4E-BP2–dependent translation in parvalbumin neurons controls epileptic seizure threshold

The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)–induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3ca^H1047R-Pvalb) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.

Epilepsy is a prevalent (0.5 to 1% of the general population) (1) heterogeneous neurological disorder affecting all age groups and is characterized by seizures and associated psychological and social stigmas (2–4). Hyperactivation of the mechanistic/mammalian target of rapamycin (mTOR) pathway has been reported in brain lesions of epileptic patients with neurodevelopmental disorders (5, 6), and human genetic studies have shown that mutations in mTOR (7, 8) and other components of its pathway are linked to epileptogenesis (6, 9–13). mTOR is a highly conserved serine/threonine protein kinase that forms two distinct complexes: mTORC1 and mTORC2. mTORC1 integrates multiple environmental and intracellular signals to modulate brain functions by controlling key cellular processes such as mRNA translation, nucleotide, lipid and mitochondrial biogenesis, and autophagy (14, 15). Germline or somatic mutations, which result in enhanced mTORC1 activity, including in PIK3CA, PTEN, AKT3, TSC1/2, RHEB, and MTOR, are associated with neurodevelopmental disorders with epilepsy (16–23). Recent studies have also identified mutations in mTORC1 upstream amino acid–sensing GATOR1-KICSTOR-Rag GTPase pathways as a common cause of epilepsy (24), revealing that mutations in GATOR1 (DEPDC5, NPRL2, and NPRL3) (25, 26) and KICSTOR (ITFG2, KPTN, SZT2, and C12ORF66) (6, 7, 27) genes are often found in epileptic pathologies. The link between the mTORC1 and epilepsy has been recapitulated in animal models with enhanced mTORC1 activity (e.g., Pten^+/−, TSC1/2^+/−, and activating mutations in Pik3ca Nestin-Cre knockin (KI), Akt3 KI, MTOR, and Rheb KI) (18, 20, 23, 28–31) while inhibition of mTORC1 reversed epileptogenesis in TSC1^GFAP-Cre and Pten^+/− mice (20, 31). Notably, the mTORC1 rapalog, everolimus, has been approved by the US Food and Drug Administration (FDA) for the treatment of epilepsy in tuberous sclerosis complex (TSC) patients (32, 33).mTORC1 is a master regulator of mRNA translation. Upon activation, mTORC1 phosphorylates S6 protein kinases 1 and 2 (S6K1/2) and 4E-binding proteins (4E-BPs) (34, 35). In the hypophosphorylated form, 4E-BPs bind and prevent the association of the cap-binding protein eIF4E with the large scaffolding protein eIF4G, thereby inhibiting the formation of the eIF4F complex (composed of eIF4E, eIF4G, and an mRNA helicase eIF4A), which is essential for the initiation of cap-dependent translation. Phosphorylation of 4E-BPs by mTORC1 results in the release of eIF4E from 4E-BPs, allowing eIF4F complex formation and initiation of translation (36, 37). Among the three 4E-BP family members (4E-BP1, 4E-BP2, and 4E-BP3), 4E-BP2 is the most abundant paralog in the mammalian brain (38, 39). A recent study (5) has identified aberrant activation of eIF4E as a major mechanism for translational changes in focal malformations of cortical development (FMCD), a condition that is often caused by brain somatic activating mutations in MTOR and presents with intractable epilepsy in children, accompanied by developmental abnormalities and autism spectrum disorder (ASD) (5, 40–42). Increased eIF4E activity has a pathogenic role in inducing epileptic seizures in FMCD as eIF4E knockdown prevented spontaneous seizures in mTOR Cys1483Tyr and Leu2427Pro mutant mice (5), which show mTORC1 hyperactivation.Despite the progress in understanding the causal link between enhanced mTORC1 activity and epilepsy, the mTORC1-downstream molecular mechanisms promoting epileptogenesis and the cell types mediating the effect on seizure threshold and severity remain poorly understood. In this work, we investigated the role of two main mTORC1-downstream effectors, 4E-BP1 and 4E-BP2, in regulating seizure susceptibility and studied the neuronal cell types mediating epileptogenic effects. We report that mice with whole-body or parvalbumin neuron–specific deletion of 4E-BP2 exhibit reduced threshold and increased severity of epileptic seizures. Moreover, we show that Pik3ca^H1047R-Pvalb mutant mice harboring a conditional parvalbumin neuron–specific KI gain-of-function mutation (H1047R) in the PIK3CA kinase domain are prone to seizures. Collectively, these findings demonstrate a central role of 4E-BP2 and parvalbumin neurons in mediating mTORC1-dependent epileptogenesis, thus expanding our understanding of cell type–specific molecular mechanisms of translation dysregulation in epilepsy and other neurodevelopmental disorders.     

