Orally Delivered Stimulus-Sensitive Nanomedicine to Harness Teduglutide Efficacy in Inflammatory Bowel Disease.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract (GIT). Glucagon-like peptide-2 (GLP-2) analogs possess high potential in the treatment of IBD by enhancing intestinal repair and attenuating inflammation. Due to the enzymatic degradation and poor intestinal absorption, GLP-2 analogs are administered parenterally, which leads to poor patient compliance. This work aims to develop IBD-targeted nanoparticles (NPs) for the oral delivery of the GLP-2 analog, Teduglutide (TED). Leveraging the overproduction of Reactive Oxygen Species (ROS) in the IBD environment, ROS-sensitive NPs are developed to target the intestinal epithelium, bypassing the mucus barrier. PEGylation of NPs facilitates mucus transposition, but subsequent PEG removal is crucial for cellular internalization. This de-PEGylation is possible by including a ROS-sensitive thioketal linker within the system. ROS-sensitive NPs are established, with the ability to fully de-PEGylate via ROS-mediated cleavage. Encapsulation of TED into NPs resulted in the absence of absorption in 3D in vitro models, potentially promoting a localized action, and avoiding adverse effects due to systemic absorption. Upon oral administration to colitis-induced mice, ROS-sensitive NPs are located in the colon, displaying healing capacity and reducing inflammation. Cleavable PEGylated NPs demonstrate effective potential in managing IBD symptoms and modulating the disease's progression.

Mis-expression of GATA6 re-programs cell fate during early hematopoiesis.

The traditional view of hematopoiesis is that myeloid cells derive from a common myeloid progenitor (CMP), whereas all lymphoid cell populations, including B, T, and natural killer (NK) cells and possibly plasmacytoid dendritic cells (pDCs), arise from a common lymphoid progenitor (CLP). In Max41 transgenic mice, nearly all B cells seem to be diverted into the granulocyte lineage. Here, we show that these mice have an excess of myeloid progenitors, but their CLP compartment is ablated, and they have few pDCs. Nevertheless, T cell and NK cell development proceeds relatively normally. These hematopoietic abnormalities result from aberrant expression of Gata6 due to serendipitous insertion of the transgene enhancer (Eµ) in its proximity. Gata6 mis-expression in Max41 transgenic progenitors promoted the gene-regulatory networks that drive myelopoiesis through increasing expression of key transcription factors, including PU.1 and C/EBPa. Thus, mis-expression of a single key regulator like GATA6 can dramatically re-program multiple aspects of hematopoiesis.

Structural and functional perspectives on interactions between synthetic cathinones and monoamine transporters.

Synthetic cathinone derivatives comprise a family of psychoactive compounds structurally related to amphetamine. Over the last decade, clandestine chemists have synthesized a consistent stream of innovative cathinone derivatives to outpace governmental regulatory restrictions. Many of these unregulated substances are produced and distributed as designer drugs. Two of the principal chemical scaffolds exploited to expand the synthetic cathinone family are methcathinone and α-pyrrolidinopentiophenone (or α-pyrrolidinovalerophenone, α-PVP). These compounds' main physiological targets are monoamine transporters, where they promote addiction by potentiating dopaminergic neurotransmission. This chapter describes techniques used to study the pharmacodynamic properties of cathinones at monoamine transporters in vitro. Biochemical techniques described include uptake inhibition and release assays in rat brain synaptosomes and in mammalian expression systems. Electrophysiological techniques include current measurements using the voltage clamp technique. We describe a Ca2+ mobilization assay wherein voltage-gated Ca2+ channels function as reporters to study the action of synthetic cathinones at monoamine transporters. We discuss results from systematic structure-activity relationship studies on simple and complex cathinones at monoamine transporters with an emphasis on identifying structural moieties that modulate potency and selectivity at these transporters. Moreover, different profiles of selectivity at monoamine transporters directly predict compounds associated with behavioral and subjective effects within animals and humans. In conclusion, clarification of the structural aspects of compounds which modulate potency and selectivity at monoamine transporters is critical to identify and predict potential addictive drugs. This knowledge may allow prompt allocation of resources toward drugs that represent the greatest threats after drugs are identified by forensic laboratories.

