A redox active rod coordination polymer from tetrakis(4-carboxylic acid biphenyl)tetrathiafulvalene.

An enlarged version of the ubiquitous tetrathiafulvalene-tetrabenzoic acid is described, with 4,4'-biphenyl moieties as spacers between the coordination moieties and the electroactive core. The obtained rectangular ligand has a 14 × 22 Å2 size and is combined with Zn(II) under solvothermal conditions to yield a coordination polymer endowed with large cavities of ca. 15 × 11 Å2/10 × 10 Å2. The topology of the material is discussed in detail using the Points of Extension and Metals (PE&M) or the Straight-rod (STR) representation, and the sqc1121 or tfo topological type of the structure is observed, respectively. Its stability towards solvent removal and electrical properties are discussed. The material does not present any permanent porosity upon desolvation according to nitrogen sorption measurements at 77 K. Nevertheless, a significant increase in conductivity is observed on compressed pellets of the material upon post-synthetic oxidation with iodine. Raman spectroscopy combined with density functional theory (DFT) calculations has been used to characterize the oxidation state of tetrakis(4-carboxylic acid biphenyl)tetrathiafulvalene for coordination polymers.

Estrogen-mediated coupling via gap junctions in the suprachiasmatic nucleus.

The circadian clock orchestrates many physiological and behavioural rhythms in mammals with 24-h periodicity, through a hierarchical organisation, with the central clock located in the suprachiasmatic nucleus (SCN) in the hypothalamus. The circuits of the SCN generate circadian rhythms with precision, relying on intrinsic coupling mechanisms, for example, neurotransmitters like arginine vasopressin (AVP), vasoactive intestinal peptide (VIP), neuronal gamma-aminobutyric acid (GABA) signalling and astrocytes connected by gap junctions composed of connexins (Cx). In female rodents, the presence of estrogen receptors (ERs) in the dorsal SCN suggests an influence of estrogen (E2) on the circuit timekeeping that could regulate circadian rhythm and coupling. To investigate this, we used SCN explants together with hypothalamic neurons and astrocytes. First, we showed that E2 stabilised the circadian amplitude in the SCN when rAVPs (receptor-associated vasopressin peptides) were inhibited. However, the phase delay induced by VIPAC2 (VIP receptors) inhibition remained unaffected by E2. We then showed that E2 exerted its effects in the SCN via ERß (estrogen receptor beta), resulting in increased expression of Cx36 and Cx43. Notably, specific inhibition of both connexins resulted in a significant reduction in circadian amplitude within the SCN. Remarkably, E2 restored the period with inhibited Cx36 but not with Cx43 inhibition. This implies that the network between astrocytes and neurons, responsible for coupling in the SCN, can be reinforced through E2. In conclusion, these findings provide new insights into how E2 regulates circadian rhythms ex vivo in an ERß-dependent manner, underscoring its crucial role in fortifying the SCN's rhythm.

Circle(s) of Life: The Circadian Clock from Birth to Death.

Most lifeforms on earth use endogenous, so-called circadian clocks to adapt to 24-h cycles in environmental demands driven by the planet's rotation around its axis. Interactions with the environment change over the course of a lifetime, and so does regulation of the circadian clock system. In this review, we summarize how circadian clocks develop in humans and experimental rodents during embryonic development, how they mature after birth and what changes occur during puberty, adolescence and with increasing age. Special emphasis is laid on the circadian regulation of reproductive systems as major organizers of life segments and life span. We discuss differences in sexes and outline potential areas for future research. Finally, potential options for medical applications of lifespan chronobiology are discussed.

The circadian neurobiology of reward.

Circadian clocks are important regulators of physiology and behavior. In the brain, circadian clocks have been described in many centers of the central reward system. They affect neurotransmitter signaling, neuroendocrine circuits, and the sensitivity to external stimulation. Circadian disruption affects reward signaling, promoting the development of behavioral and substance use disorders. In this review, we summarize our current knowledge of circadian clock-reward crosstalk. We show how chronodisruption affects reward signaling in different animal models. We then translate these findings to circadian aspects of human reward (dys-) function and its clinical implications. Finally, we devise approaches to and challenges in implementing the concepts of circadian medicine in the therapy of substance use disorders.

Bis(Vinylenedithio)-Tetrathiafulvalene-Based Coordination Networks.

