bluuebunny/crossref_metadata_2025 huggingface dataset:
Expected clinical utility of automatable prediction models for improving palliative and end-of-life care outcomes: Toward routine decision analysis before implementation
Authors: Taseen Ryeyan , Ethier Jean-François
Published: June 2021

Objective

The study sought to evaluate the expected clinical utility of automatable prediction models for increasing goals-of-care discussions (GOCDs) among hospitalized patients at the end of life (EOL).

Materials and Methods

We built a decision model from the perspective of clinicians who aim to increase GOCDs at the EOL using an automated alert system. The alternative strategies were 4 prediction models—3 random forest models and the Modified Hospital One-year Mortality Risk model—to generate alerts for patients at a high risk of 1-year mortality. They were trained on admissions from 2011 to 2016 (70 788 patients) and tested with admissions from 2017-2018 (16 490 patients). GOCDs occurring in usual care were measured with code status orders. We calculated the expected risk difference (beneficial outcomes with alerts minus beneficial outcomes without alerts among those at the EOL), the number needed to benefit (number of alerts needed to increase benefit over usual care by 1 outcome), and the net benefit (benefit minus cost) of each strategy.

Results

Models had a C-statistic between 0.79 and 0.86. A code status order occurred during 2599 of 3773 (69%) hospitalizations at the EOL. At a risk threshold corresponding to an alert prevalence of 10%, the expected risk difference ranged from 5.4% to 10.7% and the number needed to benefit ranged from 5.4 to 10.9 alerts. Using revealed preferences, only 2 models improved net benefit over usual care. A random forest model with diagnostic predictors had the highest expected value, including in sensitivity analyses.

Discussion

Prediction models with acceptable predictive validity differed meaningfully in their ability to improve over usual decision making.

Conclusions

An evaluation of clinical utility, such as by using decision curve analysis, is recommended after validating a prediction model because metrics of model predictiveness, such as the C-statistic, are not informative of clinical value.
GWAS Identifies a Region Containing theSALL1Gene in Variation of Pigmentation Intensity Within the Chestnut Coat Color of Horses
Authors: Hammons Vada , Ribeiro Leticia , Munyard Kylie , Sadeghi Raheleh , Miller Donald , Antczak Douglas , Brooks Samantha A
Published: June 2021

Chestnut coat color in horses is determined by a missense mutation within the MC1R gene. However, the intensity of the chestnut color can vary widely within individuals possessing this genotype. Here, we investigated this variation using standardized photographs of 96 horses. Each horse was ranked lightest to darkest within the cohort for phenotype by 3 blinded observers. A genome-wide association study utilizing the relative shade ranking as the phenotype and using 268 487 single-nucleotide polymorphisms (SNPs) genotyped using the Affymetrix Equine 670k array identified a single significantly associated region on chromosome 3 (P = 2.934 × 10–8). Analysis of whole-genome sequences for horses spanning the diverse range of chestnut color identified candidate SNPs within the coding sequence of the only gene in the region: SALL1. The function of SALL1 is largely unknown, though it is predicted to interact with the Hermansky-Pudlak Syndrome type 1 (HPS1) protein, which causes partial albinism in humans. However, with only one study suggesting a circumstantial influence of the SALL1 protein on pigmentation, additional work is needed to confirm this new coat color locus in larger populations and investigate the function of this protein for impacts on equine health.
Debulking surgery for malignant tumors: the current status, evidence and future perspectives
Authors: Hishida Tomoyuki , Masai Kyohei , Kaseda Kaoru , Asakura Keisuke , Asamura Hisao
Published: June 2021

Debulking surgery, also called cytoreductive surgery, is a resection of the tumor as much as possible and an intended incomplete resection for unresectable malignant tumors. Since the most important principle in surgical oncology is complete R0 resection, debulking surgery goes against the basic principle and obscures the concept of operability. However, debulking surgery has been advocated for various types of advanced malignant tumors, including gynecological cancers, urological cancers, gastrointestinal cancers, breast cancers and other malignancies, with or without adjuvant therapy. Positive data from randomized trials have been shown in subsets of ovarian cancer, renal cell carcinoma, colorectal cancer and breast cancer. However, recent trials for renal cell carcinoma, colorectal cancer and breast cancer have tended to show controversial results, mainly according to the survival improvement of nonsurgical systemic therapy alone. On the other hand, debulking surgery still has a therapeutic role for slow-growing and borderline malignant tumors, such as pseudomyxoma peritonei and thymomas. The recent understanding of tumor heterogeneity and clonal evolution responsible for malignancy and drug resistance indicates that select patients may obtain prolonged survival by the synergistic effect of debulking surgery and novel systemic therapy. This review aimed to describe the current status and evidence of debulking surgery in a cross-organ manner and to discuss future perspectives in the current era with advances in systemic therapy.
Antibiotics Use and Subsequent Risk of Colorectal Cancer: A Swedish Nationwide Population-Based Study
Authors: Lu Sai San Moon , Mohammed Zahraa , Häggström Christel , Myte Robin , Lindquist Elisabeth , Gylfe Åsa , Van Guelpen Bethany , Harlid Sophia
Published: June 2021

Background

Antibiotics use may increase colorectal cancer (CRC) risk by altering the gut microbiota, with suggestive evidence reported. Our study aims to investigate antibiotics use in relation to subsequent CRC risk.