Concussive Head Trauma Deranges Axon Initial Segment Function in Axotomized and Intact Layer 5 Pyramidal Neurons.

The axon initial segment (AIS) is a critical locus of control of action potential (AP) generation and neuronal information synthesis. Concussive traumatic brain injury gives rise to diffuse axotomy, and the majority of neocortical axonal injury arises at the AIS. Consequently, concussive traumatic brain injury might profoundly disrupt the functional specialization of this region. To investigate this hypothesis, one and two days after mild central fluid percussion injury in Thy1-YFP-H mice, we recorded high-resolution APs from axotomized and adjacent intact layer 5 pyramidal neurons and applied a second derivative (2o) analysis to measure the AIS- and soma-regional contributions to the AP upstroke. All layer 5 pyramidal neurons recorded from sham animals manifested two stark 2o peaks separated by a negative intervening slope. In contrast, within injured mice, we discovered a subset of axotomized layer 5 pyramidal neurons in which the AIS-regional 2o peak was abolished, a functional perturbation associated with diminished excitability, axonal sprouting and distention of the AIS as assessed by staining for ankyrin-G. Our analysis revealed an additional subpopulation of both axotomized and intact layer 5 pyramidal neurons that manifested a melding together of the AIS- and soma-regional 2o peaks, suggesting a more subtle aberration of sodium channel function and/or translocation of the AIS initiation zone closer to the soma. When these experiments were repeated in animals in which cyclophilin-D was knocked out, these effects were ameliorated, suggesting that trauma-induced AIS functional perturbation is associated with mitochondrial calcium dysregulation.

Emerging diagnostic methods and imaging modalities in cushing's syndrome.

Endogenous Cushing's syndrome (CS) is a rare disease characterized by prolonged glucocorticoid excess. Timely diagnosis is critical to allow prompt treatment and limit long-term disease morbidity and risk for mortality. Traditional biochemical diagnostic modalities each have limitations and sensitivities and specificities that vary significantly with diagnostic cutoff values. Biochemical evaluation is particularly complex in patients whose hypercortisolemia fluctuates daily, often requiring repetition of tests to confirm or exclude disease, and when delineating CS from physiologic, nonneoplastic states of hypercortisolism. Lastly, traditional pituitary MRI may be negative in up to 60% of patients with adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (termed "Cushing's disease" [CD]) whereas false positive pituitary MRI findings may exist in patients with ectopic ACTH secretion. Thus, differentiating CD from ectopic ACTH secretion may necessitate dynamic testing or even invasive procedures such as bilateral inferior petrosal sinus sampling. Newer methods may relieve some of the diagnostic uncertainty in CS, providing a more definitive diagnosis prior to subjecting patients to additional imaging or invasive procedures. For example, a novel method of cortisol measurement in patients with CS is scalp hair analysis, a non-invasive method yielding cortisol and cortisone values representing long-term glucocorticoid exposure of the past months. Hair cortisol and cortisone have both shown to differentiate between CS patients and controls with a high sensitivity and specificity. Moreover, advances in imaging techniques may enhance detection of ACTH-secreting pituitary adenomas. While conventional pituitary MRI may fail to identify microadenomas in patients with CD, high-resolution 3T-MRI with 3D-spoiled gradient-echo sequence has thinner sections and superior soft-tissue contrast that can detect adenomas as small as 2 mm. Similarly, functional imaging may improve the identification of ACTH-secreting adenomas noninvasively; Gallium-68-tagged corticotropin-releasing hormone (CRH) combined with PET-CT can be used to detect CRH receptors, which are upregulated on corticotroph adenomas. This technique can delineate functionality of adenomas in patients with CD from patients with ectopic ACTH secretion and false positive pituitary lesions on MRI. Here, we review emerging methods and imaging modalities for the diagnosis of CS, discussing their diagnostic accuracy, strengths and limitations, and applicability to clinical practice.

Establishing the Relative Accuracy of Using City Directories as Proxies to Define and Reconstruct Historical Alcohol Environments.