Novel coordination polymers embedding electroactive moieties present a high interest in the development of porous conducting materials. While tetrathiafulvalene (TTF) based metal-organic frameworks were reported to yield through-space conducting frameworks, the use of S-enriched scaffolds remains elusive in this field. Herein is reported the employment of bis(vinylenedithio)-tetrathiafulvalene (BVDT-TTF) functionalized with pyridine coordinating moieties in coordination polymers. Its combination with various transition metals yielded four isostructural networks, whose conductivity increased upon chemical oxidation with iodine. The oxidation was confirmed in a single-crystal to single-crystal X-ray diffraction experiment for the Cd(II) coordination polymer. Raman spectroscopy measurements and DFT calculations confirmed the oxidation state of the bulk materials, and band structure calculations assessed the ground state as an electronically localized antiferromagnetic state, while the conduction occurs in a 2D manner. These results are shedding light to comprehend how to improve through-space conductivity thanks to sulfur enriched ligands.

Suprachiasmatic to paraventricular nuclei interaction generates normal food searching rhythms in mice.

Searching for food follows a well-organized decision process in mammals to take up food only if necessary. Moreover, scavenging is preferred during their activity phase. Various time-dependent regulatory processes have been identified originating from the suprachiasmatic nuclei (SCN), which convert external light information into synchronizing output signals. However, a direct impact of the SCN on the timing of normal food searching has not yet been found. Here, we revisited the function of the SCN to affect when mice look for food. We found that this process was independent of light but modified by the palatability of the food source. Surprisingly, reducing the output from the SCN, in particular from the vasopressin releasing neurons, reduced the amount of scavenging during the early activity phase. The SCN appeared to transmit a signal to the paraventricular nuclei (PVN) via GABA receptor A1. Finally, the interaction of SCN and PVN was verified by retrograde transport-mediated complementation. None of the genetic manipulations affected the uptake of more palatable food. The data indicate that the PVN are sufficient to produce blunted food searching rhythms and are responsive to hedonistic feeding. Nevertheless, the search for normal food during the early activity phase is significantly enhanced by the SCN.

Studying Circadian Clock Entrainment by Hormonal Signals.

In mammals, molecular circadian clocks not only exist in the suprachiasmatic nucleus (SCN) but in almost all organ systems. Intriguingly, tissue clocks can operate in both isolated tissues and cell lines with endocrine signals mediating the circadian expression of local transcriptomes. This can be demonstrated by treating tissue explants with endocrine cues in a phase- and dose-dependent manner. In this chapter we provide an overview of methods to study the effects of candidate hormonal time cues on tissue clock resetting. We propose an experimental procedure based on an in vitro setup consisting of several consecutive steps in which organotypic tissue cultures or cells can be used. Our approach targets the potential resetting mechanism at three levels: the hormone, the direct clock gene target, and the tissue clock response.

Charge-Ordering and Structural Transition in the New Organic Conductor δ'-(BEDT-TTF)2CF3CF2SO3.

We report structural, transport, and optical properties and electronic structure calculations of the δ'-(BEDT-TTF)2CF3CF2SO3 (BEDT-TTF = bis(ethylenedithio)tetrathiafulvalene) organic conductor that has been synthesized by electrocrystallization. Electronic structure calculations demonstrate the quasi-one-dimensional Fermi surfaces of the compound, while the optical spectra are characteristic for a dimer-Mott insulator. The single-crystal X-ray diffraction measurements reveal the structural phase transition at 200 K from the ambient-temperature monoclinic P21/m phase to the low-temperature orthorhombic Pca21 phase, while the resistivity measurements clearly show the first order semiconductor-semiconductor transition at the same temperature. This transition is accompanied by charge-ordering as it is confirmed by splitting of charge-sensitive vibrational modes observed in the Raman and infrared spectra. The horizontal stripe charge-order pattern is suggested based on the crystal structure, band structure calculations, and optical spectra.

Glucocorticoid circadian rhythms in immune function.

Adrenal glucocorticoid (GC) hormones are important regulators of energy metabolism, brain functions, and the immune system. Their release follows robust diurnal rhythms and GCs themselves serve as entrainment signals for circadian clocks in various tissues. In the clinics, synthetic GC analogues are widely used as immunosuppressive drugs. GC inhibitory effects on the immune system are well documented and include suppression of cytokines and increased immune cell death. However, the circadian dynamics of GC action are often neglected. Synthetic GC medications fail to mimic complex GC natural rhythms. Several recent publications have shown that endogenous GCs and their daily concentration rhythms prepare the immune system to face anticipated environmental threats. That includes migration patterns that direct specific cell population to organs and tissues best exemplified by the rhythmic expression of chemoattractants and their receptors. On the other hand, chronotherapeutic approaches may benefit the treatment of immunological diseases such as asthma. In this review, we summarise our current knowledge on the circadian regulation of GCs, their role in innate and adaptive immune functions and the implications for the clinics.