Methods

This is a nationwide, population-based study with a matched case-control design (first primary CRC cases and 5 matched, cancer-free controls). Complete-population data, extracted from Swedish national registers for the period 2005-2016, were used to calculate odds ratios and 95% confidence intervals.

Results

We included 40 545 CRC cases and 202 720 controls. Using the full dataset, we found a positive association between more frequent antibiotics use and CRC, excluding antibiotics prescribed within 2 years of diagnosis attenuated results toward the null. In site-specific analyses, excluding the 2-year washout, the positive association was confined to the proximal colon (adjusted odds ratio for very high use vs no use = 1.17, 95% confidence interval = 1.05 to 1.31). For rectal cancer, an inverse association, which appears to be driven by women, was observed. Quinolones and sulfonamides and/or trimethoprims were positively associated with proximal colon cancer, whereas a more general inverse association, across antibiotics classes, was observed for rectal cancer. We found no association between methenamine hippurate, a urinary tract antiseptic not affecting the gut microbiota, and CRC risk.

Conclusions

This register-based study covering the entire population of Sweden found a robust association between antibiotics use and higher risk of proximal colon cancer and an inverse association with rectal cancer in women. This study strengthens the evidence from previous investigations and adds important insight into site-specific colorectal carcinogenesis.
Decision Science Can Inform Clinical Trade-Offs Regarding Cardiotoxic Cancer Treatments
Authors: Gillman Arielle S , Vo Jacqueline B , Nohria Anju , Ferrer Rebecca A
Published: June 2021

Cancer treatment-related cardiotoxicity (ie, heart failure, coronary artery disease, vascular diseases, arrhythmia) is a growing cancer survivorship concern within oncology practice; heart disease is the leading cause of noncancer death in cancer survivors and surpasses cancer as the leading cause of death for some cancers with higher survival rates. The issue of cardiotoxicity introduces a critical tradeoff that must be acknowledged and reconciled in clinical oncology practice: treating cancer aggressively and effectively in the present vs preventing future cardiotoxicity. Although many cancers must be treated as aggressively as possible, for others, multiple treatment options are available. Yet even when effective and less cardiotoxic treatments are available, they are not always chosen. Wariness to choose equally effective but less cardiotoxic treatment options may result in part from providers’ and patients’ reliance on “cognitive heuristics,” or mental shortcuts that people (including, research shows, medical professionals) use to simplify complex judgments. These heuristics include delay discounting, availability and affect heuristics, and default bias. In the current commentary, we describe relevant research that illuminates how use of heuristics leads to biased medical decision making and translate how this research may apply when the tradeoff between aggressive cancer treatment and preventing future cardiotoxicity is considered. We discuss the implications of these biases in oncology practice, offer potential solutions to reduce bias, and call for future research in this area.
Targeted metabolite profiling as a top-down approach to uncover interspecies diversity and identify key conserved operational features in the Calvin–Benson cycle
Authors: Stitt Mark , Luca Borghi Gian , Arrivault Stéphanie
Published: June 2021

Improving photosynthesis is a promising avenue to increase crop yield. This will be aided by better understanding of natural variance in photosynthesis. Profiling of Calvin–Benson cycle (CBC) metabolites provides a top-down strategy to uncover interspecies diversity in CBC operation. In a study of four C4 and five C3 species, principal components analysis separated C4 species from C3 species and also separated different C4 species. These separations were driven by metabolites that reflect known species differences in their biochemistry and pathways. Unexpectedly, there was also considerable diversity between the C3 species. Falling atmospheric CO2 and changing temperature, nitrogen, and water availability have driven evolution of C4 photosynthesis in multiple lineages. We propose that analogous selective pressures drove lineage-dependent evolution of the CBC in C3 species. Examples of species-dependent variation include differences in the balance between the CBC and the light reactions, and in the balance between regulated steps in the CBC. Metabolite profiles also reveal conserved features including inactivation of enzymes in low irradiance, and maintenance of CBC metabolites at relatively high levels in the absence of net CO2 fixation. These features may be important for photosynthetic efficiency in low light, fluctuating irradiance, and when stomata close due to low water availability.
Encoding the haunting of an object catalogue: on the potential of digital technologies to perpetuate or subvert the silence and bias of the early-modern archive
Authors: Ortolja-Baird Alexandra , Nyhan Julianne
Published: June 2021

