bluuebunny/crossref_metadata_2025_split huggingface dataset:
Opposing roles for TGFβ- and BMP-signaling during nascent alveolar differentiation in the developing human lung
Authors: Frum Tristan , Hsu Peggy P. , Hein Renee F.C. , Conchola Ansley S. , Zhang Charles J. , Utter Olivia R. , Anand Abhinav , Zhang Yi , Clark Sydney G. , Glass Ian , Sexton Jonathan Z. , Spence Jason R. 
Published: May 2023

AbstractAlveolar type 2 (AT2) cells function as stem cells in the adult lung and aid in repair after injury. The current study aimed to understand the signaling events that control differentiation of this therapeutically relevant cell type during human development. Using lung explant and organoid models, we identified opposing effects of TGFβ- and BMP-signaling, where inhibition of TGFβ- and activation of BMP-signaling in the context of high WNT- and FGF-signaling efficiently differentiated early lung progenitors into AT2-like cellsin vitro. AT2-like cells differentiated in this manner exhibit surfactant processing and secretion capabilities, and long-term commitment to a mature AT2 phenotype when expanded in media optimized for primary AT2 culture. Comparing AT2-like cells differentiated with TGFβ-inhibition and BMP-activation to alternative differentiation approaches revealed improved specificity to the AT2 lineage and reduced off-target cell types. These findings reveal opposing roles for TGFβ- and BMP-signaling in AT2 differentiation and provide a new strategy to generate a therapeutically relevant cell typein vitro.
Sex similarities and dopaminergic differences in interval timing
Authors: Stutt Hannah R. , Weber Matthew A. , Cole Rachael C. , Bova Alexandra S. , Ding Xin , McMurrin Madison S. , Narayanan Nandakumar S. 
Published: May 2023

ABSTRACTRodent behavioral studies have largely focused on male animals, which has limited the generalizability and conclusions of neuroscience research. Working with humans and rodents, we studied sex effects during interval timing that requires participants to estimate an interval of several seconds by making motor responses. Interval timing requires attention to the passage of time and working memory for temporal rules. We found no differences between human females and males in interval timing response times (timing accuracy) or the coefficient of variance of response times (timing precision). Consistent with prior work, we also found no differences between female and male rodents in timing accuracy or precision. In female rodents, there was no difference in interval timing between estrus and diestrus cycle stages. Because dopamine powerfully affects interval timing, we also examined sex differences with drugs targeting dopaminergic receptors. In both female and male rodents, interval timing was delayed after administration of sulpiride (D2-receptor antagonist), quinpirole (D2-receptor agonist), and SCH-23390 (D1-receptor antagonist). By contrast, after administration of SKF-81297 (D1-receptor agonist), interval timing shifted earlier only in male rodents. These data illuminate sex similarities and differences in interval timing. Our results have relevance for rodent models of both cognitive function and brain disease by increasing represenation in behavioral neuroscience.
Predicting Parkinson’s disease progression using MRI-based white matter radiomic biomarker and machine learning: a reproducibility and replicability study
Authors: Arafe Mohanad , Bhagwat Nikhil , Chatelain Yohan , Dugré Mathieu , Sokołowski Andrzej , Wang Michelle , Xiao Yiming , Sharp Madeleine , Poline Jean-Baptiste , Glatard Tristan 
Published: May 2023

