Psychotic experiences (PE) are prevalent in general and clinical populations and can increase the risk for mental disorders in young people. The Community Assessment of Psychic Experiences (CAPE) is a widely used measure to assess PE in different populations and settings. However, the current knowledge on their overall reliability is limited. We examined the reliability of the CAPE-42 and later versions, testing the role of age, sex, test scores, and clinical status as moderators. A systematic search was conducted on the Scopus, Web of Science, PubMed, EBSCOhost, ProQuest, and GoogleScholar databases. Internal consistency and temporal stability indices were examined through reliability generalization meta-analysis (RGMA). Moderators were tested through meta-regression analysis. From a pool of 1,015 records, 90 independent samples were extracted from 71 studies. Four versions showed quantitative evidence for inclusion: CAPE-42, CAPE-20, CAPE-P15, and CAPE-P8. Internal consistency indices were good (α/ω≈.725-0.917). Temporal stability was only analyzed for the CAPE-P15, yielding a moderate but not-significant effect (r=0.672). The evidence for temporal stability is scant due to the limited literature, and definitive conclusions cannot be drawn. Further evidence on other potential moderators such as adverse experiences or psychosocial functioning is required.
BACKGROUND AND HYPOTHESIS: Recent findings suggest the incidence of first-episode psychotic disorders (FEP) varies according to setting-level deprivation and cannabis use, but these factors have not been investigated together. We hypothesized deprivation would be more strongly associated with variation in FEP incidence than the prevalence of daily or high-potency cannabis use between settings. STUDY DESIGN: We used incidence data in people aged 18-64 years from 14 settings of the EU-GEI study. We estimated the prevalence of daily and high-potency cannabis use in controls as a proxy for usage in the population at-risk; multiple imputations by chained equations and poststratification weighting handled missing data and control representativeness, respectively. We modeled FEP incidence in random intercepts negative binomial regression models to investigate associations with the prevalence of cannabis use in controls, unemployment, and owner-occupancy in each setting, controlling for population density, age, sex, and migrant/ethnic group. STUDY RESULTS: Lower owner-occupancy was independently associated with increased FEP (adjusted incidence rate ratio [aIRR]: 0.76, 95% CI: 0.61-0.95) and non-affective psychosis incidence (aIRR: 0.68, 95% CI: 0.55-0.83), after multivariable adjustment. Prevalence of daily cannabis use in controls was associated with the incidence of affective psychoses (aIRR: 1.53, 95% CI: 1.02-2.31). We found no association between FEP incidence and unemployment or high-potency cannabis use prevalence. Sensitivity analyses supported these findings. CONCLUSIONS: Lower setting-level owner-occupancy and increased prevalence of daily cannabis use in controls independently contributed to setting-level variance in the incidence of different psychotic disorders. Public health interventions that reduce exposure to these harmful environmental factors could lower the population-level burden of psychotic disorders.
Atherosclerosis is a complex inflammatory disease in which the adaptive immune response plays an important role. While the overall impact of T and B cells in atherosclerosis is relatively well established, we are only beginning to understand how bidirectional T-cell/B-cell interactions can exert prominent atheroprotective and proatherogenic functions. In this review, we will focus on these T-cell/B-cell interactions and how we could use them to therapeutically target the adaptive immune response in atherosclerosis.
The structures of fourteen halochalcogenyl-phospho-nium tetra-halogen-ido-aurates(III), phosphane chalcogenide derivatives with general formula [R 1 3- nR 2 nPEX][AuX 4] (R 1 = t-butyl; R 2 = isopropyl; n = 0 to 3; E = S or Se; X = Cl or Br) are presented. The eight possible chlorido derivatives are: 17 a, n = 3, E = S; 18 a, n = 2, E = S; 19 a, n = 1, E = S; 20 a, n = 0, E = S; 21 a, n = 3, E = Se; 22 a, n = 2, E = Se; 23 a, n = 1, E = Se; and 24 a, n = 0, E = Se, and the corresponding bromido derivatives are 17 b-24 b in the same order. Structures were obtained for all compounds except for the tri-t-butyl derivatives 24 a and 24 b. Isotypy is observed for 18 a/18 b/22 a/22 b, 19 a/23 a, 17 b/21 b and 19 b/23 b. In eleven of the compounds, Xâ¯X contacts (mostly very short) are observed between the cation and anion, whereby the E-Xâ¯X groups are approximately linear and the Xâ¯X-Au angles approximately 90°. The exceptions are 17 a, 19 a and 23 a, which instead display short Eâ¯X contacts. Bond lengths in the cations correspond to single bonds P-E and E-X. For each group with constant E and X, the P-E-X bond-angle values increase monotonically with the steric bulk of the alkyl groups. The packing is analysed in terms of Eâ¯X, Xâ¯X (some between anions alone), Hâ¯X and Hâ¯Au contacts. Even for isotypic compounds, some significant differences can be discerned.
