A curated census of autophagy-modulating proteins and small molecules: Candidate targets for cancer therapy

Autophagy, a programmed process in which cell contents are delivered to lysosomes for degradation, appears to have both tumor-suppressive and tumor-promoting functions; both stimulation and inhibition of autophagy have been reported to induce cancer cell death, and particular genes and proteins have been associated both positively and negatively with autophagy. To provide a basis for incisive analysis of those complexities and ambiguities and to guide development of new autophagy-targeted treatments for cancer, we have compiled a comprehensive, curated inventory of autophagy modulators by integrating information from published siRNA screens, multiple pathway analysis algorithms, and extensive, manually curated text-mining of the literature. The resulting inventory includes 739 proteins and 385 chemicals (including drugs, small molecules, and metabolites). Because autophagy is still at an early stage of investigation, we provide extensive analysis of our sources of information and their complex relationships with each other. We conclude with a discussion of novel strategies that could potentially be used to target autophagy for cancer therapy.     

Predicting persistent inflammatory arthritis amongst early arthritis clinic patients in the UK: is musculoskeletal ultrasound required?

Introduction

Analyses of large clinical datasets from early arthritis cohorts permit the development of algorithms that may be used for outcome prediction in individual patients. The value added by routine use of musculoskeletal ultrasound (MSUS) in an early arthritis setting, as a component of such predictive algorithms, remains to be determined.

Methods

The authors undertook a retrospective analysis of a large, true-to-life, observational inception cohort of early arthritis patients in Newcastle upon Tyne, UK, which included patients with inflammatory arthralgia but no clinically swollen joints. A pragmatic, 10-minute MSUS assessment protocol was developed, and applied to each of these patients at baseline. Logistic regression was used to develop two "risk metrics" that predicted the development of a persistent inflammatory arthritis (PIA), with or without the inclusion of MSUS parameters.

Results

A total of 379 enrolled patients were assigned definitive diagnoses after ≥12 months follow-up (median 28 months), of whom 162 (42%) developed a persistent inflammatory arthritis. A risk metric derived from 12 baseline clinical and serological parameters alone had an excellent discriminatory utility with respect to an outcome of PIA (area under receiver operator characteristic (ROC) curve 0.91; 95% CI 0.88 to 0.94). The discriminatory utility of a similar metric, which incorporated MSUS parameters, was not significantly superior (area under ROC curve 0.91; 95% CI 0.89 to 0.94). Neither did this approach identify an added value of MSUS over the use of routine clinical parameters in an algorithm for discriminating PIA patients whose outcome diagnosis was rheumatoid arthritis (RA).

Conclusions

MSUS use as a routine component of assessment in an early arthritis clinic did not add substantial discriminatory value to a risk metric for predicting PIA.     

Relationship Between Respiratory Sinus Arrhythmia, Heart Period, and Caregiver-Reported Language and Cognitive Delays in Children with Autism Spectrum Disorders

The present study examines the relationship between autonomic activity and cognitive/language delays in children with autism spectrum disorder (ASD). Baseline levels of respiratory sinus arrhythmia (RSA) and heart period (HP) were assessed in 23 4–7-year old children diagnosed with ASD. The relationship between RSA, HP, and ASD behavioral symptoms was examined. Similar to prior studies on typically developing children, lower basal RSA was related to more caregiver-reported language and cognitive delays, and to the lack of language.     

Utility of the tourniquet test and the white blood cell count to differentiate dengue among acute febrile illnesses in the emergency room

Dengue often presents with non-specific clinical signs, and given the current paucity of accurate, rapid diagnostic laboratory tests, identifying easily obtainable bedside markers of dengue remains a priority. Previous studies in febrile Asian children have suggested that the combination of a positive tourniquet test (TT) and leucopenia can distinguish dengue from other febrile illnesses, but little data exists on the usefulness of these tests in adults or in the Americas. We evaluated the diagnostic accuracy of the TT and leucopenia (white blood cell count <5000/mm(3)) in identifying dengue as part of an acute febrile illness (AFI) surveillance study conducted in the Emergency Department of Saint Luke's Hospital in Ponce, Puerto Rico. From September to December 2009, 284 patients presenting to the ED with fever for 2-7 days and no identified source were enrolled. Participants were tested for influenza, dengue, leptospirosis and enteroviruses. Thirty-three (12%) patients were confirmed as having dengue; 2 had dengue co-infection with influenza and leptospirosis, respectively. An infectious etiology was determined for 141 others (136 influenza, 3 enterovirus, 2 urinary tract infections), and 110 patients had no infectious etiology identified. Fifty-two percent of laboratory-positive dengue cases had a positive TT versus 18% of patients without dengue (P<0.001), 87% of dengue cases compared to 28% of non-dengue cases had leucopenia (P<0.001). The presence of either a positive TT or leucopenia correctly identified 94% of dengue patients. The specificity and positive predictive values of these tests was significantly higher in the subset of patients without pandemic influenza A H1N1, suggesting improved discriminatory performance of these tests in the absence of concurrent dengue and influenza outbreaks. However, even during simultaneous AFI outbreaks, the absence of leucopenia combined with a negative tourniquet test may be useful to rule out dengue.     