AbstractBackgroundThe availability of reliable biomarkers of Parkinson’s disease (PD) progression is critical to the understanding of the disease and development of treatment options. Magnetic Resonance Imaging (MRI) provides a promising source of PD biomarkers, however, neuroimaging results have been shown to be markedly sensitive to analytical conditions and population sampling, which motivates investigations of their robustness. This study is part of a project to investigate the replicability of 11 structural MRI measures of PD identified in a recent review.ObjectiveThis paper attempts to reproduce (similar data, similar analysis) and replicate (variations in data and analysis) the design of the machine learning (ML) model described in [1] to predict PD progression from T1-weighted MRIs.MethodsWe used the Parkinson’s Progression Markers Initiative dataset (PPMI,ppmi-info.org) used in [1] and we followed as closely as possible the original methods. We also investigated slight methodological variations in cohort selection, feature extraction, ML model design, and evaluation techniques.ResultsThe Area under the ROC Curve (AUC) achieved by our model closely reproducing the original study remained lower than 0.5. Across all tested models, we obtained a peak AUC of 0.685, which is better than chance performance but remained lower than the AUC value of 0.795 reported in [1].ConclusionWe managed to train a model that predicts disease progression with a performance better than chance on a cohort extracted from the PPMI dataset, using methods adapted from [1]. However, the performance of this model remains substantially lower than the one reported in [1]. Our difficulties to reproduce or replicate the original work are likely explained by the relatively low sample size in the original study. We provide recommendations on how to improve the reproducibility of MRI-based ML models of PD in the future.
Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell neurons via NMDAR activation in a sex-dependent manner
Authors: Chapp Andrew D. , Nwakama Chinonso A. , Mermelstein Paul G. , Thomas Mark J. 
Published: May 2023

AbstractRecent studies have implicated the ethanol metabolite, acetic acid, as neuroactive, perhaps even more so than ethanol itself. In this study, we investigated sex-specific metabolism of ethanol (1, 2, and 4g/kg) to acetic acidin vivoto guide electrophysiology experiments in the accumbens shell (NAcSh), a key node in the mammalian reward circuit. There was a sex-dependent difference in serum acetate production, quantified via ion chromatography only at the lowest dose of ethanol (males>females).Ex vivoelectrophysiology recordings of NAcSh neurons in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh neuronal excitability in both sexes.N-methyl-D-aspartate receptor (NMDAR) antagonists, AP5, and memantine robustly attenuated the acetic acid-induced increase in excitability. Acetic acid-induced NMDAR-dependent inward currents were greater in females compared to males. These findings suggest a novel NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may influence neurophysiological effects in a key reward circuit in the brain.
Non-invasive neuromodulation of sub-regions of the human insula differentially affect pain processing and heart-rate variability
Authors: Legon Wynn , Strohman Andrew , In Alexander , Stebbins Katelyn , Payne Brighton 
Published: May 2023

ABSTRACTThe insula is a portion of the cerebral cortex folded deep within the lateral sulcus covered by the overlying opercula of the inferior frontal lobe and superior portion of the temporal lobe. The insula has been parsed into sub-regions based upon cytoarchitectonics and structural and functional connectivity with multiple lines of evidence supporting specific roles for each of these sub-regions in pain processing and interoception. In the past, causal interrogation of the insula was only possible in patients with surgically implanted electrodes. Here, we leverage the high spatial resolution combined with the deep penetration depth of low-intensity focused ultrasound (LIFU) to non-surgically modulate either the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact head evoked potentials (CHEPs) and time-frequency power as well as autonomic measures including heart-rate variability (HRV) and electrodermal response (EDR). N = 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, EDR and EEG recording. LIFU was delivered to either the AI (anterior short gyrus), PI (posterior longus gyrus) or under an inert sham condition time-locked to the heat stimulus. Results demonstrate that single-element 500 kHz LIFU is capable of individually targeting specific gyri of the insula. LIFU to both AI and PI similarly reduced perceived pain ratings but had differential effects on EEG activity. LIFU to PI affected earlier EEG amplitudes around 300 milliseconds whereas LIFU to AI affected EEG amplitudes around 500 milliseconds. In addition, only LIFU to the AI affected HRV as indexed by an increase in standard deviation of N-N intervals (SDNN) and mean HRV low frequency power. There was no effect of LIFU to either AI or PI on EDR or blood pressure. Taken together, LIFU looks to be an effective method to individually target sub-regions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus. These data have implications for the treatment of chronic pain and several neuropsychological diseases like anxiety, depression and addiction that all demonstrate abnormal activity in the insula concomitant with dysregulated autonomic function.
Inhibition of the serine/threonine kinase BUB1 reverses taxane resistance in prostate cancer
Authors: Maria Julia Martinez , Rolando DZ Lyles , Nahuel Peinetti , Alex Michael Grunfeld , Kerry L Burnstein 
Published: May 2023

