bluuebunny/crossref_metadata_2025_split huggingface dataset:
The centaur-algebra of observables
Authors: Aguilar-Gutierrez Sergio E. , Bahiru Eyoab , Espíndola Ricardo 
Published: March 2024

Abstract
This letter explores a transition in the type of von Neumann algebra for asymptotically AdS spacetimes from the implementations of the different gravitational constraints. We denote it as the centaur-algebra of observables. In the first part of the letter, we employ a class of flow geometries interpolating between AdS2 and dS2 spaces, the centaur geometries. We study the type II∞ crossed product algebra describing the semiclassical gravitational theory, and we explore the algebra of bounded sub-regions in the bulk theory following $$ T\overline{T} $$
T

T
¯

deformations of the geometry and study the gravitational constraints with respect to the quasi-local Brown-York energy of the system at a finite cutoff. In the second part, we study arbitrary asymptotically AdS spacetimes, where we implement the boundary protocol of an infalling observer modeled as a probe black hole proposed by [1] to study modifications in the algebra. In both situations, we show how incorporating the constraints requires a type II1 description.
Molecular hallmarks of ageing in amyotrophic lateral sclerosis
Authors: Jagaraj Cyril Jones , Shadfar Sina , Kashani Sara Assar , Saravanabavan Sayanthooran , Farzana Fabiha , Atkin Julie D. 
Published: March 2024

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, and spinal cord. Unfortunately, there are few effective treatments, thus there remains a critical need to find novel interventions that can mitigate against its effects. Whilst the aetiology of ALS remains unclear, ageing is the major risk factor. Ageing is a slowly progressive process marked by functional decline of an organism over its lifespan. However, it remains unclear how ageing promotes the risk of ALS. At the molecular and cellular level there are specific hallmarks characteristic of normal ageing. These hallmarks are highly inter-related and overlap significantly with each other. Moreover, whilst ageing is a normal process, there are striking similarities at the molecular level between these factors and neurodegeneration in ALS. Nine ageing hallmarks were originally proposed: genomic instability, loss of telomeres, senescence, epigenetic modifications, dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and altered inter-cellular communication. However, these were recently (2023) expanded to include dysregulation of autophagy, inflammation and dysbiosis. Hence, given the latest updates to these hallmarks, and their close association to disease processes in ALS, a new examination of their relationship to pathophysiology is warranted. In this review, we describe possible mechanisms by which normal ageing impacts on neurodegenerative mechanisms implicated in ALS, and new therapeutic interventions that may arise from this.
Systematic and quantitative analysis of stop codon readthrough in Rett syndrome nonsense mutations
Authors: Lebeda Dennis , Fierenz Adrian , Werfel Lina , Rosin-Arbesfeld Rina , Hofhuis Julia , Thoms Sven 
Published: March 2024

Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder resulting from genetic mutations in the methyl CpG binding protein 2 (MeCP2) gene. Specifically, around 35% of RTT patients harbor premature termination codons (PTCs) within the MeCP2 gene due to nonsense mutations. A promising therapeutic avenue for these individuals involves the use of aminoglycosides, which stimulate translational readthrough (TR) by causing stop codons to be interpreted as sense codons. However, the effectiveness of this treatment depends on several factors, including the type of stop codon and the surrounding nucleotides, collectively referred to as the stop codon context (SCC). Here, we develop a high-content reporter system to precisely measure TR efficiency at different SCCs, assess the recovery of the full-length MeCP2 protein, and evaluate its subcellular localization. We have conducted a comprehensive investigation into the intricate relationship between SCC characteristics and TR induction, examining a total of 14 pathogenic MeCP2 nonsense mutations with the aim to advance the prospects of personalized therapy for individuals with RTT. Our results demonstrate that TR induction can successfully restore full-length MeCP2 protein, albeit to varying degrees, contingent upon the SCC and the specific position of the PTC within the MeCP2 mRNA. TR induction can lead to the re-establishment of nuclear localization of MeCP2, indicating the potential restoration of protein functionality. In summary, our findings underscore the significance of SCC-specific approaches in the development of tailored therapies for RTT. By unraveling the relationship between SCC and TR therapy, we pave the way for personalized, individualized treatment strategies that hold promise for improving the lives of individuals affected by this debilitating neurodevelopmental disorder.

