bluuebunny/crossref_metadata_2025 huggingface dataset:
LargeTRAPPC11gene deletions as a cause of muscular dystrophy and their estimated genesis
Authors: Kopčilová Johana , Ptáčková Hana , Kramářová Tereza , Fajkusová Lenka , Réblová Kamila , Zeman Jiří , Honzík Tomáš , Zdražilová Lucie , Zámečník Josef , Balážová Patrícia , Viestová Karin , Kolníková Miriam , Hansíková Hana , Zídková Jana
Published: July 2024

Background

Transport protein particle (TRAPP) is a multiprotein complex that functions in localising proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in diseases affecting muscle, brain, eye and to some extent liver. We present three patients who are compound heterozygotes for a missense variant and a structural variant in theTRAPPC11gene.TRAPPC11structural variants have not yet been described in association with a disease. In order to reveal the estimated genesis of identified structural variants, we performed sequencing of individual breakpoint junctions and analysed the extent of homology and the presence of repetitive elements in and around the breakpoints.

Methods

Biochemical methods including isoelectric focusing on serum transferrin and apolipoprotein C-III, as well as mitochondrial respiratory chain complex activity measurements, were used. Muscle biopsy samples underwent histochemical analysis. Next-generation sequencing was employed for identifying sequence variants associated with neuromuscular disorders, and Sanger sequencing was used to confirm findings.

Results

We suppose that non-homologous end joining is a possible mechanism of deletion origin in two patients and non-allelic homologous recombination in one patient. Analyses of mitochondrial function performed in patients’ skeletal muscles revealed an imbalance of mitochondrial metabolism, which worsens with age and disease progression.

Conclusion

Our results contribute to further knowledge in the field of neuromuscular diseases and mutational mechanisms. This knowledge is important for understanding the molecular nature of human diseases and allows us to improve strategies for identifying disease-causing mutations.
A FAC potential for autostructure
Authors: Badnell N. R. , Zhang C. Y.
Published: July 2024

We describe the implementation of the current Flexible Atomic Code (FAC) unique electron central potential within the autostructure code. We show that the two codes then give the same atomic data for all practical application purposes. However, autostructure has more flexible potential options which can lead to a more accurate description of atomic processes, especially in low-charged ions.

Graphic Abstract
Predictions of the missing excited vector heavy–light mesons: the mass difference method
Authors: Allosh M. , Hapareer Moustafa Ismail , Mustafa A. Sayed , Ismail Atef
Published: July 2024

A prediction study for the not yet discovered $$c\overline{s}$$

c

s
¯

and $$b\overline{s}$$

b

s
¯

meson states of the $$1^{3}D_1$$

1
3

D
1

quantum numbers is conducted, denoted as $$D_s$$

D
s

and $$B_s$$

B
s

, respectively. By employing our method, both states of ground and excited vector mesons are considered, which predominantly correspond to the ground state vector mesons with quantum numbers $$n~ ^{2S+1}L_{J} = 1 ~ ^{3}S_1$$

n

2
S
+
1

L
J

=
1

3

S
1

and to the orbitally excited vector mesons with quantum numbers $$n~ ^{2\,S+1}L_{J} = 1~ ^{3}D_1$$

n

2

S
+
1

L
J

=
1

3

D
1

. The considered method depends on the difference in the masses for the relevant states from orbitally and ground state vector mesons. Theoretical calculations are in good agreements with newly published data.
Analysis of low-velocity impact responses in bidirectional gradient double-arrow auxetic metamaterials
Authors: Li Xuelin , Mo Zonglai , Song Shihao , Lin Jiahui , Li Zhuangzhuang , Zhou Yue , Li Jun
Published: July 2024

In this paper, we propose double-arrowed auxetic metamaterials (DAMs) featuring bidirectional wall thickness gradients. Their crushing behavior under low-velocity impact is systematically investigated using a validated finite element (FE) model. The results show that the bidirectional gradient design effectively improves the transverse necking effect observed in uniform DAMs. The bidirectional gradient configuration contributes to improved energy absorption and impact strength. Specifically, there is a 60.7% increase in specific energy absorption (SEA) and a 40.5% improvement in plateau stress, compared to uniform DAMs. Furthermore, the bidirectional gradient configuration reduces the initial peak stresses generated during the dynamic crushing process and exhibits higher crash load efficiency (CLE).
THE IMPACTS OF INNOVATION EFFICIENCY AND GOVERNMENT SUBSIDY ON EXTERNAL FINANCING: EVIDENCE FROM CHINA
Authors: CAO HONGWEI , ZHANG MIN , GUO HANGFEI , PALMER MARK
Published: July 2024