The structure of the title compound, C23H21BrN4O, contains two independent mol-ecules connected by hydrogen bonds of the type Namide-Hâ¯N≡C to form a dimer. The configuration at the exocyclic C=C double bond is E. The mol-ecules are roughly planar except for the isopropyl groups. There are minor differences in the orientations of these groups and the phenyl rings at N1. The dimers are further linked by 'weak' hydrogen bonds, two each of the types Hphen-ylâ¯O=C (Hâ¯O = 2.50, 2.51â Å) and Hphen-ylâ¯Br (Hâ¯Br = 2.89, 2.91â Å), to form ribbons parallel to the b and c axes, respectively. The studied crystal was a non-merohedral twin.
Tri-chlorido-(4-methyl-piperidine)-gold(III), [AuCl3(C6H13N)], 1, crystallizes in Pbca with Z = 8. Tri-bromido-(4-methyl-piperidine)-gold(III), [AuBr3(C6H13N)], 2, crystallizes as two polymorphs, 2a in Pnma with Z = 4 (imposed mirror symmetry) and 2b, which is isotypic to 1. The Au-N bonds trans to Cl are somewhat shorter than those trans to Br, and the Au-Cl bonds trans to N are longer than those cis to N, whereas the Au-Br bonds trans to N are slightly shorter than the cis bonds. The methyl and AuX 3 groups (X = halogen) occupy equatorial positions at the six-membered ring. The packing of all three structures involves chains of mol-ecules with offset stacking of the AuX 3 moieties associated with short Auâ¯X contacts; for 1 and 2b these are reinforced by N-Hâ¯X hydrogen bonds, whereas for 2a there are no classical hydrogen bonds and the chains are inter-connected by Brâ¯Br contacts.
PURPOSE: Initial discussions about the COVID-19 pandemic often overlooked its impact on young adults. By employing a qualitative approach nested within an ongoing general population cohort study, we seek to fill a gap in the literature by providing insights into the longer-term impact on this demographic. METHODS: Data collection involved the use of in-depth semi-structured interviews. Using a pre-determined sampling frame, we purposively recruited 30 participants based on age, gender, ethnicity, and deprivation from the Neuroscience in Psychiatry Network (NSPN). The NSPN cohort, established in 2012, consists of 2403 young people aged 14-24 at baseline, recruited from Greater London and Cambridgeshire. Interviews were conducted in Autumn 2022; data were analysed using the framework method. RESULTS: Participants were on average 28 years old (SD = 3 years, range 24-34 years; 53.3% female). The sample comprised individuals from diverse ethnic backgrounds, with 40% from non-White ethnic groups. Many young adults reported profound personal growth and a stronger sense of resilience, a perception observed across varying levels of anxiety or depression. Nevertheless, we observed substantial disruptions to their personal and professional lives such as returning to their parents' homes, often deferring other life plans, lacking mental health support, and encountering significant career challenges. CONCLUSION: Our findings highlight the complexity of pandemic impacts, demonstrating the need for supportive policies and further research to understand the circumstances under which genuine personal growth occurs, whether it is enduring or transient, and which factors influence it.