Key messages

The efficiency of readthrough induction at MeCP2 premature termination codons strongly depends on the stop codon context.

The position of the premature termination codon on the transcript influences the readthrough inducibility.

A new high-content dual reporter assay facilitates the measurement and prediction of readthrough efficiency of specific nucleotide stop contexts.

Readthrough induction results in the recovery of full-length MeCP2 and its re-localization to the nucleus.

MeCP2 requires only one of its annotated nuclear localization signals.
Construction of relatedness matrices in autopolyploid populations using low-depth high-throughput sequencing data
Authors: Bilton Timothy P. , Sharma Sanjeev Kumar , Schofield Matthew R. , Black Michael A. , Jacobs Jeanne M. E. , Bryan Glenn J. , Dodds Ken G. 
Published: March 2024

AbstractKey messageAn improved estimator of genomic relatedness using low-depth high-throughput sequencing data for autopolyploids is developed. Its outputs strongly correlate with SNP array-based estimates and are available in the package GUSrelate.AbstractHigh-throughput sequencing (HTS) methods have reduced sequencing costs and resources compared to array-based tools, facilitating the investigation of many non-model polyploid species. One important quantity that can be computed from HTS data is the genetic relatedness between all individuals in a population. However, HTS data are often messy, with multiple sources of errors (i.e. sequencing errors or missing parental alleles) which, if not accounted for, can lead to bias in genomic relatedness estimates. We derive a new estimator for constructing a genomic relationship matrix (GRM) from HTS data for autopolyploid species that accounts for errors associated with low sequencing depths, implemented in theRpackage GUSrelate. Simulations revealed that GUSrelate performed similarly to existing GRM methods at high depth but reduced bias in self-relatedness estimates when the sequencing depth was low. Using a panel consisting of 351 tetraploid potato genotypes, we found that GUSrelate produced GRMs from genotyping-by-sequencing (GBS) data that were highly correlated with a GRM computed from SNP array data, and less biased than existing methods when benchmarking against the array-based GRM estimates. GUSrelate provides researchers with a tool to reliably construct GRMs from low-depth HTS data.
Pathogen lifestyle determines host genetic signature of quantitative disease resistance loci in oilseed rape (Brassica napus)
Authors: Jacott Catherine N. , Schoonbeek Henk-jan , Sidhu Gurpinder Singh , Steuernagel Burkhard , Kirby Rachel , Zheng Xiaorong , von Tiedermann Andreas , Macioszek Violetta K. , Kononowicz Andrzej K. , Fell Heather , Fitt Bruce D. L. , Mitrousia Georgia K. , Stotz Henrik U. , Ridout Christopher J. , Wells Rachel 
Published: March 2024

Abstract
Key message
Using associative transcriptomics, our study identifies genes conferring resistance to four diverse fungal pathogens in crops, emphasizing key genetic determinants of multi-pathogen resistance.

Abstract
Crops are affected by several pathogens, but these are rarely studied in parallel to identify common and unique genetic factors controlling diseases. Broad-spectrum quantitative disease resistance (QDR) is desirable for crop breeding as it confers resistance to several pathogen species. Here, we use associative transcriptomics (AT) to identify candidate gene loci associated with Brassica napus constitutive QDR to four contrasting fungal pathogens: Alternaria brassicicola, Botrytis cinerea, Pyrenopeziza brassicae, and Verticillium longisporum. We did not identify any shared loci associated with broad-spectrum QDR to fungal pathogens with contrasting lifestyles. Instead, we observed QDR dependent on the lifestyle of the pathogen—hemibiotrophic and necrotrophic pathogens had distinct QDR responses and associated loci, including some loci associated with early immunity. Furthermore, we identify a genomic deletion associated with resistance to V. longisporum and potentially broad-spectrum QDR. This is the first time AT has been used for several pathosystems simultaneously to identify host genetic loci involved in broad-spectrum QDR. We highlight constitutive expressed candidate loci for broad-spectrum QDR with no antagonistic effects on susceptibility to the other pathogens studies as candidates for crop breeding. In conclusion, this study represents an advancement in our understanding of broad-spectrum QDR in B. napus and is a significant resource for the scientific community.
Modelling and simulation of heat flow in indexable insert drilling
Authors: Andersson Tobias , Svensson Daniel , Andersson Lassila Andreas 
Published: March 2024

