"Billion Dollar Bets" to Create Economic Opportunity for Every American

The American Dream--the notion that if you "work hard and play by the rules," you will improve your lot in life--has become impossible for Americans to achieve. That was the conclusion of nearly six out of ten people who responded to a June 2014, CNNMoney poll. In a December 2015 Harvard Institute of Politics' survey of millennials, nearly half pronounced the American Dream "dead."Given the fact that social mobility in the United States has largely remained stagnant for more than 30 years, many people doubt there's a better economic future for themselves and their children. Indeed, it will take a sustained effort to restore economic opportunity for all Americans. But according to research by The Bridgespan Group, reports of the American Dream's demise just might be premature.Drawing from an extensive research base--as well as dozens of interviews with experts and practitioners and the diverse perspectives of an advisory board--a Bridgespan team embarked on an effort to map out "what matters most" to increase upward economic mobility for millions of low-income Americans. (Learn more about our research effort in the Overview of Research.)The team identified an array of on-the-ground interventions that are already building pathways to the middle class, as well as promising innovations that are just beginning to emerge. The results of that investigation can be found in this report, "Billion Dollar Bets" to Create Economic Opportunity for Every American.We framed our research around this question: "How could a philanthropic investment of $1 billion dramatically increase upward social mobility for low-income individuals and families?" With access to capital that is flexible and adaptable, philanthropists are uniquely positioned to put social mobility on an upward trajectory. Roughly 80 percent of the largest donors aspire to impel social change, but just 20 percent of philanthropic investments above$10 million went to social-change organizations between 2000 and 2012. Philanthropists have lacked the sightlines into shovel-ready projects and they've lacked the confidence that large investments would actually impact the economic lives of many people.Our intent was to create a series of roadmaps that illustrate how investments of $1 billion might improve the lifetime earnings of millions of low-income Americans. We began by identifying four promising areas where large investments of private capital would likely catalyze population-level change.We then evaluated scores of concepts for restoring the meritocratic ideal to many more Americans. Working with our advisory board, we selected 15 of those concepts as illustrative "big bets" that span the four investment areas. To get a better understanding of the promise and pitfalls that come with any attempt to take on the social mobility challenge, we took a deeper dive into six of the proposed bets:Improve early childhood developmentEstablish clear and viable pathways to careersDecrease rates of conviction and incarcerationReduce unintended pregnanciesReduce the effect of concentrated poverty on the lives of people living in distressed neighborhoodsImprove the performance of public systems that administer and oversee social service

Controlled Burn

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Osmotic Edema Rapidly Increases Neuronal Excitability Through Activation of NMDA Receptor-Dependent Slow Inward Currents in Juvenile and Adult Hippocampus.

Cellular edema (cell swelling) is a principal component of numerous brain disorders including ischemia, cortical spreading depression, hyponatremia, and epilepsy. Cellular edema increases seizure-like activity in vitro and in vivo, largely through nonsynaptic mechanisms attributable to reduction of the extracellular space. However, the types of excitability changes occurring in individual neurons during the acute phase of cell volume increase remain unclear. Using whole-cell patch clamp techniques, we report that one of the first effects of osmotic edema on excitability of CA1 pyramidal cells is the generation of slow inward currents (SICs), which initiate after approximately 1 min. Frequency of SICs increased as osmolarity decreased in a dose-dependent manner. Imaging of real-time volume changes in astrocytes revealed that neuronal SICs occurred while astrocytes were still in the process of swelling. SICs evoked by cell swelling were mainly nonsynaptic in origin and NMDA receptor-dependent. To better understand the relationship between SICs and changes in neuronal excitability, recordings were performed in increasingly physiological conditions. In the absence of any added pharmacological reagents or imposed voltage clamp, osmotic edema induced excitatory postsynaptic potentials and burst firing over the same timecourse as SICs. Like SICs, action potentials were blocked by NMDAR antagonists. Effects were more pronounced in adult (8-20 weeks old) compared with juvenile (P15-P21) mice. Together, our results indicate that cell swelling triggered by reduced osmolarity rapidly increases neuronal excitability through activation of NMDA receptors. Our findings have important implications for understanding nonsynaptic mechanisms of epilepsy in relation to cell swelling and reduction of the extracellular space