OBJECTIVE: Determination of the real-world performance of a health care system in the treatment of status epilepticus (SE). METHODS: Prospective, multicenter population-based study of SE in Auckland, New Zealand (NZ) over 1 year, with data recorded in the EpiNet database. Focus on treatment patterns and determinants of SE duration and 30-day mortality. The incidence, etiology, ethnic discrepancies, and seizure characteristics of this cohort have been published previously. RESULTS: A total of 365 patients were included in this treatment cohort; 326 patients (89.3%) were brought to hospital because of SE, whereas 39 patients (10.7%) developed SE during a hospital admission for another reason. Overall, 190 (52.1%) had a known history of epilepsy and 254 (70.0%) presented with SE with prominent motor activity. The mean Status Epilepticus Severity Score (STESS) was 2.15 and the mean SE duration of all patients was 44 min. SE self-terminated without any treatment in 84 patients (22.7%). Earlier administration of appropriately dosed benzodiazepine in the pre-hospital setting was a major determinant of SE duration. Univariate analysis demonstrated that mortality was significantly higher in older patients, patients with longer durations of SE, higher STESS, and patients who developed SE in hospital, but these did not maintain significance with multivariate analysis. There was no difference in the performance of the health care system in the treatment of SE across ethnic groups. SIGNIFICANCE: When SE was defined as 10 continuous minutes of seizure, overall mortality was lower than expected and many patients had self-limited presentations for which no treatment was required. Although there were disparities in the incidence of SE across ethnic groups there was no difference in treatment or outcome. The finding highlights the benefit of a health care system designed to deliver universal health care.
In the structure of the title compound, C22H22N4O4·C3H7NO·H2O, the entire tricyclic system is approximately planar except for the carbon atom bearing the two methyl groups; the meth-oxy-phenyl ring is approximately perpendicular to the tricycle. All seven potential hydrogen-bond donors take part in classical hydrogen bonds. The main mol-ecule and the DMF combine to form broad ribbons parallel to the a axis and roughly parallel to the ab plane; the water mol-ecules connect the residues in the third dimension.
The structures of ten phosphane chalcogenide complexes of gold(III) halides, with general formula R 1 3-n R 2 nPEAuX 3 (R 1 = t-butyl; R 2 = i-propyl; n = 0 to 3; E = S or Se; X = Cl or Br) are presented. The eight possible chlorido derivatives are: 9a, n = 3, E = S; 10a, n = 2, E = S; 11a, n = 1, E = S; 12a, n = 0, E = S; 13a, n = 3, E = Se; 14a, n = 2, E = Se; 15a, n = 1, E = Se; and 16a, n = 0, E = Se, and the corresponding bromido derivatives are 9b-16b in the same order. Structures were obtained for 9a, 10a (and a second polymorph 10aa), 11a (and its deutero-chloro-form monosolvate 11aa), 12a (as its di-chloro-methane monosolvate), 14a, 15a (as its deutero-chloro-form monosolvate 15aa, in which the solvent mol-ecule is disordered over two positions), 9b, 11b, 13b and 15b. The structures of 11a, 15a, 11b and 15b form an isotypic set, and those of compounds 10aa and 14a form an isotypic pair. All structures have Z' = 1. The gold(III) centres show square-planar coordination geometry and the chalcogenide atoms show approximately tetra-hedral angles (except for the very wide angle in 12a, probably associated with the bulky t-butyl groups). The bond lengths at the gold atoms are lengthened with respect to the known gold(I) derivatives, and demonstrate a considerable trans influence of S and Se donor atoms on a trans Au-Cl bond. Each compound with an isopropyl group shows a short intra-molecular contact of the type C-Hmethineâ¯Xcis; these may be regarded as intra-molecular 'weak' hydrogen bonds, and they determine the orientation of the AuX 3 groups. The mol-ecular packing is analysed in terms of various short contacts such as weak hydrogen bonds C-Hâ¯X and contacts between the heavier atoms, such as Xâ¯X (9a, 10aa, 11aa, 15aa and 9b), Sâ¯S (10aa, 11a and 12a) and Sâ¯Cl (10a). The packing of the polymorphs 10a and 10aa is thus quite different. The solvent mol-ecules take part in C-Hâ¯Cl hydrogen bonds; for 15aa, a disordered solvent region at z ≃ 0 is observed. Structure 13b involves unusual inversion-symmetric dimers with Seâ¯Au and Seâ¯Br contacts, further connected by Brâ¯Br contacts.
