Showing papers by "Indiana University published in 2023"

Reconstruction of the tumor spatial microenvironment along the malignant-boundary-nonmalignant axis

Abstract: Although advances in spatial transcriptomics (ST) enlarge to unveil spatial landscape of tissues, it remains challenging to delineate pathology-relevant and cellular localizations, and interactions exclusive to a spatial niche (e.g., tumor boundary). Here, we develop Cottrazm, integrating ST with hematoxylin and eosin histological image, and single-cell transcriptomics to delineate the tumor boundary connecting malignant and non-malignant cell spots in tumor tissues, deconvolute cell-type composition at spatial location, and reconstruct cell type-specific gene expression profiles at sub-spot level. We validate the performance of Cottrazm along the malignant-boundary-nonmalignant spatial axis. We identify specific macrophage and fibroblast subtypes localized around tumor boundary that interacted with tumor cells to generate a structural boundary, which limits T cell infiltration and promotes immune exclusion in tumor microenvironment. In this work, Cottrazm provides an integrated tool framework to dissect the tumor spatial microenvironment and facilitates the discovery of functional biological insights, thereby identifying therapeutic targets in oncologic ST datasets.

Improved pulmonary function is associated with reduced inflammation after hybrid whole‐body exercise training in persons with spinal cord injury

Abstract: New Findings What is the central question of this study? Does 12 weeks of functional electrical stimulation (FES) rowing exercise training lead to suppressed systemic inflammation and an improvement in pulmonary function in persons with sub-acute spinal cord injury (SCI)? What is the main finding and its importance? Twelve weeks of FES rowing exercise improves pulmonary function and the magnitude of improvement is associated with reductions in inflammatory biomarkers. Thus, interventions targeting inflammation may lead to better pulmonary outcomes for person with sub-acute SCI. The current study was designed to test the hypotheses that (1) reducing systemic inflammation via a 12-week functional electrical stimulation rowing exercise training (FESRT) prescription results in augmented pulmonary function, and (2) the magnitude of improvement in pulmonary function is inversely associated with the magnitude of systemic inflammation suppression in persons with sub-acute (≤2 years) spinal cord injury (SCI). We conducted a retrospective analysis of a randomized controlled trial (NCT#02139436). Twenty-one participants were enrolled (standard of care (SOC; n = 9) or FESRT (n = 12)). The exercise prescription was three sessions/week at 70–85% of peak heart rate. A two-way analysis of covariance and regression analysis was used to assess group differences and associations between pulmonary function, log transformed high-sensitivity C-reactive protein (hsCRPlog) and white blood cell count (WBC). Following FESRT, clinically significant improvements in forced expiratory volume in 1 s (FEV1; 0.25 (0.08–0.43) vs. −0.06 (−0.26 to 0.15) litres) and forced vital capacity (0.22 (0.04–0.39) vs. 0.08 (−0.29 to 0.12) litres) were noted and systemic WBC (−1.45 (−2.48 to −0.50) vs. 0.41 (−0.74 to 1.56) μl) levels were suppressed compared to SOC (mean change (95% confidence interval); P < 0.05). Additionally, both ΔhsCRPlog and ΔWBC were predictors of ΔFEV1 (r2 = 0.89 and 0.43, respectively; P < 0.05). Twelve weeks of FESRT improves pulmonary function and reduces WBC in persons with sub-acute SCI. The potency of FESRT to augment pulmonary function may depend on adequate suppression of systemic inflammation.

Metal‐Mediated Oligomerization Reactions of the Cyaphide Anion

Abstract: The cyaphide anion, CP−, is shown to undergo three distinct oligomerization reactions in the coordination sphere of metals. Reductive coupling of Au(IDipp)(CP) (IDipp=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) by Sm(Cp*)2(OEt2) (Cp*=1,2,3,4,5-pentamethylcyclopentadienyl), was found to afford a tetra-metallic complex containing a 2,3-diphosphabutadiene-1,1,4,4-tetraide fragment. By contrast, non-reductive dimerization of Ni(SIDipp)(Cp)(CP) (SIDipp=1,3-bis(2,6-diisopropylphenyl)-imidazolidin-2-ylidene; Cp=cyclopentadienyl), gives rise to an asymmetric bimetallic complex containing a 1,3-diphosphacyclobutadiene-2,4-diide moiety. Spontaneous trimerization of Sc(Cp*)2(CP) results in the formation of a trimetallic complex containing a 1,3,5-triphosphabenzene-2,4,6-triide fragment. These transformations show that while cyaphido transition metal complexes can be readily accessed using metathesis reactions, many such species are unstable to further oligomerization processes.

