Development of Streams Classification System for Nutrient Criteria in Illinois

USEPApublished or submitted for publicationis peer reviewe

Environmental enrichment facilitates cocaine-cue extinction, deters reacquisition of cocaine self-administration and alters AMPAR GluA1 expression and phosphorylation

This study investigated the combination of environmental enrichment (EE) with cocaine‐cue extinction training on reacquisition of cocaine self‐administration. Rats were trained under a second‐order schedule for which responses were maintained by cocaine injections and cocaine‐paired stimuli. During three weekly extinction sessions, saline was substituted for cocaine but cocaine‐paired stimuli were presented. Rats received 4‐h periods of EE at strategic time points during extinction training, or received NoEE. Additional control rats received EE or NoEE without extinction training. One week later, reacquisition of cocaine self‐administration was evaluated for 15 sessions, and then GluA1 expression, a cellular substrate for learning and memory, was measured in selected brain regions. EE provided both 24 h before and immediately after extinction training facilitated extinction learning and deterred reacquisition of cocaine self‐administration for up to 13 sessions. Each intervention by itself (EE alone or extinction alone) was ineffective, as was EE scheduled at individual time points (EE 4 h or 24 h before, or EE immediately or 6 h after, each extinction training session). Under these conditions, rats rapidly reacquired baseline rates of cocaine self‐administration. Cocaine self‐administration alone decreased total GluA1 and/or pSer845GluA1 expression in basolateral amygdala and nucleus accumbens. Extinction training, with or without EE, opposed these changes and also increased total GluA1 in ventromedial prefrontal cortex and dorsal hippocampus. EE alone increased pSer845GluA1 and EE combined with extinction training decreased pSer845GluA1 in ventromedial prefrontal cortex. EE might be a useful adjunct to extinction therapy by enabling neuroplasticity that deters relapse to cocaine self‐administration.The authors declare no competing financial interests. These studies were supported by NSF grant SMA-0835976 to the CELEST Science of Learning Center at Boston University and by NIH grants DA024315 (KMK) and MH079407 (HYM). We thank Iris Mile, Zachary Silber, Sharone Moverman and Enjana Bylykbashi for expert technical assistance. (SMA-0835976 - NSF; DA024315 - NIH; MH079407 - NIH)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798903/Published versio

Discovery of a Mid-infrared Echo from the TDE candidate in the nucleus of ULIRG F01004-2237

We present the mid-infrared (MIR) light curves (LCs) of a tidal disruption event (TDE) candidate in the center of a nearby ultraluminous infrared galaxy (ULIRG) F01004-2237 using archival {\it WISE} and {\it NEOWISE} data from 2010 to 2016. At the peak of the optical flare, F01004-2237 was IR quiescent. About three years later, its MIR fluxes have shown a steady increase, rising by 1.34 and 1.04 mag in $3.4$ and $4.6\mu$m up to the end of 2016. The host-subtracted MIR peak luminosity is $2-3\times10^{44}$\,erg\,s$^{-1}$. We interpret the MIR LCs as an infrared echo, i.e. dust reprocessed emission of the optical flare. Fitting the MIR LCs using our dust model, we infer a dust torus of the size of a few parsecs at some inclined angle. The derived dust temperatures range from $590-850$\,K, and the warm dust mass is $\sim7\,M_{\odot}$. Such a large mass implies that the dust cannot be newly formed. We also derive the UV luminosity of $4-11\times10^{44}$\,erg\,s$^{-1}$. The inferred total IR energy is $1-2\times10^{52}$\,erg, suggesting a large dust covering factor. Finally, our dust model suggests that the long tail of the optical flare could be due to dust scattering

A Phase I Study of Abiraterone Acetate Combined with BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer.

