude of the conformational switch induced by the formation of the dinuclear rack-like complex [Cu21(terpy)2](CF3SO3)4 of ligand 1 (synthesized by reaction of 2,5-pyrazine-dicarboxaldehyde with two equivalents of N-methyl-propionohydrazide), has been determined on the basis of the X-ray structures and it was found to be of 3 A. Moreover, the correlation between the structural data and the data obtained by 2D NMR spectroscopy, is confirmed by the mean of the structural analysis herein discussed that concerns the protons involved in the NOE effects observed by NOESY spectroscopy.

Solid-state X-ray crystal structure of the HgII grid-like complex [Hg414](CF3SO3)8 of the bis-tridentate ligand 1 obtained by condensation of bis(methylhydrazino)phenylpyrimidine with pyridine-2-carboxaldehyde was determined. It confirms the previous structure determined on the basis of 1D and 2D NMR studies. The amplitude of the extension of the ligand as a result of the formation of the grid was found to be of around 15 A. The distance between the nitrogen atom of a molecule of acetonitrile and the centroid of the closest pyrimidine ring, and the distance between the oxygen atom of a triflate and the centroid of the closest pyrimidine ring are of about 3 A, thus suggesting acetonitrile-π, respectively triflate-π interactions.

A novel class of ditopic ligands, 1, was synthesized by the reaction of 2,5-pyrazine-dicarboxaldehyde with 2 equiv of acyl-/aroyl-hydrazine. Their structures were confirmed by 1D and 2D NMR and by X-ray crystallography. They gave heteroleptic Cu(II) dinuclear rack-like complexes of the formula [Cu(2)1(terpy)(2)](OTf)(4), thus undergoing shape changes of significant amplitude. The solid-state structures of these complexes were determined by X-ray crystallography. The magnetic measurements performed on the complexes revealed the presence of antiferromagnetic intramolecular interactions.

Solution and solid state studies of the complexation of Hg2+ and Pb2+ by the homologous bis-tridentate ligands 1 and 2H2 obtained by condensation of bis(methylhydrazino)phenylpyrimidine and bis(hydrazino)phenylpyrimidine, respectively, with pyridine-2-carboxaldehyde, have provided evidence for the formation of both grid and rack species. With Hg2+, there is little indication for other than grid species, the grid complex [Hg4(2H2)4](CF3SO3)8 being characterised crystallographically. With Pb2+, the only crystalline species readily isolated are rack complexes of the ligands 1 and 2H2.

Ditopic bis(acylhydrazone) ligands, derived from the reactions of carbohydrazides with 2-phenylpyrimidine-4,6-dicarbaldehyde and designed for grid formation with octahedrally coordinating transition-metal ions, exhibit a varied coordination chemistry depending upon the degree of their deprotonation. The neutral acylhydrazones are relatively poor ligands and are seemingly involved in multiple, labile complexation equilibria varying with the solvent and the particular metal salt in solution; nevertheless, grid complexes of different forms can be isolated in the solid state. Although only limited study has been made of the singly deprotonated ligands, grid species appear to be much more readily isolated. With the doubly deprotonated ligands, grid formation is strongly favoured in both the solution and solid states. As a consequence, the grid structures form spontaneously in the presence of a base by self-assembly from their components without need to preform the ditopic ligands. Extensive structural studies have been carried out both to establish the grid structures and to analyse the nature of the supramolecular interactions possible for neutral and charged grid species. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Purpose of review The current review provides a summary of recent advances in our understanding of the neuroimmune interactions which influence the development of pain associated with cancer. Recent findings Common signalling pathways, mediators and immune cell types are involved in the generation of pain as a result of both cancer and its treatment. Distinct alterations in central and peripheral neuronal function occur in multiple forms of cancer pain. Other more unusual neuroimmune processes such as graft-versus-host disease may cause cancer pain. Summary Identification of the cellular processes which underlie the generation of cancer pain provide potential novel targets for drug development and may eventually lead to improved pain management for cancer patients.