Light affects behavioral despair involving the clock gene Period 1.

Light at night has strong effects on physiology and behavior of mammals. It affects mood in humans, which is exploited as light therapy, and has been shown to reset the circadian clock in the suprachiasmatic nuclei (SCN). This resetting is paramount to align physiological and biochemical timing to the environmental light-dark cycle. Here we provide evidence that light at zeitgeber time (ZT) 22 affects mood-related behaviors also in mice by activating the clock gene Period1 (Per1) in the lateral habenula (LHb), a brain region known to modulate mood-related behaviors. We show that complete deletion of Per1 in mice led to depressive-like behavior and loss of the beneficial effects of light on this behavior. In contrast, specific deletion of Per1 in the region of the LHb did not affect mood-related behavior, but suppressed the beneficial effects of light. RNA sequence analysis in the mesolimbic dopaminergic system revealed profound changes of gene expression after a light pulse at ZT22. In the nucleus accumbens (NAc), sensory perception of smell and G-protein coupled receptor signaling were affected the most. Interestingly, most of these genes were not affected in Per1 knock-out animals, indicating that induction of Per1 by light serves as a filter for light-mediated gene expression in the brain. Taken together we show that light affects mood-related behavior in mice at least in part via induction of Per1 in the LHb with consequences on mood-related behavior and signaling mechanisms in the mesolimbic dopaminergic system.

Restructuring of the male mice peripheral circadian network after bariatric surgery.

Bariatric surgery is still the most effective long-term weight-loss therapy. Recent data indicate that surgical outcomes may be affected by diurnal food intake patterns. In this study, we aimed to investigate how surgery-induced metabolic adaptations (i.e. weight loss) interact with circadian clock function. For that reason, vertical sleeve gastrectomy (VSG) was performed in obese mice and rhythms in behavior, tissue rhythmicity, and white adipose tissue transcriptome were evaluated. VSG under constant darkness conditions led to a maximum weight loss of 18% compared to a loss of 3% after sham surgery. Post-surgical weight development was characterized by two distinct intervals of catabolic and subsequent anabolic metabolic state. Locomotor activity was not affected. However, VSG significantly increased active phase meal frequency in the anabolic state. No significant effects on clock gene rhythmicity were detected in adrenal and white adipose tissue (WAT) explant cultures. Transcriptome rhythm analyses of subcutaneous WAT revealed a reduction of cycling genes after VSG (sham: 2493 vs VSG: 1013) independent of sustained rhythms in core clock gene expression. This may be a consequence of weight loss-induced morphological reconstruction of WAT that overwrites the direct influence of the local clock machinery on the transcriptome. However, VSG altered rhythmic transcriptional regulation of WAT lipid metabolism pathways. Thus, our data suggest a reorganization of diurnal metabolic rhythms after VSG downstream of the molecular clock machinery.

Cyclin-dependent kinase 5 (CDK5) regulates the circadian clock.

Circadian oscillations emerge from transcriptional and post-translational feedback loops. An important step in generating rhythmicity is the translocation of clock components into the nucleus, which is regulated in many cases by kinases. In mammals, the kinase promoting the nuclear import of the key clock component Period 2 (PER2) is unknown. Here, we show that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian circadian clock involving phosphorylation of PER2. Knock-down of Cdk5 in the suprachiasmatic nuclei (SCN), the main coordinator site of the mammalian circadian system, shortened the free-running period in mice. CDK5 phosphorylated PER2 at serine residue 394 (S394) in a diurnal fashion. This phosphorylation facilitated interaction with Cryptochrome 1 (CRY1) and nuclear entry of the PER2-CRY1 complex. Taken together, we found that CDK5 drives nuclear entry of PER2, which is critical for establishing an adequate circadian period of the molecular circadian cycle. Of note is that CDK5 may not exclusively phosphorylate PER2, but in addition may regulate other proteins that are involved in the clock mechanism. Taken together, it appears that CDK5 is critically involved in the regulation of the circadian clock and may represent a link to various diseases affected by a derailed circadian clock.