The subjectivities that shape data collection and management have received extensive criticism, especially with regards to the digitization projects and digital archives of galleries, libraries, archives and museums (GLAM institutions). The role of digital methods for recovering data absences is increasingly receiving attention too. Conceptualizing the absence of non-hegemonic individuals from the catalogues of Sir Hans Sloane as an instance of textual haunting, this article will ask: to what extent do data-driven approaches further entrench archival absences and silences? Can digital approaches be used to highlight or recover absent data? This article will give a decisive overview of relevant literature and projects so as to examine how digital tools are being realigned to recover, or more modestly acknowledge, the vast, undocumented network of individuals who have been omitted from canonical histories. Drawing on the example of Sloane, this article will reiterate the importance of a more rigorous ethics of digital practice, and propose recommendations for the management and representation of historical data, so cultural heritage institutions and digital humanists may better inform users of the absences and subjectivities that shape digital datasets and archives. This article is built on a comprehensive survey of digital humanities’ current algorithmic approaches to absence and bias. It also presents reflections on how we, the authors, grappled with unforeseen questions of absence and bias during a Leverhulme-funded collaboration between the British Museum and University College London (UCL), entitled ‘Enlightenment Architectures: Sir Hans Sloane’s Catalogues of his collections’.
Rotational (de)-excitation of HMgNC in collision with He
Authors: Amor M A , Hammami K , Wiesenfeld L
Published: June 2021

Potential energy surface for the collision between HMgNC and He are evaluated using the high-accuracy CCSD(T)-F12 ab-initio method. This PES leads to conduct quantum dynamical scattering calculations of the rotational and hyperfine (de)-excitations rate coefficients for temperatures up to 200 K. In order to evaluate the impact of the computed data, we performed radiative transfer computations of the brightness and excitation temperatures for selected observed j = 8 to 7 transition.
Sensing and seeing associated with overlapping occipitoparietal activation in simultaneous EEG-fMRI
Authors: Scrivener Catriona L , Malik Asad , Lindner Michael , Roesch Etienne B
Published: June 2021

The presence of a change in a visual scene can influence brain activity and behavior, even in the absence of full conscious report. It may be possible for us to sense that such a change has occurred, even if we cannot specify exactly where or what it was. Despite existing evidence from electroencephalogram (EEG) and eye-tracking data, it is still unclear how this partial level of awareness relates to functional magnetic resonance imaging (fMRI) blood oxygen level dependent (BOLD) activation. Using EEG, fMRI, and a change blindness paradigm, we found multi-modal evidence to suggest that sensing a change is distinguishable from being blind to it. Specifically, trials during which participants could detect the presence of a colour change but not identify the location of the change (sense trials), were compared to those where participants could both detect and localise the change (localise or see trials), as well as change blind trials. In EEG, late parietal positivity and N2 amplitudes were larger for localised changes only, when compared to change blindness. However, ERP-informed fMRI analysis found no voxels with activation that significantly co-varied with fluctuations in single-trial late positivity amplitudes. In fMRI, a range of visual (BA17,18), parietal (BA7,40), and mid-brain (anterior cingulate, BA24) areas showed increased fMRI BOLD activation when a change was sensed, compared to change blindness. These visual and parietal areas are commonly implicated as the storage sites of visual working memory, and we therefore argue that sensing may not be explained by a lack of stored representation of the visual display. Both seeing and sensing a change were associated with an overlapping occipitoparietal network of activation when compared to blind trials, suggesting that the quality of the visual representation, rather than the lack of one, may result in partial awareness during the change blindness paradigm.
Predictors of survival in elderly patients undergoing surgery for glioblastoma
Authors: Voisin Mathew R , Sasikumar Sanskriti , Zadeh Gelareh
Published: June 2021

Background

Glioblastoma (GBM) has a median age of diagnosis of 64 years old and the incidence increases with age. An increasing number of elderly patients are being diagnosed with GBM and undergoing surgery. These patients often present with multiple medical comorbidities and have significantly worse outcomes compared to adult patients. The goal of this study was to determine clinical predictors of survival in elderly patients undergoing surgery for GBM.

Methods

Our brain tumor database was reviewed for all patients 65 years of age and older that underwent surgery for newly diagnosed GBM over a 14-year period from 2005 to 2018. Patient characteristics, comorbidities, complications, and treatment were collected. A total of 150 patients were included, and subdivided into two age categories; 65–74 years old and 75 years or older.

Results

The median OS for all patients was 9.4 months. Neither the presence nor number of medical comorbidities were associated with decreased survival (P = .9 and P = .1, respectively). Postoperative complications were associated with worse survival for all patients (HR = 2.34, P = .01) and occurred in patients in the older age category and patients with longer lengths of stay (P < .0001).