Lessons learnedThe combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored.BackgroundAndrogen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer. Preclinical data have shown that the two pathways compensate for each other when one is inhibited, and combined inhibition of AR and PI3K signaling may be a viable strategy to prevent or overcome castration resistance.MethodsThis phase I study evaluated the safety and tolerability of abiraterone acetate and prednisone combined with BEZ235, a dual PI3K and mTORC1/2 inhibitor, in men with progressive metastatic castration resistant prostate cancer (mCRPC) who have not received prior chemotherapy.ResultsSix patients (n = 6) were treated at the starting dose level of abiraterone acetate 1,000 mg with prednisone 5 mg twice daily and BEZ235 200 mg twice daily in a 3 + 3 dose escalation design. The study was terminated early because three of the six patients (50%) experienced dose-limiting toxicities: grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis. All six patients had previously progressed on abiraterone/prednisone. The median treatment duration was 27 days (range: 3-130 days). No prostate-specific antigen (PSA) decline or objective response were observed.ConclusionThe combination of standard-dose abiraterone/prednisone with BEZ235 200 mg twice daily was poorly tolerated in patients with mCRPC. The on-target and off-target effects of dual PI3K and mTORC inhibition likely contributed to the unacceptable toxicity profile. The Oncologist 2017;22:503-e43

Mid-infrared flare of TDE candidate PS16dtm: dust echo and implications for the spectral evolution

PS16dtm was classified as a candidate tidal disruption event (TDE) in a dwarf Seyfert 1 galaxy with low-mass black hole ($\sim10^6M\odot$) and has presented various intriguing photometric and spectra characteristics. Using the archival WISE and the newly released NEOWISE data, we found PS16dtm is experiencing a mid-infrared (MIR) flare which started $\sim11$ days before the first optical detection. Interpreting the MIR flare as a dust echo requires close pre-existing dust with a high covering factor, and suggests the optical flare may have brightened slowly for some time before it became bright detectable from the ground. More evidence is given at the later epochs. At the peak of the optical light curve, the new inner radius of the dust torus has grown to much larger size, a factor of 7 of the initial radius due to strong radiation field. At $\sim150$ days after the first optical detection, the dust temperature has dropped well below the sublimation temperature. Other peculiar spectral features shown by PS16dtm are the transient, prominent FeII emission lines and outflows indicated by broad absorption lines detected during the optical flare. Our model explains the enhanced FeII emission from iron newly released from the evaporated dust. The observed broad absorption line outflow could be explained by accelerated gas in the dust torus due to the radiation pressure.Comment: Accepted by ApJ, 5 figure

Combining Intravital Fluorescent Microscopy (IVFM) with Genetic Models to Study Engraftment Dynamics of Hematopoietic Cells to Bone Marrow Niches

Increasing evidence indicates that normal hematopoiesis is regulated by distinct microenvironmental cues in the BM, which include specialized cellular niches modulating critical hematopoietic stem cell (HSC) functions1,2. Indeed, a more detailed picture of the hematopoietic microenvironment is now emerging, in which the endosteal and the endothelial niches form functional units for the regulation of normal HSC and their progeny3,4,5. New studies have revealed the importance of perivascular cells, adipocytes and neuronal cells in maintaining and regulating HSC function6,7,8. Furthermore, there is evidence that cells from different lineages, i.e. myeloid and lymphoid cells, home and reside in specific niches within the BM microenvironment. However, a complete mapping of the BM microenvironment and its occupants is still in progress. Transgenic mouse strains expressing lineage specific fluorescent markers or mice genetically engineered to lack selected molecules in specific cells of the BM niche are now available. Knock-out and lineage tracking models, in combination with transplantation approaches, provide the opportunity to refine the knowledge on the role of specific "niche" cells for defined hematopoietic populations, such as HSC, B-cells, T-cells, myeloid cells and erythroid cells. This strategy can be further potentiated by merging the use of two-photon microscopy of the calvarium. By providing in vivo high resolution imaging and 3-D rendering of the BM calvarium, we can now determine precisely the location where specific hematopoietic subsets home in the BM and evaluate the kinetics of their expansion over time. Here, Lys-GFP transgenic mice (marking myeloid cells)9 and RBPJ knock-out mice (lacking canonical Notch signaling)10 are used in combination with IVFM to determine the engraftment of myeloid cells to a Notch defective BM microenvironment

Stem Cells in Aggregate Form to Enhance Chondrogenesis in Hydrogels

There are a variety of exciting hydrogel technologies being explored for cartilage regenerative medicine. Our overall goal is to explore whether using stem cells in an aggregate form may be advantageous in these applications. 3D stem cell aggregates hold great promise as they may recapitulate the in vivo skeletal tissue condensation, a property that is not typically observed in 2D culture. We considered two different stem cell sources, human umbilical cord Wharton’s jelly cells (hWJCs, currently being used in clinical trials) and rat bone marrow-derived mesenchymal stem cells (rBMSCs). The objective of the current study was to compare the influence of cell phenotype, aggregate size, and aggregate number on chondrogenic differentiation in a generic hydrogel (agarose) platform. Despite being differing cell sources, both rBMSC and hWJC aggregates were consistent in outperforming cell suspension control groups in biosynthesis and chondrogenesis. Higher cell density impacted biosynthesis favorably, and the number of aggregates positively influenced chondrogenesis. Therefore, we recommend that investigators employing hydrogels consider using cells in an aggregate form for enhanced chondrogenic performance