Emerging technologies and their potential role in sleep medicine

Abstract: Since its inception as a medical subspecialty, the field of sleep medicine has seen many technological advancements that influence the diagnosis and management of sleep disorders. Increased recognition of how disordered sleep influences cardiometabolic and other parameters of health has led to practice of constantly adapting technologies into the care of patients with sleep disorders. Understanding the role that novel technologies may have in clinical sleep medicine can help healthcare providers identify opportunities to deliver personalized sleep care to more patients. This article traces the evolution of sleep technologies, discusses the commonly used artificial intelligence driven algorithms in sleep medicine, outlines the effects of these technologies on clinical and research practice and reviews the underlying principles of emerging consumer sleep technologies.

Mechanistic Insight into Cu-Catalyzed C–N Coupling of Hindered Aryl Iodides and Anilines Using a Pyrrol-ol Ligand Enables Development of Mild and Homogeneous Reaction Conditions

Abstract: Mechanistic studies of the Cu-catalyzed C–N coupling of sterically hindered aryl iodides with sterically hindered anilines are carried out to shed light on how a recently reported pyrrol-ol ligand affects the reaction. Kinetic, spectroscopic, and computational tools help to probe the nature of the active catalyst species and the rate-determining step in the cycle. In contrast to most known Cu systems, oxidative addition is found to precede coordination of the amine. These studies help to design an efficient process under mild conditions using a fully homogeneous system as well as protocols that enable high yields by temperature scanning and controlled addition of the base. The insights obtained for the XX-type ligand may lead to a general approach for challenging substrate classes in Cu-catalyzed coupling reactions.

The HRA Organ Gallery Affords Immersive Superpowers for Building and Exploring the Human Reference Atlas with Virtual Reality

Abstract: The Human Reference Atlas (HRA, https://humanatlas.io ) funded by the NIH Human Biomolecular Atlas Program (HuBMAP, https://commonfund.nih.gov/hubmap ) and other projects engages 17 international consortia to create a spatial reference of the healthy adult human body at single-cell resolution. The specimen, biological structure, and spatial data that define the HRA are disparate in nature and benefit from a visually explicit method of data integration. Virtual reality (VR) offers unique means to enable users to explore complex data structures in a threedimensional (3D) immersive environment. On a 2D desktop application, the 3D spatiality and real-world size of the 3D reference organs of the atlas is hard to understand. If viewed in VR, the spatiality of the organs and tissue blocks mapped to the HRA can be explored in their true size and in a way that goes beyond traditional 2D user interfaces. Added 2D and 3D visualizations can then provide data-rich context. In this paper, we present the HRA Organ Gallery, a VR application to explore the atlas in an integrated VR environment. Presently, the HRA Organ Gallery features 55 3D reference organs,1,203 mapped tissue blocks from 292 demographically diverse donors and 15 providers that link to 5,000+ datasets; it also features prototype visualizations of cell type distributions and 3D protein structures. We outline our plans to support two biological use cases: on-ramping novice and expert users to HuBMAP data available via the Data Portal ( https://portal.hubmapconsortium.org ), and quality assurance/quality control (QA/QC) for HRA data providers . Code and onboarding materials are available at https://github.com/cns-iu/ccf-organ-vr-gallery#readme .

Biliteracy, playfulness and performative practices

Abstract: In this chapter, we examine biliteracy through a creative performative lens and argue that biliteracy is a creative strength and an integrated linguistic repertoire that bilingual speakers own. We discuss the emerging, inventive, and creative features of biliteracy to foreground the skills emergent bilingual children create and engaged within multiple social domains. Then, we list research that highlights bilingual and biliterate performative practices in a multicultural and pluralistic world. Lastly, we review biliteracy pedagogical performative practices in drama and play with the aim to discuss new goals and challenges of promoting biliteracy.