Subsidies from the government and financial resources from external investors play critical roles in supporting firm innovations. We develop a model to empirically investigate the role of firm innovation efficiency in government subsidy allocations and the joint effect of innovation efficiency and government subsidies on external investor decision-making in China. We collect panel data from 337 firms in China over ten years (2011–2021). The results show an inverted U-shaped relationship between innovation efficiency and government subsidies. Both government subsidies and innovation efficiency are positively associated with external financing. Government subsidies positively moderate the impact of innovation efficiency on external financing. The findings provide empirical evidence of the complex relationships among firm innovation efficiency, government subsidies and external financing. In this study, insights are provided into how Chinese government officials and external investors interpret signals of firm innovation. The findings of this study can also be used by managers to attract financial resources and by investors to make investment decisions.
WallStreetBets: Assessing the Collective Intelligence of Reddit for Investment Advice
Authors: Buz Tolga , de Melo Gerard
Published: July 2024

The WallStreetBets (WSB) community on Reddit gained prominence for its role in the GameStop saga and the resulting
meme stock
phenomenon. Concurrently, this has boosted the popularity of finance-related communities on Reddit, with the top five totaling more than 25 million subscribers at the time of writing. However, little is known about the reliability of the advice disseminated in these communities, which is a relevant research question within the field of social computing. In this study, we examine the collective intelligence of WSB, the largest and most active subreddit focused on the stock market, and assess its potential as a democratizing force in enabling access to financial knowledge. First, we establish that WSB meets several criteria to be considered a collectively intelligent crowd. Then, we test our hypothesis quantitatively by analyzing Reddit posts and financial data from a 28-month period to evaluate how successful an investor relying on WSB recommendations could have been. We define a portfolio of WSB’s most discussed stocks which shows significant growth, outperforming the S&P 500 index over the reviewed time frame. We further find that following buy signals at the time they are posted on WSB leads to positive outcomes over the long run, and that the GameStop hype merely amplified previously existing characteristics. The WSB portfolio underperforms the broader market during downturns, but recovers more quickly and achieves higher profits afterwards. The results of our work can be generalized to comparable finance-related communities, indicating that their original purpose of leisurely entertainment has already been extended towards tangible real-world value.
Elliptically Contoured Tensor-variate Distributions with Application to Image Learning
Authors: Llosa-Vite Carlos , Maitra Ranjan
Published: July 2024

Statistical analysis of tensor-valued data has largely used the tensor-variate normal (TVN) distribution that may be inadequate for data arising from distributions with heavier or lighter tails. We study a general family of elliptically contoured (EC) TV distributions and derive its characterizations, moments, marginal, and conditional distributions. We describe procedures for maximum likelihood estimation from data that are (1) uncorrelated draws from an EC distribution, (2) from a scale mixture of the TVN distribution, and (3) from an underlying but unknown EC distribution, for which we extend Tyler’s robust estimator. A detailed simulation study highlights the benefits of choosing an EC distribution over the TVN for heavier-tailed data. We develop TV classification rules using discriminant analysis and EC errors and show that they better predict cats and dogs from images in the Animal Faces-HQ dataset than the TVN-based rules. A novel tensor-on-tensor regression and TV analysis of variance (TANOVA) framework under EC errors is also demonstrated to better characterize gender, age, and ethnic origin than the usual TVN-based TANOVA in the celebrated labeled faces of the wild dataset.
Innate Immunity in Protection and Pathogenesis During Coronavirus Infections and COVID-19
Authors: Malireddi R.K. Subbarao , Sharma Bhesh Raj , Kanneganti Thirumala-Devi
Published: July 2024

The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.
Neuroimmune Interactions in the Intestine
Authors: Wallrapp Antonia , Chiu Isaac M.
Published: July 2024

Recent advances have contributed to a mechanistic understanding of neuroimmune interactions in the intestine and revealed an essential role of this cross talk for gut homeostasis and modulation of inflammatory and infectious intestinal diseases. In this review, we describe the innervation of the intestine by intrinsic and extrinsic neurons and then focus on the bidirectional communication between neurons and immune cells. First, we highlight the contribution of neuronal subtypes to the development of colitis and discuss the different immune and epithelial cell types that are regulated by neurons via the release of neuropeptides and neurotransmitters. Next, we review the role of intestinal inflammation in the development of visceral hypersensitivity and summarize how inflammatory mediators induce peripheral and central sensitization of gut-innervating sensory neurons. Finally, we outline the importance of immune cells and gut microbiota for the survival and function of different neuronal populations at homeostasis and during bacterial and helminth infection.
Challenges to the Contemporary Death Penalty in the United States
Authors: Kaplan Paul
Published: July 2024