Charge fluctuations and ethylene-group-ordering transition in ß''-(BEDT-TTF)4[(H3O)Fe(C2O4)3]⋠Y molecular charge-transfer salts.

The polarized infrared reflectance and Raman spectra of the three quasi-two-dimensional ß''-(BEDT-TTF)4[(H3O)Fe(C2O4)3]⋅Y bifunctional charge-transfer salts, where BEDT-TTF = bis(ethylenedithio)tetrathiafulvalene and Y = C6H5Br, (C6H5CN)0.17(C6H5Br)0.83, (C6H5CN)0.4(C6H5F)0.6, have been measured as a function of the temperature. Signatures of charge inhomogenity have been found in both Raman and infrared spectra of the ß''-(BEDT-TTF)4[(H3O)Fe(C2O4)3]⋅Y superconductors. A 100 K transition to a mixed insulating/metallic state is clearly seen for the first time in the temperature dependence of the electronic spectra of superconducting ß''-(BEDT-TTF)4[(H3O)Fe(C2O4)3]⋅C6H5Br. We suggest that this phase transition is due to subtle changes in the ethylene groups ordering, which are related to a structural phase transition in the anionic layer. The infrared and Raman spectra of quasi-two-dimensional metal α-'pseudo-κ'-(BEDT-TTF)4[(H3O)Fe(C2O4)3]C6H4Br2 are also investigated.

Chirality driven metallic versus semiconducting behavior in a complete series of radical cation salts based on dimethyl-ethylenedithio-tetrathiafulvalene (DM-EDT-TTF).

Enantiopure (S,S) and (R,R) dimethyl-ethylenedithio-tetrathiafulvalene (DM-EDT-TTF) 1 donors are synthesized by cross coupling followed by decarboxylation reactions. In the solid state the methyl groups are arranged in axial positions within sofa-type conformation for the six-membered rings. Crystalline radical cation salts formulated as [(S,S)-1]2PF6, [(R,R)-1]2PF6, and [(rac)-1]2PF6 are obtained by electrocrystallization. When the experiment is conducted with enantioenriched mixtures both enantiopure and racemic phases are obtained. The monoclinic enantiopure salts, containing four independent donors in the unit cell, show semiconducting behavior supported by band structure calculations of extended Hückel type. The racemic salt contains only one independent donor in the mixed valence oxidation state +0.5. Under ambient pressure the racemic material is metallic down to 120 K, while an applied pressure of 11.5 kbar completely suppresses the metal-insulator transition. Band structure calculations yield an open Fermi surface, typical for a pseudo-one-dimensional metal, with unperfected nesting, thus ruling out the possibility of charge or spin density modulations to be at the origin of the transition. Raman spectroscopy measurements, in agreement with structural analysis at 100 K, show no indication of low-temperature charge ordering in the racemic material at ambient pressure, thus suggesting Mott-type charge localization for the observed metal-insulator transition.

Charge-assisted halogen bonding: donor-acceptor complexes with variable ionicity.

Charge-assisted halogen bonding is unambiguously revealed from structural and electronic investigations of a series of isostructural charge-transfer complexes derived from iodinated tetrathiafulvalene and tetracyanoquinodimethane derivatives, (EDT-TTFI2)2(TCNQF(n)), n=0-2, which exhibit variable degrees of ionicity. The iodinated tetrathiafulvalene derivative, EDT-TTFI2, associates with tetracyanoquinodimethane (TCNQ) and its derivatives of increasing reduction potential (TCNQF, TCNQF2) through highly directional C-I⋅⋅⋅N≡C halogen-bond interactions. With the less oxidizing TCNQ acceptor, a neutral and insulating charge-transfer complex is isolated whereas with the more oxidizing TCNQF2 acceptor, an ionic, highly conducting charge-transfer salt is found, both of 2:1 stoichiometry and isostructural with the intermediate TCNQF complex, in which a neutral-ionic conversion takes place upon cooling. A correlation between the degree of charge transfer and the C-I⋅⋅⋅N≡C halogen-bond strength is established from the comparison of the structures of the three isostructural complexes at temperatures from 300 to 20 K, thus demonstrating the importance of electrostatics in the halogen-bonding interaction. The neutral-ionic conversion in (EDT-TTFI2)2(TCNQF) is further investigated through the temperature dependence of its magnetic susceptibility and the stretching modes of the C≡N groups.

Lattice dynamics through the structural phase transition in D-amphetamine sulfate.

