bluuebunny/crossref_metadata_2025 huggingface dataset:
Sesquiterpenoids from the roots of Lindera glauca and their cytotoxicity activities
Authors: Zeng Fanrong , Pan Xinyuan , Meng Xiongyu , Li Qing , Li Huaqiang
Published: April 2024

The chemical investigation of the roots of Lindera glauca guided the isolation and identification of 3 new sesquiterpenoids, namely glaucatotones J−L (1−3), and one known congener, (1β,5β)-1-hydroxyguaia-4(15),11(13)-dieno-12,5-lactone (4). The structures of new compounds were established based on comprehensive spectrographic methods, mainly including 1D & 2D NMR and HRESIMS analyses, and the absolute configurations were further confirmed by the comparison of experimental and calculated electronic circular dichroism. The cytotoxicity activities of isolates were evaluated, and the results showed that they have moderate cytotoxic activities.
Astringency and its sub-qualities: a review of astringency mechanisms and methods for measuring saliva lubrication
Authors: Wang Shaoyang , Smyth Heather E , Olarte Mantilla Sandra M , Stokes Jason R , Smith Paul A
Published: April 2024

Astringency is an important mouthfeel attribute that influences the sensory experiences of many food and beverage products. While salivary lubricity loss and increased oral friction were previously believed to be the only astringency mechanisms, recent research has demonstrated that nontactile oral receptors can trigger astringency by responding to astringents without mechanical stimulation. Various human factors have also been identified that affect individual responses to astringents. This article presents a critical review of the key research milestones contributing to the current understanding of astringency mechanisms and the instrumental approaches used to quantify perceived astringency intensity. Although various chemical assays or physical measures mimic in-mouth processes involved in astringent mouthfeel, this review highlights how one chemical or physical approach can only provide a single measure of astringency determined by a specific mechanism. Subsequently, using a single measurement to predict astringency perception is overly idealistic. Astringency has not been quantified beyond the loss of saliva lubrication; therefore, nontactile receptor-based responses must also be explored. An important question remains about whether astringency is a single perception or involves distinct sub-qualities such as pucker, drying, and roughness. Although these sub-quality lexicons have been frequently cited, most studies currently view astringency as a single perception rather than dividing it into sub-qualities and investigating the potentially independent mechanisms of each. Addressing these knowledge gaps should be an important priority for future research.
Identification and characterization of a novel type of ketohexokinase from the haloarchaeon Haloferax volcanii
Authors: Ortjohann Marius , Schönheit Peter
Published: April 2024

Ketohexokinase (KHK) catalyzes the ATP-dependent phosphorylation of fructose, forming fructose-1-phosphate and ADP. The enzyme is well studied in Eukarya, in particular in humans and other vertebrates, but homologs have not been identified in Bacteria and Archaea. Here we report the identification of a novel type of KHK from the haloarchaeon Haloferax volcanii (HvKHK). The encoding gene khk was identified as HVO_1812. The gene was expressed as a 90-kDa homodimeric protein, catalyzing the phosphorylation of fructose with a Vmax value of 59 U/mg and apparent KM values for ATP and fructose of 0.47 and 1.29 mM, respectively. Homologs of HvKHK were only identified in a few haloarchaea and halophilic Bacteria. The protein showed low sequence identity to characterized KHKs from Eukarya and phylogenetic analyses indicate that haloarchaeal KHKs are largely separated from eukaryal KHKs. This is the first report of the identification of KHKs in prokaryotes that form a novel cluster of sugar kinases within the ribokinase/pfkB superfamily.
Spherical random projection
Authors: Kang Seungwoo , Oh Hee-Seok
Published: April 2024

We propose a new method for dimension reduction of high-dimensional spherical data based on the nonlinear projection of sphere-valued data to a randomly chosen subsphere. The proposed method, spherical random projection, leads to a probabilistic lower-dimensional mapping of spherical data into a subsphere of the original. In this paper, we investigate some properties of spherical random projection, including expectation preservation and distance concentration, from which we derive an analogue of the Johnson–Lindenstrauss Lemma for spherical random projection. Clustering model selection is discussed as an application of spherical random projection, and numerical experiments are conducted using real and simulated data.
Evaluation of interleukin-8 levels in the diagnosis of invasive pulmonary aspergillosis in patients with haematological malignancies
Authors: Şensoy Levent , Atilla Aynur , Güllü Yusuf Taha , Gür Vural Demet , Turgut Mehmet , Esen Şaban , Tanyel Esra
Published: April 2024