This review focuses on empirical research about contemporary challenges to the death penalty in the United States. Challenges are factors that obstruct capital punishment, including legal or political restrictions; elimination at the federal or state level; or the hindrance of the process at its operational stages of charging, adjudicating, appeals, clemency, or executions. By the best-known measures, the death penalty has been in decline in the United States since the turn of the century. Lethal injection errors—“botches”—are arguably the most important current challenge to the institution. Wrongful capital conviction has made capital punishment less tolerable to the general public. Mitigation remains an important challenge to the death penalty. This review emphasizes botches, innocence, and mitigation but also touches on disparate impact, failure-to-deliver a social benefit, and cost. Along the way, this review proposes a framework for considering challenges as they occur on two continua of impact, a micro/meso/macro axis and a narrow/wide axis.
Submicrometer Particle Impact Dynamics and Chemistry
Authors: Burke Sally E. , Continetti Robert E.
Published: July 2024

Experimental studies of the collision phenomena of submicrometer particles is a developing field. This review examines the range of phenomena that can be observed with new experimental approaches. The primary focus is on single-particle impact studies enabled by charge detection mass spectrometry (CDMS) implemented using the Aerosol Impact Spectrometer (AIS) at the University of California, San Diego. The AIS combines electrospray ionization, aerodynamic lens techniques, CDMS, and an electrostatic linear accelerator to study the dynamics of particle impact over a wide range of incident velocities. The AIS has been used for single-particle impact experiments on positively charged particles of diverse composition, including polystyrene latex spheres, tin particles, and ice grains, over a wide range of impact velocities. Detection schemes based on induced charge measurements and time-of-flight mass spectrometry have enabled measurements of the impact inelasticity through the determination of the coefficient of restitution, measurements of the angular distributions of scattered submicrometer particles, and the chemical composition and dissociation of solute molecules in hypervelocity ice grain impacts.
Spectroscopy in Nanoscopic Cavities: Models and Recent Experiments
Authors: Bourgeois Marc R. , Pan Feng , Anyanwu C. Praise , Nixon Austin G. , Beutler Elliot K. , Dionne Jennifer A. , Goldsmith Randall H. , Masiello David J.
Published: July 2024

The ability of nanophotonic cavities to confine and store light to nanoscale dimensions has important implications for enhancing molecular, excitonic, phononic, and plasmonic optical responses. Spectroscopic signatures of processes that are ordinarily exceedingly weak such as pure absorption and Raman scattering have been brought to the single-particle limit of detection, while new emergent polaritonic states of optical matter have been realized through coupling material and photonic cavity degrees of freedom across a wide range of experimentally accessible interaction strengths. In this review, we discuss both optical and electron beam spectroscopies of cavity-coupled material systems in weak, strong, and ultrastrong coupling regimes, providing a theoretical basis for understanding the physics inherent to each while highlighting recent experimental advances and exciting future directions.
Review—Carbon Nanotube-Based Electrochemical Glucose Biosensors
Authors: Vesali-Naseh Masoud , Rastian Zahra , Moshakker Hossein
Published: July 2024

In this systematic review, all electrochemical glucose biosensors based on carbon nanotube (CNT) composites from 2001 to 2021 (n = 6807) have been reviewed. After excluding duplicates, irrelevant, and unqualified papers, 184 articles were selected for data extraction. The operating data include working electrode, test solution, detection potential, sensitivity, detection limit, linear range, response time, selectivity, enzyme coverage, Michaelis–Menten constants, and ambient condition (i.e. pH, temperature and humidity). In addition, the in vivo and in vitro media (including invasive and non-invasive detection) and the most repeated interferences have been specified. All of the CNTs-based hybrids for modifying working electrodes have been classified regarding the various components such as metallic species (elemental, oxide, alloy and complex), polymers and different electroactive species. The enzymeless and enzymatic biosensors as well as dual-enzyme electrodes using GOx, GDH, and HRP have also been categorized. Moreover, the different natural and artificial mediators and fixing agents, were determined.
The Principle for Proton Motive Force Generated by Quinones Oxidoreduction
Authors: Wang Yaotian , Liu Yuhong , Lin Mi , Wang Jianguo
Published: July 2024

