Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface.

While targeted therapy against HER2 is an effective first-line treatment in HER2 breast cancer, acquired resistance remains a clinical challenge. The pseudokinase HER3, heterodimerisation partner of HER2, is widely implicated in the resistance to HER2-mediated therapy. Here, we show that lapatinib, an ATP-competitive inhibitor of HER2, is able to induce proliferation cooperatively with the HER3 ligand neuregulin.

Progestogens in singleton gestations with preterm prelabor rupture of membranes: a systematic review and metaanalysis of randomized controlled trials.

Objective Data: Preterm prelabor rupture of membranes occurs in 3% of all pregnancies. Neonatal benefit is seen in uninfected women who do not deliver immediately after preterm prelabor rupture of membranes. The purpose of this study was to evaluate whether the administration of progestogens in singleton pregnancies prolongs pregnancy after preterm prelabor rupture of membranes.

Shifting patterns of polyribosome accumulation at synapses over the course of hippocampal long-term potentiation.

Hippocampal long-term potentiation (LTP) is a cellular memory mechanism. For LTP to endure, new protein synthesis is required immediately after induction and some of these proteins must be delivered to specific, presumably potentiated, synapses. Local synthesis in dendrites could rapidly provide new proteins to synapses, but the spatial distribution of translation following induction of LTP is not known.

Prospective use of unmanned aerial vehicles for military medical evacuation in future conflicts.

In order to continue to deliver outstanding medical care on the battlefield, the UK Defence Medical Services must continue to adapt, overcome and actively embrace change. One potential area is the rapid proliferation and sophistication of automated and remote systems such as unmanned aerial vehicles (UAVs). UAVs are already used to deliver blood to remote military locations in Afghanistan and defibrillators to those that need them in the USA and Sweden.

Protein kinase N1 critically regulates cerebellar development and long-term function.

Increasing evidence suggests that synapse dysfunctions are a major determinant of several neurodevelopmental and neurodegenerative diseases. Here we identify protein kinase N1 (PKN1) as a novel key player in fine-tuning the balance between axonal outgrowth and presynaptic differentiation in the parallel fiber-forming (PF-forming) cerebellar granule cells (Cgcs). Postnatal Pkn1-/- animals showed a defective PF-Purkinje cell (PF-PC) synapse formation.

Effect of Evidence-Based Supported Employment vs Transitional Work on Achieving Steady Work Among Veterans With Posttraumatic Stress Disorder: A Randomized Clinical Trial.

Importance: Posttraumatic stress disorder (PTSD) often interferes with a person's ability to obtain or sustain employment, which leads to premature exit from the labor force and reduced income.

Objective: To determine whether individual placement and support (IPS)-supported employment is more effective than stepwise vocational rehabilitation involving transitional work assignments at helping veterans with PTSD attain steady, competitive employment.

Design, Setting, And Participants: The Veterans Individual Placement and Support Toward Advancing Recovery (VIP-STAR) study was a prospective, multisite, randomized clinical trial that included 541 unemployed veterans with PTSD at 12 Veterans Affairs medical centers.

Gonococcal and Chlamydial Cases of Pelvic Inflammatory Disease at 2 Canadian Sexually Transmitted Infection Clinics, 2004 to 2014: A Retrospective Cross-sectional Review.

One hundred thirteen patients with gonococcal and chlamydial pelvic inflammatory disease were reviewed at 2 Canadian sexually transmitted infection clinics. Most patients (81%) with pelvic inflammatory disease were diagnosed as having chlamydia alone. Three treatment failures were seen in patients treated with ofloxacin.

Long-term potentiation expands information content of hippocampal dentate gyrus synapses.

An approach combining signal detection theory and precise 3D reconstructions from serial section electron microscopy (3DEM) was used to investigate synaptic plasticity and information storage capacity at medial perforant path synapses in adult hippocampal dentate gyrus in vivo. Induction of long-term potentiation (LTP) markedly increased the frequencies of both small and large spines measured 30 minutes later. This bidirectional expansion resulted in heterosynaptic counterbalancing of total synaptic area per unit length of granule cell dendrite.

Landscape genomics: natural selection drives the evolution of mitogenome in penguins.