Solitary fibrous tumour of the pleura: A case report

Solitary fibrous tumours of the pleura are rare pleural neoplasms that are distinct from mesothelioma. Most of them are benign, although some behave aggressively; morphological and pathological features are important in distinguishing them from mesothelioma and in predicting clinical behaviour. Solitary fibrous tumours often grow to a large size before causing symptoms, and are characteristically associated with hypertrophic pulmonary osteoarthropathy in up to 20% of cases. In cases of benign lesions, complete resection is usually curative. A case involving a 62-year-old woman who underwent surgical resection of a solitary fibrous tumour of the pleura measuring 25 cm in size is described.     

Amanita phalloides poisoning: reassessment of prognostic factors and indications for emergency liver transplantation

BACKGROUND/AIMS: Amanita phalloides poisoning is an uncommon cause of acute liver failure with an especially rapid course. The aim of this study was to re-assess transplantation criteria in patients with mushroom poisoning. METHODS: Twenty-seven patients admitted for Amanita phalloides poisoning were studied. Previously reported transplantation criteria, including the recent Ganzert's criteria, were tested retrospectively. RESULTS: The rate of fatal intoxication (death and/or transplantation) was 8/27 (30%). An interval between ingestion and diarrhea <8h was a very early predictor of a fatal outcome (accuracy of 78%). Later on, non-paracetamol and paracetamol King's College criteria were superior to Clichy's and Ganzert's criteria (accuracy of 100% compared to 85% and 85%, respectively). Encephalopathy and renal insufficiency were not constant in the fatal intoxication group. Prothrombin index below 10% 4 days or more after ingestion had a 100% accuracy for predicting a fatal outcome. CONCLUSIONS: Liver transplantation should be strongly considered in patients with an interval between ingestion and diarrhea <8h. Encephalopathy should not be an absolute prerequisite for deciding transplantation. From day 4 after ingestion, prothrombin index lower than 10% ( approximately INR of 6) alone is a reliable tool for deciding emergency transplantation.     

C-reactive protein predicts tumor necrosis factor-alpha blocker retention rate in axial ankylosing spondylitis

OBJECTIVE: In ankylosing spondylitis (AS), tumor necrosis factor (TNF) blockers are recommended for patients with high symptomatic disease activity. Few data are available about objective signs of inflammation such as increased C-reactive protein (CRP). We assessed the retention rate of TNF blockers in patients with axial AS, according to baseline CRP and other potentially predictive measures. METHODS: A retrospective study of all patients treated with TNF blockers for axial AS. Retention rate was evaluated using a survival-data analysis technique with discontinuation of the drug because of inefficacy (Kaplan-Meier method). Potential factors explaining the retention rates (demographic and clinical indicators and CRP) were evaluated using log-rank tests and a Cox proportional-hazards regression model. RESULTS: For axial AS, 175 patients received TNF blockers (men 78%, mean disease duration 12.4 +/- 9.1 yrs); 100 patients (of 143 with available data) had an increased CRP (> 10 mg/l). An increased CRP at baseline was the only variable explaining the retention rate in the Cox model (p = 0.003, hazard ratio = 3.3, 95% CI 1.5-7.3). CONCLUSION: Interruption for expert opinion of inefficacy was more frequent for patients with low baseline CRP; however, even in these patients retention was high. Increased CRP should not be considered mandatory for proposing TNF blocker treatment in axial AS.     