Resident Research Mentoring Teams: A Support Program to Increase Resident Research Productivity

Abstract: Scholarly activity is a requirement for most graduate medical education training programs. However, barriers exist for residents to accomplish projects.To evaluate the correlation between a resident research mentoring team (RRMT) program and meeting presentations and publications of resident research projects. We further plan to report feasibility of the RRMT.We performed a before-and-after study of meeting presentations and/or publication of resident research projects before institution of the RRMT (2004-2011) and post-RRMT implementation (2016-2019). The RRMT is a diverse group of faculty, statisticians, and research staff who meet regularly with residents to provide guidance for their research studies. It is part of overall research support from the department, which also includes biostatistics, database and regulatory help, travel funds, and project budget funds. Data on meeting presentations and publications were collected from Google Scholar, PubMed, Scopus, and the IUPUI ScholarWorks institutional repository, using resident and faculty names and titles of projects. Comparisons of pre- and post-RRMT groups were made.Seventy-four residents were in the pre-RRMT group and 40 were in the post-RRMT group. Post-RRMT residents published, presented, and combined published or presented their projects more frequently than those in pre-RRMT group (57.5% vs 28.4%, P=.002; 50% vs 16.2%, P=.001; 67.5% vs 37.8%, P=.002). Controlling for winning a Research Day award and pursuing a fellowship, being in the post-RRMT group was independently associated with presentation or publication of the resident research project (OR 3.62, 95% CI 1.57-8.83).Support of resident scholarly activity, such as thorough implementation of a program like the RRMT, is associated with increased presentations and publications of research projects.

Myxopapillary Ependymoma in an 11-Year-Old Patient With Right-Sided Nocturnal Thigh Pain

Abstract: This case report highlights a rare type of primary spinal cord tumor, myxopapillary ependymoma, in a pediatric patient who presented to clinic with worsening chronic unilateral thigh pain and neurologic deficits. He was appropriately treated with total gross resection of the tumor and adjuvant radiotherapy and was cleared for competitive sports without any restriction within 1 year of his diagnosis and treatment. Although most musculoskeletal complaints among pediatric patients are of benign etiology, as evidenced by our case, clinicians should have a low threshold to further investigate with advanced imaging modalities should the clinical history and examination be consistent with a more concerning pathologic process.

Quality, Safety, Accountability, and Medical Director Responsibilities

Abstract: The responsibilities of a dialysis unit medical director are specified in the ESKD Conditions for Coverage and encompass multiple quality and safety domains. The medical director guides the quality assessment and process improvement (QAPI) activities of the dialysis facility and must be familiar with quality improvement tools, possess leadership skills, and demonstrate a commitment to quality and safety by actions, not words. Multiple quality domains are subject to accountability by the Centers for Medicare and Medicaid Services (CMS) through periodic on-site surveys by state Departments of Health, payment adjustment based on quality metrics, and a publicly accessible website allowing patients and other interested parties to view outcomes at the facility. The medical director is responsible for fostering a blameless culture of safety within the facility so latent medical errors can be detected before harm occurs and changes can be implemented to minimize operator errors. Through an iterative process of improvement for both safety and quality, interventions are chosen and applied on a system level that has maximum positive impact on patient outcomes. The medical director is the “captain” of the QAPI “ship” and is key to its navigating a successful course challenged by the patient, physician, personnel, and systemic factors. This requires political and administrative skills that may not be intuitive. Nonetheless, CMS has acknowledged that the nephrologist is best suited for this role, which has and will become increasingly complex with the proliferation of quality metrics and changes in payer systems that will no doubt continue throughout the current decade.

Applying Functional MRI to Study Adolescent Substance Use

Abstract: Functional magnetic resonance imaging is a tool used to examine brain activity both at rest and in response to a variety of stimuli or tasks. Functional MRI may be applied to study correlates of substance use and risk for substance use in adolescence. In this chapter, we describe design, logistical, and analytic considerations for conducting a functional MRI research study among adolescents engaged in or at risk for substance use. Our objective is to provide readers with an introductory guide to applying functional MRI in this specialized population, as well as highlight potential resources to obtain further information.

