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Abstract Dementia refers to an umbrella phenotype of many different underlying pathologies with Alzheimer’s disease (AD) being the most common type. Neuropathological examination remains the gold standard for accurate AD diagnosis, however, most that we know about AD genetics is based on Genome-Wide Association Studies (GWAS) of clinically defined AD. Such studies have identified multiple AD susceptibility variants with a significant portion of the heritability unexplained and highlighting the phenotypic and genetic heterogeneity of the clinically defined entity. Furthermore, despite women’s increased susceptibility to dementia, there is a lack of sex-specific genetic studies and understanding of sex-specific background for the disorder. Here, we aim to tackle the heterogeneity of AD by specifically concentrating on neuropathological features and pursuing sex-specific analysis. We bring together 14 different genomic and neuropathology datasets (6960 individuals) and we integrate our GWAS findings with transcriptomic and phenotypic data aiming to also identify biomarkers for AD progression. We uncover novel genetic associations to AD neuropathology, including BIN1 and OPCML. Our sex-specific analysis points to a role for BIN1 specifically in women as well as novel AD loci including QRFPR and SGCZ. Post-GWAS analyses illuminate the functional and biological mechanisms underlying AD and reveal sex-specific differences. Finally, through PheWAS and Mendelian Randomization analysis, we identify causal links with AD neuropathology pointing to disrupted lipid metabolism, as well as impaired peripheral immune response and liver dysfunction as part of a vicious cycle that fuels neurodegeneration.

Dementia refers to an umbrella phenotype of many different underlying pathologies with Alzheimer's disease (AD) being the most common type. Neuropathological examination remains the gold standard for accurate AD diagnosis, however, most that we know about AD genetics is based on Genome-Wide Association Studies (GWAS) of clinically defined AD. Such studies have identified multiple AD susceptibility variants with a significant portion of the heritability unexplained and highlighting the phenotypic and genetic heterogeneity of the clinically defined entity. Furthermore, despite women's increased susceptibility to dementia, there is a lack of sex-specific genetic studies and understanding of sex-specific background for the disorder. Here, we aim to tackle the heterogeneity of AD by specifically concentrating on neuropathological features and pursuing sex-specific analysis. We bring together 14 different genomic and neuropathology datasets (6960 individuals) and we integrate our GWAS findings with transcriptomic and phenotypic data aiming to also identify biomarkers for AD progression. We uncover novel genetic associations to AD neuropathology, including BIN1 and OPCML. Our sex-specific analysis points to a role for BIN1 specifically in women as well as novel AD loci including QRFPR and SGCZ. Post-GWAS analyses illuminate the functional and biological mechanisms underlying AD and reveal sex-specific differences. Finally, through PheWAS and Mendelian Randomization analysis, we identify causal links with AD neuropathology pointing to disrupted lipid metabolism, as well as impaired peripheral immune response and liver dysfunction as part of a vicious cycle that fuels neurodegeneration. [ABSTRACT FROM AUTHOR]

