A case study in leveraging strategic partnerships through trust-based philanthropy

This practice note highlights a case study of leveraging strategic partnerships through trust-based philanthropy, a set of practices rooted in values, relationship building, mutual learning, and equity. It describes the motivations, planning, and execution of a symposium organized by, and held for, a Foundation and four of its grantees. The symposium led to the development of sustained pathways between and among the partners, resulting in productive collaborations and shared projects. This case study is shared to illustrate the argument that it is the responsibility of funders, and certainly in their self-interest, to eliminate competition between organizations to whom they provide financial resources and support. By facilitating trust and collaboration, funders are uniquely positioned to foster collective, higher-impact work. © 2024 The Authors. Journal of Philanthropy and Marketing published by John Wiley & Sons Ltd

Recombination rate and selection strength in HIV intra-patient evolution

The evolutionary dynamics of HIV during the chronic phase of infection is driven by the host immune response and by selective pressures exerted through drug treatment. To understand and model the evolution of HIV quantitatively, the parameters governing genetic diversification and the strength of selection need to be known. While mutation rates can be measured in single replication cycles, the relevant effective recombination rate depends on the probability of coinfection of a cell with more than one virus and can only be inferred from population data. However, most population genetic estimators for recombination rates assume absence of selection and are hence of limited applicability to HIV, since positive and purifying selection are important in HIV evolution. Here, we estimate the rate of recombination and the distribution of selection coefficients from time-resolved sequence data tracking the evolution of HIV within single patients. By examining temporal changes in the genetic composition of the population, we estimate the effective recombination to be r=1.4e-5 recombinations per site and generation. Furthermore, we provide evidence that selection coefficients of at least 15% of the observed non-synonymous polymorphisms exceed 0.8% per generation. These results provide a basis for a more detailed understanding of the evolution of HIV. A particularly interesting case is evolution in response to drug treatment, where recombination can facilitate the rapid acquisition of multiple resistance mutations. With the methods developed here, more precise and more detailed studies will be possible, as soon as data with higher time resolution and greater sample sizes is available.Comment: to appear in PLoS Computational Biolog

Multielectron effects in strong-field dissociative ionization of molecules

We study triple-ionization-induced, spatially asymmetric dissociation of N[subscript 2] using angular streaking in an elliptically polarized laser pulse in conjunction with few-cycle pump-probe experiments. The kinetic-energy-release dependent directional asymmetry in the ion sum-momentum distribution reflects the internuclear distance dependence of the fragmentation mechanism. Our results show that for 5–35-fs near-infrared laser pulses with intensities reaching 10[superscript 15] W/cm², charge exchange between nuclei plays a minor role in the triple ionization of N[subscript 2]. We demonstrate that angular streaking provides a powerful tool for probing multielectron effects in strong-field dissociative ionization of small molecules

The glycoprotein-hormones activin A and inhibin A interfere with dendritic cell maturation

<p>Abstract</p> <p>Background</p> <p>Pregnancy represents an exclusive situation in which the immune and the endocrine system cooperate to prevent rejection of the embryo by the maternal immune system. While immature dendritic cells (iDC) in the early pregnancy decidua presumably contribute to the establishment of peripheral tolerance, glycoprotein-hormones of the transforming growth factor beta (TGF-beta) family including activin A (ActA) and inhibin A (InA) are candidates that could direct the differentiation of DCs into a tolerance-inducing phenotype.</p> <p>Methods</p> <p>To test this hypothesis we generated iDCs from peripheral-blood-monocytes and exposed them to TGF-beta1, ActA, as well as InA and Dexamethasone (Dex) as controls.</p> <p>Results</p> <p>Both glycoprotein-hormones prevented up-regulation of HLA-DR during cytokine-induced DC maturation similar to Dex but did not influence the expression of CD 40, CD 83 and CD 86. Visualization of the F-actin cytoskeleton confirmed that the DCs retained a partially immature phenotype under these conditions. The T-cell stimulatory capacity of DCs was reduced after ActA and InA exposure while the secretion of cytokines and chemokines was unaffected.</p> <p>Conclusion</p> <p>These findings suggest that ActA and InA interfere with selected aspects of DC maturation and may thereby help preventing activation of allogenic T-cells by the embryo. Thus, we have identified two novel members of the TGF-beta superfamily that could promote the generation of tolerance-inducing DCs.</p

GA-NIFS: Black hole and host galaxy properties of two z≃\simeq6.8 quasars from the NIRSpec IFU