Circumcision and Buried Penis

Abstract: Circumcision involves the surgical removal of some, or all, of the prepuce from the penis and is the most commonly performed urologic procedure. This procedure may also be one of the oldest, likely predating written human history. Rates of circumcision vary widely, based on ethnic and religious background as well as local customs. Although the benefits of circumcision for removal of a scarred or otherwise diseased foreskin are well documented, routine circumcision of the otherwise healthy penis remains controversial. Reasons given to support neonatal circumcision include the prevention of urinary tract infections (UTIs), the prevention of certain sexually transmitted diseases (STDs) and reduction in the incidence of penile cancer. Although strongly debated, no evidence exists to support any adverse effects of circumcision on penile sensation or sexual function. Indications, procedures and potential complications of circumcision will be discussed. Buried penis is defined as the inadequate protrusion of the flaccid penis from the pubis. The condition can be classified as either congenital or acquired. Multiple forms exist. Indications for surgical intervention can be both cosmetic and functional. The etiology, treatment options and specific surgical procedures for this condition will be covered in this chapter.

Frozen modernity: the US-India ice trade and the cultures of colonialism

Abstract: This article examines the history of the ice trade between the United States and India that operated from the early-to-mid 19th century. I argue that the ice trade reinforced cultures of colonialism, with its ideas about nature, race, and disease. As a commodity, ice demarcated colonial from colonized space, the tropics from the temperate, and the European from the Indian body. In particular, this article focuses on three central ways in which the U.S.-India ice trade aided in the production of Calcutta’s colonial landscape. First, U.S. ice capital illuminates the commodification of nature and the creation of exchange value that was instilled through a series of movements across space, from New England’s ponds and ports, to the ship, and finally, into Calcutta’s marketplace. Once in Calcutta, American ice dislodged local ice and the established practices associated with the production of the cold. Second, the ice trade promoted discourses of modern colonizing civilization that shaped the landscapes and practices of Calcutta. Conceptions of freshness and purity proliferated through the ice trade, from the object itself, to the perishable commodities that landed in Calcutta frozen in ice. Third, I illuminate how ice was used in Calcutta, especially its promotion in colonial medicine. More than an item of luxury, ice was held to be an indispensable article in the preservation of the colonial body. Ice contained the promise of racial durability in the tropics and the very health of colonial authority. Across these three cultural elements of the ice trade, this article contributes to new geographies of global history, the mobility of race through trade, and cryopolitics.

MCAK Inhibitors Induce Aneuploidy in Triple Negative Breast Cancer Models

Abstract: Abstract Standard of care for triple negative breast cancer (TNBC) involves the use of microtubule poisons like paclitaxel, which are proposed to work by inducing lethal levels of aneuploidy in tumor cells. While these drugs are initially effective in treating cancer, dose-limiting peripheral neuropathies are common. Unfortunately, patients often relapse with drug resistant tumors. Identifying agents against targets that limit aneuploidy may be a valuable approach for therapeutic development. One potential target is the microtubule depolymerizing kinesin, MCAK, which limits aneuploidy by regulating microtubule dynamics during mitosis. Using publicly available datasets, we found that MCAK is upregulated in triple negative breast cancer and is associated with poorer prognoses. Knockdown of MCAK in tumor-derived cell lines caused a two- to five-fold reduction in the IC 50 for paclitaxel, without affecting normal cells. Using FRET and image-based assays, we screened compounds from the ChemBridge 50k library and discovered three putative MCAK inhibitors. These compounds reproduced the aneuploidy-inducing phenotype of MCAK loss, reduced clonogenic survival of TNBC cells regardless of taxane-resistance, and the most potent of the three, C4, sensitized TNBC cells to paclitaxel. Collectively, our work shows promise that MCAK may serve as both a biomarker of prognosis and as a therapeutic target. Simple Summary Triple negative breast cancer (TNBC) is the most lethal breast cancer subtype with few treatment options available. Standard of care for TNBC involves the use of taxanes, which are initially effective, but dose limiting toxicities are common, and patients often relapse with resistant tumors. Specific drugs that produce taxane-like effects may be able to improve patient quality of life and prognosis. In this study we identify three novel inhibitors of the Kinesin-13 MCAK. MCAK inhibition induces aneuploidy; similar to cells treated with taxanes. We demonstrate that MCAK is upregulated in TNBC and is associated with poorer prognoses. These MCAK inhibitors reduce the clonogenic survival of TNBC cells, and the most potent of the three inhibitors, C4, sensitizes TNBC cells to taxanes, similar to the effects of MCAK knockdown. This work will expand the field of precision medicine to include aneuploidy-inducing drugs that have the potential to improve patient outcomes.