The concept of variable stoichiometry cocrystallization is explored in halogen-bonded systems. Three novel cocrystals of 1,4-diiodotetrafluorobenzene and 3-nitropyridine with molar ratios of 1:1, 2:1, and 1:2, respectively, are prepared by slow evaporation methods. Single-crystal X-ray diffraction analysis reveals key differences between each of the nominally similar cocrystals. For instance, the 1:1 cocrystal crystallizes in the [P2.sub.1]/n space group and features a single chemically and crystallographically unique halogen bond between iodine and the pyridyl nitrogen. The 2:1 cocrystal crystallizes in the P1 space group and features a halogen bond between iodine and one of the nitro oxygens in addition to an iodine--nitrogen halogen bond. The 1:2 cocrystal crystallizes with a large unit cell (V = 9896 [A.sup.3]) in the Cc space group and features 10 crystallographically distinct iodine-nitrogen halogen bonds. Powder X-ray diffraction experiments carried out on the 1:1 and 2:1 cocrystals confirm that gentle grinding does not alter the crystal forms. [.sup.1]H [right arrow] [.sup.13]C and [.sup.19]F [right arrow] [.sup.13]C cross-polarization magic angle spinning (CP/MAS) NMR experiments performed on powdered samples of the 1:1 and 2:1 cocrystals are used as spectral editing tools to select for either the halogen bond acceptor or donor, respectively. Carbon-13 chemical shifts in the cocrystals are shown to change only very subtly relative to pure solid 1,4-diiodotetrafluorobenzene, but the shift of the carbon directly bonded to iodine nevertheless increases, consistent with halogen bond formation (e.g., a shift of +1.6 ppm for the 2:1 cocrystal). This work contributes new examples to the field of variable stoichiometry cocrystal engineering with halogen bonds. Key words: solid-state NMR, X-ray diffraction, halogen bond, cocrystal, polymorphism, stoichiometry, stoichiomorphism. Nous avons etudie le concept de cocristallisation a stoechiometrie variable dans des systemes a liaison halogene. Nous avons prepare par evaporation lente trois nouveaux cocristaux de 1,4-diiodotetrafluorobenzene et de 3-nitropyridine avec des rapports molaires de 1:1, de 2:1 et de 1:2, respectivement. L'analyse par diffraction des rayons X sur monocristal revele des differences importantes entre les cocristaux theoriquement similaires. Par exemple, le cocrystal 1:1 cristallise selon le groupe d'espace [P2.sub.1]/n et presente une seule liaison halogene, sur les plans chimique et cristallographique, entre l'iode et l'azote du groupe pyridyle. Le cocrystal 2:1 cristallise selon le groupe d'espace P1 et presente une liaison halogene entre l'iode et l'un des oxygenes du groupe nitro, en plus de la liaison halogene iode-azote. Le cocristal 1:2 cristallise en formant une grande cellule unitaire (V = 9896 [A.sup.3]) selon le groupe d'espace Cc et presente 10 liaisons halogene iode-azote distinctes sur le plan cristallographique. Des experiences de diffraction des rayons X sur poudre realisees sur les cocristaux 1:1 et 2:1 confirment qu'un broyage leger ne modifie pas les formes cristallines. Nous avons utilise des experiences de RMN [.sup.1]H [right arrow] [.sup.13]C et [.sup.19]F [right arrow] [.sup.13]C a polarisation croisee en rotation a l'angle magique (CP/MAS, cross-polarization/magic angle spinning), realisees sur des echantillons de cocristaux 1:1 et 2:1 sous forme de poudre, comme outils d'edition spectrale pour selectionner l'accepteur ou le donneur de liaison halogene, respectivement. Les deplacements chimiques du carbone-13 dans les cocris-taux ne changent que de facon tres subtile par rapport au 1,4-diiodotetrafluorobenzene solide pur, mais le deplacement du carbone directement lie a l'iode augmente neanmoins, ce qui concorde avec la formation de liaisons halogene (p. ex., un deplacement de +1,6 ppm dans le cas du cocrystal 2:1). Ces travaux apportent de nouveaux exemples au domaine de l'ingenierie des cocristaux a stoechiometrie variable comportant des liaisons halogene. [Traduit par la Redaction] Mots-cles : RMN a l'etat solide, diffraction des rayons X, liaison halogene, cocristal, polymorphisme, stoechiometrie, stoechiomorphisme., Introduction Molecular and ionic solids can adopt a range of forms depending on how they are prepared. (1,2) Such forms include pure crystalline or amorphous phases, hydrates, or solvates. In [...]

Background: Depression and anxiety occur more frequently in women and are associated with an increased risk of cardiovascular disease. Objectives: Data on the association between these psychiatric conditions and the incidence of acute heart failure (HF) and how they influence heart failure outcomes in women are lacking. We investigated this potential relationship using data from the National Inpatient Sample. Methods: We used ICD-10 codes to extract encounters for acute heart failure and/or the acute exacerbation of chronic heart failure, anxiety, and depression from the discharge data of the NIS from 2019 to 2020. We compared baseline characteristics and length of stay (LOS), cost of care (COC) and acute HF by depression/anxiety status for males and females and employed regression models to assess the influence of these psychiatric conditions on the outcomes. Results: There were 6,394,136 encounters involving females, which represented 56.6% of the sample. The prevalence of depression and anxiety were 15.7% and 16.8%, respectively. Among females, the occurrence of acute CHF did not differ by depression or anxiety status. However, Takostubo cardiomyopathy was more prevalent in those with depression (0.3% vs. 0.2%, p = 0.003) and anxiety (0.3% vs. 0.2%, p = 0.03) compared to those without these conditions. Among those with depression, LOS was significantly longer (3 days IQR: 2–6, vs. 3 days IQR:2–5 days, p < 0.001). The COC was USD 1481 more in patients with depression. On the contrary, LOS and COC were significantly lower in those without anxiety. Conclusions: Depression was associated with an increased LOS among both men and women and an increased cost of care among women. Anxiety was associated with a decreased LOS and cost of care among women, which may be related to an increased rate of against medical advice (AMA) discharges among this population. Further research is necessary to identify optimal management strategies for depression and anxiety among patients hospitalized with HF.