This study aimed to determine the level of interleukin (IL)-8 in diagnosing of invasive pulmonary aspergillosis (IPA). We conducted this study with 50 controls and 25 IPA patients with haematological malignancies. Demographic data, haematological diagnoses, chemotherapy regimen, galactomannan level, fungal culture, and computed tomography findings of the patients were evaluated prospectively. IL-8 levels were studied with the ELISA method. The mean age of patients in the case group was 60.84 ± 15.38 years, while that of the controls was 58.38 ± 16.64 years. Of the patients, 2/25 were classified as having ‘proven’, 13/25 as ‘probable’, and 10/25 as ‘possible’ invasive aspergillosis (IA). Serum IL-8 levels were found to be significantly higher in the case group compared to the controls. There was a negative correlation between serum IL-8 levels and neutrophil counts and a positive correlation with the duration of neutropenia. A significant cutoff value for serum IL-8 parameter in detecting IPA disease was obtained as ≥274 ng/l; sensitivity was 72%; specificity was 64%; PPV was 50%; and NPV was 82%. In the subgroup analysis, there was no significant difference in serum IL-8 levels between the case group and the patients in the neutropenic control group, while a significant difference was found in with the patients in the non-neutropenic control group. Serum IL-8 levels in neutropenic patients who develop IPA are not adequate in terms of both the diagnosis of the disease and predicting mortality. New, easily applicable methods with high sensitivity and specificity in diagnosing IPA are still needed.
DUVET: Resolved direct metallicity measurements in the outflow of starburst galaxy NGC 1569
Authors: Hamel-Bravo Magdalena J , Fisher Deanne B , Berg Danielle , Björgvinsson Bjarki , Bolatto Alberto D , Cameron Alex J , Chisholm John , Fielding Drummond B , Herrera-Camus Rodrigo , Kacprzak Glenn G , Li Miao , Ciraulo Barbara Mazzilli , McLeod Anna F , McPherson Daniel K , Nielsen Nikole M , Reichardt Chu Bronwyn , Vaught Ryan J Rickards , Sandstrom Karin
Published: April 2024

We present the results of direct-method metallicity measurements in the disc and outflow of the low-metallicity starburst galaxy NGC 1569. We use Keck Cosmic Web Imager observations to map the galaxy across 54″ (800 pc) along the major axis and 48″ (700 pc) along the minor axis with a spatial resolution of 1″ (∼15 pc). We detect common strong emission lines ([O iii] λ5007, H β, [O ii] λ3727) and the fainter [O iii] λ4363 auroral line, which allows us to measure electron temperature (Te) and metallicity. Theory suggests that outflows drive metals out of the disc driving observed trends between stellar mass and gas-phase metallicity. Our main result is that the metallicity in the outflow is similar to that of the disc, Zout/ZISM ≈ 1. This is consistent with previous absorption line studies in higher mass galaxies. Assumption of a mass-loading factor of $\dot{M}_{\rm out}/{\rm SFR}\sim 3$ makes the metal-loading of NGC 1569 consistent with expectations derived from the mass–metallicity relationship. Our high spatial resolution metallicity maps reveal a region around a supermassive star cluster (SSC-B) with distinctly higher metallicity and higher electron density, compared to the disc. Given the known properties of SSC-B the higher metallicity and density of this region are likely the result of star formation-driven feedback acting on the local scale. Overall, our results are consistent with the picture in which metal-enriched winds pollute the circumgalactic medium surrounding galaxies, and thus connect the small-scale feedback processes to large-scale properties of galaxy haloes.
The phytochrome-interacting factor genes PIF1 and PIF4 are functionally diversified due to divergence of promoters and proteins
Authors: Kim Hanim , Lee Nayoung , Kim Yeojae , Choi Giltsu
Published: April 2024

Phytochrome-interacting factors (PIFs) are basic helix–loop–helix transcription factors that regulate light responses downstream of phytochromes. In Arabidopsis (Arabidopsis thaliana), 8 PIFs (PIF1-8) regulate light responses, either redundantly or distinctively. Distinctive roles of PIFs may be attributed to differences in mRNA expression patterns governed by promoters or variations in molecular activities of proteins. However, elements responsible for the functional diversification of PIFs have yet to be determined. Here, we investigated the role of promoters and proteins in the functional diversification of PIF1 and PIF4 by analyzing transgenic lines expressing promoter-swapped PIF1 and PIF4, as well as chimeric PIF1 and PIF4 proteins. For seed germination, PIF1 promoter played a major role, conferring dominance to PIF1 gene with a minor contribution from PIF1 protein. Conversely, for hypocotyl elongation under red light, PIF4 protein was the major element conferring dominance to PIF4 gene with the minor contribution from PIF4 promoter. In contrast, both PIF4 promoter and PIF4 protein were required for the dominant role of PIF4 in promoting hypocotyl elongation at high ambient temperatures. Together, our results support that the functional diversification of PIF1 and PIF4 genes resulted from contributions of both promoters and proteins, with their relative importance varying depending on specific light responses.
Drug hypersensitivity reactions: review of the state of the science for prediction and diagnosis
Authors: Pallardy Marc , Bechara Rami , Whritenour Jessica , Mitchell-Ryan Shermaine , Herzyk Danuta , Lebrec Herve , Merk Hans , Gourley Ian , Komocsar Wendy J , Piccotti Joseph R , Balazs Mercedesz , Sharma Amy , Walker Dana B , Weinstock Daniel
Published: April 2024

Drug hypersensitivity reactions (DHRs) are a type of adverse drug reaction that can occur with different classes of drugs and affect multiple organ systems and patient populations. DHRs can be classified as allergic or non-allergic based on the cellular mechanisms involved. Whereas nonallergic reactions rely mainly on the innate immune system, allergic reactions involve the generation of an adaptive immune response. Consequently, drug allergies are DHRs for which an immunological mechanism, with antibody and/or T cell, is demonstrated. Despite decades of research, methods to predict the potential for a new chemical entity to cause DHRs or to correctly attribute DHRs to a specific mechanism and a specific molecule are not well-established. This review will focus on allergic reactions induced by systemically administered low-molecular weight drugs with an emphasis on drug- and patient-specific factors that could influence the development of DHRs. Strategies for predicting and diagnosing DHRs, including potential tools based on the current state of the science, will also be discussed.
S100a6 knockdown promotes the differentiation of dental epithelial cells toward the epidermal lineage instead of the odontogenic lineage
Authors: Otake Shinji , Saito Kan , Chiba Yuta , Yamada Aya , Fukumoto Satoshi
Published: April 2024

