Annexin A1 Tethers Membrane Contact Sites that Mediate ER to Endosome Cholesterol Transport

Membrane contact sites between the ER and multivesicular endosomes/bodies (MVBs) play important roles in endosome positioning and fission and in neurite outgrowth. ER-MVB contacts additionally function in epidermal growth factor receptor (EGFR) tyrosine kinase downregulation by providing sites where the ER-localized phosphatase, PTP1B, interacts with endocytosed EGFR before the receptor is sorted onto intraluminal vesicles (ILVs). Here we show that these contacts are tethered by annexin A1 and its Ca2+-dependent ligand, S100A11, and form a subpopulation of differentially regulated contact sites between the ER and endocytic organelles. Annexin A1-regulated contacts function in the transfer of ER-derived cholesterol to the MVB when low-density lipoprotein-cholesterol in endosomes is low. This sterol traffic depends on interaction between ER-localized VAP and endosomal oxysterol-binding protein ORP1L, and is required for the formation of ILVs within the MVB and thus for the spatial regulation of EGFR signaling

Iron-Intercalated Zirconium Diselenide Thin Films from the Low-Pressure Chemical Vapor Deposition of [Fe(η⁵-C₅H₄Se)₂Zr(η⁵-C₅H₅)₂]₂

Transition metal chalcogenide thin films of the type FexZrSe2 have applications in electronic devices, but their use is limited by current synthetic techniques. Here, we demonstrate the synthesis and characterization of Fe-intercalated ZrSe2 thin films on quartz substrates using the low-pressure chemical vapor deposition of the single-source precursor [Fe(η5-C5H4Se)2Zr(η5-C5H5)2]2. Powder X-ray diffraction of the film scraping and subsequent Rietveld refinement of the data showed the successful synthesis of the Fe0.14ZrSe2 phase, along with secondary phases of FeSe and ZrO2. Upon intercalation, a small optical band gap enhancement (Eg(direct)opt = 1.72 eV) is detected in comparison with that of the host material

Mineralocorticoid receptor antagonists eplerenone and spironolactone modify adrenal cortex morphology and physiology

Mineralocorticoid receptor antagonists (MRAs) are a class of anti-hypertensive drugs that act by blocking aldosterone action. The aim of this study was to evaluate whether the MRAs spironolactone and eplerenone influence adrenal cortical physiology and morphology. Spontaneous hypertensive rats (SHR, n = 18) and normotensive rats (WKY, n = 18) were randomly exposed to a daily dose of spironolactone (n = 6), eplerenone (n = 6), or no drug (n = 6) over 28 days. After that, aldosterone, corticosterone, and 11-deoxycorticosterone plasma concentrations were quantified. Adrenal glands were subjected to morphological analysis to assess lipid droplets content, capsular width, cell proliferation, and steroidogenic proteins expression. The adrenal cortex in untreated SHR showed higher lipid droplet content as than in WKY. In SHR, MRA treatment was associated with higher circulating aldosterone levels and Ki-67 expression in aldosterone-secreting cells. In WKY, the only difference observed after MRA spironolactone treatment was a narrower capsule. There was no difference in abundance of steroidogenic enzyme between groups. In conclusion, MRAs modify adrenal gland function and morphology in SHR. The effects observed within the adrenal glomerulosa with aldosterone-secreting cell proliferation and higher circulating aldosterone levels suggests that MRA treatment provokes activation of the renin angiotensin system. The prognostic value of hyperaldosteronism secondary to MRAs blockade requires further investigation.Funding: This research was funded by the Associação dos Amigos do Serviço de Endocrinologia do Hospital de São João (2020–2021). Unit for Multidisciplinary Research in Biomedicine (UMIB) is funded by the Foundation for Science and Technology (FCT)-Portugal (UIDB/00215/2020 and UIDP/00215/2020—approval date: 2019)

NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress

Transport of dietary cholesterol from endocytic organelles to the endoplasmic reticulum (ER) is essential for cholesterol homoeostasis, but the mechanism and regulation of this transport remains poorly defined. Membrane contact sites (MCS), microdomains of close membrane apposition, are gaining attention as important platforms for non-vesicular, inter-organellar communication. Here we investigate the impact of ER-endocytic organelle MCS on cholesterol transport. We report a role for Niemann-Pick type C protein 1 (NPC1) in tethering ER-endocytic organelle MCS where it interacts with the ER-localised sterol transport protein Gramd1b to regulate cholesterol egress. We show that artificially tethering MCS rescues the cholesterol accumulation that characterises NPC1-deficient cells, consistent with direct lysosome to ER cholesterol transport across MCS. Finally, we identify an expanded population of lysosome-mitochondria MCS in cells depleted of NPC1 or Gramd1b that is dependent on the late endosomal sterol-binding protein STARD3, likely underlying the mitochondrial cholesterol accumulation in NPC1-deficient cells

