bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Pvc15 D2-Pnf SP Interaction Mediates AAA ATPase Activity, Payload Stability, and Translocation into the PVC Tube Lumen
Authors: Evans Rhys , Waterfield Nicholas R. 
Published: August 2023

AbstractThePhotorhabdusvirulence cassette (PVC) is an elegant, multi-protein, contractile nanostructure which injects functionally bioactive polypeptides into the eukaryotic cytosol. Signal peptides (SPs) are N-terminal amino acid motifs from native ‘payload’ proteins which can also associate wide range of heterologous proteins to the PVC tube lumen. In addition, Pvc15 is a classic AAA ATPase encoded within the PVC operon which encodes an N-domain and tandem AAA domains D1 and D2. This work finds that Pvc15’s ATPase activity is mediated by the E555 residue situated in the Walker B motif of the sole functional ATPase domain, D2. Pvc15 multimerisation may be required to translocate payload into the PVC tube lumen, which is facilitated by intact N and D1 domains. In addition, ATPase activity requires the presence of other PVC operon components which hints at a PVC-regulated mode of action for loading. Furthermore, D2 is a chaperone for the native Pnf SP, though C-terminal truncations of the Pnf SP confers Pvc15-independent stability to the payload. These findings provide insight into the nuanced roles of the Pvc15-SP interaction for payload-PVC association and the effects that SP length and type has on payload stability and PVC-loading ability.
A neuronal relay mediates muscle-adipose communication that drives systemic metabolic adaptation to high-sugar diets
Authors: Kubrak Olga , Joergensen Anne F. , Koyama Takashi , Nagy Stanislav , Lassen Mette , Hald Jacob , Madsen Dennis , Halberg Kenneth V. , Texada Michael J. , Hansen Jakob L. , Rewitz Kim 
Published: August 2023

AbstractObesity leads to impaired insulin signaling and tissue sensitivity, which drive the onset of type 2 diabetes. Insulin resistance leads to a reduction in cellular glucose uptake, resulting in elevated blood glucose levels, which consequently cause β-cell dysfunction and development of diabetes. Although improving insulin signaling is a key target for restoring whole-body glucose homeostasis and reversing diabetes, the multi-organ mechanisms that regulate insulin signaling and tissue sensitivity are poorly defined. We screened the secretome and receptome inDrosophilato identify the underlying interorgan hormonal crosstalk affecting diet-induced insulin resistance and obesity. We identified complex interplay between muscle, neuronal, and fat tissues, mediated by the conserved BMP and LGR signaling pathways, which augments insulin signaling and improves dietary sugar tolerance. We found that muscle-derived BMP signaling is induced by sugar and governs neuronal Bursicon signaling. Acting through its LGR-family receptor, Bursicon both enhances insulin secretion and improves insulin sensitivity in adipose tissue, thereby preventing sugar-induced hyperglycemia. Inhibition of Bursicon-LGR signaling in adipose tissue exacerbates sugar-induced insulin resistance, and we discovered that this condition could be alleviated by suppressing NF-κB signaling. Our findings identify a muscle-neuronal-fat tissue axis that drives metabolic adaptation to high-sugar conditions by modulating insulin secretion and adipocyte insulin sensitivity, highlighting mechanisms that may be exploited for the development of strategies for the treatment and reversal of insulin resistance.
Signals and noise: communicating achievement through alternative credentials
Authors: Bean Martin , Grant Sheryl , Hardaker Glenn , Ward Rupert 
Published: August 2023

PurposeAlternative credentials are rapidly evolving. The purpose of this paper is to explore the challenges and opportunities arising from this evolution with particular reference to their role in education and employment.Design/methodology/approachThe paper explores the credential initiatives with a unique perspective from introducing alternative credential initiatives that have been influential in recent national policy developments. The paper is led by the experiences of the former General Manager of Microsoft's Education Products Group, former Vice-Chancellor of The Open University and the Royal Melbourne Institute of Technology University. His experiences and lessons learnt reflecting on alternative credential development during the last 30 years provides a unique insight in seeing the “signals” and moving beyond the “noise” of micro-credentials for successful integration into educational institutions.FindingsA number of key findings are identified in terms of current development challenges that impact on alternative credential use and identifying further developments. Relevant examples and references are provided throughout, with a particular focus on North America, Europe and Australasia where the most progress has been made in alternative credentials.Research limitations/implicationsImplications for those wishing to develop badging and microcredentialing solutions, especially in higher education, are identified for all seeking to maximise the success of alternative credential systems.Originality/valueMartin Bean has a unique perspective having explored credential initiatives whilst General Manager of Microsoft's Education Products Group and whilst Vice-Chancellor of The Open University and the Royal Melbourne Institute of Technology University. Martin Bean has also been influential in recent national policy developments in Australia. Martin Bean’s experiences and lessons learnt witnessing alternative credential development during the last 30 years across three continents, and within both public and private sectors, are summarised here to provide context for discussions of some of the key global concepts and related work.
Inhibition of p38MAPK signalling pathway alleviates radiation‐induced testicular damage through improving spermatogenesis
Authors: Yang Juan , Ou Xiangying , Shu Manling , Wang Jie , Zhang Xuan , Wu Zhenyu , Hao Wei , Zeng Huihong , Shao Lijian 
Published: August 2023