Background: Mitochondria play a key role in the balance of energy and heat production, and therefore the mitochondrial genome is under natural selection by environmental temperature and food availability, since starvation can generate more efficient coupling of energy production. However, selection over mitochondrial DNA (mtDNA) genes has usually been evaluated at the population level. We sequenced by NGS 12 mitogenomes and with four published genomes, assessed genetic variation in ten penguin species distributed from the equator to Antarctica.

Patterns of Exposure of Carnivores to Selected Pathogens in the Betampona Natural Reserve Landscape, Madagascar.

Carnivores of Madagascar are at increased risk of extinction due to anthropogenic loss of habitat, hunting, and interactions with introduced carnivores. Interactions between introduced and native animals also present the potential for introduction of pathogens into new geographic areas or host species. Here, we provide serologic data regarding pathogen exposure of domestic and native carnivores from the Betampona Natural Reserve Landscape, a protected area in eastern Madagascar.

Time resolved amplified FRET identifies protein kinase B activation state as a marker for poor prognosis in clear cell renal cell carcinoma.

Purpose: Clear cell Renal Cell Carcinomas (ccRCC), the largest group of renal tumours, are resistant to classical therapies. The determination of the functional state of actionable biomarkers for the assessment of these adenocarcinomas is essential. The dysregulation of the oncoprotein, PKB/Akt has been linked with poor prognoses in human cancers.

How are health literacy principles incorporated into breast cancer chemotherapy education? A review of the literature.

Background: Chemotherapy is commonly used in combination with other treatments for breast cancer. However, low adherence to chemotherapy is a growing concern, particularly among breast cancer patients. Side effects such as nausea and vomiting, fatigue, and arthralgia can contribute to reduced adherence.

Regular Physical Activity and Educational Outcomes in Youth: A Longitudinal Study.

Purpose: The objectives of this study were to determine whether longitudinal changes in accelerometer-assessed moderate-to-vigorous physical activity (MVPA) were associated with changes in educational outcomes (i.e., academic performance and mathematics engagement) and to examine whether the association was nonlinear.

Expertise in physiological breech birth: A mixed-methods study.

Background: The safety of vaginal breech birth depends on the expertise of birth attendants, yet the meaning of "expertise" remains unclear and subjectively defined. The objective of this study was to define expertise and the roles experts may play in expanding access to this service.

Methods: We performed an integrative analysis of two strands of data concerning expertise in physiological breech birth, including the following: survey data from a Delphi study involving 26 very experienced clinicians (mean experience = 135 breech births) and 2 service user representatives, and interviews from a grounded theory study of 14 clinicians more moderately experienced with physiological methods (5-30 upright breech births).

An integrated model of academic self-concept development: Academic self-concept, grades, test scores, and tracking over 6 years.

Our newly proposed integrated academic self-concept model integrates 3 major theories of academic self-concept formation and developmental perspectives into a unified conceptual and methodological framework. Relations among math self-concept (MSC), school grades, test scores, and school-level contextual effects over 6 years, from the end of primary school through the first 5 years of secondary school (a representative sample of 3,370 German students, 42 secondary schools, 50% male, M age at grade 5 = 11.75) support the (1) internal/external frame of reference model: Math school grades had positive effects on MSC, but the effects of German grades were negative; (2) reciprocal effects (longitudinal panel) model: MSC was predictive of and predicted by math test scores and school grades; (3) big-fish-little-pond effect: The effects on MSC were negative for school-average achievement based on 4 indicators (primary school grades in math and German, school-track prior to the start of secondary school, math test scores in the first year of secondary school).

Uncoupling TORC2 from AGC kinases inhibits tumour growth.

Mammalian target of rapamycin (mTOR) is a central regulator of growth and metabolism. mTOR resides in two distinct multi-protein complexes - mTORC1 and mTORC2 - with distinct upstream regulators and downstream targets. While it is possible to specifically inhibit mTORC1 with rapamycin, or inhibit both mTOR complexes together with ATP pocket directed mTOR kinase inhibitors, it is not possible to assess the specific roles for mTORC2 pharmacologically.

Mode and Rate of Evolution of Haemosporidian Mitochondrial Genomes: Timing the Radiation of Avian Parasites.

