We have developed a highly efficient microfluidic sample preconcentration device based on the electrokinetic trapping mechanism enabled by nanofluidic filters. The device, fabricated by standard photolithography and etching techniques, generates an extended space charge region within a microchannel, which was used to both collect and trap the molecules efficiently. The electrokinetic trapping and collection can be maintained for several hours, and concentration factors as high as 10(6)-10(8) have been demonstrated. This device could be useful in various bioanalysis microsystems, due to its simplicity, performance, robustness, and integrabilty to other separation and detection systems.

73Over 100 genetic loci harbor schizophrenia associated variants, yet how these common 74 variants confer risk is uncertain. The CommonMind Consortium has sequenced dorsolateral 75 prefrontal cortex RNA from schizophrenia cases (n=258) and control subjects (n=279), creating 76 the largest publicly available resource to date of gene expression and its genetic regulation; ~5 77 times larger than the latest release of GTEx. Using this resource, we find that ~20% of the 78 schizophrenia risk loci have common variants that could explain regulation of brain gene 79 expression. In five loci, these variants modulate expression of a single gene: FURIN, TSNARE1, 80 CNTN4, CLCN3 or SNAP91. Experimentally altered expression of three of them, FURIN, 81 TSNARE1, and CNTN4, perturbs the proliferation and apoptotic index of neural progenitors and 82 leads to neuroanatomical deficits in zebrafish. Furthermore, shRNA mediated knock-down of 83 FURIN in neural progenitor cells derived from human induced pluripotent stem cells produces 84 abnormal neural migration. Although 4.2% of genes (N = 693) display significant differential 85 expression between cases and controls, 44% show some evidence for differential expression. 86All fold changes are ≤ 1.33, and an independent cohort yields similar differential expression for 87 these 693 genes (r = 0.58). These findings are consistent with schizophrenia being highly 88 polygenic, as has been reported in investigations of common and rare genetic variation. Co-89 expression analyses identify a gene module that shows enrichment for genetic associations and 90 is thus relevant for schizophrenia. Taken together, these results pave the way for mechanistic 91 interpretations of genetic liability for schizophrenia and other brain diseases. 4The human brain is complicated and not well understood. Seemingly straightforward 93 fundamental information such as which genes are expressed therein and what functions they 94 perform are only partially characterized. To overcome these obstacles, we established the 95 CommonMind Consortium (CMC; www.synpase.org/CMC), a public-private partnership to 96 generate functional genomic data in brain samples obtained from autopsies of cases with and 97 without severe psychiatric disorders. The CMC is the largest existing collection of collaborating 98 brain banks and includes over 1,150 samples. A wide spectrum of data is being generated on 99 these samples including regional gene expression, epigenomics (cell-type specific histone 100 modifications and open chromatin), whole genome sequencing, and somatic mosaicism. 101 102 Schizophrenia (SCZ), affecting roughly 0.7% of adults, is a severe psychiatric disorder 103 characterized by abnormalities in thought and cognition (1). Despite a century of evidence 104 establishing its genetic basis, only recently have specific genetic risk factors been conclusively 105identified, including rare copy number variants (2) and >100 common variants (3). However, 106 there is not a one-to-one Mendelian mapping between these SCZ ris...

A perm-selective nanochannel could initiate concentration polarization near the nanochannel, significantly decreasing (increasing) the ion concentration in the anodic (cathodic) end of the nanochannel. Such strong concentration polarization can be induced even at moderate buffer concentrations because of local ion depletion (therefore thicker local Debye layer) near the nanochannel. In addition, fast fluid vortices were generated at the anodic side of the nanochannel due to the nonequilibrium electro-osmotic flow (EOF), which was at least ∼10X faster than predicted from any equilibrium EOF. This result corroborates the relation among induced EOF, concentration polarization, and limiting-current behavior.Recently, science and engineering of molecular transport within nanofluidic channels, with critical dimensions of 10-100 nm, have drawn a lot of attention with the advances in microand nanofabrication techniques [1]. In addition to various applications [2,3], nanofluidic channels can be an ideal, well-controlled experimental platform to study nanoscale molecular, fluidic, or ionic transport properties. Recent experiments strongly suggest that nanochannels thinner than ∼50 nm demonstrate unique ion-perm selectivity at low ionic strengths, due to the fact that the Debye layer thickness (λ D ) is non-negligible compared with the channel thickness in these nanochannels [4]. Often, these phenomena are explained as Debye layer overlap, with the ratio between (equilibrium) Debye length and the channel dimension as the critical parameter. While proper in explaining near-equilibrium diffusion process through the nanochannels, this reasoning becomes invalid when the (local) ionic concentrations within the system start to change significantly, which is often the case in electrokinetic driving of nanochannels. More comprehensive models that can account for the change of (local) Debye length are yet to be developed. One of the characteristic behaviors that accompany strong concentration polarization is that local electrokinetic responses can be greatly amplified, especially in the ion-depleted anodic region. The result is typically a circulating, vortexlike flow pattern with a flow speed much higher than typical (equilibrium) electro-osmotic flow (EOF). Such an "induced" or "second-kind" EOF pattern, either in front of electrodes [5] or charge gel [6], has been experimentally observed. Recently, Rubinstein and co-workers suggested that similar nonlinear electrokinetic flow in front of perm-selective membrane is the main factor behind the overlimiting current at high dc bias [7]. However, more detailed study

We use deep sequencing to identify sources of variation in mRNA splicing in the dorsolateral prefrontal cortex (DLFPC) of 450 subjects from two aging cohorts. Hundreds of aberrant pre-mRNA splicing events are reproducibly associated with Alzheimer’s disease. We also generate a catalog of splicing quantitative trait loci (sQTL) effects: splicing of 3,006 genes is influenced by genetic variation. We report that altered splicing is the mechanism for the effects of the PICALM, CLU , and PTK2B susceptibility alleles. Further, we performed a transcriptome-wide association study and identified 21 genes with significant associations to Alzheimer’s disease, many of which are found in known loci, but 8 are in novel loci. This highlights the convergence of old and new Alzheimer’s disease genes in autophagy-lysosomal-related pathways. Overall, this study of the aging brain’s transcriptome provides evidence that dysregulation of mRNA splicing is a feature of Alzheimer’s disease and is, in some cases, genetically driven.

No treatment for frontotemporal dementia (FTD), the second most common early-onset dementia, is available but therapeutics are being investigated to target the two main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hamstrung by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human iPSC-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease sub-types marked by TDP-43 inclusions. Lastly, we validated that truncated STMN2 RNA is elevated in the frontal cortex of a cohort of FTLD-TDP cases but not in controls or cases with progressive supranuclear palsy (PSP), a type of FTLD-tau. Further, in FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.