A transcriptomic investigation of heat-induced transgenerational plasticity in beetles

Abstract: Abstract In response to environmental stressors, parents can shape the developmental outcomes of their offspring by contributing non-genetic but heritable factors. The transmission of such factors can potentially allow offspring, from the beginning of their lives, to express phenotypes that match their anticipated environments. In this study, I ask whether enhanced growth in larvae of Onthophagus taurus (the bull-headed dung beetle) is modified by parental exposure to heat or by exposure of the offspring to heat during early life. I find that, irrespective of the early environment of the offspring, individuals produced by parents exposed to heat grow larger. Furthermore, taking a transcriptomic approach, I find that ecdysone signalling might mediate the transgenerational effect and that increased insulin signalling or reduced production of heat shock proteins might be responsible for the enhanced growth in larvae derived from parents exposed to heat. Together, my results provide evidence for a thermally induced transgenerational effect and a foundation for functional testing of candidate mechanisms mediating the effect.

Congenital Violaceous Plaque on the Lower Leg of a Toddler: Answer

Abstract: Méndez, Alejandra MPH*; Tholpady, Sunil S. MD PhD†,‡,§; Kowal, Rachel P. MD¶,¦ Author Information

Syntheses of Pyrimidine-Modified Seleno-DNAs as Stable Antisense Molecules

Abstract: ABSTRACT Chemically modified antisense oligonucleotides (ASO) currently in pre-clinical and clinical experiments mainly focus on the 2′-position derivatizations to enhance stability and targeting affinity. Considering the possible incompatibility of 2′-modifications with RNase H stimulation and activity, we have hypothesized that the atom specific modifications on nucleobases can retain the complex structure and RNase H activity, while enhancing ASO’s binding affinity, specificity, and stability against nucleases. Herein we report a novel strategy to explore our hypothesis by synthesizing the deoxynucleoside phosphoramidite building block with the seleno-modification at 5-position of thymidine, as well as its Se-oligonucleotides. Via X-ray crystal structural study, we found that the Se-modification was located in the major groove of nucleic acid duplex and didn’t cause the thermal and structural perturbations. Surprisingly, our nucleobase-modified Se-DNAs were exceptionally resistant to nuclease digestion, while compatible with RNase H activity. This affords a novel avenue for potential antisense modification in the form of Se-antisense oli-gonucleotides (Se-ASO).

The Intersection of Natural Landscapes, Human Health, and Adventure Experiences: Linkages and Outcomes

Abstract: Defined as nonmotorized activities and experiences usually done in a natural or nature-based environment that involve elements of challenge and either real or perceived risk, in which the outcome is uncertain but influenced by the skill and ability of the participant, outdoor adventure recreation (OAR) often involves specific types of mental states, emotions, cognitions, perceptions, motivations, and associated behaviors that often have connections to personal health. OAR activities and associated programs can facilitate the development of positive and beneficial outcomes for individuals and groups with health-related outcomes that span the range of emotional, physical, psychological, and spiritual benefits. Although the health benefits of nature have long been ascribed to, and more recently are commanding greater attention, the relationship between OAR activities and personal health has a more recent history. To date, however, research has consistently shown that adventure activities, particularly those using natural and outdoor settings, can be important in promoting a broad range of positive health outcomes. This article provides an overview of what OAR is, what activities constitute the OAR experience, and how these experiences and activities can contribute to positive health-related outcomes within a natural environment. The article concludes with implications for the future including (1) responses to the COVID-19 pandemic, (2) nature prescriptions, and (3) therapeutic programming for positive health outcomes.