Haemosporidians are a diverse group of vector-borne parasitic protozoa that includes the agents of human malaria; however, most of the described species are found in birds and reptiles. Although our understanding of these parasites' diversity has expanded by analyses of their mitochondrial genes, there is limited information on these genes' evolutionary rates. Here, 114 mitochondrial genomes (mtDNA) were studied from species belonging to four genera: Leucocytozoon, Haemoproteus, Hepatocystis, and Plasmodium.

The distribution of mosquitoes across an altitudinal gradient in the Galapagos Islands.

An avian malaria parasite (genus Plasmodium) has been detected consistently in the Galapagos Penguin (Spheniscus mendiculus) and less frequently in some passerines. We sampled three resident mosquito species (Aedes taeniorhynchus, Culex quinquefasciatus, and Aedes aegypti) using CDC light and gravid traps on three islands in 2012, 2013, and 2014. We sampled along altitudinal gradients to ask whether there are mosquito-free refugia at higher elevations as there are in Hawaii.

Etiology and Recovery of Neuromuscular Fatigue following Competitive Soccer Match-Play.

Previous research into the etiology of neuromuscular fatigue following competitive soccer match-play has primarily focused on peripheral perturbations, with limited research assessing central nervous system function in the days post-match. The aim of the present study was to examine the contribution and time-course of recovery of central and peripheral factors toward neuromuscular fatigue following competitive soccer match-play. Sixteen male semi-professional soccer players completed a 90-min soccer match.

Self-Esteem Trajectories and Their Social Determinants in Adolescents With Different Levels of Cognitive Ability.

This study examines the development of self-esteem in a sample of 138 Australian adolescents (90 males; 48 females) with cognitive abilities in the lowest 15% (L-CA) and a matched sample of 556 Australian adolescents (312 males; 244 females) with average to high levels of cognitive abilities (A/H-CA). These participants were measured annually (Grade 7 to 12). The findings showed that adolescents with L-CA and A/H-CA experience similar high and stable self-esteem trajectories that present similar relations with key predictors (sex, school usefulness and dislike, parenting, and peer integration).

Synthesis of Quaternary-Substituted Thiazolines via Halocyclization of S-Allyl Thioimidate Salts.

An efficient synthesis of S-allyl thioimidate hydrobromide salts via coupling of thioamides with allyl bromide derivatives is described. A range of mono-, di-, and trisubstituted olefins as well as alkyl- and arylthioamides with variations in electronics are tolerated. A rapid anti-diastereoselective halocyclization of these salts provides a variety of substituted alkyl- and arylthiazolines.

Loss of Protein Kinase Novel 1 (PKN1) is associated with mild systolic and diastolic contractile dysfunction, increased phospholamban Thr17 phosphorylation, and exacerbated ischaemia-reperfusion injury.

Aims: PKN1 is a stress-responsive protein kinase acting downstream of small GTP-binding proteins of the Rho/Rac family. The aim was to determine its role in endogenous cardioprotection.

Methods And Results: Hearts from PKN1 knockout (KO) or wild type (WT) littermate control mice were perfused in Langendorff mode and subjected to global ischaemia and reperfusion (I/R).

Interactions Between Carnivores in Madagascar and the Risk of Disease Transmission.

Introduced carnivores exert considerable pressure on native predators through predation, competition and disease transmission. Recent research shows that exotic carnivores negatively affect the distribution and abundance of the native and endangered carnivores of Madagascar. In this study, we provide information about the frequency and distribution of interactions between exotic (dogs and cats) and native carnivores (Eupleridae) in the Betampona Natural Reserve (BNR), Madagascar, using noninvasive camera trap surveys.

Gene expression modules in primary breast cancers as risk factors for organotropic patterns of first metastatic spread: a case control study.

Background: Metastases from primary breast cancers can involve single or multiple organs at metastatic disease diagnosis. Molecular risk factors for particular patterns of metastastic spread in a clinical population are limited.

Methods: A case-control design including 1357 primary breast cancers was used to study three distinct clinical patterns of metastasis, which occur within the first six months of metastatic disease: bone and visceral metasynchronous spread, bone-only, and visceral-only metastasis.