The Development of Organelle-localized Hsp90 Isoform-selective Inhibitors

Molecular chaperones are responsible for the maturation of nascent polypeptides and the re-maturation of denatured proteins. One chaperone family that has emerged as an attractive therapeutic target is the 90 kDa heat shock proteins (Hsp90). Hsp90 is responsible for the maturation of proteins associated with all ten hallmarks of cancer, and its inhibition results in a multidirectional attack on cancer. More than seventeen small molecule inhibitors have entered clinical trials; however, concerns have risen due to toxicities, dosing and scheduling issues, and lack of efficacy as a single agent. Therefore, alternative strategies for Hsp90 inhibition are needed to take advantage of the unique biological role of Hsp90. All of the molecules evaluated in clinical trials exhibit pan-Hsp90 inhibition and target all four Hsp90 isoforms with similar affinities. Humans express four different Hsp90 isoforms: Hsp90α and Hsp90β reside in the cytosol, Grp94 is localized to the endoplasmic reticulum, and TRAP1 is found in the mitochondria. Emerging evidence suggests that each Hsp90 isoform plays a unique role in cancer progression. Therefore, to further study the individual roles of each isoform, the development of Hsp90 isoform-selective inhibitors is highly desirable. However, the development of such inhibitors is hindered by the fact that the N-terminal ATP-binding pocket is 85% identical among all four isoforms. Described herein is the development of isoform-selective inhibitors of the ER- and mitochondria-localized Hsp90 isoforms, Grp94 and TRAP1, respectively. Grp94-selective inhibitors were evaluated in models of myocilin-associated open angle glaucoma, cancer metastasis, and multiple myeloma. TRAP1-selective inhibitors were evaluated for their ability to induce apoptosis in cancer cells. These isoform-selective inhibitors will serve as invaluable tools to continue to study the roles played by these isoforms in cancer as well as other indications

Digitization and Exogenesis

Within the field of genetic criticism, Raymonde Debray Genette coined the terms ‘en- dogenesis’ and ‘exogenesis’ to denote respectively the writing of drafts and the interaction with external source texts during the writing process. The proposed panel focuses on the ways in which exogenesis and its relationship with endogenesis can be given shape in a digital infrastructure. The case studies are the works, reading notes and personal libraries of James Joyce and Samuel Beckett

Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study

$\textbf{Background}$ Psychosis is a common presenting feature in antibody-mediated encephalitis, for which prompt recognition and treatment usually leads to remission. We aimed to investigate whether people with circumscribed schizophrenia-like illnesses have such antibodies—especially antibodies against the N-methyl-D-aspartate receptor (NMDAR)—more commonly than do healthy controls. $\textbf{Methods}$ We recruited patients aged 14–35 years presenting to any of 35 mental health services sites across England with first-episode psychosis, less than 6 weeks of treatment with antipsychotic medication, and a score of 4 or more on at least one selected Positive and Negative Syndrome Scale (PANSS) item. Patients and controls provided venous blood samples. We completed standardised symptom rating scales (PANSS, ACE-III, GAF) at baseline, and tested serum samples for antibodies against NMDAR, LGI1, CASPR2, the GABAA receptor, and the AMPA receptor using live cell-based assays. Treating clinicians assessed outcomes of ICD diagnosis and functioning (GAF) at 6 months. We included healthy controls from the general population, recruited as part of another study in Cambridge, UK. $\textbf{Findings}$ Between Feb 1, 2013, and Aug 31, 2014, we enrolled 228 patients with first-episode psychosis and 105 healthy controls. 20 (9%) of 228 patients had serum antibodies against one or more of the neuronal cell surface antibodies compared with four (4%) of 105 controls (unadjusted odds ratio 2·4, 95% CI 0·8–7·3). These associations remained non-significant when adjusted for current cigarette smoking, alcohol consumption, and illicit drug use. Seven (3%) patients had NMDAR antibodies compared with no controls (p=0·0204). The other antibodies did not differ between groups. Antibody-positive patients had lower PANSS positive, PANSS total, and catatonia scores than did antibody-negative patients. Patients had comparable scores on other PANSS items, ACE-III, and GAF at baseline, with no difference in outcomes at 6 months. $\textbf{Interpretation}$ Some patients with first-episode psychosis had antibodies against NMDAR that might be relevant to their illness, but did not differ from patients without NMDAR antibodies in clinical characteristics. Our study suggests that the only way to detect patients with these potentially pathogenic antibodies is to screen all patients with first-episode psychosis at first presentation.Medical Research Counci

Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study

$\textbf{Background}$ Psychosis is a common presenting feature in antibody-mediated encephalitis, for which prompt recognition and treatment usually leads to remission. We aimed to investigate whether people with circumscribed schizophrenia-like illnesses have such antibodies—especially antibodies against the N-methyl-D-aspartate receptor (NMDAR)—more commonly than do healthy controls. $\textbf{Methods}$ We recruited patients aged 14–35 years presenting to any of 35 mental health services sites across England with first-episode psychosis, less than 6 weeks of treatment with antipsychotic medication, and a score of 4 or more on at least one selected Positive and Negative Syndrome Scale (PANSS) item. Patients and controls provided venous blood samples. We completed standardised symptom rating scales (PANSS, ACE-III, GAF) at baseline, and tested serum samples for antibodies against NMDAR, LGI1, CASPR2, the GABAA receptor, and the AMPA receptor using live cell-based assays. Treating clinicians assessed outcomes of ICD diagnosis and functioning (GAF) at 6 months. We included healthy controls from the general population, recruited as part of another study in Cambridge, UK. $\textbf{Findings}$ Between Feb 1, 2013, and Aug 31, 2014, we enrolled 228 patients with first-episode psychosis and 105 healthy controls. 20 (9%) of 228 patients had serum antibodies against one or more of the neuronal cell surface antibodies compared with four (4%) of 105 controls (unadjusted odds ratio 2·4, 95% CI 0·8–7·3). These associations remained non-significant when adjusted for current cigarette smoking, alcohol consumption, and illicit drug use. Seven (3%) patients had NMDAR antibodies compared with no controls (p=0·0204). The other antibodies did not differ between groups. Antibody-positive patients had lower PANSS positive, PANSS total, and catatonia scores than did antibody-negative patients. Patients had comparable scores on other PANSS items, ACE-III, and GAF at baseline, with no difference in outcomes at 6 months. $\textbf{Interpretation}$ Some patients with first-episode psychosis had antibodies against NMDAR that might be relevant to their illness, but did not differ from patients without NMDAR antibodies in clinical characteristics. Our study suggests that the only way to detect patients with these potentially pathogenic antibodies is to screen all patients with first-episode psychosis at first presentation.Medical Research Counci

