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

Moteriškosios giminės vardažodžių ir įvardžių daugiskaitos vietininko raida kai kuriose rytinėse dūnininkų šnektose

<p><strong>РАЗВИТИЕ ОКОНЧАНИЯ ИМЕНИ И МЕСТОИМЕНИЯ ЖЕНСКОГО РОДА В ФОРМЕ МЕСТНОГО ПАДЕЖА МНОЖЕСТВЕННОГО ЧИСЛА В НЕКОТОРЫХ ГОВОРАХ ДУНИНИНКОВ</strong></p><p><em>Резюме</em></p><p>В статье изучаются условия обобщения окончания <em>-u·si </em>в форме местного падежа множественного числа для всех основ имени и местоимения Шаукенского говора. Основны­ми предпосылками элиминирования „гиперхарактеристики“ рода в данном окончании являются:</p><p>1. Обобщение окончания <em>-</em><em>u·si</em><em> </em>для всех основ имени мужского рода в форме множественного числа.</p><p>2. Максимальное число синкретических форм местного падежа единственного числа имен существительных мужского и женского рода.</p>Основным толчком для обобщения окончания <em>-u·si </em>для имени и местоимения женского рода считается появление окончания <em>-ie </em>(которое уже имелось в форме местного падежа ед. ч. существительных с основами на <em></em><em>o</em>, <em>ē, i </em>и на согласный) в форме местного падежа единствен­ного числа для баритолических существительных с основой на <em></em><em>ā </em>и для существительных с основой на <em></em><em>u</em>

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

Is There a Window of Heightened Suicide Risk if Patients Gain Energy in the Context of Continued Depressive Symptoms?

The authors\u27 purpose is to provide some empirical perspective on the important but understudied possibility that when people become more energetic in the context of continued depressive symptoms, suicide risk escalates. The authors studied 109 suicidal young adults; among those who initially reported substantial depression, a subgroup was identified whose energy was increasing in context of continued depressive symptoms. They were compared with others with regard to suicidality 1 month later. Results suggested that those who have incomplete remissions (of any sort) may be more ill to begin with, and this may account for higher suicide risk