Candidate loci for phenology and fruitfulness contributing to the phenotypic variability observed in grapevine

Key message

In this study, we identified several genes, which potentially contribute to phenological variation in the grapevine. This may help to maintain consistent yield and suitability of particular varieties in future climatic conditions.

Abstract

The timing of major developmental events in fruit crops differs with cultivar, weather conditions and ecological site. This plasticity results also in diverse levels of fruitfulness. Identifying the genetic factors responsible for phenology and fertility variation may help to improve these traits to better match future climates. Two Vitis vinifera populations, an F1 progeny of Syrah × Pinot Noir and a phenological core collection composed of 163 cultivars, were evaluated for phenology and fertility subtraits during three to six growing seasons in the same geographical location. The phenotypic variability in the core collection mostly overlapped with that observed in the F1 progeny and several accessions had exceeding values of phenological response. The progeny population was used together with SSR and SNP markers to map quantitative trait loci (QTLs). This allowed us to detect nine QTLs related to budburst, flowering beginning, the onset of ripening (véraison) and total fertility, explaining from 8 to 44 % of phenotypic variation. A genomic region on chromosome 15 was associated with budburst and véraison and two QTLs for fruitfulness were located on chromosomes 3 and 18. Several genes potentially affecting fertility and the timing of fruit development were proposed, based on their position and putative function. Allelic variation at these candidate loci may be explored by sampling accessions from the core collection.     

Poor Odors, Strength, and Persistence Give Their Rewards to Mutilla europaea Visiting Dangerous Wasp Nests

Social insect colonies are attractive for many arthropods. The rare velvet ant, Mutilla europaea, visit colonies of Polistes wasps, but to date it was unclear which resources it targeted therein. Our field observations and bioassays showed that velvet ants visit the colonies of the social wasp Polistes biglumis almost undisturbed and may feed on larval wasp saliva. Chemical insignificance and resistance are the characteristics that allow velvet ants to visit unharmed wasp colonies and gain such a nutritious reward.     

Digestive exophagy: Phagocyte digestion of objects too large for phagocytosis

Mammalian phagocytes carry out several essential functions, including killing and digesting infectious organisms, clearing denatured proteins, removing dead cells and removing several types of debris from the extracellular space. Many of these functions involve phagocytosis, the engulfment of a target in a specialized endocytic process and then fusion of the new phagosome with lysosomes. Phagocytes such as macrophages can phagocytose targets that are several micrometers in diameter (eg, dead cells), but in some cases they encounter much larger objects. We have studied two such examples in some detail: large deposits of lipoproteins such as those in the wall of blood vessels associated with atherosclerosis, and dead adipocytes, which are dozens of micrometers in diameter. We describe a process, which we call digestive exophagy, in which macrophages create a tight seal in contact with the target, acidify the sealed zone and secrete lysosomal contents into the contact zone. By this process, hydrolysis by lysosomal enzymes occurs in a compartment that is outside the cell. We compare this process to the well characterized digestion of bone by osteoclasts, and we point out key similarities and differences.     

Evolutionary dynamics of competing phenotype-structured populations in periodically fluctuating environments

Journal of Mathematical Biology - Living species, ranging from bacteria to animals, exist in environmental conditions that exhibit spatial and temporal heterogeneity which requires them to adapt....     

Strigolactone may interact with gibberellin to control apical dominance in pea (Pisum sativum)

The role of strigolactones as plant growth regulators has been demonstrated through research on biosynthesis and signaling mutant plants and through the use of GR24, a synthetic analog of this class of molecules. Strigolactone mutants show a bushy phenotype and GR24 application inhibits the growth of axillary buds in these mutants, thus restoring the phenotype of a wild plant, which is characterized by a stronger apical dominance. In this work, we tested the effectiveness of this chemical on pea (Pisum sativum) plants following apex removal, which disrupts apical dominance and leads to axillary bud outgrowth. Moreover, we searched for relationships between the response to the strigolactone and gibberellin metabolism by applying GR24 to both climbing and dwarf peas, the latters being mutants for gibberellin biosynthesis. The results suggest that the endogenous level of the bioactive gibberellin GA₁ might modulate the response of decapitated pea plants to GR24, by changing bud sensitivity to the applied strigolactone.     

Programmed cell death of the nucellus during Sechium edule Sw. seed development is associated with activation of caspase-like proteases

The nucellus is a maternal tissue that embeds and feeds the developing embryo and secondary endosperm. During seed development, the cells of the nucellus suffer a degenerative process soon after fertilization as the cellular endosperm expands and accumulates reserves. Nucellar cell degeneration has been considered to be a form of developmentally programmed cell death (PCD). It was investigated whether or not this degenerative process is characterized by apoptotic hallmarks. Evidence showed that cell death is mostly localized in the border region of the tissue adjacent to the expanding endosperm. Cell death is accompanied by profound changes in the morphology of the nuclei and by a huge degradation of nuclear DNA. Moreover, an increase of activity of different classes of proteinases is reported, and the induction of caspase-like proteases sensitive to specific inhibitors was detected. Nucellar caspase-like proteases are characterized by an acid pH optimum suggesting a possible localization in the vacuole.