Sleeping Beauty insertional mutagenesis reveals important genetic drivers of central nervous system embryonal tumors

Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. Significance: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET

Sleeping Beauty insertional mutagenesis reveals important genetic drivers of central nervous system embryonal tumors

Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. Significance: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET

Metabolic multi-stability and hysteresis in a model aerobe-anaerobe microbiome community

Changes in the composition of the human microbiome are associated with health and disease. Some microbiome states persist in seemingly unfavorable conditions, e.g., the proliferation of aerobe-anaerobe communities in oxygen-exposed environments in wounds or small intestinal bacterial overgrowth. However, it remains unclear how different stable microbiome states can exist under the same conditions, or why some states persist under seemingly unfavorable conditions. Here, using two microbes relevant to the human microbiome, we combine genome-scale mathematical modeling, bioreactor experiments, transcriptomics, and dynamical systems theory, to show that multi-stability and hysteresis (MSH) is a mechanism that can describe the shift from an aerobe-dominated state to a resilient, paradoxically persistent aerobe-anaerobe state. We examine the impact of changing oxygen and nutrient regimes and identify factors, including changes in metabolism and gene expression, that lead to MSH. When analyzing the transitions between the two states in this system, the familiar conceptual connection between causation and correlation is broken and MSH must be used to interpret the dynamics. Using MSH to analyze microbiome dynamics will improve our conceptual understanding of the stability of microbiome states and the transitions among microbiome states

Microsecond dynamics control the HIV-1 Envelope conformation

The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although remarkable progress has been made in understanding the structures of various Env conformations, microsecond timescale dynamics have not been studied experimentally. Here, we used time-resolved, temperature-jump small-angle x-ray scattering to monitor structural rearrangements in an HIV-1 Env SOSIP ectodomain construct with microsecond precision. In two distinct Env variants, we detected a transition that correlated with known Env structure rearrangements with a time constant in the hundreds of microseconds range. A previously unknown structural transition was also observed, which occurred with a time constant below 10 μs, and involved an order-to-disorder transition in the trimer apex. Using this information, we engineered an Env SOSIP construct that locks the trimer in the prefusion closed state by connecting adjacent protomers via disulfides. Our findings show that the microsecond timescale structural dynamics play an essential role in controlling the Env conformation with impacts on vaccine design

The effect of Mediterranean exchange flow on European time mean sea level

Using a suite of ocean model simulations and a set of dedicated twin experiments, we show that the exchange flow between the Mediterranean and the North Atlantic leads to a drop in time mean European coastal sea level along the Atlantic coast north of Gibraltar. The drop is about 7 cm along the Portuguese coast and remains apparent (though reduced) as far north as the Norwegian coast. We also show that Mediterranean time and spatial mean sea level is about 9 cm lower than it would be without the exchange flow (but assuming a small supply from the Atlantic to balance evaporation). Each of these relationships makes possible an estimate of the magnitude of the exchange flow based on sea level measurements, and estimates of 0.8 and 0.91 sverdrups are made consistent with previous determinations based mainly on current measurements in the Strait of Gibraltar

Predicting hopelessness: the interaction between optimism/pessimism and specific future expectancies

Improving our understanding of hopelessness is central to suicide prevention. This is the first study to investigate whether generalized expectancies for the future (optimism/pessimism) and specific future-oriented cognitions (future thinking) interact to predict hopelessness and dysphoria. To this end, participants completed measures of future thinking, optimism/pessimism and affect at Time 1 and measures of affect and stress at Time 2, 10-12 weeks later. Results indicated that changes in hopelessness but not dysphoria were predicted by the interaction between positive future thinking (but not negative future thinking), optimism/pessimism and stress beyond initial levels of hopelessness and dysphoria. Additional moderating analyses are also reported. These findings point to the fruits of integrating personality and cognitive processes, to better understand hopelessness

A systematic review of the relationship between rumination and suicidality

Rumination has been persistently implicated in the etiology of hopelessness and depression: proximal predictors of suicidality. As a result, research has started to examine the role of rumination in suicidality. This systematic review aims to: (i) provide a concise synopsis of the current progress in examining the relationship between rumination and suicidality; and (ii) highlight areas for future research. To this end, a search of the international literature was conducted using the three main psychological and medical databases (Psych Info [1887-October 2007], Medline [1966-October 2007] and Web of Knowledge [1981-October 2007]). Eleven studies were identified providing evidence, with one exception, of a relationship between rumination and suicidality. This systematic review has highlighted a considerable dearth of studies, specifically of case-control and prospective, clinical studies, in the worldwide literature. Key areas for future research are discussed

Deep reefs of the Great Barrier Reef offer limited thermal refuge during mass coral bleaching

Our rapidly warming climate is threatening coral reefs as thermal anomalies trigger mass coral bleaching events. Deep (or "mesophotic") coral reefs are hypothesised to act as major ecological refuges from mass bleaching, but empirical assessments are limited. We evaluated the potential of mesophotic reefs within the Great Barrier Reef (GBR) and adjacent Coral Sea to act as thermal refuges by characterising long-term temperature conditions and assessing impacts during the 2016 mass bleaching event. We found that summer upwelling initially provided thermal relief at upper mesophotic depths (40 m), but then subsided resulting in anomalously warm temperatures even at depth. Bleaching impacts on the deep reefs were severe (40% bleached and 6% dead colonies at 40 m) but significantly lower than at shallower depths (60-69% bleached and 8-12% dead at 5-25 m). While we confirm that deep reefs can offer refuge from thermal stress, we highlight important caveats in terms of the transient nature of the protection and their limited ability to provide broad ecological refuge.XL Catlin Seaview Survey; Waitt Foundation; XL Catlin Group; Underwater Earth; University of Queensland; ARC Discovery Early Career Researcher Award (DECRA) [DE160101433]; Portuguese Science and Technology Foundation (FCT) [SFRH/BPD/110285/2015]; Australian Research Council (ARC

Prospective study design and data analysis in UK Biobank

Population-based prospective studies, such as UK Biobank, are valuable for generating and testing hypotheses about the potential causes of human disease. We describe how UK Biobank's study design, data access policies, and approaches to statistical analysis can help to minimize error and improve the interpretability of research findings, with implications for other population-based prospective studies being established worldwide.</p