Tooth development is a complex process involving various signaling pathways and genes. Recent findings suggest that ion channels and transporters, including the S100 family of calcium‐binding proteins, may be involved in tooth formation. However, our knowledge in this regard is limited. Therefore, this study aimed to investigate the expression of S100 family members and their functions during tooth formation. Tooth germs were extracted from the embryonic and post‐natal mice and the expression of S100a6 was examined. Additionally, the effects of S100a6 knockdown and calcium treatment on S100a6 expression and the proliferation of SF2 cells were examined. Microarrays and single‐cell RNA‐sequencing indicated that S100a6 was highly expressed in ameloblasts. Immunostaining of mouse tooth germs showed that S100a6 was expressed in ameloblasts but not in the undifferentiated dental epithelium. Additionally, S100a6 was localized to the calcification‐forming side in enamel‐forming ameloblasts. Moreover, siRNA‐mediated S100a6 knockdown in ameloblasts reduced intracellular calcium concentration and the expression of ameloblast marker genes, indicating that S100a6 is associated with ameloblast differentiation. Furthermore, S100a6 knockdown inhibited the ERK/PI3K signaling pathway, suppressed ameloblast proliferation, and promoted the differentiation of the dental epithelium toward epidermal lineage. Conclusively, S100a6 knockdown in the dental epithelium suppresses cell proliferation via calcium and intracellular signaling and promotes differentiation of the dental epithelium toward the epidermal lineage.
Electroencephalogram Biomarkers from Anesthesia Induction to Identify Vulnerable Patients at Risk for Postoperative Delirium
Authors: Pollak Marie , Leroy Sophie , Röhr Vera , Brown Emery Neal , Spies Claudia , Koch Susanne
Published: April 2024

Background

Postoperative delirium is a common complication in elderly patients undergoing anesthesia. Even though it is increasingly recognized as an important health issue, the early detection of patients at risk for postoperative delirium remains a challenge. This study aims to identify predictors of postoperative delirium by analyzing frontal electroencephalogram at propofol-induced loss of consciousness.

Methods

This prospective, observational single-center study included patients older than 70 yr undergoing general anesthesia for a planned surgery. Frontal electroencephalogram was recorded on the day before surgery (baseline) and during anesthesia induction (1, 2, and 15 min after loss of consciousness). Postoperative patients were screened for postoperative delirium twice daily for 5 days. Spectral analysis was performed using the multitaper method. The electroencephalogram spectrum was decomposed in periodic and aperiodic (correlates to asynchronous spectrum wide activity) components. The aperiodic component is characterized by its offset (y intercept) and exponent (the slope of the curve). Computed electroencephalogram parameters were compared between patients who developed postoperative delirium and those who did not. Significant electroencephalogram parameters were included in a binary logistic regression analysis to predict vulnerability for postoperative delirium.

Results

Of 151 patients, 50 (33%) developed postoperative delirium. At 1 min after loss of consciousness, postoperative delirium patients demonstrated decreased alpha (postoperative delirium: 0.3 μV2 [0.21 to 0.71], no postoperative delirium: 0.55 μV2 [0.36 to 0.74]; P = 0.019] and beta band power [postoperative delirium: 0.27 μV2 [0.12 to 0.38], no postoperative delirium: 0.38 μV2 [0.25 to 0.48]; P = 0.003) and lower spectral edge frequency (postoperative delirium: 10.45 Hz [5.65 to 15.04], no postoperative delirium: 14.56 Hz [9.51 to 16.65]; P = 0.01). At 15 min after loss of consciousness, postoperative delirium patients displayed a decreased aperiodic offset (postoperative delirium: 0.42 μV2 (0.11 to 0.69), no postoperative delirium: 0.62 μV2 [0.37 to 0.79]; P = 0.004). The logistic regression model predicting postoperative delirium vulnerability demonstrated an area under the curve of 0.73 (0.69 to 0.75).

Conclusions

The findings suggest that electroencephalogram markers obtained during loss of consciousness at anesthesia induction may serve as electroencephalogram-based biomarkers to identify at an early time patients at risk of developing postoperative delirium.

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Investigating the Mechanisms of Intradermal Injection for Easier “Skin Booster” Treatment: A Fluid Mechanics Approach to Determine Optimal Delivery Method
Authors: Oh Seung Min , Lee Yongkoo , Lee Jae Hyuk , Oh Myungjune
Published: April 2024

Background:

The use of “skin boosters” for rejuvenating aged skin is widely used. However, the accurate injection of the skin booster into the dermal layer remains a challenge due to the density of the dermis. The purpose of this study was to investigate the optimal mechanical variables of delivery that enabled correct targeting of the product to the dermis for optimal results.

Methods:

We investigated the impact of mechanical variables (syringe diameter, needle diameter and length, and viscosity of the skin booster) on the force required for intradermal injection in porcine skin. The correlation between these variables and the injection force was examined as well.

Results:

The results show that smaller syringe diameters, larger needle diameters, shorter needle lengths, and lower viscosity of the skin boosters reduce the injection force needed for intradermal injections.