Radiological scoring methods in ankylosing spondylitis. Reliability and change over 1 and 2 years

OBJECTIVE: To compare reliability and change over time of radiological scoring methods in ankylosing spondylitis (AS). METHODS: Two trained observers scored 217 sets of radiographs from baseline and from one and 2 years' followup. Sacroiliac (SI) joints were grade 0-4 by the New York method and Stoke Ankylosing Spondylitis Spine Score (SASSS). Hips and cervical and lumbar spine were graded 0-4 by Bath Ankylosing Spondylitis Radiology Index (BASRI). BASRI spinal scores and New York SI are combined into BASRI-spine (score 2-12) and with the addition of BASRI-hips into BASRI-total (2-16). Cervical and lumbar spine were also scored in detail (SASSS, 0-36 each) and were combined into SASSS-total or "modified" SASSS (both range 0-72). To assess change a smallest detectable difference (SDD) was estimated for data on a quasi-interval scale. RESULTS: The SI scoring methods showed intra and interobserver kappa between 0.36 and 0.70. The BASRI-hip reached kappa between 0.59 and 0.84. Combined SASSS scores were most reliable, with intra and interobserver intraclass correlation coefficients (ICC) between 0.90 and 0.96. The ICC of the combined BASRI scores were also very good, ranging from 0.85 to 0.95. For SI New York, SI SASSS, and BASRI-hip, 0.3-1.2% of patients deteriorated 1 grade; 7.5% deteriorated 1 grade (6.3% of maximum score) in BASRI-spine and BASRI-total, and observers agreed in up to 48% of the cases that no change occurred. The SDD was lowest (7.5; 10% of maximum score) for "modified" SASSS. Only 0.8% of patients deteriorated more than the SDD and observers agreed in up to 92% of the cases that no change occurred. CONCLUSION: Radiological scoring methods for AS are moderately to excellently reliable. Under the selected scoring conditions (concealed time order, average of 2 observers, SDD based on interobserver data, unselected patient population) there was too little change over 2 years to be detected reliably by the scoring methods.     

Plasma ratio of angiopoietin-2 to angiopoietin-1 is a biomarker of vascular impairment in chronic obstructive pulmonary disease patients

Chronic obstructive pulmonary disease (COPD) patients have an increased risk of cardiovascular disease. Muscle biopsies have revealed that the muscle vasculature in COPD patients was characterized by a capillary rarefaction with reduced pericyte coverage. Thus, an imbalance of the plasma Angiopoietin-1 / Angiopoietin-2 (Ang2/Ang1) ratio could constitute a non-invasive marker of the muscle vascular impairment. In 14 COPD patients (65.5±5.1-year-old) and 7 HC (63.3±5.8-year-old), plasma samples were obtained at 3 time-points: before, after 5 weeks (W5), and after 10 weeks (W10) of exercise training. COPD patients showed a muscle capillary rarefaction at baseline with a reduced capillary coverage at W5 and W10. The plasma Ang2/Ang1 ratio was significantly higher in COPD patients vs. HC during the training (Group: p=0.01). The plasma Ang2/Ang1 ratio was inversely correlated with the pericyte coverage index regardless of the time period W0 (r=?0.51; p=0.02), W5 (r=?0.48; p=0.04), and W10 (r=?0.61; p<0.01). Last, in ECFC/MSC co-cultures exposed to the W10 serum from COPD patients and HC, the plasma Ang2/Ang1 at W10 were inversely correlated with calponin staining (r=?0.64. p=0.01 and r= 0.71. p<0.01, Fig. 1B), in line with a role of this plasma Ang2/Ang1 in the MSC differentiation into pericytes. Altogether, plasma Ang2/Ang1 ratio could constitute a potential marker of the vascular impairment in COPD patients.

     

Metabolic alkalosis and the response of the trout, Salmo fario, to acute severe hypoxia.

