Novel kinetoplastid-specific cAMP binding proteins identified by RNAi screening for cAMP resistance in .

Cyclic AMP signalling in trypanosomes differs from most eukaryotes due to absence of known cAMP effectors and cAMP independence of PKA. We have previously identified four genes from a genome-wide RNAi screen for resistance to the cAMP phosphodiesterase (PDE) inhibitor NPD-001. The genes were named cAMP Response Protein (CARP) 1 through 4.

Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections.

Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT.

Pleistocene-Holocene vicariance, not Anthropocene landscape change, explains the genetic structure of American black bear () populations in the American Southwest and northern Mexico.

The phylogeography of the American black bear () is characterized by isolation into glacial refugia, followed by population expansion and genetic admixture. Anthropogenic activities, including overharvest, habitat loss, and transportation infrastructure, have also influenced their landscape genetic structure. We describe the genetic structure of the American black bear in the American Southwest and northern Mexico and investigate how prehistoric and contemporary forces shaped genetic structure and influenced gene flow.

Two-eyed Seeing for youth wellness: Promoting positive outcomes with interwoven resilience resources.

Despite the challenges facing Indigenous youth and their communities due to historical and contemporary institutionalised racism in Canada, communities are drawing on the richness of their own histories to reassert their cultural heritage. Doing so supports mental health outcomes of young people in particular, as highlighted in a compelling body of research. The question facing many communities, however, is how they can facilitate such child and youth engagement in order to support related positive mental health outcomes.

Analyzing Phylogenetic Trees with a Tree Lattice Coordinate System and a Graph Polynomial.

Phylogenetic trees are a central tool in many areas of life science and medicine. They demonstrate evolutionary patterns among species, genes, and patterns of ancestry among sets of individuals. The tree shapes and branch lengths of phylogenetic trees encode evolutionary and epidemiological information.

Fever in a patient with osteomyelitis: the diagnosis could be serotonin syndrome.

Awareness of rare differential diagnoses of common clinical presentations helps promote early detection and prompt management of serious conditions. A 54-year-old man, with an infected non-union following a high tibial osteotomy, presented with an acutely discharging abscess to his proximal tibia. He was generally unwell with a bacteraemia.

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story.

The twentieth century ended with human African trypanosomiasis (HAT) epidemics raging across many parts of Africa. Resistance to existing drugs was emerging, and many programs aiming to contain the disease had ground to a halt, given previous success against HAT and the competing priorities associated with other medical crises ravaging the continent. A series of dedicated interventions and the introduction of innovative routes to develop drugs, involving Product Development Partnerships, has led to a dramatic turnaround in the fight against HAT caused by .

Eskasoni First Nation's transformation of youth mental healthcare: Partnership between a Mi'kmaq community and the ACCESS Open Minds research project in implementing innovative practice and service evaluation.

Aim: ACCESS Open Minds (ACCESS OM) is a pan-Canadian project aimed at improving youth mental healthcare. This paper describes implementation of the ACCESS OM objectives for youth mental health service transformation within a pre-existing Fish Net Model of transformative youth mental healthcare service in the First Nation community of Eskasoni, on Canada's east coast.

Methods: We describe an adaptation of the ACCESS OM service transformation objectives through the complementary blending of Indigenous and Western methodologies.

Response of pumas (Puma concolor) to migration of their primary prey in Patagonia.

Large-scale ungulate migrations result in changes in prey availability for top predators and, as a consequence, can alter predator behavior. Migration may include entire populations of prey species, but often prey populations exhibit partial migration with some individuals remaining resident and others migrating. Interactions of migratory prey and predators have been documented in North America and some other parts of the world, but are poorly studied in South America.

Reduced Mitochondrial Membrane Potential Is a Late Adaptation of Trypanosoma brucei brucei to Isometamidium Preceded by Mutations in the γ Subunit of the F1Fo-ATPase.

Background: Isometamidium is the main prophylactic drug used to prevent the infection of livestock with trypanosomes that cause Animal African Trypanosomiasis. As well as the animal infective trypanosome species, livestock can also harbor the closely related human infective subspecies T. b.

PNT1 Is a C11 Cysteine Peptidase Essential for Replication of the Trypanosome Kinetoplast.

The structure of a C11 peptidase PmC11 from the gut bacterium, Parabacteroides merdae, has recently been determined, enabling the identification and characterization of a C11 orthologue, PNT1, in the parasitic protozoon Trypanosoma brucei. A phylogenetic analysis identified PmC11 orthologues in bacteria, archaea, Chromerids, Coccidia, and Kinetoplastida, the latter being the most divergent. A primary sequence alignment of PNT1 with clostripain and PmC11 revealed the position of the characteristic His-Cys catalytic dyad (His(99) and Cys(136)), and an Asp (Asp(134)) in the potential S1 binding site.

What are the psychological effects of delivering and receiving "high-risk" survival resistance training?

Objective: To evaluate the possible mental health impact of resistance training on UK Armed Forces personnel undergoing training and the psychological effects of delivering such training.

Method: British Military personnel (n = 42) completed a battery of self-report measures on anxiety, general mental health, post-traumatic stress disorder, resiliency and training outcomes 1 month before, on the first and last day of the course and at 1-month follow-up. Resistance Instructors (RIs) (n = 40) completed a battery of self-report measures on anxiety, depression, post-traumatic stress disorder, alcohol use, sleep, burnout, leadership, and morale.

