The incremental validity of borderline personality disorder relative to major depressive disorder for suicidal ideation and deliberate self-harm in adolescents

Few studies have examined the relation between suicide-related behaviors and Borderline Personality Disorder (BPD) in adolescent samples. The current study investigated the incremental validity of BPD relative to Major Depressive Disorder (MDD) for suicide-related behaviors in a psychiatric sample of adolescents at the cross-sectional level of analysis. The sample included N = 156 consecutive admissions (55.1% female; M age = 15.47; SD = 1.41), to the adolescent treatment program of an inpatient treatment facility. Of the sample 19.2% (n = 30) met criteria for BPD on the Child Interview for DSM-IV Borderline Personality Disorder and 39.1% (n = 61) met criteria for MDD on the Computerized Diagnostic Interview Schedule for Children-IV. Results showed that BPD conferred additional risk for suicidal ideation and deliberate self-harm. Our findings support the clinical impression that BPD should be evaluated in inpatient samples of adolescents either through intake interviews or more structured assessments

Combining Membrane Potential Imaging with l-Glutamate or GABA Photorelease

Combining membrane potential imaging using voltage sensitive dyes with photolysis of l-glutamate or GABA allows the monitoring of electrical activity elicited by the neurotransmitter at different sub-cellular sites. Here we describe a simple system and some basic experimental protocols to achieve these measurements. We show how to apply the neurotransmitter and how to vary the dimension of the area of photolysis. We assess the localisation of photolysis and of the recorded membrane potential changes by depolarising the dendrites of cerebellar Purkinje neurons with l-glutamate photorelease using different experimental protocols. We further show in the apical dendrites of CA1 hippocampal pyramidal neurons how l-glutamate photorelease can be used to calibrate fluorescence changes from voltage sensitive dyes in terms of membrane potential changes (in mV) and how GABA photorelease can be used to investigate the phenomenon of shunting inhibition. We also show how GABA photorelease can be used to measure chloride-mediated changes of membrane potential under physiological conditions originating from different regions of a neuron, providing important information on the local intracellular chloride concentrations. The method and the proof of principle reported here open the gateway to a variety of important applications where the advantages of this approach are necessary

Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice

The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

SBML Level 3: an extensible format for the exchange and reuse of biological models

Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction-based models and packages that extend the core with features suited to other model types including constraint-based models, reaction-diffusion models, logical network models, and rule-based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single-cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution

Functional significance of ultraviolet feeding cues in wild turkeys

Most birds are able to sense ultraviolet (UV) visual signals. Ultraviolet wavelengths are used for plumage signaling and sexual selection among birds. The aim of our study was to determine if UV cues are also used for the process of food selection in wild turkeys (Meleagris gallopavo). We used avoidance conditioning to test the hypothesis that UV feeding cues can be used functionally for foraging behavior in wild turkeys. Female turkeys exhibited no avoidance of untreated food and 75–98% avoidance of food treated with an UV-absorbent, postingestive repellent (0.5–4% anthraquinone; wt./wt.) during repellent exposure. Male turkeys exhibited 78–99% avoidance of food treated with 0.5–4% anthraquinone. Female and male turkeys that consumed more than 200 mg and 100 mg of anthraquinone, respectively, subsequently avoided food treated only with an UV- absorbent cue. In contrast, unconditioned females consumed 58% more food treated with the UV-absorbent cue than untreated food. Thus, wild turkeys do not prefer foods associated with UV wavelengths regardless of feeding experience. We also observed 1) a weak negative correlation between body condition and intestinal parasite infection and 2) moderate, positive correlations between consumption of food treated with the conditioned UV cue and intestinal parasite infection among male turkeys. The UV feeding cue was used to maintain food avoidance during the four days subsequent to postingestive conditioning. Moreover, the consequences of consuming food treated with the postingestive, UV-absorbent repellent were necessary for conditioned avoidance of the UV-absorbent cue. These findings suggest functional significance of UV feeding cues for avian foraging behavior, the implications of which will enable subsequent investigations regarding the sensory physiology and behavioral ecology of wild birds