AbstractBackground and PurposeDamage to the testis following exposure to ionizing radiation has become an urgent problem to be solved. Here we have investigated if inhibition of p38 mitogen‐activated protein kinase (p38MAPK) signalling could alleviate radiation‐induced testicular damage.Experimental ApproachIn mice exposed to whole body radiation (2‐6 Gy), morphological changes of the epididymis and testis was measured by histochemical staining. immunohistochemical and immunofluorescence procedures and western blotting were used to monitor expression and cellular location of proteins. Expression of genes was assessed by qPCR and RNA‐Seq was used to profile gene expression.Key ResultsExposure to ionizing radiation induced dose‐dependent damage to mouse testis. The sperm quality decreased at 6 and 8 weeks after 6 Gy X‐ray radiation. Radiation decreased PLZF+ cells and increased SOX9+ cells, and affected the expression of 969 genes, compared with data from non‐irradiated mice. Expression of genes related to p38MAPK were enriched by GO analysis and were increased in the irradiated testis, and confirmed by qPCR. Levels of phospho‐p38MAPK protein increased at 28 days after irradiation. In irradiated mice, SB203580 treatment increased spermatozoa, SOX9+ cells, the area and diameter of seminiferous tubules, sperm movement rate and density. Furthermore, SB203580 treatment increased SCP3+ cells, accelerating the process of spermatogenesis.Conclusion and ImplicationsExposure to ionizing radiation clearly changed gene expression in mouse testis, involving activation of p38MAPK signalling pathways. Inhibition of p38MAPK by SB203580 partly alleviated the testicular damage caused by radiation and accelerated the recovery of sperms through promoting spermatogenesis.
Estimated lifetime benefit of novel pharmacological therapies in patients with type 2 diabetes and chronic kidney disease: A joint analysis of randomized controlled clinical trials
Authors: Heerspink Hiddo J. L. , Vart Priya , Jongs Niels , Neuen Brendon L. , Bakris George , Claggett Brian , Vaduganathan Muthiah , McCausland Finnian , Docherty Kieran F. , Jhund Pardeep S. , Solomon Scott D. , Perkovic Vlado , McMurray John J. V. 
Published: August 2023

AbstractAimTo estimate the lifetime benefit of a combination treatment of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors and mineralocorticoid‐receptor antagonists (MRA) in patients with type 2 diabetes and chronic kidney disease (CKD).Materials and MethodsThe cumulative effect of combination treatment was derived from trial‐level estimates of the effect of an SGLT2 inhibitor (canagliflozin) and MRA (finerenone) from the CREDENCE (N = 4401) and FIDELIO (N = 5734) trials, respectively. The cumulative effect was applied to the control group of patients with type 2 diabetes in the DAPA‐CKD trial (N = 1451) to estimate long‐term gains in event‐free and overall survival. The analysis was repeated in an observational study. The primary outcome was a composite endpoint of doubling of serum creatinine, end‐stage kidney disease or death because of kidney failure.ResultsThe hazard ratio of combination treatment for the primary outcome was 0.50 [95% confidence interval (CI): 0.44, 0.57]. At age 50 years, the estimated event‐free survival from the primary outcome was 16.7 years (95% CI: 18.1, 21.0) with combination treatment versus 10.0 years (95% CI: 6.8, 12.3) with angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers resulting in an incremental gain of 6.7 years (95% CI: 5.5, 7.9). In an observational study, the estimated gain in event‐free survival regarding primary outcome was 6.3 years (95% CI: 5.2, 7.3). In a conservative scenario, assuming low adherence (70% of the observed adherence) and less pronounced efficacy (70% of the observed efficacy with 2% yearly decline) of combination therapy, gain in event‐free survival regarding primary outcome was 2.5 years (95% CI: 2.0, 2.9).ConclusionsCombined disease‐modifying treatment with an SGLT2 inhibitor and MRA in patients with type 2 diabetes and CKD may substantially increase the number of years free from kidney failure and mortality.
Development of a novel Fc fusion protein dual glucagon‐like peptide‐1 and gastric inhibitory polypeptide receptor agonists
Authors: Jiang Peng , Sun Ningyuan , Yang Wen , Xiao Lin , Zhou Linjun , Gu Baohua , Li Yong , Li Lijia , Li Jing , Li Xiaoping , Li Wenjia , Guo Linfeng 
Published: August 2023