Conclusions:

During the administration of skin booster injections, clinicians should take into account optimal conditions that facilitate intradermal injections, thus maximizing rejuvenating outcomes. Furthermore, manufacturers of skin boosters should formulate the products with decreased viscosity and provide the product in conjunction with appropriate needles and syringes, designed to optimize ease of injection.
Pushing the Limits of Reach for the Pedicled Anterolateral Thigh Flap
Authors: Liang Weihao , Chen Hsing-Fu , Jeng Seng-Feng , Shih Hsiang-Shun
Published: April 2024

The pedicled anterolateral thigh flap, although tremendously versatile, may be limited in reach, especially in challenging clinical cases. Traditional methods to extend its reach may remain insufficient or unavailable. We describe two modifications to the conventional pedicled flap to extend its reach to the limits, namely (1) selecting a distal perforator supplemented by the nonsizeable perforator harvest technique, and (2) the double-pivot technique adding an additional rotation to the flap à la propeller perforator flap. The increased reach not only improves reconstructive success, but also opens up new applications for this workhorse flap.
Dextromethorphan moderates reward deficiency associated with central serotonin transporter availability in 3,4-methylenedioxy-methamphetamine-treated animals
Authors: Chiu Chuang-Hsin , Ma Kuo-Hsing , Huang Eagle Yi-Kung , Chang Hsien-Wen , Weng Shao-Ju , Yu Tsung-Hsun , Farn Shiou-Shiow , Kuo Yu-Yeh , Huang Wen-Sheng , Cheng Cheng-Yi , Tao Pao-Luh , Yeh Skye Hsin-Hsien
Published: April 2024

Background:

The neurotoxicity of 3,4-methylenedioxy-methamphetamine (MDMA) to the serotonergic system is well-documented. Dextromethorphan (DM), an antitussive drug, decreased morphine- or methamphetamine (MA)-induced reward in rats and may prevent MDMA-induced serotonergic deficiency in primates, as indicated by increased serotonin transporter (SERT) availability. We aimed to investigate the effects of DM on reward, behavioral sensitization, and neurotoxicity associated with loss of SERT induced by chronic MDMA administration in rats.

Methods:

Conditioned place preference (CPP) and locomotor activity tests were used to evaluate drug-induced reward and behavioral sensitization; 4-[18F]-ADAM/animal-PET and immunohistochemistry were used to explore the effects of DM on MDMA-induced loss of SERT.

Results:

MDMA significantly reduced SERT binding in the rat brain; however, co-administration of DM significantly restored SERT, enhancing the recovery rate at day 14 by an average of ~23% compared to the MDMA group. In confirmation of the PET findings, immunochemistry revealed MDMA reduced SERT immunoactivity in all brain regions, whereas DM markedly increased the serotonergic fiber density after MDMA induction.

Conclusion:

Behavioral tests and in vivo longitudinal PET imaging demonstrated the CPP indexes and locomotor activities of the reward system correlate negatively with PET 4-[18F]ADAM SERT activity in the reward system. Our findings suggest MDMA induces functional abnormalities in a network of brain regions important to decision-making processes and the motivation circuit. DM may exert neuroprotective effects to reverse MDMA-induced neurotoxicity.
A Focus on Leadership Communication and Feeling Valued to Prevent Burnout and Turnover Among Healthcare Professionals
Authors: Young Amy M. , Aronoff Chloe , Goel Sandy , Jerome Matthew , Brower Kirk J.
Published: April 2024

Objective

The purpose of this study was to examine the relative importance of leadership communication in predicting burnout and intention to stay among faculty and staff while controlling for other factors such as satisfaction with compensation and work-home flexibility.

Methods

This study involved a secondary analysis of data derived from an organizational engagement survey that included 2336 faculty members (75% response rate) and 17,664 staff members (72% response rate).

Results

Effective leadership communication was a stronger predictor of burnout and intent to stay than satisfaction with compensation and work-home flexibility. Feeling valued by the organization mediated the relationship between leadership communication and the outcome variables.

Conclusions

Leadership communication provides a low-cost solution to burnout and staff shortages and is primarily effective because it conveys to both faculty and staff that they are valued by the organization.
The Impact of Next-generation Sequencing on Interobserver Agreement and Diagnostic Accuracy of Desmoplastic Melanocytic Neoplasms
Authors: Chen Alice , Sharma Natasha , Patel Pragi , Olivares Shantel , Bahrami Armita , Barnhill Raymond L. , Blokx Willeke A.M. , Bosenberg Marcus , Busam Klaus J. , de La Fouchardière Arnaud , Duncan Lyn M. , Elder David E. , Ko Jennifer S. , Landman Gilles , Lazar Alexander J. , Lezcano Cecilia , Lowe Lori , Maher Nigel , Massi Daniela , Messina Jane , Mihic-Probst Daniela , Parker Douglas C. , Redpath Margaret , Scolyer Richard A. , Shea Christopher R. , Spatz Alan , Tron Victor , Xu Xiaowei , Yeh Iwei , Jung Yun Sook , Zembowicz Artur , Gerami Pedram
Published: April 2024