AbstractBackground:Men with incurable castration resistant prostate cancer (CRPC) are typically treated with taxanes; however, drug resistance rapidly develops. Thus, overcoming taxane resistant PC is a major clinical need. We previously identified a seven gene network in aggressive CRPC, which includes the mitotic serine threonine kinaseBUB1, a major regulator of the spindle assembly checkpoint (SAC). Alterations in mitotic kinases (and SAC malfunction) are associated with advanced PC and taxane resistance development and thereby represent potential vulnerabilities.Methods:We evaluated BUB1 expression in publicly available data sets and in existing and newly generated taxane resistant PC cells. The effects of BUB1 depletion on the growth of a panel of PC and non-tumorigenic prostate epithelial cells was determined. We examined the capacity of pharmacologic inhibition of BUB1 kinase to reverse taxane-resistant PC growth. We evaluated the role of the prevalent androgen receptor variant AR-V7, in regulating BUB1 expression and taxane resistance.Results:BUB1 mRNA was over-expressed in PC, metastatic castration resistant prostate cancer (mCRPC) and in tumors of patients treated with taxane-based chemotherapeutics compared to benign prostate tissue. Furthermore, BUB1 levels were elevated in taxane resistant PC cell lines compared to their sensitive counterparts. BUB1 depletion decreased growth of CRPC cells through delayed mitosis but did not affect proliferation of androgen dependent (ADPC) or non-tumorigenic prostate epithelial cells. Furthermore, BUB1 inhibition with the specific kinase inhibitor, BAY1816032, re-sensitized taxane resistant CRPC cells to the clinically used drugs, docetaxel and cabazitaxel. Consistent with AR-V7 regulation of BUB1, we also found that AR-V7 was elevated in taxane resistant CRPC cells. Moreover, ectopic expression of AR-V7 in CRPC cells that lack this protein resulted in increased BUB1 and conferred docetaxel resistance. BUB1 pharmacologic inhibition in combination with taxanes sensitized AR-V7 expressing CRPC cells to docetaxel treatment.Conclusion:These data support BUB1 as an exploitable and therapeutically tractable vulnerability in taxane resistant CRPC including in AR variant driven CRPC.
Refinement of Multiconformer Ensemble Models from Multi-temperature X-ray Diffraction Data
Authors: Du Siyuan , Wankowicz Stephanie A. , Yabukarski Filip , Doukov Tzanko , Herschlag Daniel , Fraser James S. 
Published: May 2023

AbstractConformational ensembles underlie all protein functions. Thus, acquiring atomic-level ensemble models that accurately represent conformational heterogeneity is vital to deepen our understanding of how proteins work. Modeling ensemble information from X-ray diffraction data has been challenging, as traditional cryo-crystallography restricts conformational variability while minimizing radiation damage. Recent advances have enabled the collection of high quality diffraction data at ambient temperatures, revealing innate conformational heterogeneity and temperature-driven changes. Here, we used diffraction datasets for Proteinase K collected at temperatures ranging from 313 to 363K to provide a tutorial for the refinement of multiconformer ensemble models. Integrating automated sampling and refinement tools with manual adjustments, we obtained multiconformer models that describe alternative backbone and sidechain conformations, their relative occupancies, and interconnections between conformers. Our models revealed extensive and diverse conformational changes across temperature, including increased bound peptide ligand occupancies, different Ca2+binding site configurations and altered rotameric distributions. These insights emphasize the value and need for multiconformer model refinement to extract ensemble information from diffraction data and to understand ensemble-function relationships.
Mitotic spindle positioning protein (MISP) is an actin bundler that senses ADP-actin and binds near the pointed ends of filaments
Authors: Morales E. Angelo , Tyska Matthew J. 
Published: May 2023