Users of the microbond test assume that a microbond resin droplet's properties are equivalent to a macroscale specimen. However, there is currently no standardised methodology for determining the cure state of droplet specimens used in the microbond test. In this paper, we present a technique for microbond test users to better understand the properties of thermoset droplet specimens. Utilising a conventional benchtop spectrometer, a novel sample preparation technique involving curing epoxy droplets on thin-steel filaments allowed for high-throughput determination of the microbond droplet cure state. The parity between steel filament and glass fibre microbond samples was confirmed by infrared microspectroscopy. It is shown that cure schedules used in manufacturing composite parts produced microbond droplets with degrees of cure lower than that of bulk matrix specimens subjected to an identical thermal history. Testable microbond droplets could only be prepared for commercial resin systems when introducing a room temperature pre-curing time of at least 2 h. It is concluded that microbond testing should be supported by some droplet cure state characterisation methods to ensure that interfacial effects are not artefacts of droplet sample preparation. [ABSTRACT FROM AUTHOR]

Chalcogen bonds (ChB) are moderately strong, directional, and specific non‐covalent interactions that have garnered substantial interest over the last decades. Specifically, the presence of two σ‐holes offers great potential for crystal engineering, catalysis, biochemistry, and molecular sensing. However, ChB applications are currently hampered by a lack of methods to characterize and control chalcogen bonds. Here, we report on the influence of various substituents (halogens, cyano, and methyl groups) on the observed self‐complementary ChB networks of 2,1,3‐benzoselenadiazoles. From molecular electrostatic potential calculations, we show that the electrostatic surface potentials (ESP) of the σ‐holes on selenium are largely influenced by the electron‐withdrawing character of these substituents. Structural analyses via X‐ray diffraction reveal a variety of ChB geometries and binding modes that are rationalized via the computed ESP maps, although the structure of 5,6‐dimethyl‐2,1,3‐benzoselenadiazole also demonstrates the influence of steric interactions. 77Se solid‐state magic‐angle spinning NMR spectroscopy, in particular the analysis of the selenium chemical shift tensors, is found to be an effective probe able to characterize both structural and electrostatic features of these self‐complementary ChB systems. We find a positive correlation between the value of the ESP maxima at the σ‐holes and the experimentally measured 77Se isotropic chemical shift, while the skew of the chemical shift tensor is established as a metric which is reflective of the ChB binding motif. [ABSTRACT FROM AUTHOR]

Lithium salts continue to find pharmaceutical applications, particularly as psychiatric medications. As with any active pharmaceutical ingredient, structural polymorphism is an important concern for lithium-based medications that can influence solubility and other physicochemical properties. Here we report a 13C, 1H, and 7Li magic-angle spinning solid-state nuclear magnetic resonance (MAS SSNMR) study of two 1:1 polymorphic ionic cocrystals of lithium 4-methoxybenzoate and L-proline (L4MPRO(α) and L4MPRO(β)). One-dimensional 13C cross-polarization MAS and two-dimensional heteronuclear correlation NMR spectra hint at differential mobilities of the proline and benzoate moieties for the two polymorphs. Five key resonances differ in 13C chemical shift by more than 1 ppm between the two polymorphs, clearly distinguishing between them. Gauge-including projector-augmented-wave density functional theory calculations of 13C and 1H magnetic shielding constants correlate strongly with the experimental chemical shifts for both polymorphs. R2 and root-mean-square deviation metrics are shown to be insufficient in the case of 13C, but sufficient in the case of 1H, for differentiating between the polymorphs. 7Li satellite-transition MAS NMR of both polymorphs are identical, as are the computed lithium magnetic shielding constants, demonstrating the insensitivity of 7Li NMR to polymorphism in these samples. This work highlights the utility of solid-state NMR spectroscopy for examining ionic salt cocrystals and also highlights some caveats in this regard. [ABSTRACT FROM AUTHOR]

Macrocycle formation that relies upon trans metal coordination of appropriately placed pyridine ligands within an arylene ethynylene construct provides rapid and reliable access to molecular rotators encapsulated within macrocyclic stators. Showing no significant close contacts to the central rotators, X‐ray crystallography of AgI‐coordinated macrocycles provides plausibility for unobstructed rotation or wobbling of rotators within the central cavity. Solid‐state 13C NMR of PdII‐coordinated macrocycles supports the notion of unobstructed movement of simple arenes in the crystal lattice. Solution 1H NMR studies indicate complete and immediate macrocycle formation upon the introduction of PdII to the pyridyl‐based ligand at room temperature. Moreover, the formed macrocycle is stable in solution; a lack of significant changes in the 1H NMR spectrum upon cooling to −50 °C is consistent with the absence of dynamic behavior. The synthetic route to these macrocycles is expedient and modular, providing access to rather complex constructs in four simple steps involving Sonogashira coupling and deprotection reactions. [ABSTRACT FROM AUTHOR]