Segmentation of Vascular Structures and Hematopoietic Cells in 3-D Microscopy Images and Quantitative Analysis

In this paper, we present image processing methods for quantitative study of how the bone marrow microenvironment changes (characterized by altered vascular structure and hematopoietic cell distribution) caused by diseases or various factors. We develop algorithms that automatically segment vascular structures and hematopoietic cells in 3-D microscopy images, perform quantitative analysis of the properties of the segmented vascular structures and cells, and examine how such properties change. In processing images, we apply local thresholding to segment vessels, and add post-processing steps to deal with imaging artifacts. We propose an improved watershed algorithm that relies on both intensity and shape information and can separate multiple overlapping cells better than common watershed methods. We then quantitatively compute various features of the vascular structures and hematopoietic cells, such as the branches and sizes of vessels and the distribution of cells. In analyzing vascular properties, we provide algorithms for pruning fake vessel segments and branches based on vessel skeletons. Our algorithms can segment vascular structures and hematopoietic cells with good quality. We use our methods to quantitatively examine the changes in the bone marrow microenvironment caused by the deletion of Notch pathway. Our quantitative analysis reveals property changes in samples with deleted Notch pathway. Our tool is useful for biologists to quantitatively measure changes in the bone marrow microenvironment, for developing possible therapeutic strategies to help the bone marrow microenvironment recovery

Cultural Humility and Cultural Brokering in Professional Training: Insights from People of Color (POC) and Persons with Disabilities (PWD)

This conceptual paper reflects the collaborative work of LEND trainees and faculty exploring the need to shift from “cultural competencies” to “cultural humility” in training programs. The authors draw on their lived experiences as members of racially/ethnically marginalized groups, members of the disability community, and advocates for equity in accessibility. Collectively, the authors highlight some of the challenges and opportunities in supporting diverse trainees in professional- and discipline-specific training programs. and in the provision of services the trainees provide to care-recipients across a variety of fields. This paper includes a series of case vignettes in order to: examine individual authors’ experiences working in health-related systems as a representatives from a marginalized communities as individuals who identify as people of color (POC), persons with a disability (PWD) or PWD-POC. Informed by literature in the field alongside lived experiences, this paper identifies problematic systemic, attitudinal, and cultural elements that can limit the benefit that trainees receive in training programs and offers suggestions for mediating these limiting factors to more successfully mentor trainees who are POC, PWD, or PWD-POC. Implications for training programs in addressing diversity, equity, and inclusion through the incorporation of cultural humility and cultural brokering are highlighted

Sterilization of granulomas is common in both active and latent tuberculosis despite extensive within-host variability in bacterial killing

Over 30% of the world’s population is infected with Mycobacterium tuberculosis (Mtb), yet only ~5–10% will develop clinical disease1. Despite considerable effort, we understand little about what distinguishes individuals who progress to active tuberculosis (TB) from those who remain latent for decades. The variable course of disease is recapitulated in cynomolgus macaques infected with Mtb2. Active disease in macaques is defined by clinical, microbiologic and immunologic signs and occurs in ~45% of animals, while the remaining are clinically asymptomatic2,3. Here, we use barcoded Mtb isolates and quantitative measures of culturable and cumulative bacterial burden to show that most lesions are likely founded by a single bacterium and reach similar maximum burdens. Despite common origins, the fate of individual lesions varies substantially within the same host. Strikingly, in active disease, the host sterilizes some lesions even while others progress. Our data suggest that lesional heterogeneity arises, in part, through differential killing of bacteria after the onset of adaptive immunity. Thus, individual lesions follow diverse and overlapping trajectories, suggesting critical responses occur at a lesional level to ultimately determine the clinical outcome of infection. Defining the local factors that dictate outcome will be important in developing effective interventions to prevent active TB