A convergent route toward nitrogen-bridged BODIPY oligomers has been developed. The synthetic key step is a Buchwald-Hartwig cross-coupling reaction of an α-amino-BODIPY and the respective halide. Not only does the selective synthesis provide control of the oligomer size, but the facile preparative procedure also enables easy access to these types of dyes. Furthermore, functionalized examples were accessible via brominated derivatives.
Mechanical load is a potent regulator of cardiac structure and function. Although high workload during heart failure is associated with disruption of cardiomyocyte t-tubules and Ca2+ homeostasis, it remains unclear whether changes in preload and afterload may promote adaptive t-tubule remodelling. We examined this issue by first investigating isolated effects of stepwise increases in load in cultured rat papillary muscles. Both preload and afterload increases produced a biphasic response, with the highest t-tubule densities observed at moderate loads, whereas excessively low and high loads resulted in low t-tubule levels. To determine the baseline position of the heart on this bell-shaped curve, mice were subjected to mildly elevated preload or afterload (1 week of aortic shunt or banding). Both interventions resulted in compensated cardiac function linked to increased t-tubule density, consistent with ascension up the rising limb of the curve. Similar t-tubule proliferation was observed in human patients with moderately increased preload or afterload (mitral valve regurgitation, aortic stenosis). T-tubule growth was associated with larger Ca2+ transients, linked to upregulation of L-type Ca2+ channels, Na+-Ca2+ exchanger, mechanosensors and regulators of t-tubule structure. By contrast, marked elevation of cardiac load in rodents and patients advanced the heart down the declining limb of the t-tubule-load relationship. This bell-shaped relationship was lost in the absence of electrical stimulation, indicating a key role of systolic stress in controlling t-tubule plasticity. In conclusion, modest augmentation of workload promotes compensatory increases in t-tubule density and Ca2+ cycling, whereas this adaptation is reversed in overloaded hearts during heart failure progression. KEY POINTS: Excised papillary muscle experiments demonstrated a bell-shaped relationship between cardiomyocyte t-tubule density and workload (preload or afterload), which was only present when muscles were electrically stimulated. The in vivo heart at baseline is positioned on the rising phase of this curve because moderate increases in preload (mice with brief aortic shunt surgery, patients with mitral valve regurgitation) resulted in t-tubule growth. Moderate increases in afterload (mice and patients with mild aortic banding/stenosis) similarly increased t-tubule density. T-tubule proliferation was associated with larger Ca2+ transients, with upregulation of the L-type Ca2+ channel, Na+-Ca2+ exchanger, mechanosensors and regulators of t-tubule structure. By contrast, marked elevation of cardiac load in rodents and patients placed the heart on the declining phase of the t-tubule-load relationship, promoting heart failure progression. The dependence of t-tubule structure on preload and afterload thus enables both compensatory and maladaptive remodelling, in rodents and humans.
The antibacterial activity of silver species is well-established; however, their mechanism of action has not been adequately explored. Furthermore, issues of low-molecular silver compounds with cytotoxicity, stability, and solubility hamper their progress to drug leads. We have investigated silver N-heterocyclic carbene (NHC) halido complexes [(NHC)AgX, X = Cl, Br, and I] as a promising new type of antibacterial silver organometallics. Spectroscopic studies and conductometry established a higher stability for the complexes with iodide ligands, and nephelometry indicated that the complexes could be administered in solutions with physiological chloride levels. The complexes showed a broad spectrum of strong activity against pathogenic Gram-negative bacteria. However, there was no significant activity against Gram-positive strains. Further studies clarified that tryptone and yeast extract, as components of the culture media, were responsible for this lack of activity. The reduction of biofilm formation and a strong inhibition of both glutathione and thioredoxin reductases with IC50 values in the nanomolar range were confirmed for selected compounds. In addition to their improved physicochemical properties, the compounds with iodide ligands did not display cytotoxic effects, unlike the other silver complexes. In summary, silver NHC complexes with iodide secondary ligands represent a useful scaffold for nontoxic silver organometallics with improved physicochemical properties and a distinct mechanism of action that is based on inhibition of thioredoxin and glutathione reductases.
