The Reverse Brazil Nut Problem: Competition between Percolation and Condensation

In the Brazil nut problem (BNP), hard spheres with larger diameters rise to the top. There are various explanations (percolation, reorganization, convection), but a broad understanding or control of this effect is by no means acheived. A theory is presented for the crossover from the BNP to the reverse Brazil nut problem (RBNP) based on a competition between the percolation effect and the condensation of hard spheres. The crossover condition is determined, and the theoretical predictions are compared to Molecular Dynamics simulations in two and three dimensions.Comment: 9 pages which includes 7 figure

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

A horizontal Brazil-nut effect and its reverse

Transport effects in a monolayer consisting of a binary granular mixture, confined in a horizontally vibrating circular dish, are studied experimentally and compared with a reduced theoretical model. Depending on the ratio of the particles' material density and size, migration of the larger particles occurs either towards the boundary or to the center of the circular container. These directed motions show similarities to the Brazil-nut effect and its reverse form

Novel ion exchange resin-based combination drug-delivery system for treatment of gastro esophageal reflux diseases

The present study involves preparation and characterization of a combination tablet of ranitidine in immediate release form and domperidone in sustained release form, using ion exchange resins. Ranitidine lowers acid secretion, while domperidone release over a prolonged period improves gastric motility thus justifying this combination in gastro esophageal reflux diseases (GERD) and ensuring patient compliance. Drug loading was carried out by batch method & resinates were characterized using FTIR, XRPD. Resinates were formulated as a combination tablet and evaluated for tablet properties & in vitro drug release. Resinates provided sustained release of domperidone and immediate release of ranitidine. IR and X-ray studies indicate complexation of drug and resin along with monomolecular distribution of drugs in amorphous form in the resin matrix. The tablets of resinate combination showed good tablet properties. In-vitro drug release gave desired release profiles and ex-vivo drug absorption studies carried out by placing everted rat intestine in dissolution medium indicated statistically significant similarity in absorption from test and marketed formulation. The novelty of this study is that the retardation in release of domperidone from resinates is achieved by presence of weak resin in the formulation.<br>O presente estudo envolve a preparação e a caracterização de associação do comprimido de ranitidina de liberação imediata e domperidona de liberação prolongada, utilizando resinas de troca iônica. A ranitidina diminui a secreção ácida, enquanto a liberação prolongada de domperidona melhora a motilidade gástica, justificando, dessa forma, a associação em doenças de refluxo gastroesofágico (DRGE) e garantindo a adesão do paciente. A carga de fármaco foi efetuada pelo método em batelada e os resinatos, caracterizados utilizando-se FTIR e XRPD. Os resinatos foram formulados como comprimido da associação e avaliados com relação às propriedades dos comprimidos e liberação do fármaco in vitro. Os resinatos proporcionaram a liberação prolongada da domperidona e a liberação imediata da ranitidina. IV e estudos de difração de raios X indicaram a complexação do fármaco e da resina junto com a distribuição monomolecular dos fármacos, em estado amorfo, na matriz da resina. Os comprimidos da associação do resinato apresentaram boas propriedades. Obtiveram-se os perfis de liberação in vitro e os estudos de absorção dos fármacos ex vivo realizados com intestino de rato em meio de dissolução indicaram semelhança significativa na absorção entre as formulações teste e comercializada. A inovação do trabalho é que o retardamento da liberação da domperidona dos resinatos é atingido pela presença de resina fraca na formulação