AbstractAimTo develop and investigate an imbalanced dual gastric inhibitory polypeptide receptor (GIPR)/glucagon‐like peptide‐1 receptor (GLP‐1 R) agonist with Fc fusion protein structure.MethodsWe designed and constructed an Fc fusion protein that is a dual agonist (HEC‐CG115) with an empirically optimized potency ratio for GLP‐1R and GIPR. The long‐term effects of HEC‐CG115 on body weight and glycaemic control were evaluated in diet‐induced obese mice and diabetic db/db mice. Repeat dose toxicity assays were performed to investigate the safety profile of HEC‐CG115 in Sprague‐Dawley rats.ResultsHEC‐CG115 displayed high potency for GIPR and relatively low potency for GLP‐1R, and we labelled it ‘imbalanced’. In animal models, HEC‐CG115 (3 nmol/kg) led to more weight loss than semaglutide at a higher dose (10 nmol/kg) in diet‐induced obese model mice. HEC‐CG115 (one dose every 3 days) reduced fasting blood glucose and glycated haemoglobin levels similar to those after semaglutide (once daily) at the same dose. In a 4‐week subcutaneous toxicity study conducted to assess the biosafety of HEC‐CG115, the no observed adverse effect level was determined to be 3 mg/kg.ConclusionHEC‐CG115 is a novel Fc fusion protein with imbalanced dual agonism that shows superior weight loss, glycaemic control and metabolic improvement in animal models, and has an optimal safety profile according to a repeat‐dose toxicity study. Therefore, the use of HEC‐CG115 appears to be safe and effective for the treatment of obesity and type 2 diabetes.
Size, but not sex, predicts pinch force and exoskeleton mechanical properties in crayfish of the genus Faxonius
Authors: Benson Derek M. , Clotfelter Ethan D. 
Published: August 2023

AbstractStudies of animal weaponry and defensive structures rarely take into consideration their underlying mechanical properties. We measured the compressive strength and thickness of the exoskeleton of the claw (chela) in two North American crayfish species, Faxonius virilis and F. limosus. We performed similar measures on the carapace, a body region not directly involved in agonistic contests. Males of both species generated significantly stronger maximum pinch forces than females. However, these differences can be attributed to differences in claw size between the sexes. The thickness (ultrastructure) of the claw exoskeleton was a significant predictor of its compressive strength and likely explained the difference in compressive strength we observed between the two species. Neither claw thickness nor claw compressive strength was correlated with maximum pinch force. Additionally, we found that crayfish body size was a strong predictor of carapace compressive strength and thickness, whereas sex was not. The claw had greater compressive strength and thickness than the corresponding values for the carapace. Our study shows that the mechanical properties of the crayfish exoskeleton are largely a function of size and highlights the need to integrate mechanical properties into studies of animal morphology and performance.
Gastrointestinal hospitalization during COVID‐19 pandemic in the United States: Analysis of a nationwide inpatient sample
Authors: Wang Yichen , Huang Yuting , Zheng Ting , Sun Chenyu , Yang Keming , Pang Maoyin 
Published: August 2023