The proton motive force across the inner mitochondrial membrane drives adenosine triphosphate synthesis. Q-cycle is a mechanism of the proton motive force generation. Its essential feature is a bifurcation and forming semiquinone, which remains contentious. Three cathodic waves of benzoquinone appeared in dilute phosphate buffered solution (pH 3.35), which was attributed to dramatic pH change at electrode surface. These waves indicated that at different potential of the electrode, benzoquinone accepted the protons from H3O+, H2PO4
−, and H2O, and produced H2O, HPO4
2−, and OH−, respectively. It revealed that the pKa of hydroquinone was dependent on the potential of the electrode and external oxidant, which was attributed to the nature of proton-coupled electron transfer of quinone oxidoreduction. We proposed a mechanism that the proton motive force was directly produced by the reductant at Qi site and the oxidant at Qo site through quinone oxidoreduction.
Solid Oxide Cell Reactor Model for Transient and Stationary Electrochemical H2O and CO2 Conversion Process Studies
Authors: Sedeqi F. , Santhanam S. , Riegraf M. , Riedel M. , Heddrich M. P. , Ansar S. A.
Published: July 2024

The ability of high-temperature solid oxide cell (SOC) electrochemical reactors to efficiently convert atmospheric carbon to high value chemicals for industrial and energy storage applications via

CO

2

and co-electrolysis makes them a key technology for active carbon utilisation. However, due to additional operational risks from thermochemical reactions on thermal management, limited experimental capacity, and relative novelty,

CO

2

and co-electrolysis lag behind steam electrolysis in large-scale adoption. Here, a 1D+1D SOC model based on fundamental first principles considering three-dimensional heat transfer was improved via a unique method for representing co-electrolysis electrochemistry, solving with low computational effort. Validation against experimental data for two compositions and pressures, showed high levels of accuracy with respect to characteristic cell voltages, temperatures, and outlet compositions. The model also showed

CO

2

reduction during co-electrolysis mainly occurred via reverse water gas shift, while

CO

2

electrolysis still accounted for up to 35% of the total share. Pressurised co-electrolysis operation promotes exothermic methanation, causing pronounced heating of the reactor, consequently reducing the isothermal current density. Therefore, low to moderate pressurisation is likely most suited for coupling with downstream synthesis processes to avoid the installation of unnecessarily large systems and associated high costs.
The Influence of CdS on the Structural and Optical Properties of Nano ZnWO4
Authors: Heiba Zein K. , Farag Noura M. , Abozied Asmaa M. , Badawi Ali , Mohamed Mohamed Bakr
Published: July 2024

We investigated the influence of CdS on the structural and optical properties of nano ZnWO4 for optical applications. (1−x)ZnWO4/xCdS (x; 0 to 0.25) heterojunctions were formed and the structure and microstructure of the ZnWO4 and CdS phases developed were investigated using Rietveld refinement analysis for synchrotron X-ray diffraction data. Phase analysis revealed the phase percentage of the CdS phase is always less than the nominated value (x), implying merging of some Cd and S into ZnWO4. Raman spectra showed CdS peaks, confirming the existence of CdS. Scanning electron microscopy showed two distinct morphologies: plate-like particles (ZnWO4 phase) and spherical shape (CdS phase). UV–vis diffuse measurements revealed enhancement of absorbance and reduction in reflectance and transmittance, in the range 300–56 nm, as the amount of CdS (x) increased in the (1−x)ZnWO4/xCdS system. Band gap of the ZnWO4 phase reduced from 4.0 eV for x = 0.0 to 3.9, 3.6, and 2.9 eV for x = 0.05, 0.1, and 0.25, respectively. The highest refractive index values were obtained as the amount of CdS reached 0.05. Impact of alloying on linear and nonlinear parameters and emitted photoluminescence spectra was studied. Upon loading ZnWO4 with CdS, the PL intensity is greatly quenched and the whole spectrum is red shifted, from 480 to 540 nm. CIE chromaticity diagrams show that ZnWO4 sample without any doping exhibits a blue color while the doped system reveals green-yellow colors.
Supplementary Figure 9 from GPR1 and CMKLR1 Control Lipid Metabolism to Support the Development of Clear Cell Renal Cell Carcinoma
Authors: Wang Dazhi , Mahmud Iqbal , Thakur Vijay S. , Tan Sze Kiat , Isom Daniel G. , Lombard David B. , Gonzalgo Mark L. , Kryvenko Oleksandr N. , Lorenzi Philip L. , Tcheuyap Vanina T. , Brugarolas James , Welford Scott M.
Published: July 2024