Conclusions

The presence of medical comorbidities is not a reason to exclude patients with GBM from surgical consideration. Excluding EOR and adjuvant treatment, postoperative complication is the most significant predictor of survival in elderly patients. Postoperative complications are associated with a longer LOS and are more common in patients 75 years of age and older.
Relapsed Babesia microti Infection Following Allogeneic Hematopoietic Cell Transplantation in a Patient With B-cell Acute Lymphoblastic Leukemia: Case Report and Review of the Literature
Authors: Rosenblatt Joshua , Leung Annie , Baneman Emily , Fuller Risa , Taimur Sarah , Paniz-Mondolfi Alberto E , Malone Adriana K , Kirkman Laura , Jacobs Samantha E
Published: June 2021

A patient with relapsed/refractory B-cell acute lymphoblastic leukemia developed babesiosis before allogeneic hematopoietic cell transplantation while on atovaquone for Pneumocystis jirovecii pneumonia prophylaxis. Despite receiving a prolonged course of atovaquone and azithromycin until whole-blood Babesia microti DNA was no longer detected by polymerase chain reaction, her post-transplant course was complicated by relapsed babesiosis. We investigate the potential host and parasite characteristics causing relapsing/persistent infection.
Transmission of SARS-CoV-2 in Inpatient and Outpatient Settings in a Veterans Affairs Health Care System
Authors: Jinadatha Chetan , Jones Lucas D , Choi Hosoon , Chatterjee Piyali , Hwang Munok , Redmond Sarah N , Navas Maria E , Zabarsky Trina F , Bhullar Davinder , Cadnum Jennifer L , Donskey Curtis J
Published: June 2021

Background

Health care personnel and patients are at risk to acquire severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in health care settings, including in outpatient clinics and ancillary care areas.

Methods

Between May 1, 2020, and January 31, 2021, we identified clusters of 3 or more coronavirus disease 2019 (COVID-19) cases in which nosocomial transmission was suspected in a Veterans Affairs health care system. Asymptomatic employees and patients were tested for SARS-CoV-2 if they were identified as being at risk through contact tracing investigations; for 7 clusters, all personnel and/or patients in a shared work area were tested regardless of exposure history. Whole-genome sequencing was performed to determine the relatedness of SARS-CoV-2 samples from the clusters and from control employees and patients.

Results

Of 14 clusters investigated, 7 occurred in community-based outpatient clinics, 1 in the emergency department, 3 in ancillary care areas, and 3 on hospital medical/surgical wards that did not provide care for patients with known COVID-19 infection. Eighty-one of 82 (99%) symptomatic COVID-19 cases and 31 of 35 (89%) asymptomatic cases occurred in health care personnel. Sequencing analysis provided support for several transmission events between coworkers and in 2 cases supported transmission from health care personnel to patients. There were no documented transmissions from patients to personnel.

Conclusions

Clusters of COVID-19 with nosocomial transmission predominantly involved health care personnel and often occurred in outpatient clinics and ancillary care areas. There is a need for improved measures to prevent transmission of SARS-CoV-2 by health care personnel in inpatient and outpatient settings.
Speaking in Hands: Early Modern Preaching and Signed Languages for the Deaf
Authors: Oates Rosamund
Published: June 2021

This article demonstrates that deaf men and women were integrated into early modern communities through use of sign language, and that Protestant concerns about preaching and hearing promoted sign language as a legitimate form of communication. Historians have believed that the Protestant emphasis on preaching excluded deaf people from heaven. However, not only did contemporaries believe that deaf people could be saved, but debates on this topic prompted a wider assessment of the nature of hearing loss and sensory knowledge. Discussions about deafness therefore had implications for all congregations, as English preachers used well-known manual gestures from rhetorical texts to make their sermons accessible for both the ‘spiritually’ and the ‘physically’ deaf. The experiences of deaf people in early modern England demonstrate the importance of religious practices in shaping perceptions of disability and impairment. By focusing on deaf parishioners, it is possible to explore some of the impacts of the Reformation on ideas of embodiment while modifying literary accounts of the representation of disability in the period. A little-known part of early modern history, the role of preachers in the evolution of signed languages for the deaf offers new perspectives on Reformation history and the growing field of disability history.
SlHair2 Regulates the Initiation and Elongation of Type I Trichomes on Tomato Leaves and Stems
Authors: Chun Jae-In , Kim Seong-Min , Kim Heejin , Cho Jae-Yong , Kwon Hyun-Woo , Kim Jeong-Il , Seo Jang-Kyun , Jung Choonkyun , Kang Jin-Ho
Published: June 2021

Trichomes are hair-like structures that are essential for abiotic and biotic stress responses. Tomato Hair (H), encoding a C2H2 zinc finger protein, was found to regulate the multicellular trichomes on stems. Here, we characterized Solyc10g078990 (hereafter Hair2, H2), its closest homolog, to examine whether it was involved in trichome development. The H2 gene was highly expressed in the leaves, and its protein contained a single C2H2 domain and was localized to the nucleus. The number and length of type I trichomes on the leaves and stems of knock-out h2 plants were reduced when compared to the wild-type, while overexpression increased their number and length. An auto-activation test with various truncated forms of H2 using yeast two-hybrid (Y2H) suggested that H2 acts as a transcriptional regulator or co-activator and that its N-terminal region is important for auto-activation. Y2H and pull-down analyses showed that H2 interacts with Woolly (Wo), which regulates the development of type I trichomes in tomato. Luciferase complementation imaging assays confirmed that they had direct interactions, implying that H2 and Wo function together to regulate the development of trichomes. These results suggest that H2 has a role in the initiation and elongation of type I trichomes in tomato.
Partners of female patients with rheumatoid arthritis and reproductive decision-making: a constructivist grounded theory study
Authors: Garg Ria , Rebić Nevena , Amiri Neda , Hazlewood Glen , Baldwin Corisande , Ensworth Stephanie , Proulx Laurie , De Vera Mary A
Published: June 2021