Development of Glucose Regularted Protein 94-Selective Inhibitors Based on the Bnlm and Radamide Scaffold

Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure–activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm

Taxonomic patterns in the zoonotic potential of mammalian viruses

Predicting and simplifying which pathogens may spill over from animals to humans is a major priority in infectious disease biology. Many efforts to determine which viruses are at risk of spillover use a subset of viral traits to find trait-based associations with spillover. We adapt a new method—phylofactorization—to identify not traits but lineages of viruses at risk of spilling over. Phylofactorization is used to partition the International Committee on Taxonomy of Viruses viral taxonomy based on non-human host range of viruses and whether there exists evidence the viruses have infected humans. We identify clades on a range of taxonomic levels with high or low propensities to spillover, thereby simplifying the classification of zoonotic potential of mammalian viruses. Phylofactorization by whether a virus is zoonotic yields many disjoint clades of viruses containing few to no representatives that have spilled over to humans. Phylofactorization by non-human host breadth yields several clades with significantly higher host breadth. We connect the phylogenetic factors above with life-histories of clades, revisit trait-based analyses, and illustrate how cladistic coarse-graining of zoonotic potential can refine trait-based analyses by illuminating clade-specific determinants of spillover risk

Oceanographic variability in the South Pacific Convergence Zone region over the last 210 years from multi-site coral Sr/Ca records

In the South Pacific Convergence Zone (SPCZ), the variability in a sub-seasonally resolved microatoll Porites colony Sr/Ca record from Tonga and a previously published high-resolution record from Fiji are strongly influenced by sea surface temperature (SST) over the calibration period from 1981 to 2004 (R2 = 0.67–0.68). However, the Sr/Ca-derived SST correlation to instrumental SST decreases back in time. The lower frequency secular trend (~1°C) and decadal-scale (~2–3°C) modes in Sr/Ca-derived SST are almost two times larger than that observed in instrumental SST. The coral Sr/Ca records suggest that local effects on SST generate larger amplitude variability than gridded SST products indicate. Reconstructed δ ¹⁸O of seawater (δ ¹⁸Osw) at these sites correlate with instrumental sea surface salinity (SSS; r = 0.64–0.67) but not local precipitation (r = −0.10 to −0.22) demonstrating that the advection and mixing of different salinity water masses may be the predominant control on δ¹⁸Osw in this region. The Sr/Ca records indicate SST warming over the last 100 years and appears to be related to the expansion of the western Pacific warm pool (WPWP) including an increasing rate of expansion in the last ~20 years. The reconstructed δ¹⁸Osw over the last 100 years also shows surface water freshening across the SPCZ. The warming and freshening of the surface ocean in our study area suggests that the SPCZ has been shifting (expanding) southeast, possibly related to the southward shift and intensification of the South Pacific gyre over the last 50 years in response to strengthened westerly winds

Coherent emotional perception from body expressions and the voice

Perceiving emotion from multiple modalities enhances the perceptual sensitivity of an individual. This allows more accurate judgments of others’ emotional states, which is crucial to appropriate social interactions. It is known that body expressions effectively convey emotional messages, although fewer studies have examined how this information is combined with the auditory cues. The present study used event-related potentials (ERP) to investigate the interaction between emotional body expressions and vocalizations. We also examined emotional congruency between auditory and visual information to determine how preceding visual context influences later auditory processing. Consistent with prior findings, a reduced N1 amplitude was observed in the audiovisual condition compared to an auditory-only condition. While this component was not sensitive to the modality congruency, the P2 was sensitive to the emotionally incompatible audiovisual pairs. Further, the direction of these congruency effects was different in terms of facilitation or suppression based on the preceding contexts. Overall, the results indicate a functionally dissociated mechanism underlying two stages of emotional processing whereby N1 is involved in cross-modal processing, whereas P2 is related to assessing a unifying perceptual content. These data also indicate that emotion integration can be affected by the specific emotion that is presented

An empirical model of the Earth's horizontal wind fields: HWM07

The new Horizontal Wind Model (HWM07) provides a statistical representation of the horizontal wind fields of the Earth's atmosphere from the ground to the exosphere (0-500 km). It represents over 50 years of satellite, rocket, and ground-based wind measurements via a compact Fortran 90 subroutine. The computer model is a function of geographic location, altitude, day of the year, solar local time, and geomagnetic activity. It includes representations of the zonal mean circulation, stationary planetary waves, migrating tides, and the seasonal modulation thereof. HWM07 is composed of two components, a quiet time component for the background state described in this paper and a geomagnetic storm time component (DWM07) described in a companion paper