AbstractBackground and AimWe aim to systematically investigate gastrointestinal (GI) hospitalizations in the United States during the early phase of the COVID‐19 pandemic on a national level and the consequence that may inform practice and policies.MethodsA retrospective cross‐sectional analysis of adult hospitalizations with GI‐related diagnoses or procedures in the United States in 2020 was used, with hospitalizations from 2016 to 2019 used for contextual information.ResultsHospitalizations with principal and secondary GI diagnoses decreased by 13.3% and 8.2% from 2019 to 2020, respectively. Most GI diagnoses decreased in 2020, with a few exceptions including alcoholic liver disease (increased by 7.8% as a principal diagnosis) and acute liver failure (increased by 11.6% as a secondary diagnosis). The mortality rate of hospitalizations with GI disease increased in 2020 compared with 2019 (for principal diagnosis: adjusted odds ratio 1.08, 95% confidence interval 1.03–1.13, P = 0.001; for secondary diagnosis: adjusted odds ratio 1.10, 95% confidence interval 1.07–1.13, P < 0.001). Most GI procedures decreased except for a notable 8.3% increase in gastrostomy. The per‐GI‐hospitalization rate of procedures increased for hospitalizations with a principal GI diagnosis (56.4% vs 55.6%, P = 0.003) or unchanged for hospitalizations with secondary GI diagnoses (18.3% vs 18.2%, P = 0.512).ConclusionThe COVID‐19 pandemic resulted in a decrease in the volume of GI hospitalizations and procedures in 2020, but there was an increase in the mortality rate and some specific diagnoses including alcoholic liver disease and acute liver failure. These findings will likely enlighten future research and healthcare resource allocation for GI diseases.
Physiologic hormone administration improves HbA1C in Native Americans with type 2 diabetes: A retrospective study and review of insulin secretion and action
Authors: Rebello Candida J. , Morales Tyler S. , Chuon Katsya , Dong Shu , Lam V. Tyrone , Purner Dan , Lewis Stanley , Lakey Jonathan , Beyl Robbie A. , Greenway Frank L. 
Published: August 2023

SummaryInsulin is secreted in pulses from pancreatic beta‐cells, and these oscillations maintain fasting plasma glucose levels within a narrow normal range. Within islets, beta‐cells exhibit tight synchronization of regular oscillations. This control circuit is disrupted in type 2 diabetes, and irregularities in pulse frequency and amplitude occur. The prevalence of type 2 diabetes is three times higher in American Indian and Native Alaskans compared to Whites, and their genetic ancestry is associated with low beta‐cell function. Obesity in this population compounds their vulnerability to adverse outcomes. The purpose of this article is to review insulin secretion and action and its interaction with race. We also present the results from a 6‐month retrospective chart review of metabolic outcomes following intravenous physiologic hormone administration to 10 Native Americans. We found reductions in hemoglobin A1C (baseline: 9.03% ± 2.08%, 6 months: 7.03% ± 0.73%, p = 0.008), fasting glucose (baseline: 176.0 ± 42.85 mg/dL, 6 months: 137.11 ± 17.05 mg/dL, p = 0.02), homeostatic model assessment of insulin resistance (baseline: 10.39 ± 4.66, 6 months: 7.74 ± 4.22, p = 0.008), and triglycerides (baseline: 212.20 ± 101.44, 6 months: 165.50 ± 76.48 mg/dL, p = 0.02). Physiologic hormone administration may improve components of the metabolic syndrome. The therapy warrants investigation in randomized controlled trials.
A new method for extracting conodonts and radiolarians from chert with NaOH solution
Authors: Rigo Manuel , Onoue Tetsuji , Wu Qiangwang , Tomimatsu Yuki , Santello Lisa , Du Yixing , Jin Xin , Bertinelli Angela 
Published: August 2023

AbstractMicrofossils are important components of sedimentary rocks used for palaeontological, biostratigraphic, palaeoenvironmental and palaeoclimatic investigations. They are usually extracted from rocks using an acid solution, which might vary depending on the embedding rock lithology. Here we propose a new method using common NaOH (sodium hydroxide; soda) to digest cherts (micro‐ and cryptocrystalline quartz) instead of the standard technique based on HF (hydrofluoric acid). This new method allows the collection of undamaged specimens of different kinds of microfossils, such as conodonts, radiolarians, teeth and dermal scales, the minerology of which is still preserved (e.g. biogenic apatite in conodonts). The use of soda is thus recommended, as it is less dangerous, less expensive, and it better preserves the extracted microfossils both in shape and mineralogy.
Why you should be a religious skeptic
Authors: Gäb Sebastian 
Published: August 2023