Anti-Bacterial Agents , Glutathione Reductase , Gram-Negative Bacteria , Microbial Sensitivity Tests , Silver , Thioredoxin-Disulfide Reductase , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Silver/chemistry , Silver/pharmacology , Thioredoxin-Disulfide Reductase/antagonists & inhibitors , Glutathione Reductase/antagonists & inhibitors , Glutathione Reductase/metabolism , Gram-Negative Bacteria/drug effects , Humans , Biofilms/drug effects , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Thioredoxins , Gram-Positive Bacteria/drug effects , Methane/analogs & derivatives , Methane/chemistry , Methane/pharmacology
BACKGROUND: Schools in the United Kingdom and elsewhere are expected to protect and promote pupil mental health. However, many school staff members do not feel confident in identifying and responding to pupil mental health difficulties and report wanting additional training in this area. OBJECTIVE: We aimed to explore the feasibility of Kognito's At-Risk for Elementary School Educators, a brief, interactive web-based training program that uses a simulation-based approach to improve school staff's knowledge and skills in supporting pupil mental health. METHODS: We conducted a mixed methods, nonrandomized feasibility study of At-Risk for Elementary School Educators in 6 UK primary schools. Our outcomes were (1) school staff's self-efficacy and preparedness to identify and respond to pupil mental health difficulties, (2) school staff's identification of mental health difficulties and increased risk of mental health difficulties, (3) mental health support for identified pupils (including conversations about concerns, documentation of concerns, in-class and in-school support, and referral and access to specialist mental health services), and (4) the acceptability and practicality of the training. We assessed these outcomes using a series of questionnaires completed at baseline (T1), 1 week after the training (T2), and 3 months after the training (T3), as well as semistructured qualitative interviews. Following guidance for feasibility studies, we assessed quantitative outcomes across time points by comparing medians and IQRs and analyzed qualitative data using reflexive thematic analysis. RESULTS: A total of 108 teachers and teaching assistants (TAs) completed T1 questionnaires, 89 (82.4%) completed T2 questionnaires, and 70 (64.8%) completed T3 questionnaires; 54 (50%) completed all 3. Eight school staff members, including teachers, TAs, mental health leads, and senior leaders, participated in the interviews. School staff reported greater confidence and preparedness in identifying and responding to mental health difficulties after completing the training. The proportion of pupils whom they identified as having mental health difficulties or increased risk declined slightly over time (medianT1=10%; medianT2=10%; medianT3=7.4%), but findings suggested a slight increase in accuracy compared with a validated screening measure (the Strengths and Difficulties Questionnaire). In-school mental health support outcomes for identified pupils improved after the training, with increases in formal documentation and communication of concerns as well as provision of in-class and in-school support. Referrals and access to external mental health services remained constant. The qualitative findings indicated that school staff perceived the training as useful, practical, and acceptable. CONCLUSIONS: The findings suggest that brief, interactive web-based training programs such as At-Risk for Elementary School Educators are a feasible means to improve the identification of and response to mental health difficulties in UK primary schools. Such training may help address the high prevalence of mental health difficulties in this age group by helping facilitate access to care and support.