The polarized infrared and Raman spectra of the single-crystalline D-amphetamine sulfate have been measured as a function of temperature in the vicinity of the structural phase transition. Infrared and Raman-active modes are identified and assigned. Significant signatures of the structural phase transition are observed in the temperature dependence of infrared modes both of the D-amphetamine unit and the sulfate anion. The changes reflect differences in the unit cell between low- and high-temperature phases of the D-amphetamine sulfate. Temperature dependence of the vibrational mode parameters displays pronounced hysteresis between 333 and 338 K that is extended over a smaller temperature range than 325-345 K found in the earlier DSC study.

Experimental and theoretical investigation of vibrational spectra of coordination polymers based on TCE-TTF.

The room-temperature infrared and Raman spectra of a series of four isostructural polymeric salts of 2,3,6,7-tetrakis(2-cyanoethylthio)-tetrathiafulvalene (TCE-TTF) with paramagnetic (Co(II), Mn(II)) and diamagnetic (Zn(II), Cd(II)) ions, together with BF(4)(-) or ClO(4)(-) anions are reported. Infrared and Raman-active modes are identified and assigned based on theoretical calculations for neutral and ionized TCE-TTF using density functional theory (DFT) methods. It is confirmed that the TCE-TTF molecules in all the materials investigated are fully ionized and interact in the crystal structure through cyanoethylthio groups. The vibrational modes related to the C=C stretching vibrations of TCE-TTF are analyzed assuming the occurrence of electron-molecular vibration coupling (EMV). The presence of the antisymmetric C=C dimeric mode provides evidence that charge transfer takes place between TCE-TTF molecules belonging to neighboring polymeric networks.

Structural distortions upon oxidation in heteroleptic [Cp(2)W(dmit)] tungsten dithiolene complex: combined structural, spectroscopic, and magnetic studies.

Four different cation radical salts are obtained upon electrocrystallization of [Cp(2)W(dmit)] (dmit = 1,3-dithiole-2-thione-4,5-dithiolato) in the presence of the BF(4)(-), PF(6)(-), Br(-), and [Au(CN)(2)](-) anions. In these formally d(1) cations, the WS(2)C(2) metallacycle is folded along the S···S hinge to different extents in the four salts, an illustration of the noninnocent character of the dithiolate ligand. Structural characteristics and the charge distribution on atoms, for neutral and ionized complexes with various folding angles, were calculated using DFT methods, together with the normal vibrational modes and theoretical Raman spectra. Raman spectra of neutral complex [Cp(2)W(dmit)] and its salts formed with BF(4)(-), AsF(6)(-), PF(6)(-), Br(-), and [Au(CN)(2)](-) anions were measured using the red excitation (λ = 632.8 nm). A correlation between the folding angle of the metallacycle and the Raman spectroscopic properties is analyzed. The bands attributed to the C═C and C-S stretching modes shift toward higher and lower frequencies by about 0.3-0.4 cm(-1) deg(-1), respectively. The solid state structural and magnetic properties of the three salts are analyzed and compared with those of the corresponding molybdenum complexes. Temperature dependence of the magnetic susceptibility shows the presence of one-dimensional antiferromagnetic interactions in the BF(4)(-), PF(6)(-), and [Au(CN)(2)](-) salts, while an antiferromagnetic ground state is identified in the Br(-) salt below T(Néel) = 7 K. Interactions are systematically weaker in the tungsten salts than in the isostructural molybdenum analogs, a consequence of the decreased spin density on the dithiolene ligand in the tungsten complexes.

IR and Raman spectra of beta''-(BEDT-TTF)(2)RCH(2)SO(3) (R = SF(5), CF(3)): dimerization related to hydrogen bonding.

The beta''-(BEDT-TTF)(2)CF(3)CH(2)SO(3) organic conductor has been synthesized by electrocrystallization. The crystal structure was determined by single-crystal X-ray diffraction and electronic properties examined. The polarized IR reflectance of beta''-(BEDT-TTF)(2)SF(5)CH(2)SO(3) and beta''-(BEDT-TTF)(2)CF(3)CH(2)SO(3), as well as Raman spectra of beta''-(BEDT-TTF)(2)CF(3)CH(2)SO(3) have been measured as a function of temperature. Both materials display charge-nonequivalence within the whole temperature range and unusual activation of vibronic modes with lowering the temperature. In particular, electron-molecular vibration coupling is involved in the activation of the nu(27) mode. The effect is discussed in terms of lattice dimerization involving hydrogen bonding between the anion layer and the conducting BEDT-TTF layer.