Lessons Learned: Feasibility of a Discussion Prompting Tool to Increase Fertility Risk Discussion Among Adolescent Oncology Families

The purpose of this study was to explore the feasibility of distributing a prompting tool (stress egg) in order to increase discussions about fertility risk and preservation (FP) among female adolescent oncology patients, parents, and healthcare providers (HCP). 200 eggs were distributed to four pediatric oncology centers. Qualitative interviews were completed with healthcare staff (N=7) after 6 months of distribution to newly diagnosed female oncology patients ages 12-18. Interviews showed that the main barriers to distribution of the prompt were: forgetting to distribute the eggs; uncertainty about the significance of fertility; and uncertainty about fertility issues in general for female adolescent cancer patients. The scientific community must continually explore effective avenues of communication to ensure such information is received. The stress egg has potential to impact a cancer survivor’s outlook on future partnering, family life, and self-concept when used in conjunction with policy

Active machine learning-driven experimentation to determine compound effects on protein patterns

Abstract High throughput screening determines the effects of many conditions on a given biological target. Currently, to estimate the effects of those conditions on other targets requires either strong modeling assumptions (e.g. similarities among targets) or separate screens. Ideally, data-driven experimentation could be used to learn accurate models for many conditions and targets without doing all possible experiments. We have previously described an active machine learning algorithm that can iteratively choose small sets of experiments to learn models of multiple effects. We now show that, with no prior knowledge and with liquid handling robotics and automated microscopy under its control, this learner accurately learned the effects of 48 chemical compounds on the subcellular localization of 48 proteins while performing only 29% of all possible experiments. The results represent the first practical demonstration of the utility of active learningdriven biological experimentation in which the set of possible phenotypes is unknown in advance

Hippocampal and Cortical Pyramidal Neurons Swell in Parallel with Astrocytes during Acute Hypoosmolar Stress

Normal nervous system function is critically dependent on the balance of water and ions in the extracellular space (ECS). Pathological reduction in brain interstitial osmolarity results in osmotically-driven flux of water into cells, causing cellular edema which reduces the ECS and increases neuronal excitability and risk of seizures. Astrocytes are widely considered to be particularly susceptible to cellular edema due to selective expression of the water channel aquaporin-4 (AQP4). The apparent resistance of pyramidal neurons to osmotic swelling has been attributed to lack of functional water channels. In this study we report rapid volume changes in CA1 pyramidal cells in hypoosmolar ACSF (hACSF) that are equivalent to volume changes in astrocytes across a variety of conditions. Astrocyte and neuronal swelling was significant within 1 min of exposure to 17 or 40% hACSF, was rapidly reversible upon return to normosmolar ACSF, and repeatable upon re-exposure to hACSF. Neuronal swelling was not an artifact of patch clamp, occurred deep in tissue, was similar at physiological vs. room temperature, and occurred in both juvenile and adult hippocampal slices. Neuronal swelling was neither inhibited by TTX, nor by antagonists of NMDA or AMPA receptors, suggesting that it was not occurring as a result of excitotoxicity. Surprisingly, genetic deletion of AQP4 did not inhibit, but rather augmented, astrocyte swelling in severe hypoosmolar conditions. Taken together, our results indicate that neurons are not osmoresistant as previously reported, and that osmotic swelling is driven by an AQP4-independent mechanism

Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation.