Independence from Kinetoplast DNA maintenance and expression is associated with multidrug resistance in Trypanosoma brucei in vitro.

It is well known that several antitrypanosomatid drugs accumulate in the parasite's mitochondrion, where they often bind to the organellar DNA, the kinetoplast. To what extent this property relates to the mode of action of these compounds has remained largely unquantified. Here we show that single point mutations that remove the dependence of laboratory strains of the sleeping sickness parasite Trypanosoma brucei on a functional kinetoplast result in significant resistance to the diamidine and phenanthridine drug classes.

Single point mutations in ATP synthase compensate for mitochondrial genome loss in trypanosomes.

Viability of the tsetse fly-transmitted African trypanosome Trypanosoma brucei depends on maintenance and expression of its kinetoplast (kDNA), the mitochondrial genome of this parasite and a putative target for veterinary and human antitrypanosomatid drugs. However, the closely related animal pathogens T. evansi and T.

Cyclic AMP effectors in African trypanosomes revealed by genome-scale RNA interference library screening for resistance to the phosphodiesterase inhibitor CpdA.

One of the most promising new targets for trypanocidal drugs to emerge in recent years is the cyclic AMP (cAMP) phosphodiesterase (PDE) activity encoded by TbrPDEB1 and TbrPDEB2. These genes were genetically confirmed as essential, and a high-affinity inhibitor, CpdA, displays potent antitrypanosomal activity. To identify effectors of the elevated cAMP levels resulting from CpdA action and, consequently, potential sites for adaptations giving resistance to PDE inhibitors, resistance to the drug was induced.

An initial evaluation of the clinical and fitness for work outcomes of a military group behavioural activation programme.

Background: Behavioural Activation (BA) is an evidence-based psychological treatment for depression based on behavioural theory. However, in common with other talking therapies, there is limited evidence about occupational factors related to treatment. This is an important gap in the research given the emphasis placed on employment considerations in recent service initiatives.

Pharmacological validation of Trypanosoma brucei phosphodiesterases as novel drug targets.

The development of drugs for neglected infectious diseases often uses parasite-specific enzymes as targets. We here demonstrate that parasite enzymes with highly conserved human homologs may represent a promising reservoir of new potential drug targets. The cyclic nucleotide-specific phosphodiesterases (PDEs) of Trypanosoma brucei, causative agent of the fatal human sleeping sickness, are essential for the parasite.

Patient preferences for the delivery of military mental health services.

Objective: Knowledge of patients' preferences of military mental health care is required to inform service planning. The objective was to inform service planning by quantifying, and identifying predictors of, patient preferences for mental health care providers and location of facilities.

Method: Sociodemographic and service characteristics and concerns about stigma were investigated for patients presenting to 4 U.

Cyclic-nucleotide signalling in protozoa.

Compared with the impressive progress in understanding signal transduction pathways and mechanisms in mammalian systems, advances in protozoan signalling processes, including cyclic nucleotide metabolism, have been very slow. This is in large part connected to the fact that the components of these pathways are very different in the protozoan parasites, as confirmed by the recently completed genome. For instance, kinetoplastids have no equivalents to the mammalian Class I adenylyl cyclases (ACs) in their genomes nor any of the subunits of the associated G-proteins.

Do stigma and other perceived barriers to mental health care differ across Armed Forces?

Objectives: Military organizations are keen to address barriers to mental health care yet stigma and barriers to care remain little understood, especially potential cultural differences between Armed Forces. The aim of this study was to compare data collected by the US, UK, Australian, New Zealand and Canadian militaries using Hoge et al.'s perceived stigma and barriers to care measure (Combat duty in Iraq and Afghanistan, mental health problems and barriers to care.

Curcuminoid analogs with potent activity against Trypanosoma and Leishmania species.

The natural curcuminoids curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) have been chemically modified to give 46 analogs and 8 pairs of 1:1 mixture of curcuminoid analogs and these parent curcuminoids and their analogs were assessed against protozoa of the Trypanosoma and Leishmania species. The parent curcuminoids exhibited low antitrypanosomal activity (EC(50) for our drug-sensitive Trypanosoma brucei brucei line (WT) of compounds 1, 2 and 3 are 2.5, 4.

Propidium iodide-based methods for monitoring drug action in the kinetoplastidae: comparison with the Alamar Blue assay.

The urgent need for new drug development for African trypanosomiasis is widely recognized. This requires reliable and informative high-throughput assays. Currently, drug action is determined with a fluorimetric/colorimetric assay based on the metabolism of the dye Alamar Blue (resazurin) by live cells.

Culture: what is its effect on stress in the military?

Culture provides the unwritten rules that inform and shape expected behaviors. To date, little research has been conducted into the attitudes or opinions that service personnel hold toward mental health issues. This article examines current literature and research into the recognition of mental health problems in the military and potential organizational barriers to care including stigma and the specific characteristics of a military culture such as the significant reliance on buddy support.

Stigma and the military: evaluation of a PTSD psychoeducational program.

Trauma risk management (TRiM) is an intensive posttraumatic stress disorder (PTSD) psychoeducational management strategy based on peer-group risk assessment developed by the UK Royal Navy (RN). TRiM seeks to modify attitudes about PTSD, stress, and help-seeking and trains military personnel to identify at-risk individuals and refer them for early intervention. This quasiexperimental study found that TRiM training significantly improved attitudes about PTSD, stress, and help-seeking from TRiM-trained personnel.