Internet , Mental Health , Humans , United Kingdom , Male , Female , Feasibility Studies , Adult , Surveys and Questionnaires , Child , School Teachers/psychology , Schools
BACKGROUND: Persistent opioid use (POU) is common after surgery and is associated with an increased risk of mortality and morbidity. There have been no population-based studies exploring POU in opioid-naïve surgical patients in New Zealand (NZ). This study aimed to determine the incidence and risk factors for POU in opioid-naïve patients undergoing surgery in all NZ hospitals. METHOD: We included all opioid-naïve patients who underwent surgery without a concomitant trauma diagnosis and received opioids after discharge from any NZ hospital between January 2007 and December 2019. Patients were considered opioid naïve if no opioids had been dispensed to them or if they did not have a prior diagnosis of an opioid-use disorder up to 365 days preceding the index date. The primary outcome was the incidence of POU, defined a priori as opioid use after discharge between 91 and 365 days. We used a multivariable logistic regression to identify risk factors for POU. RESULTS: We identified 1789,407 patients undergoing surgery with no concomitant diagnosis of trauma; 377,144 (21.1%) were dispensed opioids and 260,726 patients were eligible and included in the analysis. Of those included in the final sample, 23,656 (9.1%; 95% confidence interval [CI], 9.0%-9.2%) developed POU. Risk factors related to how opioids were prescribed included: changing to different opioid(s) after discharge (adjusted odds ratio [aOR], 3.21; 95% CI, 3.04-3.38), receiving multiple opioids on discharge (aOR, 1.37; 95% CI, 1.29-1.45), and higher total oral morphine equivalents (>400 mg) (aOR, 1.23; 95% CI, 1.23-1.45). Conversely, patients who were coprescribed nonopioid analgesics on discharge had lower odds of POU (aOR, 0.91; 95% CI, 0.87-0.95). Only small differences were observed between different ethnicities. Other risk factors associated with increased risk of POU included undergoing neurosurgery (aOR, 2.02; 95% CI, 1.83-2.24), higher comorbidity burden (aOR, 1.90; 95% CI, 1.75-2.07), preoperative nonopioid analgesic use (aOR, 1.65; 95% CI, 1.60-1.71), smoking (aOR, 1.44; 95% CI, 1.35-1.54), and preoperative hypnotics use (aOR, 1.35; 95% CI, 1.28-1.42). CONCLUSIONS: Approximately 1 in 11 opioid-naïve patients who were dispensed opioids on surgical discharge, developed POU. Potentially modifiable risk factors for POU, related to how opioids were prescribed included changing opioids after discharge, receiving multiple opioids, and higher total dose of opioids given on discharge. Clinicians should discuss the possibility of developing POU with patients before and after surgery and consider potentially modifiable risk factors for POU when prescribing analgesia on discharge after surgery.
In the title compound, C12H11N3OS, the inter-planar angle between the pyrazole and benzo-thia-zole rings is 3.31â (7)°. In the three-dimensional mol-ecular packing, the carbonyl oxygen acts as acceptor to four C-H donors (with one Hâ¯O as short as 2.25â Å), while one methyl hydrogen is part of the three-centre system Hâ¯(S, O). A double layer structure parallel to (01) can be recognized as a subsection of the packing.
In the structure of the title compound, C19H19N3O5S·C4H8O2, the two independent dioxane mol-ecules each display inversion symmetry. The pyrazole ring is approximately parallel to the aromatic ring of the oxy-ethanone group and approximately perpendicular to the tolyl ring of the sulfonyl substituent. An extensive system of classical and 'weak' hydrogen bonds connects the residues to form a layer structure parallel to (201), within which dimeric subunits are conspicuous; neighbouring layers are connected by classical hydrogen bonds to dioxanes and by 'weak' hydrogen bonds from Htol-yl donors.