Fibroblast to myofibroblast differentiation is crucial for the initial healing response but excessive myofibroblast activation leads to pathological fibrosis. Therefore, it is imperative to understand the mechanisms underlying myofibroblast formation. Here we report that mitochondrial calcium (mCa2+) signaling is a regulatory mechanism in myofibroblast differentiation and fibrosis. We demonstrate that fibrotic signaling alters gating of the mitochondrial calcium uniporter (mtCU) in a MICU1-dependent fashion to reduce mCa2+ uptake and induce coordinated changes in metabolism, i.e., increased glycolysis feeding anabolic pathways and glutaminolysis yielding increased α-ketoglutarate (αKG) bioavailability. mCa2+-dependent metabolic reprogramming leads to the activation of αKG-dependent histone demethylases, enhancing chromatin accessibility in loci specific to the myofibroblast gene program, resulting in differentiation. Our results uncover an important role for the mtCU beyond metabolic regulation and cell death and demonstrate that mCa2+ signaling regulates the epigenome to influence cellular differentiation

Tracing a toad invasion: lack of mitochondrial DNA variation, haplotype origins, and potential distribution of introduced Duttaphrynus melanostictus in Madagascar

The black-spined toad, Duttaphrynus melanostictus, is widespread in South and South-East (SE) Asia, although recent molecular analyses have revealed that it represents a species complex (here called the D. melanostictus complex). Invasive populations of this toad have been detected in Madagascar since, at least, 2014. We here trace the origin of this introduction based on mitochondrial DNA sequences of 340 samples. All 102 specimens from Madagascar have identical sequences pointing to a single introduction event. Their haplotype corresponds to a lineage occurring in Cambodia, China, Laos, Thailand, Vietnam, and some locations of eastern Myanmar and northern Malaysia, here named the SE Asian lineage. Within this lineage, specimens from one location in Cambodia and three locations in Vietnam have the same haplotype as found in Madagascar. This includes Ho Chi Minh City, which has a major seaport and might have been the source for the introduction. Species distribution models suggest that the current range of the Madagascan invasive population is within the bioclimatic space occupied by the SE Asian lineage in its native range. The potential invasion zone in Madagascar is narrower than suggested by models from localities representing the full range of the D. melanostictus complex. Thus, an accurate taxonomy is essential for such inferences, but it remains uncertain if the toad might be able to spread beyond the potential suitable range because (1) knowledge on species-delimitation of the complex is insufficient, and (2) the native range in SE Asia might be influenced by historical biogeography or competition

The EGS Grading Scale For Skin And Soft Tissue Infections Is Predictive Of Poor Outcomes : A Multicenter Validation Study

Introduction: Over the last five years, the American Association for the Surgery of Trauma (AAST) has developed grading scales for Emergency General Surgery (EGS) diseases. In a prior validation study using diverticulitis, the grading scales were predictive of complications and length of stay. As EGS encompasses diverse diseases, the purpose of this study was to validate the grading scale concept against a different disease process with a higher associated mortality. We hypothesized that the grading scale would be predictive of complications, length of stay and mortality in skin and soft tissue infections (STI). Methods: This multi-institutional trial encompassed 12 centers. Data collected included demographic variables, disease characteristics and outcomes such as mortality, overall complications, hospital and ICU length of stay. The EGS scale for STI was used to grade each infection and two surgeons graded each case to evaluate inter-rater reliability. Results: 1170 patients were included in this study. Inter-rater reliability was moderate (kappa coefficient 0.472-0.642, with 64-76% agreement). Higher grades (IV and V) corresponded to significantly higher LRINEC scores when compared with lower EGS grades. Patients with grade IV and V STI had significantly increased odds of all complications, as well as ICU and overall length of stay. These associations remained significant in logistic regression controlling for age, gender, comorbidities, mental status and hospital-level volume. Grade V disease was significantly associated with mortality as well. Conclusion: This validation effort demonstrates that Grade IV and V STI are significantly predictive of complications, hospital length of stay and mortality. Though predictive ability does not improve linearly with STI grade, this is consistent with the clinical disease process, in which lower grades represent cellulitis and abscess and higher grades are invasive infections. This second validation study confirms the EGS grading scale as predictive, and easily used, in disparate disease processes