Trout (Salmo fario) were acutely transferred from seawater to freshwater in order to induce blood metabolic alkalosis (cf. Maxime et al., J. Comp. Physiol. 160: 31-39, 1990). After 2 weeks, the fish were exposed to severe environmental hypoxia (final water oxygen partial pressure, PWO2 = 25-45 Torr, reached within 20 min), to assess the impact of the experimentally induced alkalosis, and hence increased haemoglobin-oxygen (Hb-O2) affinity, on various aspects of the hypoxic response. This was accomplished by monitoring oxygen partial pressure and total oxygen content of arterial blood (PaO2 and CaO2), extracellular pH (pHe), red blood cell (RBC) intracellular pH (pHi), and the concentrations of plasma adrenaline, noradrenaline, lactate and haemoglobin (Hb) at 5 min intervals. Blood from normoxic fish exhibited high pHe and RBC pHi values (8.32 +/- 0.02 and 7.53 +/- 0.03, respectively). During hypoxia PaO2 declined to 10 Torr within 25 min; the first 5 min provoked increases of pHe and pHi to 8.43 +/- 0.03 and 7.71 +/- 0.03, respectively; thereafter, pHe decreased whilst pHi remained elevated. The blood lactate concentration increased from 2.30 +/- 0.76 mmol.L-1 in normoxia to 14.94 +/- 5.7 mmol.L-1 at the conclusion (60 min) of the hypoxic exposure and catecholamine levels also increased progressively (from 2.94 +/- 0.51 and 1.90 +/- 0.50 nmol.L-1, in normoxia, to 191.91 +/- 64.25 and 72.00 +/- 25.02 nmol.L-1, at their highest levels, for adrenaline and noradrenaline, respectively). Determination of the PaO2 thresholds for lactate and catecholamine release demonstrated that these substances appeared in the bloodstream when the degree of O2 saturation of the haemoglobin fell below 60%. The results demonstrate that initial blood alkalosis does not prevent the typical physiological responses of trout to hypoxia but simply shifts to lower PaO2 values the threshold at which these responses begin.     

The structural origin of second harmonic generation in fascia

Fascia tissue is rich in collagen type I proteins and can be imaged by second harmonic generation (SHG) microscopy. While identifying the overall alignment of the collagen fibrils is evident from those images, the tridimensional structural origin for the observation of SHG signal is more complex than it apparently seems. Those images reveal that the noncentrosymmetric (piezoelectric) structures are distributed heterogeneously on spatial dimensions inferior to the resolution provided by the nonlinear optical microscope (sub-micron). Using piezoresponse force microscopy (PFM), we show that an individual collagen fibril has a noncentrosymmetric structural organization. Fibrils are found to be arranged in nano-domains where the anisotropic axis is preserved along the fibrillar axis, while across the collagen sheets, the phase of the second order nonlinear susceptibility is changing by 180 degrees between adjacent nano-domains. This complex architecture of noncentrosymmetric nano-domains governs the coherent addition of 2ω light within the focal volume and the observed features in the SHG images taken in fascia.OCIS codes: (180.4315) Nonlinear microscopy, (190.4160) Multiharmonic generation     

Molecular chains of coordinated dimolybdenum isonicotinate paddlewheel clusters

A growing focus on the use of coordination polymers for active device applications motivates the search for candidate materials with integrated and optimized charge transport modes. We show herein the synthesis of a linear coordination polymer comprised of Mo₂(INA)₄ (INA = isonicotinate) metal–organic clusters. Single-crystal X-ray structure determination shows that this cluster crystallizes into one-dimensional molecular chains, whose INA-linked Mo₂ cores engage in alternate axial and equatorial binding motifs along the chain axis. Electron paramagnetic resonance spectra, absorption spectra, and density functional theory calculations show that the aforementioned linear coordination environment significantly modifies the electronic structure of the clusters. This work expands the synthetic foundation for assembly of coordination polymers with tailorable dimensionalities and charge transport properties.

Linear molecular chains of coordinated dimolybdenum isonicotinate clusters.