The structures of 16 phosphane chalcogenide complexes of gold(I) halides, with the general formula R 1 3- nR 2 nPEAuX (R 1 = t-butyl; R 2 = isopropyl; n = 0 to 3; E = S or Se; X = Cl, Br or I), are presented. The eight possible chlorido derivatives are: 1a, n = 3, E = S; 2a, n = 2, E = S; 3a, n = 1, E = S; 4a, n = 0, E = S; 5a, n = 3, E = Se; 6a, n = 2, E = Se; 7a, n = 1, E = Se; and 8a, n = 0, E = Se, and the corresponding bromido derivatives are 1b-8b in the same order. However, 2a and 2b were badly disordered and 8a was not obtained. The iodido derivatives are 2c, 6c and 7c (numbered as for the series a and b). All structures are solvent-free and all have Z' = 1 except for 6b and 6c (Z' = 2). All mol-ecules show the expected linear geometry at gold and approximately tetra-hedral angles P-E-Au. The presence of bulky ligands forces some short intra-molecular contacts, in particular Hâ¯Au and Hâ¯E. The Au-E bond lengths have a slight but consistent tendency to be longer when trans to a softer X ligand, and vice versa. The five compounds 1a, 5a, 6a, 1b and 5b form an isotypic set, despite the different alkyl groups in 6a. Compounds 3a/3b, 4b/8b and 6b/6c form isotypic pairs. The crystal packing can be analysed in terms of various types of secondary inter-actions, of which the most frequent are 'weak' hydrogen bonds from methine hydrogen atoms to the halogenido ligands. For the structure type 1a, Hâ¯X and Hâ¯E contacts combine to form a layer structure. For 3a/3b, the packing is almost featureless, but can be described in terms of a double-layer structure involving borderline Hâ¯Cl/Br and Hâ¯S contacts. In 4a and 4b/8b, which lack methine groups, Cmeth-yl-Hâ¯X contacts combine to form layer structures. In 7a/7b, short C-Hâ¯X inter-actions form chains of mol-ecules that are further linked by association of short Auâ¯Se contacts to form a layer structure. The packing of compound 6b/6c can conveniently be analysed for each independent mol-ecule separately, because they occupy different regions of the cell. Mol-ecule 1 forms chains in which the mol-ecules are linked by a Cmethineâ¯Au contact. The mol-ecules 2 associate via a short Seâ¯Se contact and a short Hâ¯X contact to form a layer structure. The packing of compound 2c can be described in terms of two short Cmethine-Hâ¯I contacts, which combine to form a corrugated ribbon structure. Compound 7c is the only compound in this paper to feature Auâ¯Au contacts, which lead to twofold-symmetric dimers. Apart from this, the packing is almost featureless, consisting of layers with only translation symmetry except for two very borderline Auâ¯H contacts.
The apolipoprotein E É4 allele is the primary genetic risk factor for the sporadic type of Alzheimer's disease. However, the mechanisms by which apolipoprotein E É4 are associated with neurodegeneration are still poorly understood. We applied the Neurite Orientation Dispersion Model to characterize the effects of apolipoprotein É4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Data from 1954 participants were included from the PREVENT-Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non-carriers and 757 apolipoprotein E É4 carriers). Structural MRI datasets were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index maps from diffusion MRI datasets. Primary analyses were focused on (i) the main effects of apolipoprotein E É4, and (ii) the interactions of apolipoprotein E É4 with age and education on lobar and vertex-wise Orientation Dispersion Index and implemented using Permutation Analysis of Linear Models. There were apolipoprotein E É4 × age interactions in the temporo-parietal and frontal lobes, indicating steeper age-dependent Orientation Dispersion Index changes in apolipoprotein E É4 carriers. Steeper age-related Orientation Dispersion Index declines were observed among apolipoprotein E É4 carriers with lower years of education. We demonstrated that apolipoprotein E É4 worsened age-related Orientation Dispersion Index decreases in brain regions typically associated with atrophy patterns of Alzheimer's disease. This finding also suggests that apolipoprotein E É4 may hasten the onset age of dementia by accelerating age-dependent reductions in cortical Orientation Dispersion Index.
The RING E3 ubiquitin ligase UHRF1 is an established cofactor for DNA methylation inheritance. Nucleosomal engagement through histone and DNA interactions directs UHRF1 ubiquitin ligase activity toward lysines on histone H3 tails, creating binding sites for DNMT1 through ubiquitin interacting motifs (UIM1 and UIM2). Here, we profile contributions of UHRF1 and DNMT1 to genome-wide DNA methylation inheritance and dissect specific roles for ubiquitin signaling in this process. We reveal DNA methylation maintenance at low-density CpGs is vulnerable to disruption of UHRF1 ubiquitin ligase activity and DNMT1 ubiquitin reading activity through UIM1. Hypomethylation of low-density CpGs in this manner induces formation of partially methylated domains (PMD), a methylation signature observed across human cancers. Furthermore, disrupting DNMT1 UIM2 function abolishes DNA methylation maintenance. Collectively, we show DNMT1-dependent DNA methylation inheritance is a ubiquitin-regulated process and suggest a disrupted UHRF1-DNMT1 ubiquitin signaling axis contributes to the development of PMDs in human cancers.
