Viral co-infection, autoimmunity, and CSF HIV antibody profiles in HIV central nervous system escape.

Antiretroviral therapy (ART) suppresses plasma and cerebrospinal fluid (CSF) HIV replication. Neurosymptomatic (NS) CSF escape is a rare exception in which CNS HIV replication occurs in the setting of neurologic impairment. The origins of NS escape are not fully understood. We performed a case-control study of asymptomatic (AS) escape and NS escape subjects with HIV-negative subjects as controls in which we investigated differential immunoreactivity to self-antigens in the CSF of NS escape by employing neuroanatomic CSF immunostaining and massively multiplexed self-antigen serology (PhIP-Seq). Additionally, we utilized pan-viral serology (VirScan) to deeply profile the CSF anti-viral antibody response and metagenomic next-generation sequencing (mNGS) for pathogen detection. We detected Epstein-Barr virus (EBV) DNA more frequently in the CSF of NS escape subjects than in AS escape subjects. Based on immunostaining and PhIP-Seq, there was evidence for increased immunoreactivity against self-antigens in NS escape CSF. Finally, VirScan revealed several immunodominant epitopes that map to the HIV envelope and gag proteins in the CSF of AS and NS escape subjects. Whether these additional inflammatory markers are byproducts of an HIV-driven process or whether they independently contribute to the neuropathogenesis of NS escape will require further study.

High and low density patches in simulated liquid water.

We present insights into the nature of structural heterogeneities in liquid water by characterizing the empty space within the hydrogen bond network. Using molecular dynamics simulations, we show that density fluctuations create regions of empty space characterized by a diverse morphology - from spherical to fractal-like voids. These voids allow for the identification of low and high density patches of the liquid, encompassing short (0.3-0.5 nm) as well as long (1-2 nm) length-scales. In addition, we show that the formation of these patches is coupled to collective fluctuations involving the topology of hydrogen-bonded rings of water molecules. In particular, water molecules in the high density patches tend to be slightly more tetrahedral - which is consistent with the predictions of the hydrophobic effect.

Universal Rim Thickness in Unsteady Sheet Fragmentation.

Unsteady fragmentation of a fluid bulk into droplets is important for epidemiology as it governs the transport of pathogens from sneezes and coughs, or from contaminated crops in agriculture. It is also ubiquitous in industrial processes such as paint, coating, and combustion. Unsteady fragmentation is distinct from steady fragmentation on which most theoretical efforts have been focused thus far. We address this gap by studying a canonical unsteady fragmentation process: the breakup from a drop impact on a finite surface where the drop fluid is transferred to a free expanding sheet of time-varying properties and bounded by a rim of time-varying thickness. The continuous rim destabilization selects the final spray droplets, yet this process remains poorly understood. We combine theory with advanced image analysis to study the unsteady rim destabilization. We show that, at all times, the rim thickness is governed by a local instantaneous Bond number equal to unity, defined with the instantaneous, local, unsteady rim acceleration. This criterion is found to be robust and universal for a family of unsteady inviscid fluid sheet fragmentation phenomena, from impacts of drops on various surface geometries to impacts on films. We discuss under which viscous and viscoelastic conditions the criterion continues to govern the unsteady rim thickness.

Systems level-based RNAi screening by high content analysis identifies UBR5 as a regulator of estrogen receptor-α protein levels and activity.

Estrogen receptor-α (ERα) is a central transcription factor that regulates mammary gland physiology and a key driver in breast cancer. In the present study, we aimed to identify novel modulators of ERα-mediated transcriptional regulation via a custom-built siRNA library screen. This screen was directed against a variety of coregulators, transcription modifiers, signaling molecules and DNA damage response proteins. By utilizing a microscopy-based, multi-end point, estrogen responsive biosensor cell line platform, the primary screen identified a wide range of factors that altered ERα protein levels, chromatin remodeling and mRNA output. We then focused on UBR5, a ubiquitin ligase and known oncogene that modulates ERα protein levels and transcriptional output. Finally, we demonstrated that UBR5 also affects endogenous ERα target genes and E2-mediated cell proliferation in breast cancer cells. In conclusion, our multi-end point RNAi screen identified novel modulators of ERα levels and activity, and provided a robust systems level view of factors involved in mechanisms of nuclear receptor action and pathophysiology. Utilizing a high throughput RNAi screening approach we identified UBR5, a protein commonly amplified in breast cancer, as a novel regulator of ERα protein levels and transcriptional activity.

Cervicogenic headache: results of computer-based measurements of cervical spine mobility in 15 patients.

Head and neck pain are often attributed to impaired mobility of the cervical spine. No established methods exist to examine such an impaired mobility objectively in patients with cervicogenic headache. Therefore, functional roentgenograms of the cervical spine in maximum ventral and dorsal flexion were analyzed in 15 patients with cervicogenic headache and in 18 controls. Qualitative radiologic evaluation showed no significant differences in either group. A computer-based technique to assess the mobility of the cervical spine demonstrated a statistically pronounced hypomobility of the craniocervical joints C0/C2 and an impaired overall mobility of the upper cervical spine (C0-C5) in the cervicogenic headache group. The most evident hypomotility was found in segment C0/C1. Interesting was, furthermore, a probably compensatory hypermotility in segment C6/C7. These findings did not correlate with the results of the qualitative radiologic evaluation.