Supplementary Figure 9
Data from CD58 Alterations Govern Antitumor Immune Responses by Inducing PDL1 and IDO in Diffuse Large B-Cell Lymphoma
Authors: Xu Xiyue , Zhang Yidan , Lu Yaxiao , Zhang Xiaoyan , Zhao Cuicui , Wang Jiesong , Guan Qingpei , Feng Yingfang , Gao Meng , Yu Jingwei , Song Zheng , Liu Xia , Golchehre Zahra , Li Lanfang , Ren Weicheng , Pan-Hammarström Qiang , Zhang Huilai , Wang Xianhuo
Published: July 2024

Abstract
Recurrent abnormalities in immune surveillance–related genes affect the progression of diffuse large B-cell lymphoma (DLBCL) and modulate the response to therapeutic interventions. CD58 interacts with the CD2 receptor on T cells and NK cells and is recurrently mutated and deleted in DLBCL, suggesting that it may play a role in regulating antitumor immunity. In this study, we comprehensively analyzed the genomic characteristics of CD58 through targeted next-generation sequencing, RNA sequencing (RNA-seq), whole-exome sequencing, and single-cell RNA-seq in patients with newly diagnosed DLBCL. The CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled patients with DLBCL. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free survival and overall survival. Single-cell RNA-seq revealed that CD58 expression in tumor cells was negatively correlated with CD8+ T-cell exhaustion/dysfunction status. Insufficient T-cell activation resulting from CD58 alterations could not be attributed solely to CD2 signaling. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the LYN/CD22/SH2 domain–containing phosphatase 1 (SHP1) axis, thereby limiting PDL1 and IDO expression. Elevated PDL1 and IDO expression in CD58-deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to chimeric antigen receptor T-cell therapy. Direct activation of CD58–CD2 costimulatory signaling in combination with anti-PDL1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to chimeric antigen receptor T-cell therapy. Collectively, this work identified the multiple roles of CD58 in regulating antitumor immune responses in DLBCL.

Significance: Loss of CD58 mediates immune evasion and therapy resistance in diffuse large B-cell lymphoma by upregulating PDL1 and IDO through LYN/CD22/SHP1 signaling, providing potential targets and therapeutic strategies to improve patient treatment.
Supplementary Figure S1 from ETS1, a Target Gene of the EWSR1::FLI1 Fusion Oncoprotein, Regulates the Expression of the Focal Adhesion Protein TENSIN3
Authors: Ebegboni Vernon Justice , Jones Tamara L. , Brownmiller Tayvia , Zhao Patrick X. , Pehrsson Erica C. , Sundara Rajan Soumya , Caplen Natasha J.
Published: July 2024

EWSR1::FLI1 repressed gene targets defined using EWS cell lines exhibit a broader range of expression in EWS primary tumors.
Supplementary Figure S3 from Vasorin Exocytosed from Glioma Cells Facilitates Angiogenesis via VEGFR2/AKT Signaling Pathway
Authors: Zhong Ying , Kang Hui , Ma Ziqing , Li Jiayu , Qin Zixi , Zhang Zixuan , Li Peiwen , Zhong Ying , Wang Lihui
Published: July 2024

Immunofluorescence staining showing HUVECs uptake of Flag tag peptide
Supplementary Table 2 from Germline Testing Identifies Pathogenic/Likely Pathogenic Variants in Patients with Pancreatic Neuroendocrine Tumors
Authors: Mohindroo Chirayu , Baydogan Seyda , Agarwal Parul , Wright Robin D. , Prakash Laura R. , Mork Maureen E. , Klein Alison P. , Laheru Daniel A. , Maxwell Jessica E. , Katz Matthew H.G. , Dasari Arvind , Kim Michael P. , He Jin , McAllister Florencia , De Jesus-Acosta Ana
Published: July 2024

Supplementary Table 2: Variety of genes tested in the unselected cohort (83–86)
Data from Metabolic Reprogramming of Tumor-Associated Macrophages Using Glutamine Antagonist JHU083 Drives Tumor Immunity in Myeloid-Rich Prostate and Bladder Cancers
Authors: Praharaj Monali , Shen Fan , Lee Alex J. , Zhao Liang , Nirschl Thomas R. , Theodros Debebe , Singh Alok K. , Wang Xiaoxu , Adusei Kenneth M. , Lombardo Kara A. , Williams Raekwon A. , Sena Laura A. , Thompson Elizabeth A. , Tam Ada , Yegnasubramanian Srinivasan , Pearce Edward J. , Leone Robert D. , Alt Jesse , Rais Rana , Slusher Barbara S. , Pardoll Drew M. , Powell Jonathan D. , Zarif Jelani C.
Published: July 2024