OBJECTIVE: Research on alcohol environments has established that poorer and minoritized communities are frequently overburdened by off-premise outlets (e.g., liquor stores). These outlets have more associated harms, including increased alcohol consumption and crime rates. Little, if any, research has shown how these socio-spatial disparities in exposure have grown or shifted over time, and no studies have established a method for re-creating historical alcohol environments. METHOD: Our results suggest that in our study city of Flint, MI, disparities in the alcohol environment have narrowed since 1950. Although liquor stores are still more likely to be located in poorer and more heavily African American neighborhoods, the pattern has become insignificant over time. Furthermore, the number of alcohol outlets per capita has declined. Thus, although the city remains more overburdened with alcohol outlets than its suburbs, the disparity has shrunk. CONCLUSIONS: This work has implications for those working in alcohol prevention and policy, as well as in urban planning. Practitioners and researchers can use this method to model alcohol availability over time in their own communities, which helps better inform the discussion on disparities experienced in poor and minoritized neighborhoods.

Linking Historical Discriminatory Housing Patterns to the Contemporary Alcohol Environment.

Research on alcohol outlet density consistently shows greater disparities in exposure in disinvested communities. Likewise, structural racism via discriminatory housing practices has created many of the issues that beset contemporary disinvested neighborhoods. Little work, however, has examined the relationship between housing practices and alcohol outlet disparities. The central premise of our work is that these discriminatory and inequitable practices create distinctions in the alcohol environment, and that such disparities have implications for work on alcohol policy. Here we link alcohol outlet density with a spatial database examining redlining, blockbusting, and gentrification in Baltimore, Maryland, and Flint, Michigan (two cities with common experiences of urban disinvestment over the last 50 years). Standard measures are used to account for the impacts of neighborhood racial, socioeconomic, and housing composition in a multilevel model. Our findings highlight that gentrification and redlining are strongly associated with alcohol outlet density, while blockbusting is not. Gentrification and redlining also frequently co-occur in inner-urban areas, while the more suburban phenomenon of blockbusting rarely overlaps with either. These findings further contextualize nascent work on structural racism in housing that illustrates important disparities along the lines of these distinct practices. Future work should consider how legacy impacts of discriminatory housing patterns impact our communities today.

Using trajectory modeling of spatio-temporal trends to illustrate disparities in COVID-19 death in flint and Genesee County, Michigan.

COVID-19's rapid onset left many public health entities scrambling. But establishing community-academic partnerships to digest data and create advocacy steps offers an opportunity to link research to action. Here we document disparities in COVID-19 death uncovered during a collaboration between a health department and university research center. We geocoded COVID-19 deaths in Genesee County, Michigan, to model clusters during two waves in spring and fall 2020. We then aggregated these deaths to census block groups, where group-based trajectory modeling identified latent patterns of change and continuity. Linking with socioeconomic data, we identified the most affected communities. We discovered a geographic and racial gap in COVID-19 deaths during the first wave, largely eliminated during the second. Our partnership generated added and immediate value for community partners, including around prevention, testing, treatment, and vaccination. Our identification of the aforementioned racial disparity helped our community nearly eliminate disparities during the second wave.

Bridging the gap between fundamental research and product development of long acting injectable PLGA microspheres.

INTRODUCTION: Long-acting Injectable PLGA microspheres have gained more and more interest and attention in the field of life cycle management of pharmaceutical products due to their biocompatibility and biodegradability. So far, a multitude of trial-and-error experiments at lab scale have been used for establishing the correlation relationship between critical process parameters, critical material attributes and critical quality attributes. However, few published studies have elaborated on the development of PLGA microspheres from an industrial perspective. AREAS COVERED: In this review, the scale-up feasibility of translational technologies of PLGA microspheres manufacturing has been evaluated. Additionally, state-of-the-art of technologies and facilities in PLGA development have been summarized. Meanwhile, the industrial knowledge matrix of PLGA microspheres development and research is establishing which provides comprehensive insight for understanding properties of PLGA microspheres as controlled/sustained release vehicle. EXPERT OPINION: There is still big gap between fundamental research in academic institute and product development in pharmaceuticals. Therefore, the difference and connection between them should be identified gradually for better understanding of PLGA microspheres development.