AbstractIn machining, the heat generated during the process deforms the components and the final shape might not meet specified tolerances. There is therefore a need for a compensation strategy which requires knowledge of the workpiece temperature field and the associated thermal distortions. In this work, a methodology is presented for the determination of the heat load for indexable insert drilling of AISI 4140. Compared to previous research, this work has introduced a varying heat load. The heat load is extracted from thermo-mechanical finite element simulations for different nominal chip thicknesses and cutting speeds using the coupled Eulerian-Lagrangian formulation of an orthogonal turning process. The heat load is then transferred to a simplified 2D axisymmetric heat transfer model where the in-process temperature field in the workpiece is predicted. To verify the methodology, the predicted temperatures are compared to the experimentally measured temperatures for various feed rates. It is found that the model is capable of predicting the workpiece temperatures reasonably well. However, the methodology needs to be further explored to validate its applicability.
Prescriptions of homeopathic remedies at the expense of the German statutory health insurance from 1985 to 2021: scientific, legal and pharmacoeconomic analysis
Authors: Leemhuis Hauke , Seifert Roland 
Published: March 2024

AbstractThe prescription of homeopathic remedies at the expense of the statutory health insurance (SHI) system in Germany has been criticized for years due to a lack of evidence. Now, on the planned abolition of the reimbursement of homeopathic medicines in Germany, the debate on this topic has been reignited. The aim of this paper is to show the costs and their development over time incurred by homeopathic remedies in the healthcare system from 1985 to 2021. For this purpose, 15 selected homeopathic medicines were chosen from the drug prescription report (Arzneiverordnungsreport) and analyzed with regard to their development of DDD (Defined Daily Dose) using data from the Wissenschaftliches Institut der Ortskrankenkassen (WidO, Scientific Institute of the General Local Health Insurance Funds) and compared with their respective rational pharmacological alternatives. The price comparison was based on the DDD costs and the pharmacy retail price of the smallest packaging in each case. The clinical study situation for the preparations was also analyzed. For this purpose, the clinical studies provided by the manufacturer and those on PubMed were divided into evidence levels and analyzed. In addition, the presentation of homeopathic remedies on company websites, in online pharmacies, in specialist information and package leaflets was analyzed with regard to side effects, interactions, indication, and information on the alleged effect/proof of efficacy. In many media, information on homeopathic medicines remained incomplete, and non-compliance with the Therapeutic Product Advertising Act (Heilmittelwerbegesetz) was noted. Naming of the products if often very suggestive, too. Manufacturers’ claims of efficacy go far beyond what can be considered proven in terms of evidence-based medicine and the quality of most clinical studies is poor. Homeopathic remedies are on average significantly more expensive than their rational pharmacological alternatives. Furthermore, DDD costs have continued to rise over the years analyzed. In aggregate, from a pharmacoeconomic, legal, and scientific perspective, abolition of reimbursement of homeopathic medicines in Germany at the expense of the SHI system is well justified.
Changes in distinct brain systems identified with fMRI during smoking cessation treatment with varenicline: a review
Authors: Panagopoulos Vassilis N. , Bailey Alexis , Kostopoulos George K. , Ioannides Andreas A. 
Published: March 2024

Abstract
Background
Varenicline is considered one of the most effective treatment options for smoking cessation. Nonetheless, it is only modestly effective. A deeper comprehension of the effects of varenicline by means of the in-depth review of relevant fMRI studies may assist in paving the development of more targeted and effective treatments.

Methodology
A search of PubMed and Google Scholar databases was conducted with the keywords “functional magnetic resonance imaging” or “fMRI”, and “varenicline”. All peer-reviewed articles regarding the assessment of smokers with fMRI while undergoing treatment with varenicline and meeting the predefined criteria were included.

Results
Several studies utilizing different methodologies and targeting different aspects of brain function were identified. During nicotine withdrawal, decreased mesocorticolimbic activity and increased amygdala activity, as well as elevated amygdala-insula and insula-default-mode-network functional connectivity are alleviated by varenicline under specific testing conditions. However, other nicotine withdrawal-induced changes, including the decreased reward responsivity of the ventral striatum, the bilateral dorsal striatum and the anterior cingulate cortex are not influenced by varenicline suggesting a task-dependent divergence in neurocircuitry activation. Under satiety, varenicline treatment is associated with diminished cue-induced activation of the ventral striatum and medial orbitofrontal cortex concomitant with reduced cravings; during the resting state, varenicline induces activation of the lateral orbitofrontal cortex and suppression of the right amygdala.