Synthesis and characterization of hybrid organic-inorganic materials based on sulphonated polyamideimide and silica

The preparation of hybrid organic–inorganic membrane materials based on a sulphonated polyamideimide resin and silica filler has been studied. The method allows the sol–gel process to proceed in the presence of a high molecular weight polyamideimide, resulting in well dispersed silica nanoparticles (<50 nm) within the polymer matrix with chemical bonding between the organic and inorganic phases. Tetraethoxysilane (TEOS) was used as the silica precursor and the organosilicate networks were bonded to the polymer matrix via a coupling agent aminopropyltriethoxysilane (APTrEOS). The structure and properties of these hybrid materials were characterized via a range of techniques including FTIR, TGA, DSC, SEM and contact angle analysis. It was found that the compatibility between organic and inorganic phases has been greatly enhanced by the incorporation of APTrEOS. The thermal stability and hydrophilic properties of hybrid materials have also been significantly improved

IFNβ Protects Neurons from Damage in a Murine Model of HIV-1 Associated Brain Injury.

Infection with human immunodeficiency virus-1 (HIV-1) causes brain injury. Type I interferons (IFNα/β) are critical mediators of any anti-viral immune response and IFNβ has been implicated in the temporary control of lentiviral infection in the brain. Here we show that transgenic mice expressing HIV-1 envelope glycoprotein 120 in their central nervous system (HIVgp120tg) mount a transient IFNβ response and provide evidence that IFNβ confers neuronal protection against HIVgp120 toxicity. In cerebrocortical cell cultures, neuroprotection by IFNβ against gp120 toxicity is dependent on IFNα receptor 1 (IFNAR1) and the β-chemokine CCL4, as IFNAR1 deficiency and neutralizing antibodies against CCL4, respectively, abolish the neuroprotective effects. We find in vivo that IFNβ mRNA is significantly increased in HIVgp120tg brains at 1.5, but not 3 or 6 months of age. However, a four-week intranasal IFNβ treatment of HIVgp120tg mice starting at 3.5 months of age increases expression of CCL4 and concomitantly protects neuronal dendrites and pre-synaptic terminals in cortex and hippocampus from gp120-induced damage. Moreover, in vivo and in vitro data suggests astrocytes are a major source of IFNβ-induced CCL4. Altogether, our results suggest exogenous IFNβ as a neuroprotective factor that has potential to ameliorate in vivo HIVgp120-induced brain injury

Precursors for Atmospheric Plasma-Enhanced Sintering: Low-Temperature Inkjet Printing of Conductive Copper

Bidentate diamine and amino-alcohol ligands have been used to form solid, water-soluble, and air-stable monomeric copper complexes of the type [Cu(NH2CH2CH(R)Y)2(NO3)2] (1, R=H, Y=NH2; 2, R=H, Y=OH; 3, R=Me, Y=OH). The complexes were characterized by elemental analysis, mass spectrometry, infrared spectroscopy, thermal gravimetric analysis, and single-crystal X-ray diffraction. Irrespective of their decomposition temperature, precursors 1–3 yield highly conductive copper features [1.5×10−6Ω m (±5×10−7Ω m)] upon atmospheric-pressure plasma-enhanced sintering

Accessing new 2D semiconductors with optical band gap: synthesis of iron-intercalated titanium diselenide thin films via LPCVD

Fe-doped TiSe2 thin-films were synthesized via low pressure chemical vapor deposition (LPCVD) of a single source precursor: [Fe(η⁵-C₅H₄Se)₂Ti(η⁵-C₅H₅)₂]₂ (1). Samples were heated at 1000 °C for 1–18 h and cooled to room temperature following two different protocols, which promoted the formation of different phases. The resulting films were analyzed by grazing incidence X-ray diffraction (GIXRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM) and UV/vis spectroscopy. An investigation of the Fe doping limit from a parallel pyrolysis study of FeₓTiSe₂ powders produced in situ during LPCVD depositions has shown an increase in the Fe–TiSe₂–Fe layer width with Fe at% increase. Powders were analyzed using powder X-ray diffraction (PXRD) involving Rietveld refinement and XPS. UV/vis measurements of the semiconducting thin films show a shift in band gap with iron doping from 0.1 eV (TiSe₂) to 1.46 eV (Fe₀.₄₆TiSe₂)