AbstractMost philosophers of religion subscribe to some variety of religious realism: they believe that religious statements aim at capturing a mind‐independent reality and are true precisely if they successfully do so. Curiously, most religious realists also believe that at least some of our religious beliefs are rationally justified. In this paper, I argue that these positions are actually at odds with each other. Religious realists should rather be religious skeptics. I first argue that realism always implies the possibility of our beliefs being false. Then, I develop a Copernican argument to show that we have no reason to believe that we are in an epistemically privileged position where we could be confident that our particular belief is justified while all competing beliefs are not. This seems impossible for two reasons: (a) From a probabilistic point of view (adopting a principle of mediocrity), it is highly unlikely that current humans have the maximum of epistemic capacities possible. Rather, our ability to understand reality is limited, so we should expect at least some parts of religious reality to remain unknown to us. (b) From a deep‐time perspective, humanity has not pondered religious questions for long. We are probably still in the early stages of our cognitive evolution, and so we should treat our religious beliefs as provisional and open to revision.
Abstract A012: Investigating the heterogeneity and clinical significance of tumor-associated macrophages in renal cell carcinoma milieu
Authors: Zavacky Evelyn M. , Kim Minjun , Madrigal Ariel , Mehrjoo Zohreh , Spicer Jonathon , Tanguay Simon , Brimo Fadi , Najafabadi Hamed , Riazalhosseini Yasser 
Published: August 2023

Abstract
Background: Tumor-associated macrophages (TAMs) exert a range of immunomodulatory functions in the tumor microenvironment (TME) and have been considered key regulators of tumor development. The interactions of TAMs with cancer and stromal cells in the TME have been shown to promote and sustain tumor progression; however, TAMs are largely phenotypically and functionally heterogeneous. Studies at a single-cell level are therefore necessary to understand biological and clinical relevance of heterogeneity of TAMs. Objective: To investigate the heterogeneity of TAM populations in renal cell carcinoma (RCC), the most common form of Kidney cancer, and to determine their connections to patient outcome. Methods and Results: We leverage single-cell RNA sequencing analysis of six primary RCC tumors and three Lung metastatic clear cell RCC (ccRCC) tumors, from which we identified eight TAM and two monocyte clusters shared across all nine patient tissue samples. Differential gene expression and pathway analyses revealed distinct subsets of upregulated genes and cellular pathways activated in each subpopulation. Survival analysis using gene signatures characteristic of each TAM population in datasets of ccRCC tumors (n=533) from TCGA revealed two subpopulations associated with poor patient outcome in ccRCC. Of these, one subpopulation, which we labelled as TAM-8, was characterized by upregulation of pro-inflammatory cytokines, chemokines, and growth factors such as CCL20, CXCL8, and IL1A/B. To our knowledge, this TAM population has not been described in RCC previously. We performed additional in silico functional analyses to further characterize the function of TAM-8 subpopulation, which indicated an active role in promoting immune cell infiltration and angiogenesis via various pro-inflammatory signaling pathways. Conclusion: This study provides new insight into the heterogeneity of TAM populations in RCC and defines CCL20/CXCL8/IL1High TAM-8 population as a potential driver of poor outcome and a candidate therapeutic target.
Citation Format: Evelyn M. Zavacky, Minjun Kim, Ariel Madrigal, Zohreh Mehrjoo, Jonathon Spicer, Simon Tanguay, Fadi Brimo, Hamed Najafabadi, Yasser Riazalhosseini. Investigating the heterogeneity and clinical significance of tumor-associated macrophages in renal cell carcinoma milieu [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A012.
Abstract A015: Injury-associated transcriptional state transitions in early renal carcinogenesis
Authors: Hirosue Shoko , Ge Jianfeng , Castillon Leticia , Rodrigues Paulo , Bihary Dóra , Speed Alyson , Wesolowski Ludovic , Caraffini Veronica , Warren Anne Y. , Stewart Grant D. , Welsh Sarah J. , Mitchell Thomas J. , Matakidou Athena , Seyednasrollah Fatemeh S. , Samarajiwa Shamith A. , Vanharanta Sakari 
Published: August 2023

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR002) of the Conference Program/Proceedings.
Citation Format: Shoko Hirosue, Jianfeng Ge, Leticia Castillon, Paulo Rodrigues, Dóra Bihary, Alyson Speed, Ludovic Wesolowski, Veronica Caraffini, Anne Y. Warren, Grant D. Stewart, Sarah J. Welsh, Thomas J. Mitchell, Athena Matakidou, Fatemeh S. Seyednasrollah, Shamith A. Samarajiwa, Sakari Vanharanta. Injury-associated transcriptional state transitions in early renal carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A015.