Photosensitized [4+2]‐ and [2+2]‐Cycloaddition Reactions of <i>N</i>‐Sulfonylimines

Abstract: The synthesis of polycyclic compounds is of high interest due to the prevalence of these motifs in drugs and natural products. Herein, we report on the stereoselective construction of 3D bicyclic scaffolds and azetidine derivatives by modulation of N-sulfonylimines to achieve either [4+2]- or [2+2]-cycloaddition reactions. The utility of the method was established by further modulation of the product. Mechanistic studies are also included, which support reaction via Dexter energy transfer.

Cardioinformatics Advancements in Healthcare and Biotechnology

Abstract: HomeCirculation: Genomic and Precision MedicineAhead of PrintCardioinformatics Advancements in Healthcare and Biotechnology No AccessArticle CommentaryRequest AccessAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessArticle CommentaryRequest AccessCardioinformatics Advancements in Healthcare and Biotechnology Bohdan B. Khomtchouk Bohdan B. KhomtchoukBohdan B. Khomtchouk Correspondence to: Bohdan Khomtchouk, PhD, 535 W. Michigan Street, Informatics & Communications Technology Complex, IT477, Indianapolis, IN 46202 USA. Email E-mail Address: [email protected] https://orcid.org/0000-0001-9607-7528 Department of BioHealth Informatics, Luddy School of Informatics, Computing & Engineering, Indiana University, Indianapolis, IN. Krannert Cardiovascular Research Center, Center for Diabetes and Metabolic Diseases, Center for Computational Biology & Bioinformatics, Indiana University School of Medicine, Indianapolis, IN. Search for more papers by this author Originally published15 Jun 2023https://doi.org/10.1161/CIRCGEN.123.004119Circulation: Genomic and Precision Medicine. 2023;0:e004119FootnotesFor Sources of Funding and Disclosures, see page XXX.Correspondence to: Bohdan Khomtchouk, PhD, 535 W. Michigan Street, Informatics & Communications Technology Complex, IT477, Indianapolis, IN 46202 USA. Email [email protected]edu Previous Back to top Next FiguresReferencesRelatedDetails Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.123.004119PMID: 37317844 Originally publishedJune 15, 2023 Keywordsbiobanksdrug discoverycardioinformaticsdatabasesprecision medicinePDF download Advertisement SubjectsBig Data and Data StandardsOmicsPrecision Medicine

Introducing a Comprehensive Set of Stratospheric Aerosol Injection Strategies

Abstract: Abstract. Stratospheric aerosol injection (SAI) comes with a wide range of possible design choices, such as the location and timing of the injection. Different injection strategies can yield different climate responses; therefore, making informed future decisions on SAI requires an understanding of the range of possible climate outcomes. Yet to date, there has been no systematic exploration of a comprehensive set of SAI strategies. This limits the ability to determine which effects are robust across different strategies and which depend on specific injection choices, or to determine if there are underlying trade-offs between different climate goals. This study systematically explores how the choice of SAI strategy affects climate responses. Here, we introduce four hemispherically-symmetric injection strategies, all of which are designed to maintain the same global mean surface temperature: an annual injection at the equator (EQ), an annual injection of equal amounts of SO2 at 15° N and 15° S (15N+15S), an annual injection of equal amounts of SO2 at 30° N and 30° S (30N+30S), and a polar injection strategy that injects equal amounts of SO2 at 60° N and 60° S only during spring in each hemisphere (60N+60S). We compare these four hemispherically-symmetric SAI strategies with a more complex injection strategy that injects different quantities of SO2 at 30° N, 15° N, 15° S, and 30° S in order to maintain not only the global mean surface temperature but also its large scale horizontal gradients. We find that the choice of SAI strategy notably affects the spatial distribution of aerosol optical depths, injection efficiency, and various surface climate responses. Among other findings, we show that injecting in subtropics produces more global cooling per unit injection, with the EQ and the 60N+60S cases requiring, respectively, 59 % and 50 % more injection than the 30N+30S case to meet the same global mean temperature target. Injecting at higher latitudes results in larger equator-to-pole temperature gradients. While all five strategies restore September Arctic sea ice, the high-latitude injection one is more effective due to the SAI-induced cooling occurring preferentially at higher latitudes.