Over the past few decades, researchers have developed and investigated coordination polymers (CP) encompassing an extensive range of architectures.^1–3 Interest in CPs most frequently focuses on their large accessible surface areas, especially in the case of porous metal–organic frameworks, and on their significantly tunable geometries. These features have led to the application of CPs in molecular sieving,^4–6 contaminant encapsulation,^7–9 catalysis,^10–12 and sensing.^13,14 With increased attention towards use of CPs as electrochemical and electronic materials,^13,15,16 there is a need to incorporate and optimize charge transport pathways within the framework of these extended solids. The integration of coupled redox-active entities as part of the CP framework can facilitate charge delocalization and thereby engender long-range electronic transport pathways. This strategy has recently been employed to produce electrochemically- and electronically-active CP frameworks.^16,17We drew our attention to di-metallic tetracarboxylate clusters with metal–metal multiple bonds because of their tendency to form Class III Robin-Day mixed-valence complexes.^18–20 These four-fold symmetric paddlewheel clusters exhibit redox behavior, and there is spectroscopic evidence for electronic communication within small supramolecular units of these clusters joined by organic or organometallic linkers.^21–25 By comparison, the assembly of these clusters into extended solids and an interrogation of their properties is less developed. Obtaining well-defined and structurally robust CPs from these clusters can also be challenging.^26–31Motivated by these challenges and opportunities, we have recently focused on Mo₂(INA)₄ as a new building block for CPs. We previously reported the preparation of CP crystals comprised of commensurately stacked two-dimensional lattices of fully coordinated Mo₂(INA)₄ clusters.³² In this work, we were interested in accessing other crystal topologies containing the same molecular cluster. A red crystalline precipitate forms after refluxing a solution of Mo₂(OAc)₄, excess isonicotinic acid (H-INA), and trace acetic acid in dimethylformamide (DMF) for 2 days (Scheme 1). Electrospray ionization mass spectrometry of a solution of this red precipitate in dimethylsulfoxide (DMSO) and acetonitrile reveals peaks centered around m/z = 681 with isotopic patterning (Fig. S1^†). This value matches the theoretical mass of Mo₂(INA)₄. The organic composition of the crystalline product is further verified by nuclear magnetic resonance (NMR) experiments following acid digestion of the precipitate (Fig. S2^†). These data confirm that the crystalline product (1) of the reaction outlined in Scheme 1 is comprised of the Mo₂(INA)₄ cluster.Open in a separate windowScheme 1Ligand exchange followed by polymerization yields product 1 after 2 days.Large single crystals of 1 were obtained by stirring the aforementioned reaction (Scheme 1) at 60 rpm (Fig. S3^†). The structure of these single crystals was determined by X-ray crystallography (Fig. 1 and Table S1^†). The crystal structure of 1 contains one-dimensional (1D) chains comprised of Mo₂(INA)₄ clusters that alternately bind through axial and equatorial binding sites. One DMF solvent molecule is coordinated to each of two Lewis acidic axial Mo sites on every other cluster. This coordination motif is supported by proton NMR data showing a DMF-to-INA ratio of approximately 1 : 4.07 in acid-digested samples of 1 (Fig. S2^†). The Mo–Mo bond lengths in the two clusters are 2.1219(5) Å and 2.1189(5) Å. These distances are within the anticipated range of lengths for Mo–Mo quadruple bonds (2.06–2.17 Å as described by Murillo et al.) and consistent with axial coordination of a strongly donating ligand such as pyridine.^22,33,34 Furthermore, we observe a Raman band at 383 cm⁻¹ (Fig. S4^†), which is relatively weaker than that anticipated for axially under-coordinated Mo₂ complexes, and treat this observation as further evidence for the axial donation effect.^22,34 We note that the Mo₂ centers within each molecular chain are coordinatively saturated and do not bond to pyridines from neighboring chains (Fig. S5^†).Open in a separate windowFig. 1Structure of the 1D coordination polymer (1) showing the paddlewheel units that alternately bond through axial Mo (cyan) and equatorial N (blue) binding sites. Ellipsoids are shown at 50% probability level. Disorder and H atoms have been omitted for clarity.We next characterized the phase purity, stability, and porosity of bulk samples of 1. First, powder X-ray diffraction (pXRD) patterns collected from products precipitated across a range of stir rates (60–300 rpm) match well with the pXRD pattern simulated from the single-crystal XRD data discussed above (Fig. 2 and S3^†). These data suggest that a single common crystal phase is produced regardless of stir rate, though stir rates <100 rpm are conducive to the formation of high-quality single crystals. Second, Fourier transform infrared (FT-IR) spectroscopy data show no evidence of H-INA or Mo₂(OAc)₄ in the bulk crystalline powder (Fig. S6^†), suggesting good purity of our bulk samples. Third, thermogravimetric analysis shows a mass loss of 10.1% between 190 °C and 252 °C that can be attributed to the loss of coordinated DMF molecules, which account for 9.7% of the 1D CP (Fig. S7^†). Upon further heating, the sample rapidly loses mass above 350 °C and likely degrades. Finally, nitrogen gas adsorption measurements on the crystalline powder yield a Brunauer–Emmett–Teller (BET) surface area of 325.8 m² g⁻¹ (Fig. S8^†). We note that this modest BET surface area is reasonable given the tight packing of the 1D chains within 1 (Fig. S5^†).Open in a separate windowFig. 