ABSTRACTActin bundling proteins crosslink filaments into polarized structures that shape and support membrane protrusions including filopodia, microvilli, and stereocilia. In the case of epithelial microvilli, mitotic spindle positioning protein (MISP) is an actin bundler that localizes specifically to the basal rootlets, where the pointed ends of core bundle filaments converge. Previous studies established that MISP is prevented from binding more distal segments of the core bundle by competition with other actin binding proteins. Yet whether MISP holds a preference for binding directly to rootlet actin remains an open question. Usingin vitroTIRF microscopy assays, we found that MISP exhibits a clear binding preference for filaments enriched in ADP-actin monomers. Consistent with this, assays with actively growing actin filaments revealed that MISP binds at or near their pointed ends. Moreover, although substrate attached MISP assembles filament bundles in parallel and antiparallel configurations, in solution MISP assembles parallel bundles consisting of multiple filaments exhibiting uniform polarity. These discoveries highlight nucleotide state sensing as a mechanism for sorting actin bundlers along filaments and driving their accumulation near filament ends. Such localized binding might drive parallel bundle formation and/or locally modulate bundle mechanical properties in microvilli and related protrusions.
Direct androgen receptor regulation of sexually dimorphic gene expression in the mammalian kidney
Authors: Xiong Lingyun , Liu Jing , Han Seung Yub , Koppitch Kari , Guo Jin-Jin , Rommelfanger Megan , Gao Fan , Hallgrimsdottir Ingileif B. , Pachter Lior , Kim Junhyong , MacLean Adam L. , McMahon Andrew P. 
Published: May 2023

AbstractMammalian organs exhibit distinct physiology, disease susceptibility and injury responses between the sexes. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments. Bulk RNA-seq data demonstrated sex differences were established from 4 and 8 weeks after birth under gonadal control. Hormone injection studies and genetic removal of androgen and estrogen receptors demonstrated androgen receptor (AR) mediated regulation of gene activity in PT cells as the regulatory mechanism. Interestingly, caloric restriction feminizes the male kidney. Single-nuclear multiomic analysis identified putative cis-regulatory regions and cooperating factors mediating PT responses to AR activity in the mouse kidney. In the human kidney, a limited set of genes showed conserved sex-linked regulation while analysis of the mouse liver underscored organ-specific differences in the regulation of sexually dimorphic gene expression. These findings raise interesting questions on the evolution, physiological significance, and disease and metabolic linkage, of sexually dimorphic gene activity.
Review of learning materials of an ecology course at Universitas Terbuka
Authors: Hewindati Yuni Tri , Kurniati Handayani Sri , Zuhairi Aminudin , Gerungan Raflen Aril 
Published: May 2023

PurposeThis article presented the results of studies that examined the appropriateness of the content, readability of printed learning materials and the effectiveness of external resources in ecology course offered at Universitas Terbuka. To integrate external resources, links to their websites were provided in the printed materials.Design/methodology/approachAn in-depth interview with a content expert was employed to review the course content, while digital and printed learning materials were reviewed for readability and to determine the usefulness of the external resources. A total of 47 students completed surveys and a focus group discussion that included in-depth interviews were conducted with 21 selected students.FindingsThe results revealed that the content of ecology course was conceptually valid. However, two key aspects needed to be emphasized, including the application of ecology phenomena for further development of the science and its applications in real-life situations. Regarding readability, students stated that the course materials were easily comprehended. In terms of the benefit, 79% of the students found the external resources interesting and helpful in understanding the learning materials.Practical implicationsPrinted learning materials were crucial for students, specifically those residing in remote areas. Therefore, the institution should ensure that the materials were high-quality, easy to comprehend and enriched with up-to-date content/materials through scannable links to external resources.Originality/valueThe value added to the findings of this study was that the provision of links to external resources within printed learning materials improves students' understanding of the course content.
Viewing humanitarian project closure through the lens of an ethics of the temporary
Authors: Eckenwiler Lisa , Hunt Matthew R. , Crismo Jan Joy Louise G. , Conde Elyse , Hyppolite Shelley-Rose , Luneta Mayfourth , Munoz-Beaulieu Isabel , Mohammed Saeed Handreen , Schwartz Lisa 
Published: May 2023