Small fibre neuropathy (SFN) is characterised by structural injury selectively affecting small diameter sensory and/or autonomic axons. The clinical presentation is dominated by pain. SFN complicates a number of common diseases such as diabetes mellitus and is likely to be increasingly encountered. The diagnosis of SFN is demanding as clinical features can be vague and nerve conduction studies normal. New diagnostic techniques, in particular measurement of intraepidermal nerve fibre density, have significantly improved the diagnostic efficiency of SFN. Management is focused on the treatment of the underlying cause and analgesia, as there is no neuroprotective therapy. A recent and significant advance is the finding that a proportion of cases labelled as idiopathic SFN are in fact associated with gain of function mutations of the voltage-gated sodium channels Nav1.7 and Nav1.8 (encoded by the genes SCN9A and SCN10A, respectively). There is a further group of heritable painful conditions in which gain of function mutations in ion channels alter excitability of sensory neurones but do not cause frank axon degeneration; these include mutations in Nav1.7 (causing erythromelalgia and paroxysmal extreme pain disorder) and TRPA1 (resulting in familial episodic pain disorder). These conditions are exceptionally rare but have provided great insight into the nociceptive system as well as yielding potential analgesic drug targets. In patients with no pre-existing risk factor, the investigation of an underlying cause of SFN should be systematic and appropriate for the patient population. In this review, we focus on how to incorporate recent developments in the diagnosis and pathophysiology of SFN into clinical practice.

Summary Study participants with HIV-associated sensory polyneuropathy (HIV-SN) had higher plasma triglyceride concentrations, depression, anxiety, catastrophizing scores, and prevalence of insomnia than HIV participants without HIV-SN., HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of HIV infection and a major source of morbidity. A cross-sectional deep profiling study examining HIV-SN was conducted in people living with HIV in a high resource setting using a battery of measures which included the following: parameters of pain and sensory symptoms (7 day pain diary, Neuropathic Pain Symptom Inventory [NPSI] and Brief Pain Inventory [BPI]), sensory innervation (structured neurological examination, quantitative sensory testing [QST] and intraepidermal nerve fibre density [IENFD]), psychological state (Pain Anxiety Symptoms Scale-20 [PASS-20], Depression Anxiety and Positive Outlook Scale [DAPOS], and Pain Catastrophizing Scale [PCS], insomnia (Insomnia Severity Index [ISI]), and quality of life (Short Form (36) Health Survey [SF-36]). The diagnostic utility of the Brief Peripheral Neuropathy Screen (BPNS), Utah Early Neuropathy Scale (UENS), and Toronto Clinical Scoring System (TCSS) were evaluated. Thirty-six healthy volunteers and 66 HIV infected participants were recruited. A novel triumvirate case definition for HIV-SN was used that required 2 out of 3 of the following: 2 or more abnormal QST findings, reduced IENFD, and signs of a peripheral neuropathy on a structured neurological examination. Of those with HIV, 42% fulfilled the case definition for HIV-SN (n = 28), of whom 75% (n = 21) reported pain. The most frequent QST abnormalities in HIV-SN were loss of function in mechanical and vibration detection. Structured clinical examination was superior to QST or IENFD in HIV-SN diagnosis. HIV-SN participants had higher plasma triglyceride, concentrations depression, anxiety and catastrophizing scores, and prevalence of insomnia than HIV participants without HIV-SN.

The triazine derived ligand reacts with one equivalent of Co(II) salts to give complexes whose architecture depends on the solvent employed: the [2 x 2]-grid like tetranuclear complex and the pincer-like mononuclear complex, obtained respectively by crystallization from nitromethane and from acetonitrile may be interconverted reversibly, the grid-pincer conversion being markedly accelerated by adding an amine.

