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Eradicating leukemia requires a deep understanding of the interaction between leukemic cells and their protective microenvironment. The CXCL12/CXCR4 axis has been postulated as a critical pathway dictating leukemia stem cell (LSC) chemoresistance in AML due to its role in controlling cellular egress from the marrow. Nevertheless, the cellular source of CXCL12 in the acute myeloid leukemia (AML) microenvironment and the mechanism by which CXCL12 exerts its protective role in vivo remain unresolved. Here, we show that CXCL12 produced by Prx1+ mesenchymal cells but not by mature osteolineage cells provide the necessary cues for the maintenance of LSCs in the marrow of an MLL::AF9-induced AML model. Prx1+ cells promote survival of LSCs by modulating energy metabolism and the REDOX balance in LSCs. Deletion of Cxcl12leads to the accumulation of reactive oxygen species and DNA damage in LSCs, impairing their ability to perpetuate leukemia in transplantation experiments, a defect that can be attenuated by antioxidant therapy. Importantly, our data suggest that this phenomenon appears to be conserved in human patients. Hence, we have identified Prx1+ mesenchymal cells as an integral part of the complex niche-AML metabolic intertwining, pointing towards CXCL12/CXCR4 as a target to eradicate parenchymal LSCs in AML.

Objective:This study examined the impact of a peer-based mindfulness and yoga intervention to reduce interpersonal violence in a network of young adults experiencing homelessness (YAEH). Method:A network of YAEH (n=58) accessing homelessness drop-in services in Los Angeles, CA, completed a baseline and follow-up self-administered survey. After applying a violence minimization machine-learning algorithm to baseline data, 12 YAEH were identified and invited to participate in the Mindfulness and Yoga Peer Ambassador Training for Health (MYPATH). The training consisted of a 3-hour intensive followed by seven weekly 1-hour sessions. The training introduced mindfulness and yoga as tools and practices to increase emotion regulation and reduce impulsivity in the context of interpersonal and community violence. Follow-up data were collected 2 months after baseline. Results:Results revealed increased trait mindfulness (i.e., a tendency or trait rather than a particular practice or in-the-moment experience), increased mindfulness and yoga practice frequency, and reduced violence-engagement behaviors in the network of YAEH. Conclusions:The current study provides preliminary support for the effectiveness of the intervention in decreasing network-level violence and demonstrates the feasibility of implementing a peer-based intervention to promote mindfulness and yoga practice in a network of YAEH.

An efficient crystallization screening method is important in drug design to yield high resolution crystallographic structures of protein–ligand complexes to understand inhibitor selectivity and potency for various members of an enzyme family. The strategy starts with a single condition for each protein–ligand complex, and more trials encompassing all polymorph crystallization conditions are included later, eventually defaulting to a more extensive screening for difficult cases. The polymorph screening approach relies on an intrinsic positive feedback mechanism. New polymorphs are constantly discovered since certain ligands favor variant lattices. The new best diffracting polymorph is selected for single-conditions testing, ensuring that as more forms are discovered, the resolution of the structures obtained improves. Continual optimization of the conditions for all crystal forms yields new solutions that become increasingly effective in protein–ligand crystallization trials. More polymorphs imply more lattices suitable to accommodate ligands of greater diversity. Wider seeding opportunities combined with optimized enzyme-specific crystallization conditions improves the outcome and accelerates the screening process so that a conventional full-range crystallization screening is only rarely needed. Having tested this approach with a large repertoire of 100 ligands and 4 enzymes, we expect the method to perform equally well on similar drug-discovery projects.

Objective:Youth experiencing homelessness are at risk for HIV and need interventions to prevent risky sex behaviors. We tested the feasibility of using artificial intelligence (AI) to select peer change agents (PCAs) to deliver HIV prevention messages among youth experiencing homelessness. Method:We used a pretest–posttest quasi-experimental design. In the AI condition (n= 62), 11 PCAs were selected via AI algorithm; in the popularity comparison (n= 55), 11 PCAs were selected 6 months later based on maximum degree centrality (most ties to others in the network). All PCAs were trained to promote HIV testing and condom use among their peers. Participants were clients at a drop-in center in Los Angeles, CA. HIV testing and condom use were assessed via a self-administered, computer-based survey at baseline (n= 117), 1 month (n= 86, 74%), and 3 months (n= 70, 60%). Results:At 3 months, rates of HIV testing increased among participants in the AI condition relative to the comparison group (18.8% vs. 8.1%), as did condom use during anal sex (12.1% vs. 3.3%) and vaginal sex (29.2% vs. 23.7%). Conclusions:AI-enhanced PCA intervention is a feasible method for engaging youth experiencing homelessness in HIV prevention.

The accuracy of X-ray diffraction data is directly related to how the X-ray detector records photons. Here we describe the application of a direct-detection charge-integrating pixel-array detector (JUNGFRAU) in macromolecular crystallography (MX). JUNGFRAU features a uniform response on the subpixel level, linear behavior toward high photon rates, and low-noise performance across the whole dynamic range. We demonstrate that these features allow accurate MX data to be recorded at unprecedented speed. We also demonstrate improvements over previous-generation detectors in terms of data quality, using native single-wavelength anomalous diffraction (SAD) phasing, for thaumatin, lysozyme, and aminopeptidase N. Our results suggest that the JUNGFRAU detector will substantially improve the performance of synchrotron MX beamlines and equip them for future synchrotron light sources.

Old Wistar rats (16–17 months) were trained in a two-way active avoidance task for 5 consecutive days (10 trials/day). Immediately after each training session a lateral hypothalamic intracranial self-stimulation session (ICSS group) or a sham-treatment session (Control group) was given to the animals. Long-term retention was tested 7 days after the last acquisition session. ICSS treatment led to a significant improvement in acquisition. In the long-term retention session the level of avoidance in both groups was similar to that achieved in the last acquisition session, although differences among groups failed to reach statistical significance. These results are compared with those obtained in previous experiments with young adult rats. While ICSS facilitated the process of acquisition in both young and old rats (however, it was much more powerful in young animals), further experiments are needed to elucidate whether this effect is long-lasting in old rats, as occurs in young adult subjects.