Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

In vitro effect of glucocorticoids on nasal polyps Efeito in vitro de glicocorticosteróides sobre pólipos nasais

Glucocorticoids are considered the main treatment option for nasal polyps, but their effect is only recently being understood. AIM: To evaluate whether fluticasone propionate (FP) inhibits the inflammatory process induced by TNF-alpha in vitro, and to assess if NF-kappaB is associated to this inhibition. STUDY DESIGN: Experimental in vitro study. MATERIALS AND METHODS: Nasal polyp fibroblasts were cultured during 24 hours. Three different concentrations of FP (1, 10 and 100 nM, added to TNF-alpha) were compared to negative (without additive) and positive (TNF-alpha) controls. Gene expression (RTQ-PCR) and protein concentration (ELISA) of VCAM-1, ICAM-1, eotaxin and RANTES were measured, as well as the nuclear translocation of NF-kappaB. RESULTS: TNF-alpha significantly increased protein concentration and RNA expression of all the studied molecules, as well as the nuclear translocation of NF-kappaB, when compared to the negative control. FP decreased these parameters in a dose-dependent manner, statistically different from positive control up to 100nM. CONCLUSIONS: FP extensively inhibited inflammatory recruiters, at both protein and RNA levels, confirming the ability of glucocorticoids to modulate the inflammatory process in nasal polyps. This inhibition was associated to decreased NF-kappaB nuclear translocation, demonstrating that this is an important mechanism of glucocorticoids action for nasal polyps.<br>Glicocorticoides são considerados a principal opção terapêutica para polipose nasossinusal, mas seus efeitos estão sendo descobertos apenas recentemente. OBJETIVO: Avaliar se proprionato de fluticasona (FP) inibe in vitro o processo inflamatório induzido por TNF-alfa, e se NF-kappaB está associado a esta inibição. FORMA DE ESTUDO: Experimental in vitro. MATERIAIS E MÉTODOS: Fibroblastos de pólipos nasais foram cultivados por 24 horas. Três concentrações diferentes de FP (1, 10 e 100nM, além do TNF-alfa) foram comparados a controles negativo (sem aditivo) e positivo (TNF-alfa). Expressão gênica (RTQ-PCR) concentração proteica (ELISA) de VCAM-1, ICAM-1, eotaxin e RANTES foram medidos, assim como a translocação nuclear de NF-kappaB. RESULTADOS: TNF-alfa aumentou significativamente a concentração proteica e expressão gênica de todas molé¬culas estudadas, assim como a translocação nuclear de NF-kappaB, quando comparado ao controle negativo. O FP diminuiu estes parâmetros numa forma dose-dependente, diferente estatisticamente do controle positivo até 100nM. CONCLUSÕES: O FP extensivamente inibiu os recrutadores inflamatórios, em níveis proteicos e gênicos, confirmando a habilidade dos glicocorticoides em modular o processo inflamatório na polipose nasossinusal. Esta inibição esteve associada à diminuição da translocação nuclear de NF-kappaB, demonstrando que este é um importante mecanismo de ação dos glicocorticoide na polipose nasossinusal

Chemistry of Iridium(I) Cyclooctadiene Compounds with Thiapentadienyl, Sulfinylpentadienyl, and Butadienesulfonyl Ligands