Objective

Partners of patients with RA often take on supportive roles given the debilitating nature of RA. Our objective was to explore the perspectives, attitudes and experiences of partners of female patients with RA regarding reproductive experiences and decision-making.

Methods

We conducted a qualitative study involving semi-structured interviews with partners of female patients with RA. We defined a partner as an individual within a romantic relationship. Constructivist grounded theory was applied to interview transcripts to identify and conceptualize themes.

Results

We interviewed 10 partners of female patients with RA (10 males; mean age, 35 [23–56] years), of whom 40% had at least one child with a female patient with RA and did not desire additional children. We identified four themes representing stages of reproductive decision-making: (1) developing an understanding of RA, (2) contemplating future family decision-making, (3) initiating reproductive decision-making with partner, and (4) reflecting on past reproductive experiences. Participants contemplated their attitudes and perspectives regarding pregnancy and used available information to support their partner’s medication decisions. When reflecting on their reproductive experiences, participants shared the impacts of past reproductive decisions on their romantic relationship and their mental health and wellbeing.

Conclusion

Our study highlights the need for comprehensive support for both female patients with RA and their partners at all stages of reproductive decision-making. Health-care providers can identify opportunities for intervention that involves female patients with RA and their partners to minimize stress and its negative impacts on the family.
Evolutionary history of Sundaland shrews (Eulipotyphla: Soricidae:Crocidura) with a focus on Borneo
Authors: Hinckley Arlo , Camacho-Sanchez Miguel , Ruedi Manuel , Hawkins Melissa T R , Mullon Madeleine , Cornellas Anna , Tuh Yit Yuh Fred , Leonard Jennifer A
Published: June 2021

The hyperdiverse shrew genus Crocidura is one of few small mammal genera distributed across Sundaland and all of its boundaries. This represents a rare opportunity to study the geological history of this region through the evolutionary history of these shrews. We generate a phylogeny of all recognized species of Sundaland Crocidura and show that most speciation events took place during the Pleistocene, prior to the inundation of the Sunda Shelf around 400 000 years ago. We find east–west differentiation within two separate lineages on Borneo, and that the current taxonomy of its two endemic species does not reflect evolutionary history, but ecophenotypic variation of plastic traits related to elevation. Sulawesi shrews are monophyletic, with a single notable exception: the black-footed shrew (C. nigripes). We show that the black-footed shrew diverged from its relatives on Borneo recently, suggesting a human-assisted breach of Wallace’s line. Overall, the number of Crocidura species, especially on Borneo, probably remains an underestimate.
Metabolism, the microbiome, and the circadian clock
Authors: Hooper Lora V. , Wang Yuhao , Kuang Zheng
Published: June 2021

The intestinal microbiota has been identified as an environmental factor that markedly impacts energy storage and body fat accumulation, yet the underlying mechanisms remain unclear. We have shown that the microbiota regulates body composition through the circadian transcription factor NFIL3. Nfil3 transcription oscillates diurnally in intestinal epithelial cells and the amplitude of the circadian oscillation is controlled by the microbiota through group 3 innate lymphoid cells (ILC3), STAT3, and the epithelial cell circadian clock. NFIL3 controls expression of a circadian lipid metabolic program and regulates lipid absorption and export in intestinal epithelial cells. These findings provide mechanistic insight into how the intestinal microbiota regulates body composition and establish NFIL3 as an essential molecular link among the microbiota, the circadian clock, and host metabolism.

Support or Funding Information

NIH grant R01 DK070855 (L.V.H.); Burroughs Wellcome Foundation Investigators in the Pathogenesis of Infectious Diseases Award (L.V.H.); the Welch Foundation (L.V.H.), and the Howard Hughes Medical Institute (L.V.H.)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Interrogating endogenous neuromodulatory GPCR signal processing by real‐time imaging of cAMP dynamics through intact neuronal circuits
Authors: Muntean Brian S , Zucca Stefano , MacMullen Courtney M , Dao Maria T , Johnston Caitlin , Iwamoto Hideki , Blakely Randy D , Davis Ronald L , Martemyanov Kirill A
Published: June 2021