The α2δ-1 subunit of voltage-gated calcium channels is upregulated after sensory nerve injury and is also the therapeutic target of gabapentinoid drugs. It is therefore likely to play a key role in the development of neuropathic pain. In this study, we have examined mice in which α2δ-1 gene expression is disrupted, to determine whether α2δ-1 is involved in various modalities of nociception, and for the development of behavioral hypersensitivity after partial sciatic nerve ligation (PSNL). We find that naive α2δ-1−/−mice show a marked behavioral deficit in mechanical and cold sensitivity, but no change in thermal nociception threshold. The lower mechanical sensitivity is mirrored by a reducedin vivoelectrophysiological response of dorsal horn wide dynamic range neurons. The CaV2.2 level is reduced in brain and spinal cord synaptosomes from α2δ-1−/−mice, and α2δ-1−/−DRG neurons exhibit lower calcium channel current density. Furthermore, a significantly smaller number of DRG neurons respond to the TRPM8 agonist menthol. After PSNL, α2δ-1−/−mice show delayed mechanical hypersensitivity, which only develops at 11 d after surgery, whereas in wild-type littermates it is maximal at the earliest time point measured (3 d). There is no compensatory upregulation of α2δ-2 or α2δ-3 after PSNL in α2δ-1−/−mice, and other transcripts, including neuropeptide Y and activating transcription factor-3, are upregulated normally. Furthermore, the ability of pregabalin to alleviate mechanical hypersensitivity is lost in PSNL α2δ-1−/−mice. Thus, α2δ-1 is essential for rapid development of mechanical hypersensitivity in a nerve injury model of neuropathic pain.

An interconversion between a binuclear Cu(I) double helicate and a tetranuclear Cu(II) grid is reported. The passage from the Cu(I) double helicate to the Cu(II) grid occurs through oxidation of Cu(I) into Cu(II) or through displacement of Cu(I) by Cu(II). The conversion of the Cu(II) grid into the Cu(I) double helicate occurs through treatment of the grid with triflic acid, reduction of Cu(II) with ascorbic acid, and neutralization with triethylamine. During the studies, in order to ascertain the structure of Cu(I) complexes, a heteroleptic binuclear Cu(I) double helicate was generated.

We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (DIV). The identified mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration. The investigated patients presented with PEM, while age of onset was very different (3 vs. 61 years of age). Electrophysiological characterization revealed that the early onset A1746G mutation leads to a marked hyperpolarizing shift in voltage dependence of steady-state activation, larger window currents, faster activation kinetics (time-to-peak current) and recovery from steady-state inactivation compared to wild-type Nav1.7, indicating a pronounced gain-of-function. Furthermore, we found a hyperpolarizing shift in voltage dependence of slow inactivation, which is another feature commonly found in Nav1.7 mutations associated with PEM. In silico neuron simulation revealed reduced firing thresholds and increased repetitive firing, both indicating hyperexcitability. The late-onset W1538R mutation also revealed gain-of-function properties, although to a lesser extent. Our findings demonstrate that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected. This supports the view that the degree of biophysical property changes caused by a mutation may have an impact on age of clinical manifestation of PEM. In summary, these findings extent the genotype–phenotype correlation profile for SCN9A and highlight a new region of Nav1.7 that is implicated in PEM. Electronic supplementary material The online version of this article (doi:10.1007/s12017-012-8216-8) contains supplementary material, which is available to authorized users.

Summary Using a composite diagnostic-neuroimaging approach, this study shows the modulatory effects of pleasant cooling on pain-related cortical regions in a subject suffering from inherited erythromelalgia., We identified a patient with severe inherited erythromelalgia secondary to an L858F mutation in the voltage-gated sodium channel Nav1.7. The patient reported severe ongoing foot pain, which was exquisitely sensitive to limb cooling. We confirmed this heat hypersensitivity using quantitative sensory testing. Additionally, we employed a novel perfusion imaging technique in a simple block design to assess her baseline erythromelalgia pain vs cooling relief. Robust activations of key pain, pain-affect, and reward-related centres were observed. This combined approach allowed us to confirm the presence of a temperature-sensitive channelopathy of peripheral neurons and to investigate the neural correlates of tonic neuropathic pain and relief in a single subject.