2Experimental pXRD pattern for powder precipitated from a DMF solution stirred at 300 rpm (blue), and simulated pXRD pattern obtained from single-crystal XRD data of 1 (red).Finally, we sought to analyze the electronic structure of 1 with absorption spectroscopy, density-functional theory (DFT) calculations, and electron paramagnetic resonance (EPR) spectroscopy. A diffuse reflectance UV-vis spectrum collected from a powder sample of 1 exhibits a broad absorption feature between ∼400 and 600 nm (Fig. 3a). The UV-vis absorption spectrum of a solution sample of 1 dissolved in DMF exhibits a significant feature centered at ∼470 nm. We ascribe the modest absorption shoulder at ∼570 nm to absorption by remnant 1D CP chains. We used computational methods^35,36 to examine orbital interactions and electronic transitions that may be responsible for the absorption features identified above. Single point energies and molecular orbitals were calculated from coordinates taken directly from the single-crystal structure of 1. The B3LYP functional was used with the 6-31g* basis set for H, C, N, O and the Stuttgart/Dresden effective core potential for Mo. In the ground state, the first four highest-energy occupied molecular orbitals are all metal-centered, with discrete energy levels, localized electron density, and little sharing between the two coordinatively distinct clusters (Fig. S9^†). These computational results suggest that charge (e.g. introduced from an external circuit or generated chemically in situ) would likely remain localized on the individual clusters comprising 1.Open in a separate windowFig. 3(a) UV-vis spectra of 1 in powder form (red) and dissolved in DMF (blue). (b) DFT calculated HOMO and LUMO orbitals of the monomer. (c) DFT calculated HOMO and LUMO orbitals of the dimer.We performed time-dependent DFT (TD-DFT) calculations to identify possible optical transitions in 1. We did so by considering the electronic structure of a single Mo₂(INA)₄ cluster coordinated by a DMF molecule at both axial sites, and of two Mo₂(INA)₄ clusters having the same coordination environment as observed in the crystal structure of 1. Henceforth we will refer to the former as the monomer and the latter as the dimer. For the monomer, calculations identify a 2.44 eV (508 nm) transition primarily between a HOMO of Mo₂δ character and a ligand-based π* LUMO, which is nearly degenerate with several higher lying LUMO orbitals (Fig. 3b and S10^†). The character of this transition is typical of the metal–ligand charge transfer (MLCT) transitions reported in analogous transition-metal complexes. We note that the calculated HOMO–LUMO transition energy for the monomer is in reasonable agreement with the 470 nm feature observed in the absorption spectrum of the solution sample of 1 dissolved in DMF. On the basis of these data we can assign the aforementioned 470 nm feature to absorption by the isolated monomer.Turning our attention to the dimer, TD-DFT calculations identify a 2.19 eV (566 nm) transition primarily between a HOMO of Mo₂δ character and a ligand-based π* LUMO orbital (Fig. 3c and S11^†). We also note two higher energy MLCT transitions primarily from HOMO to LUMO+5 and from HOMO−1 to LUMO+1 with energies of 2.59 eV (479 nm) and 2.61 eV (475 nm), respectively (Fig. S11^†). Notably, while the two higher energy MLCT transitions involve LUMO orbitals located on the INA ligands perpendicular to the dimer axis, the lower energy MLCT transition at 2.19 eV involves a LUMO orbital of the INA ligand along the dimer axis.The calculated dimer transition energies cover much of the broad absorption envelope observed in the spectrum of the powder of 1. In particular, the low energy MLCT transition at 566 nm calculated for the dimer likely accounts for the significant absorption at wavelengths greater than 500 nm (Fig. 3a). These data suggest the dimer is a good simulant of the electronic properties of 1. This is a reasonable expectation given that 1 can be viewed, from a structural standpoint, as a linear polymer chain of the dimers. We can conclude that our 1D CP has an electronic structure comprised of dimer-like MLCT states arising from a lifting of the degeneracy of monomer orbitals due to their altered symmetry in the 1D chain.Our results show that the alternating coordination environment along the backbone of our 1D CP gives rise to a unique chain topology with a distinct electronic structure and function. Further evidence for the functionally distinct nature of 1 over the monomer is provided by X-band electron paramagnetic resonance (EPR) spectroscopy. An EPR spectrum collected from a powder sample of 1 at 20 K reveals an EPR active system with weak hyperfine structure owing to ⁹⁵Mo and ⁹⁷Mo isotopes, which have I = 5/2 nuclear spin (Fig. 4). This spectrum is qualitatively similar to spectra reported for EPR active Mo₂^V species in transition metal alkoxide-bridged dimolybdenum clusters.²³ This suggests the presence of Mo^II and Mo^III centers in 1 that may have formed during partial oxidation of the powder sample. It is anticipated that the hole is equally present on both Mo atoms as expected from the Class III Robin-Day classification of such systems. We simulated the experimental EPR spectrum by modelling our 1D CP system as a single axial paramagnet and obtained g values of g_‖ = 1.895 and g_⊥ = 1.935 and a perpendicular hyperfine coupling constant A_⊥ of 3.9 mT (Fig. 4 and S12^†).³⁷ The hyperfine coupling observed for our 1D CP is consistent with values reported for systems containing isolated Mo₂^V ions.²³ Moreover, the fact that a single paramagnet model was sufficient to simulate the EPR spectrum suggests that the two distinct coordination environments are fairly similar electronically. Though our EPR data provide evidence for charge localization³⁸ on Mo₂ centers, we cannot exclude the possibility for photo-induced intra-chain (or indeed inter-chain) charge transport arising from population of the low energy LUMO orbital on each bridging INA ligand.Open in a separate windowFig. 4Experimental EPR spectrum of 1 collected at 20 K (blue) and 9.44 GHz. In EasySpin, a fifth-order background correction was applied and the system was modeled as an axial paramagnet with g_‖ = 1.895 and g_⊥ = 1.935 (red).In summary, we have synthesized through a one-step ligand substitution reaction a new inorganic cluster comprised of a quadruply bonded dimolybdenum core coordinated by 4 equatorial isonicotinate ligands: Mo₂(INA)₄. Single-crystal XRD data show that recrystallization of this cluster from DMF yields a 1D molecular chain wherein the clusters alternately coordinate to one another through axial and equatorial binding sites (1). pXRD, FT-IR, and NMR data confirm the phase and compositional purity of this 1D CP in the bulk. UV-vis spectroscopy and DFT calculations reveal an electronic structure for 1 that is distinct from an individual solvated Mo₂(INA)₄ monomer owing to the alternating coordination environment present along the chain. This work establishes the synthetic foundation for assembly of CPs from discrete molecular clusters that have the potential to support through-framework charge transport due to mixed-valence mechanisms. We also envision utilizing the molecular building block discussed herein for the assembly of CPs with tailorable dimensionalities or hierarchies.     

