Drug2ways: Reasoning over causal paths in biological networks for drug discovery

Elucidating the causal mechanisms responsible for disease can reveal potential therapeutic targets for pharmacological intervention and, accordingly, guide drug repositioning and discovery. In essence, the topology of a network can reveal the impact a drug candidate may have on a given biological state, leading the way for enhanced disease characterization and the design of advanced therapies. Network-based approaches, in particular, are highly suited for these purposes as they hold the capacity to identify the molecular mechanisms underlying disease. Here, we present drug2ways, a novel methodology that leverages multimodal causal networks for predicting drug candidates. Drug2ways implements an efficient algorithm which reasons over causal paths in large-scale biological networks to propose drug candidates for a given disease. We validate our approach using clinical trial information and demonstrate how drug2ways can be used for multiple applications to identify: i) single-target drug candidates, ii) candidates with polypharmacological properties that can optimize multiple targets, and iii) candidates for combination therapy. Finally, we make drug2ways available to the scientific community as a Python package that enables conducting these applications on multiple standard network formats.     

An alkaline shift induces the heat shock response in Escherichia coli.

Activation of heat shock response was observed after an alkaline shift of extracellular pH: it peaked at 5 to 10 min, as was previously reported for the heat-induced response, and was dependent on a functional rpoH gene, which is the positive regulator of the heat shock response. An induction of over sixfold was observed for dnaK and groE. The response was induced by the alkalization of extracellular pH but not by the alkalization of intracellular pH. An acidic shift of extracellular pH failed to activate the heat shock response, showing that the response is specific to the alkaline shift.     

Exploited for pets: the harvest and trade of amphibians and reptiles from Indonesian New Guinea

Over-exploitation of wildlife is a significant threat to global biodiversity, but addressing the sustainability of harvests can be difficult when trade is conducted illegally. The wildlife trade is driven chiefly by consumer demand, largely in developed nations (but increasingly in Asia), and more species are traded to meet international demand for pets than for any other purpose. We surveyed traders of amphibians and reptiles in the Indonesian provinces of Maluku, West Papua and Papua between September 2010 and April 2011. We recorded 5,370 individuals representing 52 species collected solely for the pet trade. At least 44?% were either fully protected or had not been allocated a harvest quota, making their harvest and trade illegal. Approximately half were listed within the Convention on International Trade in Endangered Species of Wild Fauna and Flora. Trade operates via a complex chain, with hunters receiving little income compared to middlemen and exporters. Examination of Indonesian harvest quotas for amphibians and reptiles suggests limited knowledge of species distributions, with quotas often set for species in provinces where they do not occur. Illegal trade is due, partly, to an inadequate understanding of the species being traded and is facilitated by poor monitoring and enforcement at key trade hubs. As a first step to combatting illegal trade, and to better understand the effects of harvest on wild populations, we recommend the need for increased monitoring and enforcement, improving the knowledge base of species traded and educating consumers about the effects their demand for pets has on these species.     

Economic incentives for conservation: beekeeping and Saturniidae caterpillar utilization by rural communities

The economic viability of the wildlife based enterprises (bee-keeping and caterpillar utilization) in Malawi is discussed in relation to conventional agricultural enterprises (maize, beans and ground-nuts). A strong incentive emerges for rural people to adopt wildlife management as an adjunct to subsistence agriculture, and therefore, to promote conservation of natural ecosystems and wildlife habitats in the face of growing human population and demand for land. Dependence on agriculture has depleted the wildlife resource outside protected areas and has been less effective in improving the wealth and living standards of most rural people. This study illustrates that the Malawi Department of National Parks and Wildlife needs to introduce economic incentives that integrate biological conservation with economic development for the rural people. The management programme involves the adoption of a rotation burning policy that promotes vegetation coppicing, eases harvesting and promotes high caterpillar yields.     

A proposed neural pathway for vocalization in South African clawed frogs,Xenopus laevis

Vocalizations of South African clawed frogs are produced by contractions of laryngeal muscles innervated by motor neurons of the caudal medulla (within cranial nerve nucleus IX-X). We have traced afferents to laryngeal motor neurons in male and female frogs using retrograde axonal transport of horseradish peroxidase conjugated to wheat germ agglutinin (HRP-WGA). After iontophoretic injection of HRP-WGA into n. IX-X, retrogradely labelled neurons were seen in the contralateral n. IX-X, in rhombencephalic reticular nuclei, and in the pre-trigeminal nucleus of the dorsal tegmental area (DTAM) of both males and females.     

Organellar Calcium Buffers

Ca²⁺ is an important intracellular messenger affecting many diverse processes. In eukaryotic cells, Ca²⁺ storage is achieved within specific intracellular organelles, especially the endoplasmic/sarcoplasmic reticulum, in which Ca²⁺ is buffered by specific proteins known as Ca²⁺ buffers. Ca²⁺ buffers are a diverse group of proteins, varying in their affinities and capacities for Ca²⁺, but they typically also carry out other functions within the cell. The wide range of organelles containing Ca²⁺ and the evidence supporting cross-talk between these organelles suggest the existence of a dynamic network of organellar Ca²⁺ signaling, mediated by a variety of organellar Ca²⁺ buffers.