Somatostatin interneurons exhibit enhanced functional output and resilience to axotomy after mild traumatic brain injury.

Mild traumatic brain injury (mTBI) gives rise to a remarkable breadth of pathobiological consequences, principal among which are traumatic axonal injury and perturbation of the functional integrity of neuronal networks that may arise secondary to the elimination of the presynaptic contribution of axotomized neurons. Because there exists a vast diversity of neocortical neuron subtypes, it is imperative to elucidate the relative vulnerability to axotomy among different subtypes. Toward this end, we exploited SOM-IRES-Cre mice to investigate the consequences of the central fluid percussion model of mTBI on the microanatomical integrity and the functional efficacy of the somatostatin (SOM) interneuron population, one of the principal subtypes of neocortical interneuron. We found that the SOM population is resilient to axotomy, representing only 10% of the global burden of inhibitory interneuron axotomy, a result congruous with past work demonstrating that parvalbumin (PV) interneurons bear most of the burden of interneuron axotomy. However, the intact structure of SOM interneurons after injury did not translate to normal cellular function. One day after mTBI, the SOM population is more intrinsically excitable and demonstrates enhanced synaptic efficacy upon post-synaptic layer 5 pyramidal neurons as measured by optogenetics, yet the global evoked inhibitory tone within layer 5 is stable. Simultaneously, there exists a significant increase in the frequency of miniature inhibitory post-synaptic currents within layer 5 pyramidal neurons. These results are consistent with a scheme in which 1 day after mTBI, SOM interneurons are stimulated to compensate for the release from inhibition of layer 5 pyramidal neurons secondary to the disproportionate axotomy of PV interneurons. The enhancement of SOM interneuron intrinsic excitability and synaptic efficacy may represent the initial phase of a dynamic process of attempted autoregulation of neocortical network homeostasis secondary to mTBI.

Trajectory Modeling of Spatio-Temporal Trends in COVID-19 Incidence in Flint and Genesee County, Michigan.

PURPOSE: The establishment of community-academic partnerships to digest data and create actionable policy and advocacy steps is of continuing importance. In this paper, we document COVID-19 racial and geographic disparities uncovered via a collaboration between a local health department and university research center. METHODS: We leverage individual level data for all COVID-19 cases aggregated to the census block group level, where group-based trajectory modeling was employed to identify latent patterns of change and continuity in COVID-19 diagnoses. RESULTS: Linking with socioeconomic data from the census, we identified the types of communities most heavily affected by each of Michigan's two waves (in spring and fall of 2020). This includes a geographic and racial gap in COVID-19 cases during the first wave, which is largely eliminated during the second wave. CONCLUSIONS: Our work has been extremely valuable for community partners, informing community-level response toward testing, treatment, and vaccination. In particular, identifying and conducting advocacy on the sizeable racial disparity in COVID-19 cases during the first wave in spring 2020 helped our community nearly eliminate disparities throughout the second wave in fall 2020.

Evolution of Neuroendocrine Tumor Therapy.

To better understand developments in treatment of neuroendocrine tumors of the gastroenteropancreatic system, and the pivotal roles of native somatostatin and its long-acting analogues play in normal peptide regulation and neuropeptide excess associated with neuroendocrine tumors (NETs), this article delineates and defines distinct eras in the history and discovery of gastrointestinal endocrinology. We highlight the collaboration between academia and industry in basic science and the clinical research that advanced Lu-177-DOTATATE to approval as standard of care therapy for low-grade NETs. Examples of new radioisotopes and therapy compounds currently in development for diagnosis and therapy for high-grade NETs are also discussed.

Are Metropolitan Areas Primed for Success? A Prosperity Risk Index for Evaluating Economic Development Patterns.