Abstract
Glutamine metabolism in tumor microenvironments critically regulates antitumor immunity. Using the glutamine-antagonist prodrug JHU083, we report potent tumor growth inhibition in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes. We show JHU083-mediated glutamine antagonism in tumor microenvironments induced by TNF, proinflammatory, and mTORC1 signaling in intratumoral TAM clusters. JHU083-reprogrammed TAMs also exhibited increased tumor cell phagocytosis and diminished proangiogenic capacities. In vivo inhibition of TAM glutamine consumption resulted in increased glycolysis, a broken tricarboxylic acid (TCA) cycle, and purine metabolism disruption. Although the antitumor effect of glutamine antagonism on tumor-infiltrating T cells was moderate, JHU083 promoted a stem cell–like phenotype in CD8+ T cells and decreased the abundance of regulatory T cells. Finally, JHU083 caused a global shutdown in glutamine-utilizing metabolic pathways in tumor cells, leading to reduced HIF-1α, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key antitumor features. Altogether, our findings demonstrate that targeting glutamine with JHU083 led to suppressed tumor growth as well as reprogramming of immunosuppressive TAMs within prostate and bladder tumors that promoted antitumor immune responses. JHU083 can offer an effective therapeutic benefit for tumor types that are enriched in immunosuppressive TAMs.
A Multicenter Real-life Prospective Study of Axicabtagene Ciloleucel versus Tisagenlecleucel Toxicity and Outcomes in Large B-cell Lymphomas
Authors: Stella Federico , Chiappella Annalisa , Casadei Beatrice , Bramanti Stefania , Ljevar Silva , Chiusolo Patrizia , Di Rocco Alice , Tisi Maria C. , Carrabba Matteo G. , Cutini Ilaria , Martino Massimo , Dodero Anna , Bonifazi Francesca , Santoro Armando , Sorà Federica , Botto Barbara , Barbui Anna M. , Russo Domenico , Musso Maurizio , Grillo Giovanni , Krampera Mauro , Olivieri Jacopo , Ladetto Marco , Cavallo Federica , Massaia Massimo , Arcaini Luca , Pennisi Martina , Zinzani Pier L. , Miceli Rosalba , Corradini Paolo
Published: July 2024

This real-world prospective observational study across 21 Italian centers (CART-SIE) compares axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) outcomes in 485 patients with relapsed/refractory large B-cell lymphoma with baseline characteristics matched by stabilized inverse propensity score weighting. Axi-cel versus tisa-cel had higher all-grade cytokine release syndrome (78.6% vs. 89.3%, P = 0.0017) and neurotoxicity (9.9% vs. 32.2%, P < 0.0001) but also superior progression-free survival (PFS) at 1 year (46.5% vs. 34.1%, P = 0.0009). Even among patients who failed bridging therapy, axi-cel PFS was superior to tisa-cel (37.5% vs. 22.7%, P = 0.0059). Differences in overall survival and high-grade immune toxicities were not significant. The CAR-HEMATOTOX score not only predicted hematologic toxicity but also 1-year survival outcomes (51.5% in CAR-HEMATOTOX high vs. 77.2% in CAR-HEMATOTOX low, P < 0.0001). Twenty patients developed second primary malignancies, including two cases of T-cell neoplasms. These findings enable more informed selection of anti-CD19 CAR T-cell therapy, balancing bridging, safety, and efficacy considerations for individual patients.

Significance: The findings of this study on 485 patients with relapsed/refractory large B-cell lymphoma treated with commercial axi-cel and tisa-cel indicate axi-cel’s superior PFS after propensity score weighting. The predictive utility of CAR-HEMATOTOX in assessing not only toxicity but also outcomes across both CAR T-cell products may guide future risk-stratified management strategies.
A Kinome-Wide Synthetic Lethal CRISPR/Cas9 Screen Reveals That mTOR Inhibition Prevents Adaptive Resistance to CDK4/CDK6 Blockade in HNSCC
Authors: Goto Yusuke , Koshizuka Keiichi , Ando Toshinori , Izumi Hiroki , Wu Xingyu , Sato Kuniaki , Ishikawa Tomohiko , Ford Kyle , Feng Xiaodong , Wang Zhiyong , Arang Nadia , Allevato Michael M. , Kishore Ayush , Mali Prashant , Gutkind J. Silvio
Published: July 2024