The majority of neuromodulators exert their effects by activating G protein coupled receptors (GPCRs) which shape neuronal properties through the regulation of second messengers. The mechanisms of signal decoding at GPCRs amidst diversity of the effects associated with their ctivation remains elusive. Furthermore, there is a paucity of understanding of how GPCRs signal to produce unique responses impacting cellular physiology while converging on a limited set of second messenger signaling cascades. Although significant progress has been made studying GPCRs in reconstituted systems, information decoding processes by GPCRs in an endogenous setting is understood less due to a lack of appropriate tools. Here, we developed a novel in vivo reagent that allows monitoring GPCR signaling in the endogenous setting from genetically defined populations of cells. The approach takes advantage of knock‐in mice engineered to express a genetically encoded FRET‐based cAMP biosensor in a Cre‐dependent fashion. We applied this reagent to study integration of GPCR signals in striatal medium spiny neurons both in culture and in brain slices where intact circuits were activated by optogenetics. Combined with CRISPR/Cas9 genomic editing, this approach enabled us to identify individual receptors and analyze their contributions to downstream signaling in the native environment. We identified key spatial differences in pharmacological responsiveness by comparing dendritic regions with the neuronal cell body as well as plasma membrane and internal cellular signaling compartments. We then conducted comparative analysis of GPCR signaling mediated by two opposing circuits modulated by the neurotransmitter dopamine, revealing the mechanisms of dopaminergic processing as well as major differences in the generation of discrete second messenger signatures. We further demonstrate how cAMP signal processing mechanisms contribute to allostatic adaptations that imbalance tuning between striatal output neurons that may underlie states of reward and aversion.

Support or Funding Information

NIH 1R01DK110621, APS STRIDE Undergraduate Summer Research Fellowship 1R25HL115473‐01.

This work was supported by NIH grants: DA041207 (to B.S.M.), DA036596 (to K.A.M.), and DA026405 (to K.A.M.).
Correlation of Securin and Ki67 in Invasive Breast Carcinoma
Authors: Talaat Iman Mamdouh , Hamoudi Rifat Akram , Soliman Nada Mahmoud , Oweiss Nagwa Youssef , Omar Abbas Mohammed
Published: June 2021

Introduction

Apart from skin malignancies, breast cancer ranks the second most common malignancy in females worldwide. The increasing trends of breast cancer have led to plethora of studies in attempt to identify biological markers that may identify patients who may develop local recurrence or metastasis. Among those are proliferation markers which encompass ki67 and Pituitary Derived Tumour‐Transforming Growth Protein (PTTG).

Aims

To identify the role of securin (PTTG) as prognostic marker in invasive breast carcinoma and its possible relation to ki67 and evaluate the use of ImmunoRatio® as a tool for calculating ki67 and labelling indices.

Methods

Securin and Ki67 immunohistochemical staining was performed on tissue microarray sections representative of 118 patients diagnosed with invasive breast carcinoma from 2005 to 2011. Assessment of immunohistochemical staining was carried out using both visual counting and ImmunoRatio®. The 118 cases were categorized into 2 groups according to their clinical outcome; the first group (G1) (n=77) comprised patients who were disease‐free while the second group (G2) (n=41) included patients who developed either recurrence and/or metastasis at the end of 24 months follow up duration.

Results

Both securin and Ki67 labelling indices (LIs) obtained by visual counting were significantly higher in G2, while only securin LIs acquired by ImmunoRatio® were significantly higher in G2. Securin assessment by visual counting was the most accurate (AUC=0.775) in identifying patients who will likely suffer from recurrence or distant metastasis. Pearson correlation showed r=63.8%, p < 0.001 for Ki67 and r=67.1%, p <0.001 for securin. Linear regression analysis showed significant correlation between Ki67 and securin, B = 1.75, p < 0.001.

Conclusion

The present results suggest that securin may have superior value to ki67 highlighting intra‐tumoural heterogeneity regions in invasive breast carcinoma patients' with poor clinical outcome. Better correlation between securin visual counting and ImmunoRatio® suggests that securin provides more uniform staining pattern than Ki67 in breast cancer.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hybrid experimental‐mathematical methods for probing dynamic proteome organization during viral infections
Authors: Cristea Ileana M.
Published: June 2021

Every year, a major cause of human disease and death worldwide is infection with the various viral pathogens that are intrinsic to our ecosystem. The outcomes of viral infections derive from dynamic virus‐host cell interactions that function either in promoting virus replication or in host defense against invading pathogens. An essential component of these virus‐host interactions is spatial organization. Eukaryotic viruses replicate within highly organized host cells that compartmentalize their vast cellular proteomes within organelles. Alterations in organelle shape, composition, function, and dynamics are prominent features of virus replication cycles, although the knowledge of the mechanisms involved remains limited.

This presentation will describe the integration of experimental studies, mathematical modeling and inference methods for understanding the dynamic regulation of organelles during viral infection. The experimental methods presented will include live‐cell microscopy and quantitative mass spectrometry‐based proteomics for characterizing both organelle changes and virus‐host protein interactions during the progression of an infection. These studies discovered 1) dynamic changes in organelle composition, 2) translocation of cellular proteins from one subcellular compartment to another, and 3) temporal virus‐host protein interactions within organelles that induce alterations in host biological pathways (Figure 1).