Next-generation sequencing (NGS) is increasingly being utilized as an ancillary tool for diagnostically challenging melanocytic neoplasms. It is incumbent upon the pathology community to perform studies assessing the benefits and limitations of these tools in specific diagnostic scenarios. One of the most challenging diagnostic scenarios faced by skin pathologists involves accurate diagnosis of desmoplastic melanocytic neoplasms (DMNs). In this study, 20 expert melanoma pathologists rendered a diagnosis on 47 DMNs based on hematoxylin and eosin sections with demographic information. After submitting their diagnosis, the experts were given the same cases, but this time with comprehensive genomic sequencing results, and asked to render a diagnosis again. Identification of desmoplastic melanoma (DM) improved by 7%, and this difference was statistically significant (P<0.05). In addition, among the 15 melanoma cases, in the pregenomic assessment, only 12 were favored to be DM by the experts, while after genomics, this improved to 14 of the cases being favored to be DM. In fact, some cases resulting in metastatic disease had a substantial increase in the number of experts recognizing them as DM after genomics. The impact of the genomic findings was less dramatic among benign and intermediate-grade desmoplastic tumors (BIDTs). Interobserver agreement also improved, with the Fleiss multirater Kappa being 0.36 before genomics to 0.4 after genomics. NGS has the potential to improve diagnostic accuracy in the assessment of desmoplastic melanocytic tumors. The degree of improvement will be most substantial among pathologists with some background and experience in bioinformatics and melanoma genetics.
Prognostic Immunohistochemistry for Ki-67 and OTP on Small Biopsies of Pulmonary Carcinoid Tumors
Authors: Naso Julia R. , Jenkins Sarah M. , Roden Anja C. , Yi Euhee S. , Lo Ying-Chun , Bois Melanie C. , Maleszewski Joseph J. , Aubry Marie Christine , Boland Jennifer M.
Published: April 2024

Prognostic stratification of pulmonary carcinoids into “typical” and “atypical” categories requires examination of large tissue volume. However, there is a need for tools that provide similar prognostic information on small biopsy samples. Ki-67 and OTP immunohistochemistry have shown promising prognostic value in studies of resected pulmonary carcinoids, but prognostic value when using biopsy/cytology specimens is unclear. Ki-67 immunohistochemistry was performed on small biopsy/cytology specimens from pulmonary carcinoid tumors (n=139), and labeling index was scored via automated image analysis of at least 500 cells. OTP immunohistochemistry was performed on 70 cases with sufficient tissue and scored as positive or negative (<20% tumor nuclei staining). Higher Ki-67 index was associated with worse disease-specific progression-free survival (ds-PFS), with 3% and 4% thresholds having similarly strong associations with ds-PFS (P<0.001, hazard ratio ≥11). Three-year ds-PFS was 98% for patients with Ki-67 <3% and 89% for patients with Ki-67≥3% (P=0.0006). The optimal Ki-67 threshold for prediction of typical versus atypical carcinoid histology on subsequent resection was 3.21 (AUC 0.68). Negative OTP staining approached significance with atypical carcinoid histology (P=0.06) but not with ds-PFS (P=0.24, hazard ratio=3.45), although sample size was limited. We propose that Ki-67 immunohistochemistry may contribute to risk stratification for carcinoid tumor patients based on small biopsy samples. Identification of a 3% hot-spot Ki-67 threshold as optimal for prediction of ds-PFS is notable as a 3% Ki-67 threshold is currently used for gastrointestinal neuroendocrine tumor stratification, allowing consideration of a unified classification system across organ systems.
Engagement in Distance Healthcare Simulation Debriefing
Authors: Palaganas Janice C. , Mosher Cynthia J. , Morton Alex , Foronda Cynthia , Cheng Adam , Anderson Terry
Published: April 2024

Summary Statement

Understanding distance health care simulation debriefing is crucial in light of the increased use of and emerging technology in remote education for reasons of accessibility, global collaboration, and continuous professional development. This article is a confluence of a number of previously published studies designed to serve as a foundation to develop the concept of “engagement in health care distance simulation debriefing” using the Schwartz-Barcott & Kim hybrid mixed methods model. The model uses 3 phases: theoretical (a realist systematic review of the literature), fieldwork (3 exploratory studies and 2 pilot experimental studies), and analytical (analysis of the theoretical and fieldwork findings through expert discussion). This study defines the concept of “engagement in health care simulation distance debriefing” through exploration of its uses and analysis in literature, interviews, and expert review. The hybrid approach to the analysis provided rigor to generate a new, reflective conceptual model. This conceptual model defines the complexity in engagement during distance debriefing and helps shape the development of simulationists and debriefers, leading to more effective distance simulations and debriefings.
Experimental type 1 diabetes metabolically rejuvenates CD8+T cells for improved control of tumor growth through an IGF1-IGF1R axis
Authors: Sarkar Anirban , Dhar Sukanya , Bera Saurav , Chakravarti Mohona , Verma Ayushi , Prasad Parash , Sultana Jasmine , Das Juhina , Saha Akata , Bhuniya Avishek , Guha Ipsita , Dasgupta Shayani , Roy Sib Sankar , Banerjee Saptak , Roy Subir , Bhar Debarati , Storkus Walter J. , Baral Rathindranath , Datta Dipak , Bose Anamika
Published: April 2024