The comprehensive genomic analysis of the head and neck squamous cell carcinoma (HNSCC) oncogenome revealed the frequent loss of p16INK4A (CDKN2A) and amplification of cyclin D1 genes in most human papillomavirus–negative HNSCC lesions. However, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown modest effects in the clinic. The aberrant activation of the PI3K/mTOR pathway is highly prevalent in HNSCC, and recent clinical trials have shown promising clinical efficacy of mTOR inhibitors (mTORi) in the neoadjuvant and adjuvant settings but not in patients with advanced HNSCC. By implementing a kinome-wide CRISPR/Cas9 screen, we identified cell-cycle inhibition as a synthetic lethal target for mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergism in HNSCC-derived cells in vitro and in vivo. Remarkably, we found that an adaptive increase in cyclin E1 (CCNE1) expression upon palbociclib treatment underlies the rapid acquired resistance to this CDK4/6 inhibitor. Mechanistically, mTORi inhibits the formation of eIF4G–CCNE1 mRNA complexes, with the consequent reduction in mRNA translation and CCNE1 protein expression. Our findings suggest that mTORi reverts the adaptive resistance to palbociclib. This provides a multimodal therapeutic option for HNSCC by cotargeting mTOR and CDK4/6, which in turn may halt the emergence of palbociclib resistance.

Significance:

A kinome-wide CRISPR/Cas9 screen identified cell-cycle inhibition as a synthetic lethal target of mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergistic effects in HNSCC. Mechanistically, mTORis inhibited palbociclib-induced increase in CCNE1.
Navigating Problematic Bauhaus Inheritances: Critiques, Implications, and Questions from the Bauhaus of the Seas NEB Lighthouse
Authors: Torretta Nicholas B. , Pestana Mariana , Duarte Frederico , Predroso-Roussado Cristiano , Seixas Luisa Metelo , Nisi Valentina , Nunes Nuno Jardim
Published: July 2024

In 2020, Europe announced the New European Bauhaus (NEB). While the initiative intends to achieve EU sustainability goals, framing it under the name of the Bauhaus brings various challenges and issues to the fore. In this article, we analyze the critiques of the original Bauhaus and the NEB to understand the challenges that the NEB lighthouse project Bauhaus of the Seas Sails (BoSS) inherits by adhering to the Bauhaus vision and name. We unveil the problematic dynamics of Eurocentric modernity's myths of universalism and better living through technology and on the Bauhaus's and NEB's position in global power structures. Instead of assuming a tabula rasa approach and replicating problematic structures unknowingly, we bring these three aspects to BoSS to find questions as orientation points to help steer away from problematic aspects inherited by reanimating the Bauhaus name and its legacy.
Characteristics of Gravity Waves in Opposing Phases of the QBO: A Reanalysis Perspective with ERA5
Authors: Pahlavan Hamid A. , Wallace John M. , Fu Qiang , Alexander M. Joan
Published: July 2024

Gravity waves dispersing upward through the tropical stratosphere during opposing phases of the QBO are investigated using ERA5 data for 1979–2019. Log–log plots of two-sided zonal wavenumber–frequency spectra of vertical velocity, and cospectra representing the vertical flux of zonal momentum in the tropical lower stratosphere, exhibit distinctive gravity wave signatures across space and time scales ranging over two orders of magnitude. Spectra of the vertical flux of momentum are indicative of a strong dissipation of westward-propagating gravity waves during the easterly phase and vice versa. This selective “wind filtering” of the waves as they disperse upward imprints the vertical structure of the zonal flow on the resolved wave spectra, characteristic of (re)analysis and/or free-running models. The three-dimensional structures of the gravity waves are documented in composites of the vertical velocity field relative to grid-resolved tropospheric downwelling events at individual reference grid points along the equator. In the absence of a background zonal flow, the waves radiate outward and upward from their respective reference grid points in concentric rings. When a zonal flow is present, the rings are displaced downstream relative to the source and they are amplified upstream of the source and attenuated downstream of it, such that instead of rings, they assume the form of arcs. The log–log spectral representation of wind filtering of equatorial waves by the zonal flow in this paper can be used to diagnose the performance of high-resolution models designed to simulate the circulation of the tropical stratosphere.
How dating apps fail sexual minorities: Hyperpersonal failure as a framework for understanding challenges in developing long-term relationships
Authors: Chan Lik Sam , Chui Don Lok Tung
Published: July 2024