The value of these integrative methods is demonstrated by the identification of mechanisms through which viruses remodel subcellular organelle function to suppress host defense and promote viral replication. Furthermore, our findings are starting to uncover how viruses regulate the dynamics of organelle biogenesis during infection. Overall, these studies highlight how integrative omic technologies can help paint a picture of the pathogen's life cycle and aid in the future development of antiviral therapies.

Support or Funding Information

NIH grants GM114141 and HL127640, and Mallinckrodt Scholar Award

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Elevated Thrombospondin‐2 Contributes to Delayed Wound Healing in Diabetes
Authors: Kunkemoeller Britta , Kyriakides Themis R.
Published: June 2021

Impaired wound healing is a major complication of diabetes and can lead to the development of chronic wounds in a significant portion of diabetes patients. Despite the risks posed by impaired healing, treatment strategies for diabetic wounds remain limited due to an incomplete understanding of the underlying pathological mechanisms. Previous studies have demonstrated that overexpression of thrombospondin‐2 (TSP2), a matricellular protein released after tissue injury, is associated with significant delays in dermal healing in various mouse models. Consistently, wounds lacking TSP2 (TSP2 KO) heal faster than wounds in wild‐type mice or mice with elevated TSP2. Thus, the present study aimed to examine the role of TSP2 in delayed healing in diabetes.

First, we evaluated TSP2 expression in human wounds, and found that TSP2 is elevated in wounds from diabetes patients. Then, to determine TSP2's contribution to impaired healing in diabetes, we developed a novel diabetic TSP2 KO mouse model. Though these db/db TSP2 KO mice develop obesity and hyperglycemia comparable to db/db mice, db/db TSP2 KO mice exhibit significantly improved healing. Moreover, primary fibroblasts isolated from db/db TSP2 KO mice exhibit improved migration, providing mechanistic insight into the accelerated healing in these mice. We also studied TSP2 expression in fibroblasts, the major source of TSP2 in the wound, to explore the mechanisms leading to its overexpression in diabetes. Our results showed that TSP2 expression is increased in hyperglycemia, through increased activation of the hexosamine biosynthesis pathway and subsequent O‐GlcNAc modification of transcriptional elements. Overall, the results of this study indicate for the first time that: 1) TSP2 expression is elevated in diabetes and hyperglycemia and 2) TSP2 contributes to impaired healing in diabetes. These results represent a novel role for TSP2 in diabetes complications and a novel target for improving wound healing in diabetes.

Support or Funding Information

NIH HL107205, NIH GM 072194, Gruber Science Fellowship

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Roles of GPR39, a Zinc‐Sensing Receptor, in the Regulation of Barrier Function of Intestinal Epithelial Cells
Authors: Chantivas Thanyatorn , Pongkorpsakol Pawin , Muanprasat Chatchai
Published: June 2021

Zinc deficiency is associated with several gastrointestinal diseases such as diarrhea and IBD, whose pathogenesis is partly due to impaired intestinal barrier function. This observation suggests the beneficial role of zinc in regulating intestinal barrier function. The aim of this study was to investigate the effect of GPR39, a zinc‐sensing receptor, on intestinal barrier function and its underlying mechanisms. The results showed that treatment of T84 cell monolayers with TC‐G 1008, a GPR39 agonist significantly increased their transepithelial electrical resistance (TEER), indicating increased intestinal barrier function. The TC‐G 1008‐induced increase in TEER was in a time‐ and dose‐dependent manner. Moreover, co‐treatment with compound C, an AMPK inhibitor, completely abolished the effect of GPR39 agonist on TEER. This result suggests that AMPK may mediate the action of GPR39 agonist. In support of this notion, western blot analysis demonstrated that TC‐G 1008 time‐dependently induced AMPK phosphorylation, which reached its maximum at 2 hours paralleling the change in TER. Taken together, our results indicate that GPR39 activation can improve intestinal barrier function through an AMPK‐dependent pathway. This study provides an insight into the roles of GPR39 in the control of intestinal epithelial barrier integrity, which may be important for understanding pathogenesis or developing treatment of intestinal diseases.

Support or Funding Information

This work was supported by grants BRG5980008 from Thailand Research Fund and Mahidol University and Tonkla Ramathibodi Project from Faculty of Medicine Ramathibodi Hospital, Mahidol University.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mapping Platelet Responses in Native American Populations
Authors: Stein Sarah J. , Rodezno Tania G. , Graber Katelyn N. , Hora Kirby A. , Clarke Santa M. , Pahlke Rachel S. , Abbott Karla M. , Larson Mark K.
Published: June 2021