Abstract

Epidemiological studies suggest that patients with pre-existing type 1 diabetes (T1D) have a decreased risk of developing melanoma, prostate cancer, and breast cancer, although the underlying mechanism remains to be elucidated. In translational modelling, we observed that streptozotocin (STZ) induced T1D mice exhibited restricted melanoma and carcinoma (mammary, lung and colon) growth in association with extended overall survival. Tumor-infiltrating CD8+T cells were found to be responsible for tumor growth restriction. Tumor infiltrating CD8+T cells but not tumor cells themselves exhibited higher glycolytic and cytotoxic activities in T1D hosts. Such improved anti-tumor T cell function was linked to selective upregulated expression of insulin-like growth factor 1, insulin-like growth factor 1 receptor, and phospho-mTOR in CD8+T cells in the TME. T1D patient derived CD8+T cells displayed superior activationin vitroafter tumor antigen stimulation vs. non-diabetic CD8+T cells. Activation of T1D patient derived CD8+T cells was sensitive to targeted antagonism of IGF1R and mTOR, supporting the operational involvement of the IGF1R-mTOR signaling axis. Our results suggest that selective activation of the intrinsic IGF1R-mTOR signaling axis in CD8+T cells represents a preferred endpoint to achieving more effective immunotherapy outcomes and improved cancer patient management.

Significance

Experimental type 1 diabetes decelerates tumor growth through metabolic activation of cytotoxic T cells dependent on an IGF1R-mTOR signaling pathway. CD8+IGF1R+IGF1+T cells play a crucial role in T1D dependent tumor control.
Estrogen Receptor Gene Expression Prediction from H&E Whole Slide Images
Authors: Srinivas Anvita A. , Jaroensri Ronnachai , Wulczyn Ellery , Wren James H. , Thompson Elaine E. , Olson Niels , Beckers Fabien , Miao Melissa , Liu Yun , Chen Po-Hsuan Cameron , Steiner David F.
Published: April 2024

Gene expression profiling (GEP) provides valuable information for the care of breast cancer patients. However, the test itself is expensive and can take a long time to process. In contrast, microscopic examination of hematoxylin and eosin (H&E) stained tissue is inexpensive, fast, and integrated into the standard of care. This work explores the possibility of predictingESR1gene expression from H&E images, and its use in predicting clinical variables and patient outcomes. We utilized a weakly supervised method to train a deep learning model to predictESR1expression from whole slide images, and achieved 0.57 [95% CI: 0.46, 0.67] Pearson’s correlation with the ground truth value. OurESR1expression prediction achieved an AUROC of 0.81 [0.74, 0.87] in predicting clinical ER status obtained using an immunohistochemistry staining technique, and a c-index of 0.59 [0.52, 0.65] in predicting progression-free interval for the patients in our cohort. This work further demonstrates the potential to infer gene expression from H&E stained images in a manner that shows meaningful associations with clinical variables. Because obtaining H&E stained images is substantially easier and faster than genetic testing, the capability to derive molecular genetic information from these images may increase access to this type of information for patient risk stratification and provide research insights into molecular-morphological associations.
Intracranial neural representation of phenomenal and access consciousness in the human brain
Authors: Fang Zepeng , Dang Yuanyuan , Li Xiaoli , Zhao Qianchuan , Zhang Mingsha , Zhao Hulin
Published: April 2024

After more than 30 years of extensive investigation, impressive progress has been made in identifying the neural correlates of consciousness (NCC). However, the functional role of spatiotemporally distinct consciousness-related neural activity in conscious perception is debated. Based on empirical EEG findings, e.g., of the enhanced early negative wave and late positive wave under conscious conditions, an influential framework proposed that consciousness-related neural activities could be dissociated into two distinct processes: phenomenal and access consciousness. This framework has been supported mainly by comparison of neural activity between report and no-report paradigms; however, though hotly debated, its authenticity has not been examined in a single paradigm with more informative intracranial recordings. In the present study, we employed a novel visual awareness task and recorded the local field potential (LFP) of epilepsy patients with electrodes implanted in cortical and subcortical regions. Overall, we found that the latency of visual awareness-related activity exhibited a bimodal distribution, and the recording sites with short and long latencies were largely separated in location, except in the lateral prefrontal cortex (lPFC). The mixture of short and long latencies in the lPFC indicates that it plays a critical role in linking phenomenal and access consciousness. However, the division between the two is not as simple as the central sulcus, as proposed previously. Moreover, in 4 patients with electrodes implanted in the bilateral prefrontal cortex, early awareness-related activity was confined to the contralateral side, while late awareness-related activity appeared on both sides. Finally, Granger causality analysis showed that awareness-related information flowed from the early sites to the late sites. These results provide the first LFP evidence of neural correlates of phenomenal and access consciousness, which sheds light on the spatiotemporal dynamics of NCC in the human brain.
Should regional species loss be faster, or slower, than local loss? It depends on density-dependent rate of death
Authors: Keil Petr , Clark Adam T. , Barták Vojtěch , Leroy François
Published: April 2024