Urban areas differ greatly in their exposure to economic change, their trajectory toward recovery and growth, and the extent to which development and equity are paired. Some of this differentiation can be explained by regional dynamics, policies, and migration flows that influence the composition of economic activity, land use, and population characteristics. Simultaneously, the fortunes of center cities are known to often correlate with metropolitan characteristics, yet the interaction of socio-spatial conditions with multi-level governance and development processes-particularly with respect to how prosperity is shared across municipal lines and is distributed among communities-is under-researched. In this article, we use a GIS-based and quantitative approach to characterize such patterns and evaluate regional differences among 117 mid-sized metropolitan areas in the Eastern US with a population between 250,000 and 2,500,000. Our analysis rests on initial GIS-based inquiries to define city, urbanized area, county, and core-based statistical area-level measures of municipal fragmentation, geographic sprawl, racial segregation, economic inequality, and overall poverty. These five characteristics are combined to propose a prosperity risk index for each region. Further, indicators of economic performance such as job and population growth are inverted to create an economic vulnerability index. An interaction model is run to determine relationships among the indices to highlight both the regional differences in these characteristics that became noticeably significant in the analysis and the linkages of spatial patterns of economic growth and social equity. Analyzing these multi-scalar regional dynamics illuminates the socio-spatial patterns that deserve attention in urban economic development theory and, subsequently, offers a framework for evaluating public policy and development practices. We likewise offer two comparisons of outliers as a means of illustrating potential directions urban areas can take toward economic development. These findings are valuable for local economic development practitioners who may be seeking further contextual/comparative information on urban regions, or for others interested in understanding the dynamics behind urban planning that may drive regional competitiveness and prosperity.

The population randomization observation process (PROP) assessment method: using systematic habitation observations of street segments to establish household-level epidemiologic population samples.

BACKGROUND: Identifying and intervening on health disparities requires representative community public health data. For cities with high vacancy and transient populations, traditional methods of population estimation for refining random samples are not feasible. The aim of this project was to develop a novel method for systematic observations to establish community epidemiologic samples. RESULTS: We devised a four-step population randomization observation process for Flint, Michigan, USA: (1) Use recent total population data for community areas (i.e., neighborhoods) to establish the proportional sample size for each area, (2) Randomly select street segments of each community area, (3) Deploy raters to conduct observations about habitation for each randomly selected segment, and (4) Complete observations for second and third street segments, depending on vacancy levels. We implemented this systematic observation process on 400 randomly selected street segments. Of these, 130 (32.5%) required assessment of secondary segments due to high vacancy. Among the 130 primary segments, 28 (21.5%) required assessment of tertiary (or more) segments. For 71.5% of the 400 primary street segments, there was consensus among raters on whether the dwelling inhabited or uninhabited. CONCLUSION: Houses observed with this method could have easily been considered uninhabited via other methods. This could cause residents of ambiguous dwellings (likely to be the most marginalized residents with highest levels of unmet health needs) to be underrepresented in the resultant sample.

LIGHTCURVE PHOTOMETRY OPPORTUNITIES: 2019 JANUARY-MARCH.

We present lists of asteroid photometry opportunities for objects reaching a favorable apparition and have no or poorly-defined lightcurve parameters. Additional data on these objects will help with shape and spin axis modeling via lightcurve inversion. We also include lists of objects that will or might be radar targets. Lightcurves for these objects can help constrain pole solutions and/or remove rotation period ambiguities that might not come from using radar data alone.

LIGHTCURVE PHOTOMETRY OPPORTUNITIES: 2019 APRIL-JUNE.

We present lists of asteroid photometry opportunities for objects reaching a favorable apparition and have no or poorly-defined lightcurve parameters. Additional data on these objects will help with shape and spin axis modeling via lightcurve inversion. We also include lists of objects that will or might be radar targets. Lightcurves for these objects can help constrain pole solutions and/or remove rotation period ambiguities that might not come from using radar data alone.

LIGHTCURVE PHOTOMETRY OPPORTUNITIES: 2019 JULY-SEPTEMBER.

We present lists of asteroid photometry opportunities for objects reaching a favorable apparition and have no or poorly-defined lightcurve parameters. Additional data on these objects will help with shape and spin axis modeling via lightcurve inversion. We also include lists of objects that will or might be radar targets. Lightcurves for these objects can help constrain pole solutions and/or remove rotation period ambiguities that might not come from using radar data alone.