Conclusions
The current review provides important clues with regard to the neurobiological mechanism of action of varenicline and highlights promising research opportunities regarding the development of more selective and effective treatments and predictive biomarkers for treatment efficacy.
Upper bounds for the critical values of homology classes of loops
Authors: Rademacher Hans-Bert 
Published: March 2024

AbstractIn this short note we discuss upper bounds for the critical values of homology classes in the based and free loop space of compact manifolds carrying a Riemannian or Finsler metric of positive Ricci curvature. In particular it follows that a shortest closed geodesic on a compact and simply-connected n-dimensional manifold of positive Ricci curvature $$\text {Ric}\ge n-1$$

Ric
≥
n
-
1

has length $$\le n \pi .$$

≤
n
π
.

This improves the bound $$8\pi (n-1)$$

8
π
(
n
-
1
)

given by Rotman (Positive Ricci curvature and the length of a shortest periodic geodesic. arXiv:2203.09492, 2022).
Combination of IL-33 with PD-1 blockade augment mILC2s-mediated anti-tumor immunity
Authors: Yue Jiawei , Guo Hui , Xu Peng , Ma Jinhong , Shi Weifeng , Wu Yumin 
Published: March 2024

Abstract
Background
Group 2 innate lymphoid cells (ILC2s) represent one of the main tissue-specific innate lymphoid cell populations, which are key drivers of cytokine secretion in their occupational niche. However, the precise involvement of ILC2s in cancer immunity and their potential impact on immunotherapeutic approaches remain poorly understood.

Methods
The proportion of ILC2s originating from various tissue sources were quantified through flow cytometry, along with the determination of CD4+ T cell and CD8+ T cell percentages. Flow cytometry was also employed to assess IFN-γ production and programmed cell death protein-1 (PD-1) expression in T cells. Immunohistochemistry was utilized to detect IL-33 expression in tumor tissues, while immunofluorescence was employed to confirm the infiltration of ILC2s in both murine and human tumor tissues.

Results
In this study, we provide evidence that intra-tumoral ILC2s in lung adenocarcinoma (LUAD) exist in a quiescent state. However, the activation of intra-tumoral ILC2s is induced by IL-33 specifically in a natural ILC2s (nILC2, ST2+KLRG1−) phenotype. Considering the pivotal role of PD-1 in cancer immunotherapy and its immunoregulatory functions, we investigated the synergistic effects of IL-33 and anti-PD-1 and found that their combination enhances anti-tumor immunity and improves the efficacy of immunotherapy. Moreover, this combination leads to the upregulation of activated mature ILC2s (mILC2, ST2+KLRG1+) phenotype, thereby highlighting the activated ILC2s as a novel enhancer of the immunoregulatory properties of anti-PD-1.

Conclusions
Collectively, these findings underscore the significance of ILC2s and their contribution to the anti-tumor response in the context of cancer immunotherapy. Consequently, the simultaneous targeting of ILC2s and T cells represents a potentially promising and widely applicable strategy for immunotherapeutic interventions.
Oct4 activates IL-17A to orchestrate M2 macrophage polarization and cervical cancer metastasis
Authors: Bian Zhuoqiong , Wu Xiaoling , Chen Qing , Gao Qing , Xue Xiang , Wang Yidong 
Published: March 2024

Abstract
Background
Cervical cancer is a common malignant tumor in the female. Interleukin (IL)-17A is a proinflammatory factor and exerts a vital function in inflammatory diseases and cancers. M2 macrophage has been confirmed to promote tumor development. Nevertheless, it is not yet known whether IL-17A facilitates cervical cancer development by inducing M2 macrophage polarization. Therefore, this study was conducted to investigate the regulatory effect of IL-17A on M2 macrophage polarization and the underlying mechanism in cervical cancer development.

Methods
RT-qPCR was utilized for testing IL-17A expression in cancer tissues and cells. Flow cytometry was applied to evaluate the M1 or M2 macrophage polarization. Cell proliferative, migratory, and invasive capabilities were measured through colony formation and transwell assays. ChIP and luciferase reporter assays were applied to determine the interaction between IL-17A and octamer-binding transcription factor 4 (OCT4).