1

Assessment of the rate of species loss, which we also label extinction, is an urgent task. However, the rate depends on spatial grain (average areaA) over which it is assessed—local species loss can be on average faster, or slower, than regional or global loss. Ecological mechanisms behind this discrepancy are unclear. We propose that the relationship between extinction rate andAis driven by two classical ecological phenomena: the Allee effect and the Janzen-Connell effect. Specifically, we hypothesize that (i) when per-individual probability of death (Pdeath) decreases with population densityN(as in Allee effects), per-species extinction rate (Px) should be high at regional grains, and low locally. (ii) In contrast, whenPdeathincreases withN(as in Janzen-Connell effects),Pxshould be low regionally, but high locally. (iii) Total counts of extinct species (Ex) should follow a more complex relationship withA, as they also depend on drivers of the species-area relationship (SAR) prior to extinctions, such as intraspecific aggregation, species pools, and species-abundance distributions. We tested these hypotheses using simulation experiments, the first based on point patterns, the second on a system of generalized Lotka-Volterra equations. In both experiments, we used a single continuous parameter that moved between the Allee effect, no relationship betweenPdeathandN, and the Janzen-Connell effect. We found support for our hypotheses, but only when regional species-abundance distributions were uneven enough to provide sufficiently rare or common species for Allee or Janzen-Connell to act on. In all, we have theoretically demonstrated a mechanism behind different rates of biodiversity change at different spatial grains which has been observed in empirical data.
Activation of hypoactive parvalbumin-positive fast-spiking interneuron restores dentate inhibition to prevent epileptiform activity in the mouse intrahippocampal kainate model of temporal lobe epilepsy
Authors: Lee Sang-Hun , Kang Young-Jin , Smith Bret N.
Published: April 2024

Parvalbumin-positive (PV+) GABAergic interneurons in the dentate gyrus provide powerful perisomatic inhibition of dentate granule cells (DGCs) to prevent overexcitation and maintain the stability of dentate gyrus circuits. Most dentate PV+ interneurons survive status epilepticus, but surviving PV+ interneuron mediated inhibition is compromised in the dentate gyrus shortly after status epilepticus, contributing to epileptogenesis in temporal lobe epilepsy. It is uncertain whether the impaired activity of dentate PV+ interneurons recovers at later times or if it continues for months following status epilepticus. The development of compensatory modifications related to PV+ interneuron circuits in the months following status epilepticus is unknown, although reduced dentate GABAergic inhibition persists long after status epilepticus. We employed PV immunostaining and whole-cell patch-clamp recordings from dentate PV+ interneurons and DGCs in slices from male and female sham controls and intrahippocampal kainate (IHK) treated mice that developed spontaneous seizures months after status epilepticus to study epilepsy-associated changes in dentate PV+ interneuron circuits. We found that the number of dentate PV+ cells was reduced in IHK treated mice. Electrical recordings showed that: 1) Action potential firing rates of dentate PV+ interneurons were reduced in IHK treated mice up to four months after status epilepticus; 2) Spontaneous inhibitory postsynaptic currents (sIPSCs) in DGCs exhibited reduced frequency but increased amplitude in IHK treated mice; and 3) The amplitude of evoked IPSCs in DGCs by optogenetic activation of dentate PV+ cells was upregulated without changes in short-term plasticity. Video-EEG recordings revealed that IHK treated mice showed spontaneous epileptiform activity in the dentate gyrus and that chemogenetic activation of PV+ interneurons abolished the epileptiform activity. Our results suggest not only that the compensatory changes in PV+ interneuron circuits develop after IHK treatment, but also that increased PV+ interneuron mediated inhibition in the dentate gyrus may compensate for cell loss and reduced intrinsic excitability of dentate PV+ interneurons to stop seizures in temporal lobe epilepsy.

Highlights

Reduced number of dentate PV+ interneurons in TLE mice

Persistently reduced action potential firing rates of dentate PV+ interneurons in TLE mice

Enhanced amplitude but decreased frequency of spontaneous IPSCs in the dentate gyrus in TLE mice

Increased amplitude of evoked IPSCs mediated by dentate PV+ interneurons in TLE mice

Chemogenetic activation of PV+ interneurons prevents epileptiform activity in TLE mice
Mitochondrial heteroplasmy improves risk prediction for myeloid neoplasms
Authors: Hong Yun Soo , Pasca Sergiu , Shi Wen , Puiu Daniela , Lake Nicole J , Lek Monkol , Ru Meng , Grove Megan , Prizment Anna , Joshu Corinne E. , Platz Elizabeth A. , Guallar Eliseo , Arking Dan E. , Gondek Lukasz P.
Published: April 2024

The most well-known pathogenic risk factor for myeloid neoplasms (MN) is clonal hematopoiesis of indeterminate potential (CHIP)1. However, MN can develop in CHIP negative individuals, indicating that additional markers of clonal expansion might also be informative. Heteroplasmy, defined as the presence of mitochondrial DNA (mtDNA) mutations in a subset of cellular mtDNA, has been associated with hematological malignancies2and could represent a marker of clonal expansion3. However, the relationship between heteroplamsy and CHIP, as well as its association with the incidence of MN in the general population is not known. In this study, we explored the association between somatic mtDNA and nuclear DNA (nDNA) mutations (mito-nuclear interaction), its impact on MN incidence, and whether its inclusion to the latest CHIP-based MN prediction algorithm could improve risk stratification in over 440,000 participants in the UK Biobank and Atherosclerosis Risk in Communities (ARIC) studies. We found that heteroplasmy count and heteroplasmic variants predicted to be more deleterious were enriched in individuals with CHIP, particularly in those with significantly expanded clones (VAF ≥20%), with more than one CHIP mutation, and with mutations in the spliceosome machinery. Individuals with both heteroplasmy and CHIP were more likely to develop MN than participants with either entity alone. Furthermore, we found a significant and independent association of predicted pathogenic effect of heteroplasmic variants with incident MN, suggesting a causal role of mtDNA variations in MN pathogenesis, even in the absence of CHIP. Finally, incorporating heteroplasmy into an existing risk score model for MN in individuals with CHIP significantly improved the sensitivity by 13.1% and identified 34.4% more cases in the high-risk group (10-year risk ≥10%). In sum, our findings suggest that heteroplasmy, in addition to being a marker of clonal expansion, may be a causal biomarker of MN development, with clinical utility in the general population.
Health Utility Adjusted Survival: a Composite Endpoint for Clinical Trial Designs
Authors: Deng Yangqing , de Almeida John R. , Xu Wei
Published: April 2024

