Suicide Related Phenotypes in a Bipolar Sample:Genetic Underpinnings

Suicide in Bipolar Disorder (BD) is a relevant clinical concern. Genetics may shape the individual risk for suicide behavior in BD, together with known clinical factors. The lack of consistent replication in BD may be associated with its multigenetic component. In the present contribution we analyzed a sample of BD individuals (from STEP-BD database) to identify the genetic variants potentially associated with three different suicide-related phenotypes: (1) a feeling that the life was not worth living; (2) fantasies about committing a violent suicide; (3) previous attempted suicide. The sample under analysis included 1115 BD individuals. None of the SNPs reached genome-wide significance. However, a trend of association was evidenced for rs2767403, an intron variant of AOPEP gene, in association with phenotype #1 (p = 5.977 × 10−6). The molecular pathway analysis showed a significant enrichment in all the investigated phenotypes on pathways related to post synaptic signaling, neurotransmission and neurodevelopment. Further, NOTCH signaling or the γ-aminobutyric acid (GABA)-ergic signaling were found to be associated with specific suicide-related phenotypes. The present investigation contributes to the hypothesis that the genetic architecture of suicide behaviors in BD is related to alteration of entire pathways rather than single genes. In particular, our molecular pathway analysis points on some specific molecular events that could be the focus of further research in this field

Assessing crystallisation kinetics of Zr metal-organic frameworks through turbidity measurements to inform rapid microwave-assisted synthesis

Controlling the crystallisation of metal‐organic frameworks (MOFs), network solids of metal ions or clusters connected by organic ligands, is often hindered by the significant number of synthetic variables inherent to their synthesis. Coordination modulation, the addition of monotopic competing ligands to solvothermal syntheses, can allow tuning of physical properties (particle size, porosity, surface chemistry), enhance crystallinity, and select desired phases, by modifying the kinetics of self‐assembly, but its mechanism(s) are poorly understood. Herein, we use turbidity measurements to assess the effects of modulation on the solvothermal synthesis of the prototypical Zr terephthalate MOF UiO‐66 and apply the knowledge gained to its rapid microwave synthesis. The studied experimental parameters ‐ temperature, reagent concentration, reagent aging, metal precursor, water content, and modulator addition ‐ all influence the time taken for onset of nucleation, and subsequently allow microwave synthesis of UiO‐66 in as little as one minute. The simple, low cost turbidity measurements align closely with previously reported in situ synchrotron X‐ray diffraction studies, proving their simplicity and utility for probing the nucleation of complex materials while offering significant insights to the synthetic chemist

Stargardt Phenotype Associated With Two ELOVL4 Promoter Variants and ELOVL4 Downregulation: New Possible Perspective to Etiopathogenesis?

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NGAL as an early biomarker of kidney disease in Joubert syndrome: three brothers compared.

Joubert syndrome (JBTS) is a rare autosomal recessive disorder with an underestimated prevalence due to lack of recognition of clinical signs or failure to diagnose this pathology. JBTS is clinically heterogeneous, and it is characterized by a multiple organ involvement predominantly due to the requirement for Joubert gene function in several tissues. Renal disease affects approximately 30% of patients with JBTS, presenting itself in most cases as nephronophthisis (NPHP), a structural tubulo-interstitial disorder characterized by thickened basal membrane of the tubular epithelium and progressive interstitial fibrosis, associated with cysts at the cortico-medullary junction. We propose three cases concerning three patients with JBTS having different years of illness and degrees of renal impairment, evaluating the parameters of renal function at the time of genetic diagnosis and seen after a follow-up of 7 years. We measured neutrophil gelatinase-associated lipocalin (NGAL), considered as an excellent predictor of kidney injury, to evaluate whether this biomarker might be an early biomarker for JBTS-related kidney disease. NGAL was high in all three cases, but with different levels, indicating a tubular suffering typical of this syndrome, with dissimilar severity in the analyzed subjects. NGAL could represent an early indicator of renal damage useful to start an intensive nephrologic follow-up

Rapid and scale-independent microfluidic manufacture of liposomes entrapping protein incorporating in-line purification and at-line size monitoring

Within this paper we present work that has the ability to de-risk the translation of liposomes from bench to the clinic. We have used microfluidics for the rapid and scale-independent manufacture of liposomes and have incorporated in-line purification and at-line monitoring of particle size. Using this process, we have manufactured a range of neutral and anionic liposomes incorporating protein. Factors investigated include the microfluidics operating parameters (flow rate ratio (FRR) and total flow rate (TFR)) and the liposome formulation. From these studies, we demonstrate that FRR is a key factor influencing liposome size, protein loading and release profiles. The liposome formulations produced by microfluidics offer high protein loading (20–35%) compared to production by sonication or extrusion (<5%). This high loading achieved by microfluidics results from the manufacturing process and is independent of lipid selection and concentration across the range tested. Using in-line purification and at-line size monitoring, we outline the normal operating range for effective production of size controlled (60–100 nm), homogenous (PDI <0.2) high load liposomes. This easy microfluidic process provides a translational manufacturing pathway for liposomes in a wide-range of applications