Results
IL-17A expression and concentration were high in metastatic tissues and cells of cervical cancer. IL-17A was found to facilitate M2 macrophage polarization in cervical cancer. Furthermore, IL-17A facilitated the macrophage-mediated promotion of cervical cancer cell proliferative, migratory, and invasive capabilities. Mechanistic assays manifested that Oct4 binds to and transcriptionally activated IL-17A in cervical cancer cells. Furthermore, Oct4 promoted cervical cancer cell malignant phenotype and M2 macrophage polarization by activating the p38 pathway that, in turn, upregulated IL-17A. Additionally, in vivo experiments confirmed that Oct4 knockdown reduced tumor growth and metastasis.

Conclusion
Oct4 triggers IL-17A to facilitate the polarization of M2 macrophages, which promotes cervical cancer cell metastasis.
Riboflavin-LSD1 axis participates in the in vivo tumor-associated macrophage morphology in human colorectal liver metastases
Authors: Soldani Cristiana , De Simone Giulia , Polidoro Michela Anna , Morabito Aurelia , Franceschini Barbara , Colombo Federico Simone , Anselmo Achille , Milana Flavio , Lleo Ana , Torzilli Guido , Pastorelli Roberta , Donadon Matteo , Brunelli Laura 
Published: March 2024

AbstractTumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME). In colorectal liver metastasis (CLM), TAM morphology correlates with prognosis, with smaller TAMs (S-TAMs) conferring a more favorable prognosis than larger TAMs (L-TAMs). However, the metabolic profile of in vivo human TAM populations remains unknown. Multiparametric flow cytometry was used to freshly isolate S- and L-TAMs from surgically resected CLM patients (n = 14S-, 14L-TAMs). Mass spectrometry-based metabolomics analyses were implemented for the metabolic characterization of TAM populations. Gene expression analysis and protein activity were used to support the biochemical effects of the enzyme–substrate link between riboflavin and (lysine-specific demethylase 1A, LSD1) with TAM morphologies. L-TAMs were characterized by a positive correlation and a strong association between riboflavin and TAM morphologies. Riboflavin in both L-TAMs and in-vitro M2 polarized macrophages modulates LSD1 protein expression and activity. The inflammatory stimuli promoted by TNFα induced the increased expression of riboflavin transporter SLC52A3 and LSD1 in M2 macrophages. The modulation of the riboflavin-LSD1 axis represents a potential target for reprogramming TAM subtypes, paving the way for promising anti-tumor therapeutic strategies.
Ectopic CXCR2 expression cells improve the anti-tumor efficiency of CAR-T cells and remodel the immune microenvironment of pancreatic ductal adenocarcinoma
Authors: Dai Zhengjie , Lin Xuan , Wang Xu , Zou Xuan , Yan Yu , Wang Ruijie , Chen Yusheng , Tasiheng Yesiboli , Ma Mingjian , Wang Xu , Cheng He , Yu Xianjun , Liu Chen 
Published: March 2024

Abstract
Background
Recent progressions in CAR-T cell therapy against pancreatic ductal adenocarcinoma (PDAC) remain disappointing, which are partially attributed to the immunosuppressive microenvironment including macrophage-mediated T cell repletion.

Methods
We first characterized the expression patterns of macrophage-relevant chemokines and identified CXCR2 as the key factor regulating T cell trafficking and tumor-specific accumulation in PDAC microenvironment. After that, we synthesized and introduced a CXCR2 expression cascade into Claudin18.2 CAR-T cells and compared the behaviors of CAR-T cells in vitro and in vivo. The therapeutic potential of CXCR2 CAR-T was evaluated in two different allogeneic models: subcutaneous allografts and metastatic PDAC models.

Results
The results showed that CXCR2 CAR-T not only reduced the size of allografted PDAC tumors, but also completely eliminated the formation of metastases. Lastly, we investigated the tumor tissues and found that expression of ectopic CXCR2 significantly improved tumor-targeted infiltration and residence of T cells and reduced the presence of MDSCs and CXCR2 + macrophages in PDAC microenvironment.

Conclusion
Our studies suggested that ectopic CXCR2 played a significant and promising role in improving the efficiency of CAR-T therapy against primary and metastatic PDAC and partially reversed the immune-suppressive microenvironment.