Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death

Glaucoma, a major cause of blindness worldwide, is a neurodegenerative optic neuropathy in which vision loss is caused by loss of retinal ganglion cells (RGCs). To better define the pathways mediating RGC death and identify targets for the development of neuroprotective drugs, we developed a high-throughput RNA interference screen with primary RGCs and used it to screen the full mouse kinome. The screen identified dual leucine zipper kinase (DLK) as a key neuroprotective target in RGCs. In cultured RGCs, DLK signaling is both necessary and sufficient for cell death. DLK undergoes robust posttranscriptional up-regulation in response to axonal injury in vitro and in vivo. Using a conditional knockout approach, we confirmed that DLK is required for RGC JNK activation and cell death in a rodent model of optic neuropathy. In addition, tozasertib, a small molecule protein kinase inhibitor with activity against DLK, protects RGCs from cell death in rodent glaucoma and traumatic optic neuropathy models. Together, our results establish a previously undescribed drug/drug target combination in glaucoma, identify an early marker of RGC injury, and provide a starting point for the development of more specific neuroprotective DLK inhibitors for the treatment of glaucoma, nonglaucomatous forms of optic neuropathy, and perhaps other CNS neurodegenerations

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer

Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3 and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized Luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

Effects of tuberculosis and HIV infection on whole-body protein metabolism during feeding, measured by the [15N]glycine method

Background: Tuberculosis (TB) and HIV infection are wasting diseases that frequently occur together and have severe consequences on nutritional status.Objective: The objective was to determine the effects of TB and HIV, separately and together, on protein metabolism.Design: Protein metabolism was determined in the fed state in 11 healthy control subjects, in 10 patients with HIV infection without TB or other active infection (HIV group), in 10 patients with active TB without HIV infection (TB group), and in 8 patients with HIV infection and active TB (HIVTB group) with the use of oral [15N]glycine and measurement of enrichment in urinary urea and ammonia.Results: Whole-body protein flux and degradation were lower in the HIV group than in the control group (mean flux: 3.53 ± 0.40 compared with 4.75 ± 0.97 g · kg lean body mass-1 · 12 h-1; P = 0.002). Protein flux, synthesis, and degradation were not significantly different between the control group and the TB and HIVTB groups. Net protein balance was strongly anabolic in the control, HIV, and TB groups but was neutral in the HIVTB group (P < 0.001 for comparison between groups).Conclusions: HIV infection was associated with a significant down-regulation of whole-body protein flux. TB alone was not associated with abnormal protein metabolism, but net anabolism in the fed state was impaired in the HIVTB group

Distribution of cephalopods from plankton surveys around the British Isles

Cephalopods (n = 515) were identified from a series of plankton and fine meshed mid-water trawls, taken between 1977 and 1999, around the British Isles. The collections were not directed at cephalopods, but provide valuable information on the distribution of planktonic species and on the paralarvae of the benthic species. The most abundant species in neritic areas were the octopod Eledone cirrhosa and the sepiolids, Sepietta oweniana and Sepiola atlantica. Eledone cirrhosa were common in samples to the north and west of Scotland, particularly in early summer. The mantle lengths of E. cirrhosa were 4-8 mm, indicating a brief planktonic existence or, perhaps, net avoidance by larger specimens. In the shelf-break collections from the west of Scotland and Ireland the squids Brachioteuthis spp., Gonatus sp., Teuthowenia megalops and rynchoteuthions of the Ommastrephidae were abundant. Two types of rhynchoteuthion were found and were probably Todarodes sagittatus, Illex coindetii or Todaropsis eblanae. Despite the abundance of Loligo forbesi around the British Isles, it was rarely taken in plankton collections, probably indicating that it does not have a planktonic paralarva

Scavenging by megabenthos and demersal fish on the South Georgia slope

The scavenging megafauna of the South Georgia and Shag Rocks slope in the south-west Atlantic (625-15 19 m) were investigated using autonomous baited camera systems. Two surveys were conducted: the first in 1997 (13 deployments) used a conventional 35 mm stills camera with a 200 J flash, whilst the second in 2000 (1 5 deployments) used low-light digital video cameras. The scavenging community responded rapidly to the arrival of bait on the sea floor and was dominated by stone crabs (Lithodidae) and toothfish (Dissostichus eleginoides). Stone crabs took up residence around the bait until it was consumed, with a maximum number of 108 in the field of view after four hours. The most frequently observed crab species was Paralomis formosa. Paralomis spinosissima, Neolithodes diomedea and Lithodes sp., were also observed. Toothfish were the most frequently observed scavenging fish and were seen during all but one deployment, typically making brief visits (1-2 min) to the bait, but appeared startled by the flash in the 1997 survey. Labriform swimming (sculling with the pectoral fins) was the principal form of locomotion in toothfish (0.22 body lengths (BL) sec-I), but they were capable of more rapid sub-carangiform (using caudal trunk and fin) motion (3 BL sec-I) when startled. Other scavenging fish observed included the blue-hake Antimora rostrata, grenadiers (Macrourus spp.), skates, liparids and zoarcids

Distribution, demography and discard mortality of crabs caught as bycatch in an experimental pot fishery for toothfish (Dissostichus eleginoides) in the South Atlantic

Between March 2000 and April 2001 two commercial fishing vessels fished for toothfish (Dissostichus eleginoides) off South Georgia using pots. A significant number of lithodid crabs (three species of Paralomis spp.) were caught as bycatch. Paralomis spinosissima occurred in shallow water, generally shallower than 700 m. Paralomis anamerae, not previously reported from this area and therefore representing a considerable southerly extension in the reported geographic range of this species, had an intermediate depth distribution from 400 to 800 m. Paralomis formosa was present in shallow waters but reached much higher catch levels (and, presumably, densities) between 800 and 1400 m. Differences were also noted in depth distribution of the sexes and size of crabs. Depth, soak time, and area were found to significantly influence crab catch rates. Few crabs (3% of P. spinosissima and 7% of P. formosa) were males above the legal size limit and could therefore be retained. All other crabs were discarded. Most crabs (>99% of P. formosa, >97% of P. spinosissima, and >90% of P. anamerae) were lively on arrival on deck and at subsequent discard. Mortality rates estimated from re-immersion experiments indicated that on the vessel where pots were emptied directly onto the factory conveyor belt 78–89% of crabs would survive discarding, whereas on the vessel where crabs were emptied down a vertical chute prior to being sorted, survivorship was 38–58%. Of the three, P. anamerae was the most vulnerable to handling onboard and sub-sequent discarding. Paralomis spinosissima seemed more vulnerable than P. formosa