Platelets, key cellular components in normal hemostasis, can contribute to cardiovascular disease progression and are altered by certain drug therapies. These effects occur via a wide array of protein receptors that can respond to various in vivo signals and pharmaceutical products. Research has shown that the degree of platelet reactivity to either cellular signals or drugs may vary widely among individuals based upon the presence of receptor allele polymorphisms enriched within certain ethnicities. For example, African American populations have a variant in the thrombin receptor PAR‐4 that results in greater degrees of platelet activation and refractivity towards anti‐platelet medications compared to Caucasian populations (Edelstein et al., 2014, Blood 124: 3450–3458). As such, we novelly compared Caucasian and Native American populations by mapping platelet responses to five agonists that target distinct platelet receptors. Twenty‐five Native American subjects were studied along with age and sex‐matched Caucasian subjects. Flow cytometric analysis of platelet GPIIb/IIIa integrin conformational activation was used to measure the dose‐response effects of agonists on platelet activation, and SPSS was used to perform statistical analyses. Results showed that Native American subjects displayed higher levels of activation in response to lower doses of adenosine diphosphate (ADP) and thrombin receptor activating peptide (TRAP) compared to Caucasian subjects. However, no activation profile differences were observed following agonism of collagen, thromboxane, or von Willebrand factor receptors. This implies that medications targeting ADP and/or thrombin receptors could have varying responses in patients, or that those medications may not be optimal when treating patients with these receptor‐response variances. The data provide insight into possible platelet receptor variants between Native Americans and Caucasians that warrants further investigation.

Support or Funding Information

Research was supported in part by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (P20GM103443), as well as funding from the National Science Foundation/EPSCoR program [IIA‐1355423], the state of South Dakota, and an undergraduate fellowship from the American Physiological Society.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Delineating the age‐related attenuation of vascular function: evidence supporting the efficacy of single passive leg movement.
Authors: Hydren Jay R. , Boxterman Ryan M. , Trinity Joel D. , Gifford Jayson R. , Kwon Oh Sung , Kithas Andrew C. , Richardson Russell S.
Published: June 2021

Passive leg movement (PLM), performed continuously, is a promising clinically relevant assessment of peripheral vascular function which declines with age. To further refine PLM, this study evaluated the efficacy of a single PLM (sPLM) to delineate between young and old healthy males based on vascular function.

Methods

Twelve healthy young (26±5 yr) and 12 old (70±7 yr) underwent sPLM: blood flow was assessed by Doppler ultrasound at baseline, during, and for one minute after a single leg movement (range of motion 90°). Blood pressure was continuously recorded by finger photoplethysmography. Factor analysis assessed covariance. If a significant age difference emerged, a cut score was determined by a receiver operator characteristic curve analysis. Data are mean±SD.

Results

All blood flow and leg vascular conductance measures loaded into one factor (standardized loading ≥ 0.85), indicating the only physiological measure needed was blood flow. Baseline blood flows were similar between groups (p=0.626). Peak increase in blood flow from baseline was significantly attenuated in the old (Young: 717±227, Old: 260±97 ml·min−1, p<0.001; cut score: 485 ml·min−1, sensitivity 1, specificity 1) as was the total sPLM‐induced blood flow, above baseline, for 45 seconds (Young: 155±67, Old: 26±17ml, p<0.001; cut score: 72 ml, sensitivity 1, specificity 1).

Conclusion

sPLM, a simplified version of PLM, demonstrated strong qualities of a screening test for peripheral vascular function, evidenced by revealing the age‐related reduction in peripheral hyperemic response with clearly delineated cut scores. Indicating, sPLM has strong potential as an accurate screening test for age‐related attenuations in peripheral vascular function.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Standardizing the Isolation, Culture‐Expansion, and Cryopreservation of Canine Umbilical‐Cord Derived Mesenchymal Stromal Cells
Authors: Cromer Adrienne , Lillich James , Weiss Mark
Published: June 2021

Mesenchymal stromal cells (MSCs) hold great promise in the field of regenerative medicine due to their ability to enable functional recovery in inflammatory injuries such as Crohn's disease and osteoarthritis. Currently, the MSC literature is focused on rodents for preclinical models of disease or clinical testing in human patients. We are interested in using the canine as a large animal model of human diseases. In this regard, the canine MSC literature lags behind human and rodent MSC, and most work on canine MSCs has focused upon bone marrow and adipose tissue‐derived with wide variation in isolation techniques. From surveying the literature and our pilot work, canine MSCs are more difficult to culture than human or rodent MSCs, have longer population doubling times, and earlier senesce. Here, a reproducible protocol for isolation and expansion of canine umbilical cord MSCs is provided. This method produces 10× greater yield per gram of tissue than other published methods. Gelatin‐coating of tissue culture plates greatly increases colony‐forming units‐fibroblast efficiency and decreases population doubling times. In addition, MSCs were able to be cultured longer before senescing, thereby increasing their cumulative population doublings. In summary, our understanding of the culture conditions needed for canine MSCs lags behind that of other species. Gelatin‐coating of tissue culture plates appears to be important for reproducible canine MSC culture. Currently, we are testing differentiation and characterization protocols to offer as standardized methods for the field.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.