Measuring secondary nucleation through single crystal seeding

This article presents a novel assessment method for secondary nucleation rates using a well-controlled, small scale seeding procedure. The procedure comprises the seeding of a well-monitored, stirred, supersaturated solution by a carefully selected single crystal under conditions at which spontaneous nucleation does not occur. The determined number of particles in time were translated to a suspension density using a calibration performed with monodisperse polymer spheres. The increasing crystal suspension density in time subsequently allowed the determination of the secondary nucleation rate under very specific conditions of supersaturation and temperature. The secondary nucleation rate was measured as a function of seed crystal size and supersaturation. It was observed that the time elapsed between the moment a single seed crystal is added and the moment the suspension density started to increase is larger when the seeded crystals are smaller and the supersaturation is lower. A systematic study of secondary nucleation at different supersaturations led to the determination of a supersaturation threshold for secondary nucleation, which could be used in industrial crystallization process design to identify process conditions with the right secondary nucleation rate behavior

Bioinspired silica as drug delivery systems and their biocompatibility

Silica nanoparticles have been shown to have great potential as drug delivery systems (DDS), however, their fabrication often involves harsh chemicals and energy intensive laborious methods. This work details the employment of a bioinspired "green" method for the controlled synthesis of silica, use of the products to entrap and release drug molecules and their cytotoxicity in order to develop novel DDS. Bioinspired silica synthesis occurs at pH 7, room temperature and in less than 5 minutes, resulting in a rapid, cheaper and greener route. Drugs were loaded into silica during the silica formation, thus allowing a one step and one pot method for simultaneous silica synthesis and drug loading. We established that the drug release profile can be modulated by synthetic parameters, which can allow design of tailored DDS. A systematic investigation using a two level factorial design was adopted in order to identify the key synthetic parameters and quantify their effects on silica formation, drug loading and drug release. The observation that these new DDS are considerably less cytotoxic than their current counterparts, and exhibit additional benefits such as green synthesis and ease of functionalization, strengthens the argument for their future use in DDS and other biomedical applications. © 2014 the Partner Organisations

On the aggregation and nucleation mechanism of the monoclonal antibody anti-CD20 near liquid-liquid phase separation (LLPS)

The crystallization of Anti-CD20, a full-length monoclonal antibody, has been studied in the PEG400/Na2SO4/Water system near Liquid-Liquid Phase Separation (LLPS) conditions by both sitting-drop vapour diffusion and batch methods. In order to understand the Anti-CD20 crystallization propensity in the solvent system of different compositions, we investigated some measurable parameters, normally used to assess protein conformational and colloidal stability in solution, with the aim to understand the aggregation mechanism of this complex biomacromolecule. We propose that under crystallization conditions a minor population of specifically aggregated protein molecules are present. While this minor species hardly contributes to the measured average solution behaviour, it induces and promotes crystal formation. The existence of this minor species is the result of the LLPS occurring concomitantly under crystallization conditions

Protein carbonyl group content in patients affected by familiar chronic nail candidiasis.

Familiar chronic nail candidiasis (FCNC) is a rare disorder characterized by early-onset infections caused by different species of Candida, restricted to the nail of the hands and feet, and associated with a low serum concentration of intercellular adhesion molecule 1. Host defense mechanisms against candidiasis require the cooperation of many immune cells through several candidacidal mechanisms, including oxygen-dependent killing mechanisms, mediated by a superoxide anion radical myeloperoxidase--H2O2--halide system, and reactive nitrogen intermediates. We analyzed protein carbonyl groups (considered a useful marker of oxidative stress) in the serum of patients belonging to a five-generation Italian family with an isolated form of FCNC. Serum protein carbonyl groups in FCNC patients were significantly lower than those measured in healthy donors. Also, if this hypothesis is merely speculative, we could suggest that the decreased circulating level of protein carbonyl groups in these patients is not a marker of a lower oxidative stress condition, but might be linked to a lower protease activity

Characterization of (0-3) piezocomposite materials for transducer applications

In this study, we have developed and characterized two different (0-3) piezoelectric composite materials with potential to be used in sensing applications. The composite materials were made using Polydimethylsiloxane (PDMS) as the polymer matrix with Barium Titanate (BaTiO3), and Lead Zirconate Titanate (PZT51) as the dielectric fillers. Thin film samples of the (0-3) piezocomposites were prepared using a solution mixing and spin coating method to produce composites with (0-3) connectivity pattern and layer thickness of mathbf{100} mumathbf{m}, The microstructure of the piezocomposites were analyzed using a scanning electron microscope to determine the connectivity structure and homogeneity of the piezocomposites. The mechanical properties of the composites were determined using the method of Oliver and Pharr. FTIR analysis was used to determine the effects of the fillers on the structure of the piezocomposite. The average piezoelectric pmb{d}{mathit{33}} coefficient of the piezocomposites were also measured using the laser vibrometer technique and determined to be 30 pm/V for the piezocomposite consisting of Barium Titanate (BaTiO3) and 32 pm/V for the piezocomposite consisting of Lead Zirconate Titanate (PZT51)