PurposeIn this paper, the authors propose a new lens to examine international humanitarian organizations' responsibilities in the context of project closure, what authors call “an ethics of the temporary”. The authors offer this as an orienting ethical ideal to facilitate the moral imagination of humanitarian planners, practitioners and stakeholders.Design/methodology/approachThe authors drew on recent philosophical work on responsibilities for global justice to analyze an ethical concern inherent to humanitarian practice, the proper scope of responsibility in the context of closure of humanitarian projects.FindingsThe ethics of the temporary includes four elements: situating humanitarian action temporally with attention to the past and how it shapes a current crisis and crisis response, focusing attention on anticipating and seeking to mitigate potential harm, promoting sustainability and greater equity going forward and emphasizing inclusive, collaborative approaches. The authors propose a set of questions that can foster discussion and reflection about the scope of humanitarian responsibilities at project closure.Practical implicationsAlthough the authors' work is primarily conceptual, it has many practical implications for humanitarian policy and practice. It can support critical reflection and offers a process for considering the scope of responsibility at project closure and decisions around how to close a given intervention in a manner that avoids causing harm and advances equity.Originality/valueVery little work has been done on ethical closure of humanitarian projects. Most literature offers critiques. This essay contributes a new approach to closure, the ethical ideal and practice of an ethics of the temporary.
Research on forestry labor input measurement and forestry industry development in China
Authors: Zhang Bei , Jiang Xuemei 
Published: May 2023

PurposeAt present, China’s forestry development is mainly driven by the traditional production factors such as forestry labor force, land resources and capital and thus the top priority of forestry development is to optimize forestry production factors. Scientific and effective forestry labor input has a significant role in promoting the development of forestry industry. Given that the actual input to forestry labor is not clear, the accuracy of the forestry industry development may be slightly affected. Based on the monitoring project of collective forest tenure reform (RCFT), this paper uses the survey data of 3,500 rural households in seven provinces of China from 2010 to 2014 and 2016 to 2017 to measure the actual labor force in China, and empirically analyzes and studies the factors influencing the development of forestry industry based on the provincial data of forestry in China, and further discusses the heterogeneous impact of forestry production factors on the development of forestry industry.Design/methodology/approachIn this paper, the generalized least squares estimation model is used to calculate the actual number of forestry labor in China, and then the Cobb–Douglas production function is selected to explore the influencing factors of forestry industry development.FindingsThe results show that the actual number of forestry labor force in China continues to decline and the degree of reduction varies from different regions. The forestry labor is a major factor that promotes the development of the forestry industry, but this promotion is affected by the low matching degree between the forestry production factors and thus further inhibits the development of the forestry industry. Due to the time lag of the reform, the implementation of RCFT first weakens and then promotes the development of forestry production. Further on, the forestry labor input is heterogeneous in land resource endowment, forestry investment source and the proportion of management personnel.Originality/valueTherefore, researches show that the feasible way to promote the development of forestry industry is to expand the scale of forestry labor force, optimize the mutual allocation of forestry production factors, enhance the input of human capital in forestry and deepen the RCFT.
Daily work engagement is a process through which daily micro-events at work influence life satisfaction
Authors: Junça Silva Ana , Caetano António , Rueff Rita 
Published: May 2023

PurposeDrawing upon the conservation of resources theory, the authors expected that daily micro-events, daily hassles and uplifts at work influenced well-being via work engagement at the daily level.Design/methodology/approachThe authors conducted two diary studies. In study 1, 181 workers answered a daily questionnaire for four working days (N = 181 × 4 = 724). In study 2, 51 workers filled in a questionnaire for ten consecutive working days (N = 51 × 10 = 510).FindingsIn study 1, the results demonstrated that work engagement fully mediated the effects of daily uplifts on well-being and partially mediated the effects of daily hassles on well-being. The results of study 2 revealed a full mediation for both kinds of daily micro-events. Hence, daily uplifts stimulated work engagement, which, in turn, enhanced well-being, and daily hassles minimized work engagement and, consequently, well-being.Originality/valueThe relationships explored provide new theoretical elements for models that explain well-being.