The metathesis reaction of [(η⁴-COD)­Ir­(μ-Cl)]₂ (<b>4</b>) with two equivalents of the sodium thiapentadienide (<b>1Na</b>) or potassium sulfinylpentadienide salt (<b>2K</b>) led to the formation of the corresponding dimers [(η⁴-COD)­Ir­(μ₂-1-2,5-η-CH₂CHCHCHS)]₂ (<b>5</b>) and [(η⁴-COD)­Ir­(μ₂-1-2,5-η-CH₂CHCHCHSO)]₂ (<b>9</b>). The single-crystal analysis of <b>5</b> and <b>9</b> reveals the presence of the thiapentadienyl or sulfinylpentadienyl ligands bridging through the sulfur atoms and the terminal double bonds to both iridium centers. Treatment of <b>5</b> with two equivalents of PMe₃ produces [(η⁴-COD)­Ir­(1-2,5-η-CH₂CHCHCHS)­PMe₃] (<b>6</b>), while compound Ir­(1-2,5-η-CH₂CHCHCHS)­(CO)­(PPh₃)₂ (<b>8</b>) is obtained from reaction of Ir­(CO)­(Cl)­(PPh₃)₂ (<b>7</b>) with potassium thiapentadienide (<b>1K</b>). The ¹H and ¹³C NMR support the preferred U conformation and the same η^2,1-bonding mode of the thiapentadienyl ligand in each case. The reaction of <b>4</b> with butadienesulfinate salts M­[CH₂CHCHCHSO₂] (<b>3M</b>) (M = Li, K) affords the ion-pair complexes [(η⁴-COD)­IrCl­(1-2,5-η-CH₂CHCHCHS­(O₂^–M⁺)] (M = Li, <b>10</b>; M = K, <b>11</b>). Compound (η⁴-COD)­Ir­(μ-Cl)­(1-2-η-S,O-μ-OSOCHCHCHCH₂)­Ir­(η⁴-COD) (<b>12</b>) can be isolated if the reaction of <b>4</b> with <b>3K</b> is carried out at low temperature and after a short period of time in solution. The crystal structure of <b>12</b> shows a dinuclear compound where the butadienesulfonyl is bridging through the S and one of the O atoms to the iridium center. In solution, <b>12</b> dissociates in the presence of coordinating solvents, such as DMSO-<i>d</i>₆ or THF-<i>d</i>₈, while the dinuclear asymmetric structure of <b>12</b> remains in CDCl₃. The series of pentacoordinated Ir­(I) complexes of general formula [(η⁴-COD)­Ir­(1-2,5-η-CH₂CHCHCHSO₂)­L] (L = PMe₃, <b>14</b>; PMe₂Ph, <b>15</b>; PMePh₂, <b>16</b>; PPh₃, <b>17</b>; DMSO, <b>18</b>; and CO, <b>19</b>) can be obtained, under mild conditions, from <b>11</b> and the corresponding ligand L, which shows different σ or π donor–acceptor properties. The disubstituted phosphine derivative [(η⁴-COD)­Ir­(5-η-CH₂CHCHCHSO₂)­(PMe₃)₂] (<b>20</b>) can be prepared directly from <b>14</b> and an excess of PMe₃. A comparative study of these derivatives was carried out through the analysis of the IR, mass spectrometry, and ¹H, ¹³C, and ³¹P NMR spectroscopy, as well as through the crystalline structures of <b>12</b>, <b>14</b>, <b>15</b>, and <b>17</b>–<b>20</b>, and allowed establishing trends among them. The presence of the butadienesulfonyl ligand in complexes <b>14</b>–<b>19</b> induces a total asymmetry that is reflected through the ¹H and ¹³C NMR. The preferred coordination mode (1-2,5-η-) in the butadienesulfonyl ligand for complexes <b>14</b>–<b>19</b> was confirmed. A better synthetic procedure for <b>14</b> is described if [(η⁴-COD)­IrClPMe₃] (<b>21</b>) reacts with <b>3K</b>. In contrast, no synthetic advantage was found in the formation of <b>17</b> or <b>20</b> when [(η⁴-COD)­IrClPPh₃] (<b>22</b>) or [(η⁴-COD)­IrCl­(PMe₃)₂] (<b>23</b>) is used as a precursor. Monitoring reactions through ¹H and ³¹P NMR of <b>11</b>, <b>12</b>, and <b>14</b> in the presence of PMe₃ and <b>23</b> with <b>3K</b> afforded mixtures of compounds, from which an equilibrium in the reaction mixture is proposed

A Mutation in the SH2 Domain of STAT2 Prolongs Tyrosine Phosphorylation of STAT1 and Promotes Type I IFN-induced Apoptosis

Type I interferons (IFN-α/β) induce apoptosis in certain tumor cell lines but not others. Here we describe a mutation in STAT2 that confers an apoptotic effect in tumor cells in response to type I IFNs. This mutation was introduced in a conserved motif, PYTK, located in the STAT SH2 domain, which is shared by STAT1, STAT2, and STAT3. To test whether the tyrosine in this motif might be phosphorylated and affect signaling, Y631 of STAT2 was mutated to phenylalanine (Y631F). Although it was determined that Y631 was not phosphorylated, the Y631F mutation conferred sustained signaling and induction of IFN-stimulated genes. This prolonged IFN response was associated with sustained tyrosine phosphorylation of STAT1 and STAT2 and their mutual association as heterodimers, which resulted from resistance to dephosphorylation by the nuclear tyrosine phosphatase TcPTP. Finally, cells bearing the Y631F mutation in STAT2 underwent apoptosis after IFN-α stimulation compared with wild-type STAT2. Therefore, this mutation reveals that a prolonged response to IFN-α could account for one difference between tumor cell lines that undergo IFN-α–induced apoptosis compared with those that display an antiproliferative response but do not die

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Background: Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. Methods: NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. Findings: Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. Funding: Bayer and Janssen