Abstract

Many randomized trials have used overall survival as the primary endpoint for establishing non-inferiority of one treatment compared to another. However, if a treatment is non-inferior to another treatment in terms of overall survival, clinicians may be interested in further exploring which treatment results in better health utility scores for patients. Examining health utility in a secondary analysis is feasible, however, since health utility is not the primary endpoint, it is usually not considered in the sample size calculation, hence the power to detect a difference of health utility is not guaranteed. Furthermore, often the premise of non-inferiority trials is to test the assumption that an intervention provides superior quality of life or toxicity profile without compromising the survival when compared to the existing standard. Based on this consideration, it may be beneficial to consider both survival and utility when designing a trial. There have been methods that can combine survival and quality of life into a single measure, but they either have strong restrictions or lack theoretical frameworks. In this manuscript, we propose a method called HUS (Health Utility adjusted Survival), which can combine survival outcome and longitudinal utility measures for treatment comparison. We propose an innovative statistical framework as well as procedures to conduct power analysis and sample size calculation. By comprehensive simulation studies involving summary statistics from the PET-NECK trial,1we demonstrate that our new approach can achieve superior power performance using relatively small sample sizes, and our composite endpoint can be considered as an alternative to overall survival in future clinical trial design and analysis where both survival and health utility are of interest.
Spin and Susceptibility Effects of Electromagnetic Self-Force in Effective Field Theory
Authors: Jakobsen Gustav Uhre
Published: April 2024

The classic Abraham-Lorentz-Dirac self-force of pointlike particles is generalized within an effective field theory setup to include linear spin and susceptibility effects described perturbatively, in that setup, by effective couplings in the action. Electromagnetic self-interactions of the pointlike particle are integrated out using the in-in supersymmetric worldline quantum field theory formalism. Divergences are regularized with dimensional regularization, and the resulting equations of motion are in terms only of an external electromagnetic field and the particle degrees of freedom.

Published by the American Physical Society
2024
Shallow Bound States and Hints for Broad Resonances with Quark Content
b¯c¯ud
in
B−D¯
and
B*−D¯
Scattering from Lattice QCD
Authors: Alexandrou Constantia , Finkenrath Jacob , Leontiou Theodoros , Meinel Stefan , Pflaumer Martin , Wagner Marc
Published: April 2024

We present the first determination of the energy dependence of the B−D¯ and B*−D¯ isospin-0, S-wave scattering amplitudes both below and above the thresholds using lattice QCD, which allows us to investigate rigorously whether mixed bottom-charm b¯c¯ud tetraquarks exist as bound states or resonances. The scattering phase shifts are obtained using Lüscher’s method from the energy spectra in two different volumes. To ensure that no relevant energy level is missed, we use large, symmetric 7×7 and 8×8 correlation matrices that include, at both source and sink, B(*)−D¯ scattering operators with the lowest three or four possible back-to-back momenta in addition to local b¯c¯ud operators. We fit the energy dependence of the extracted scattering phase shifts using effective-range expansions. We observe sharp peaks in the B(*)−D¯ scattering rates close to the thresholds, which are associated with shallow bound states, either genuine or virtual, a few MeV or less below the B(*)−D¯ thresholds. In addition, we find hints for resonances with masses of order 100 MeV above the thresholds and decay widths of order 200 MeV.

Published by the American Physical Society
2024
Moderating effect of subsidy policy on intention to purchase residential rooftop solar panel systems
Authors: Kumar Ganesh , Nayak Jogendra Kumar
Published: April 2024

Purpose

The adoption of residential rooftop solar panel systems (SPS) in India is at a nascent stage. Therefore, this study aimed to examine the factors affecting consumers’ intention to purchase SPS by expanding the theory of planned behavior (TPB) with three environmental psychology factors. The study was targeted at potential users’ intention to purchase SPS, thus it further explored the moderating role of perceived government subsidy policy (PGSP) in determining consumers’ purchase intention of SPS.

Design/methodology/approach

Using G*power software, the minimum sample size of 189 was calculated; accordingly, 292 valid responses were gathered from potential users of SPS from three Indian states, namely Rajasthan, Punjab and Haryana, via an online questionnaire survey with the help of purposive sampling method. Structural equation modeling technique of partial least squares was employed to analyze the data.

Findings

Results demonstrated that attitude, subjective norms, perceived behavioral control, perceived consumer effectiveness (PCE) and PGSP significantly influence purchase intention of SPS. Green trust and green self-identity did not influence the purchase intention of SPS. Further, PGSP strengthens the effect of attitude, green trust, PCE on purchase intention of SPS while it weakens the effect of subjective norms on purchase intention of SPS.

Originality/value

This study contributes to the existing literature by integrating green trust, green self-identity, PCE and PGSP into the TPB model to better understand factors affecting consumers’ purchase intention towards SPS in India.