Integral Field Spectroscopy (IFS) with JWST NIRSpec will significantly improve our understanding of the first quasars, by providing spatially resolved, infrared spectroscopic capabilities which cover key rest-frame optical emission lines that have been previously unobservable. Here we present our results from the first two z>6 quasars observed as a part of the Galaxy Assembly with NIRSpec IFS (GA-NIFS) GTO program, DELS J0411-0907 at z=6.82 and VDES J0020-3653 at z=6.86. By observing the H$\beta$, [OIII], and H$\alpha$ emission lines in these high-z quasars for the first time, we measure accurate black hole masses, $M_{\rm{BH}}=1.85e9$ and $2.9e9$M$_\odot$, corresponding to Eddington ratios of $\lambda_{\rm{Edd}}=0.8$ and 0.4 for DELS J0411-0907 and VDES J0020-3653 respectively. These provide a key comparison for existing estimates from the more uncertain MgII line. We perform quasar-host decomposition using models of the quasars' broad lines to measure the underlying host galaxies. We also discover multiple emission line regions surrounding each of the host galaxies, which are likely companion galaxies undergoing mergers with these hosts. We measure the star formation rates, excitation mechanisms, and dynamical masses of the hosts and companions, measuring the $M_{\rm{BH}}/M_{\rm{dyn}}$ ratios at high-z using these estimators for the first time. DELS J0411-0907 and VDES J0020-3653 both lie above the local black hole--host mass relation, and are consistent with the existing observations of $z\gtrsim6$ quasar host galaxies with ALMA. We detect ionized outflows in [OIII] and H$\beta$ from both quasars, with mass outflow rates of 58 and 525 M$_{\odot}$/yr for DELS J0411-0907 and VDES J0020-3653, much larger than their host star formation rates of <33 and <54 M$_\odot$/yr. This work highlights the exceptional capabilities of the JWST NIRSpec IFU for observing quasars in the early Universe.Comment: 27 pages, 10 figures. Resubmitted to A&A after significant revisions. If you have cited values from our first version, please check this version and update accordingly, as many values have changed slightly thanks to improvements in our analysi

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Effects of chronic ethanol exposure on neuronal function in the prefrontal cortex and extended amygdala

Chronic alcohol consumption and withdrawal leads to anxiety, escalated alcohol drinking behavior, and alcohol dependence. Alterations in the function of key structures within the cortico-limbic neural circuit have been implicated in underlying the negative behavioral consequences of chronic alcohol exposure in both humans and rodents. Here, we used chronic intermittent ethanol vapor exposure (CIE) in male C57BL/6J mice to evaluate the effects of chronic alcohol exposure and withdrawal on anxiety-like behavior and basal synaptic function and neuronal excitability in prefrontal cortical and extended amygdala brain regions. Forty-eight hours after four cycles of CIE, mice were either assayed in the marble burying test (MBT) or their brains were harvested and whole-cell electrophysiological recordings were performed in the prelimbic and infralimbic medial prefrontal cortex (PLC and ILC), the lateral and medial central nucleus of the amygdala (lCeA and mCeA), and the dorsal and ventral bed nucleus of the stria terminalis (dBNST and vBNST). Ethanol-exposed mice displayed increased anxiety in the MBT compared to air-exposed controls, and alterations in neuronal function were observed in all brain structures examined, including several distinct differences between subregions within each structure. Chronic ethanol exposure induced hyperexcitability of the ILC, as well as a shift toward excitation in synaptic drive and hyperexcitability of vBNST neurons; in contrast, there was a net inhibition of the CeA. This study reveals extensive effects of chronic ethanol exposure on the basal function of cortico-limbic brain regions, suggests that there may be complex interactions between these regions in the regulation of ethanol-dependent alterations in anxiety state, and highlights the need for future examination of projection-specific effects of ethanol in cortico-limbic circuitry

Researching Memory in Early Modern Studies

This essay pursues the study of early modern memory across a chronologically, conceptually and thematically broad canvas in order to address key questions about the historicity of memory and the methodologies of memory studies. First, what is the value for our understanding of early modern memory practices of transporting the methodologies of contemporary memory studies backwards, using them to study the memorial culture of a time before living memory? Second, what happens to the cross-disciplinary project of memory studies when it is taken to a distant period, one that had its own highly self-conscious and much debated cultures of remembering? Drawing on evidence and debates from a range of disciplinary locations, but primarily focusing on literary and historical studies, the essay interrogates crucial differences and commonalities between memory studies and early modern studies

Impact of Federal, State, and Local Housing Policies on Disparities in Cardiovascular Disease in Black/African American Men and Women: From Policy to Pathways to Biology

Racist and discriminatory federal, state, and local housing policies significantly contribute to disparities in cardiovascular disease incidence and mortality for individuals that self-identify as Black or African American. Here we highlight three key housing policies – “redlining,” zoning, and the construction of highways – which have wrought a powerful, sustained, and destructive impact on cardiovascular health in Black/African American communities. Redlining and highway construction policies have restricted access to quality health care, increased exposure to carcinogens such as PM2.5, and increased exposure to extreme heat. At the root of these policy decisions are longstanding, toxic societal factors including racism, segregation, and discrimination, which also serve to perpetuate racial inequities in cardiovascular health. Here, we review these societal and structural factors and then link them with biological processes such as telomere shortening, allostatic load, oxidative stress, and tissue inflammation. Lastly, we focus on the impact of inflammation on the immune system and the molecular mechanisms by which the inflamed immune microenvironment promotes the formation of atherosclerotic plaques. We propose that racial residential segregation and discrimination increases tissue inflammation and cytokine production, resulting in dysregulated immune signaling, which promotes plaque formation and cardiovascular disease. This framework has the power to link structural racism not only to cardiovascular disease, but also to cancer