Taking empowerment into account: the response of community-based organisations to the HIV care needs of men who have sex with men in West Africa (CohMSM ANRS 12324 – Expertise France)

ABSTRACT

Empowerment is an ongoing process through which individuals and communities appropriate power and acquire the capability to function autonomously. Research on empowerment in men who have sex with men (MSM) is lacking in community-based contexts. We investigated the relationship between willingness to be empowered and HIV care needs in West African MSM accessing community-based organisations’ (CBO) services. Fifty-three interviews were administered to HIV-negative MSM participating in the CohMSM study (Mali, Burkina Faso, Côte d’Ivoire, Togo). Five indicators of empowerment were identified from a discourse analysis: (i) motivation to access HIV services, (ii) willingness to improve HIV services, (iii) desire to be involved in new activities, (iv) desire to participate in such services, (v) willingness to collaborate in decision making. Based on these indicators, participants were classified into two profiles: high (19/53, 36%) and low (34/53, 64%) level of willingness to be empowered (HWE, LWE). Using a thematic analysis, HWE participants were focused on collective benefit (preventive follow-up, questions about MSM identity), while LWE participants were centred on individual benefit (medical care). CBOs should consider empowerment as a tool to advance collective health benefits for MSM. To improve empowerment in MSM, specific training on issues regarding sexual identity and stigma is needed for CBO providers.