PDZ domains are protein interaction domains that are found in cytoplasmic proteins involved in signaling pathways and subcellular transport. Their roles in the control of cell growth, cell polarity, and cell adhesion in response to cell contact render this family of proteins targets during the development of cancer. Targeting of these network hubs by the oncoprotein E6 of “high-risk” human papillomaviruses (HPVs) serves to effect the efficient disruption of cellular processes. Using NMR, we have solved the three-dimensional solution structure of an extended construct of the second PDZ domain of MAGI-1 (MAGI-1 PDZ1) alone and bound to a peptide derived from the C-terminus of HPV16 E6, and we have characterized the changes in backbone dynamics and hydrogen bonding that occur upon binding. The binding event induces quenching of high-frequency motions in the C-terminal tail of the PDZ domain, which contacts the peptide upstream of the canonical X-[T/S]-X-[L/V] binding motif. Mutations designed in the C-terminal flanking region of the PDZ domain resulted in a significant decrease in binding affinity for E6 peptides. This detailed analysis supports the notion of a global response of the PDZ domain to the binding event, with effects propagated to distal sites, and reveals unexpected roles for the sequences flanking the canonical PDZ domain boundaries.

The present chapter is focused on how synthetic molecular machines (e.g. shuttles, switches and molecular motors) and size switches (conversions between polymers and their units, i.e., conversions between relatively large and small molecules) can function through covalent changes. Amongst the interesting examples of devices herein presented are molecular motors and size switches based on dynamic covalent chemistry which is an area of constitutional dynamic chemistry.

The shape of ligand strands composed of six-membered aza-heterocycles (het) connected at the alpha and alpha' positions by hydrazone (hyz) units is determined in a predictable fashion by the nature of the heterocyclic groups (pyridine, pyrimidine, pyrazine etc.), and covers the range from extended linear to compact helical structures. The binding of metal ions to the coordination subunits, defined by the het-hyz sequences, leads to marked shape changes by inter-converting bent and linear conformations of the subunits, thus inducing relative motions of strand domains either in the same (con-sense, "twirling") or in opposite (dis-sense, "flapping") directions. The amplitude of the motion induced by metal-ion binding and release and the relative directions of the formal motions can be controlled by the nature of the heterocyclic units. Thus, motions around a central 4,6-disubstituted pyrimidine are dis-sense motions, whereas there are con-sense motions around a central 2,5-disubstituted pyrazine unit, as illustrated by model ligands 1 and 2, respectively. The more extended helical 3 and undulating (zigzag shape) 4 ligands undergo larger-amplitude motions combining the relative displacements displayed by 1 and 2. Ligands 3 and 4 form linear tetranuclear Pb(II) and Zn(II) complexes, thus producing an extension motion. The same holds for [Ru(4)(terpy)(4)](PF(6))(8) (terpy=terpyridine). Reversible acid-base-triggered molecular motions have been generated with [Zn(4)(4)(OTf)(8)] (TfOH=triflic acid).

The coordinative behaviour of two bis(hydrazone)triazine-based ligands in the presence of Pb(II) was investigated. Free ligand, pincer-like and stick-like complexes' X-ray structures are described. The ligands adopt a pyridine-like coordinative behaviour for Pb(II)/ligand molar ratio equal to 1/2 and 1/1, and a pyrimidine-like coordinative behaviour for Pb(II)/ligand molar ratio equal to 2/1. The complexation processes are reversible and may be modulated by external stimuli. They generate conformational and motional behaviour through interconversion of three entities, free ligand, pincer and stick complex.

Eine HIV-Infektion ist neben Diabetes mellitus eine der haufigsten Ursachen fur eine Polyneuropathie. Dabei zahlt die distal symmetrische HIV-assoziierte Polyneuropathie zur haufigsten neurologischen Erkrankung bei HIV-Infektion. Auch toxische Wirkungen der hochaktiven antiretroviralen Therapie (HAART) und neurotoxischer antiretroviraler Substanzen, die zur Behandlung eingesetzt werden, erhohen das Risiko fur eine Polyneuropathie. Dennoch sind Studien zur Thematik Mangelware. Einzelheiten der sensorischen Nervenfunktionsstorungen und ihre Beziehung zur Symptomatik und psychischen Morbiditat sowie Diagnostik nach den Parametern des Deutschen Forschungsverbunds Neuropathischer Schmerz analysierten Tudor J.C. Phillips und Kollegen aus Grosbritannien und Deutschland.