Physiological and Pathological Roles in Human Adrenal of the Glomeruli-Defining Matrix Protein NPNT (Nephronectin)

Primary aldosteronism is a common cause of hypertension, which becomes refractory if undiagnosed, but potentially curable when caused by an aldosterone-producing adenoma (APA). The discovery of somatic mutations and differences in clinical presentations led to recognition of small but common zona glomerulosa (ZG)-like adenomas, distinct from classical large zona fasciculata-like adenomas. The inverse correlation between APA size and aldosterone synthase expression prompted us to undertake a systematic study of genotype-phenotype relationships. After a microarray comparing tumor subtypes, in which NPNT ($\textit{nephronectin}$) was the most highly (>12-fold) upregulated gene in ZG-like APAs, we aimed to determine its role in physiological and pathological aldosterone production. NPNT was identified by immunohistochemistry as a secreted matrix protein expressed exclusively around aldosterone-producing glomeruli in normal adrenal ZG and in aldosterone-dense ZG-like APAs; the highest expression was in ZG-like APAs with gain-of-function $\textit{CTNNB1}$ mutations, whose removal cured hypertension in our patients. NPNT was absent from normal zona fasciculata, zona fasciculata-like APAs, and ZG adjacent to an APA. NPNT production was regulated by canonical Wnt pathway, and $\textit{NPNT}$ overexpression or silencing increased or reduced aldosterone, respectively. NPNT was proadhesive in primary adrenal and APA cells but antiadhesive and antiapoptotic in immortalized adrenocortical cells. The discovery of $\textit{NPNT}$ in the adrenal helped recognition of a common subtype of APAs and a pathway by which Wnt regulates aldosterone production. We propose that this arises through NPNT's binding to cell-surface integrins, stimulating cell-cell contact within glomeruli, which define ZG. Therefore, NPNT or its cognate integrin could present a novel therapeutic target.This research was funded by grants from the National Institute for Health Research (NIHR) Senior Investigator award (NF-SI-0512-10052) to M.J. Brown. A.E.D. Teo is supported by the Agency for Science, Technology and Research (A*STAR) Singapore. This study is also supported by Wellcome Trust Translational Medicine and Therapeutics award to M.J. Brown (085686/Z/08/A). S. Garg is supported by the British Heart Foundation (FS/14/75/31134). J. Zhou is supported by the Cambridge Overseas Trust. Additional support was provided by the NIHR Cambridge Biomedical Research Centre (Cardiovascular and Metabolic, and Human Tissue Bank)

Adjustable Gastric Banding Conversion to One Anastomosis Gastric Bypass: Data Analysis of a Multicenter Database

Introduction: One anastomosis gastric bypass (OAGB) has been proposed as a rescue technique for laparoscopic adjustable gastric banding (LAGB) poor responders. Aim: We sought to analyze, complications, mortality, and medium-term weight loss results after LAGB conversion to OAGB. Methods: Data analysis of an international multicenter database. Results: One hundred eighty-nine LAGB-to-OAGB operations were retrospectively analyzed. Eighty-seven (46.0%) were converted in one stage. Patients operated on in two stages had a higher preoperative body mass index (BMI) (37.9 vs. 41.3 kg/m2, p = 0.0007) and were more likely to have encountered technical complications, such as slippage or erosions (36% vs. 78%, p < 0.0001). Postoperative complications occurred in 4.8% of the patients (4.6% and 4.9% in the one-stage and the two-stage group, respectively). Leak rate, bleeding episodes, and mortality were 2.6%, 0.5%, and 0.5%, respectively. The final BMI was 30.2 at a mean follow-up of 31.4 months. Follow-up at 1, 3, and 5 years was 100%, 88%, and 70%, respectively. Conclusion: Conversion from LAGB to OAGB is safe and effective. The one-stage approach appears to be the preferred option in non-complicate cases, while the two-step approach is mostly done for more complicated cases.info:eu-repo/semantics/publishedVersio