Phenomena such as anticooperativity and competition among non‐covalent bond donors and acceptors are key considerations when exploring the polymorphic and stoichiomorphic landscapes of binary and higher‐order cocrystalline architectures. We describe the preparation of four cocrystals of 1,3,5‐trifluoro‐2,4,6‐triiodobenzene with N‐heterocyclic compounds, namely acridine, 3‐aminopyridine, 4‐methylaminopyridine, and 1,2‐di(4‐pyridyl)ethane. The cocrystals, which are characterized by single‐crystal and powder X‐ray diffraction experiments, all show moderately strong and directional iodine⋅⋅⋅nitrogen halogen bonds with reduced distance parameters ranging from 0.79 to 0.92 and carbon‐iodine⋅⋅⋅nitrogen bond angles ranging from 165.4(3) to 175.31(7)°. The cocrystal comprising 1,3,5‐trifluoro‐2,4,6‐triiodobenzene and acridine provides a relatively rare example where all three halogen bond donor sites form halogen bonds with three acceptor molecules, overcoming an anticooperative effect. This effect manifests itself through the lengthening of non‐halogen‐bonded C−I bonds, weakening their potential to form halogen bonds. The effect is only observed once two halogen bonds have been formed to 1,3,5‐trifluoro‐2,4,6‐triiodobenzene; one such bond does not appear to be adequate. Among the four cocrystals studied, competition between the pyridyl nitrogen atoms and the amine nitrogen atoms suggests that the former are the preferred halogen bond acceptors. Analysis by Hirshfeld fingerprint plots and 13C and 19F magic‐angle spinning solid‐state nuclear magnetic resonance (NMR) spectroscopy provides additional insights into the prevalence of various short contacts in the crystal structures and into the spectral response to halogen‐bond‐induced cocrystallization. [ABSTRACT FROM AUTHOR]

Three novel chalcogen‐bonded cocrystals featuring 3,4‐dicyano‐1,2,5‐selenodiazole (C4N4Se) or 3,4‐dicyano‐1,2,5‐tellurodiazole (C4N4Te) as chalcogen‐bond donors and hydroquinone (C6H6O2), tetraphenylphosphonium chloride (C24H20P+·Cl−) or tetraethylphosphonium chloride (C8H20P+·Cl−) as chalcogen‐bond acceptors have been prepared and characterized by single‐crystal X‐ray diffraction (XRD), powder X‐ray diffraction and 77Se/125Te magic‐angle spinning solid‐state NMR spectroscopy. The single‐crystal XRD results show that the chalcogenodiazole molecules interact with the electron donors through two σ‐holes on each of the chalcogen atoms, which results in highly directional and moderately strong chalcogen bonds. Powder XRD confirms that the crystalline phases are preserved upon moderate grinding of the samples for solid‐state NMR experiments. Measurement of 77Se and 125Te chemical shift tensors via magic‐angle spinning solid‐state NMR spectroscopy confirms the number of magnetically unique chalcogen sites in each asymmetric unit and reveals the impact of chalcogen‐bond formation on the local electronic structure. These NMR data are further assessed in the context of analogous data for a wider range of crystalline chalcogen‐bonded systems. [ABSTRACT FROM AUTHOR]

Halogen bonding to phosphorus atoms remains uncommon, with relatively few examples reported in the literature. Here, the preparation and investigation of the cocrystal bis(dicyclohexylphenylphosphine)(1,6-diiodoperfluorohexane) by X-ray crystallography and solid-state multinuclear magnetic resonance spectroscopy is described. The crystal structure features two crystallographically unique C--I...P halogen bonds [dI...P = 3.090 (5) A, 3.264 (5) A ] and crystallographic disorder of one of the 1,6-diiodoperfluorohexane molecules. The first of these is the shortest and most linear I...P halogen bond reported to date. 13C, 19F, and 31P magic angle spinning solid-state NMR spectra are reported. A 31P chemical shift change of -7.0 p.p.m. in the cocrystal relative to pure dicyclohexylphenylphosphine, consistent with halogen bond formation, is noted. This work establishes iodoperfluoroalkanes as viable halogen bond donors when paired with phosphorus acceptors, and also shows that dicyclohexylphenylphosphine can act as a practical halogen bond acceptor. [ABSTRACT FROM AUTHOR]