Online dating and dating apps are meant to help sexual minorities find romantic partners, but they have also presented challenges and obstacles. Based on 27 in-depth interviews with lesbian, gay, and bisexual dating app users living in Taiwan, this exploratory study proposes the concept of hyperpersonal failure as a holistic framework for understanding these challenges. This framework specifies four types of failure, each corresponding to one element in the original hyperpersonal communication model: the failure to present oneself (online daters as the sender), the failure to meet conversational expectations (the channel), the failure to develop positive impressions of the targets (online daters as the receiver), and the failure to obtain responses (the feedback). The study also discusses how the affordances of online environments contribute to hyperpersonal failure. Overall, the framework has the potential to shed light on online dating in general, extending beyond the experiences of sexual minorities.
Genetic deletion of JAM-C in preleukemic cells rewires leukemic stem cell gene expression program in AML
Authors: Grenier Julien M. P. , Testut Céline , Bal Matthieu , Bardin Florence , De Grandis Maria , Gelsi-Boyer Véronique , Vernerey Julien , Delahaye Marjorie , Granjeaud Samuel , Zemmour Christophe , Spinella Jean-François , Chavakis Triantafyllos , Mancini Stéphane J. C. , Boher Jean-Marie , Hébert Josée , Sauvageau Guy , Vey Norbert , Schwaller Jürg , Hospital Marie-Anne , Fauriat Cyril , Aurrand-Lions Michel
Published: July 2024

The leukemic stem cell (LSC) score LSC-17 based on a stemness–related gene expression signature is an indicator of poor disease outcome in acute myeloid leukemia (AML). However, it is not known whether “niche anchoring” of LSC affects disease evolution. To address this issue, we conditionally inactivated the adhesion molecule JAM-C (Junctional Adhesion Molecule-C) expressed by hematopoietic stem cells (HSCs) and LSCs in an inducible mixed-lineage leukemia (iMLL)-AF9–driven AML mouse model. Deletion of Jam3 (encoding JAM-C) before induction of the leukemia–initiating iMLL-AF9 fusion resulted in a shift from long-term to short-term HSC expansion, without affecting disease initiation and progression. In vitro experiments showed that JAM-C controlled leukemic cell nesting irrespective of the bone marrow stromal cells used. RNA sequencing performed on leukemic HSCs isolated from diseased mice revealed that genes upregulated in Jam3-deficient animals belonged to activation protein-1 (AP-1) and tumor necrosis factor α (TNF-α)/NF-κB pathways. Human orthologs of dysregulated genes allowed to identify a score that was distinct from, and complementary to, the LSC-17 score. Substratification of patients with AML using LSC-17 and AP-1/TNF-α genes signature defined 4 groups with median survival ranging from <1 year to a median of “not reached” after 8 years. Finally, coculture experiments showed that AP-1 activation in leukemic cells was dependent on the nature of stromal cells. Altogether, our results identify the AP-1/TNF-α gene signature as a proxy of LSC anchoring in bone marrow niches, which improves the prognostic value of the LSC-17 score. This trial was registered at www.ClinicalTrials.gov as #NCT02320656.
Risk of transformation by frontline management in follicular and marginal zone lymphomas: a US population–based analysis
Authors: Florindez Jorge A. , Chihara Dai , Reis Isildinha M. , Lossos Izidore S. , Alderuccio Juan Pablo
Published: July 2024

Follicular lymphoma (FL) and marginal zone lymphoma (MZL) often have long overall survival (OS), however, high-grade transformation (HGT) to diffuse large B-cell lymphoma markedly reduces survival. The roles of upfront treatment vs observation on the incidence and outcome of HGT remain unclear. Thus, we analyzed a Surveillance, Epidemiology, and End Results database to address this question. Patients diagnosed with FL grades 1 to 2 or MZL between 2000 and 2020 were included. Fine-Gray models estimated the impact of covariates on HGT cumulative incidence and lymphoma-specific survival (LSS) and Cox regression on OS. HGT occurred in 4.2% of 23 384 patients with FL and 2.5% of 20 530 patients with MZL. The 5- and 10-year HGT cumulative incidence rates were 2.80% and 4.87% for FL, and 1.74% and 2.95% for MZL, respectively, which are notably lower than in earlier studies. The annual HGT incidence rate peaked in the first 2 years, then steadily declined over 2 decades for FL and all MZL subtypes. In FL, upfront observation vs treatment increases HGT risk (sub-distribution hazard ratio [SHR], 1.23; 95% confidence interval [CI], 1.09-1.40; P < .001) and barely affects OS (hazard ratio [HR], 0.95; 95% CI, 0.90-0.99; P = .03). Conversely, upfront observation was associated with lower HGT risk in nodal (SHR, 0.71; 95% CI, 0.53-0.94; P = .01) and extranodal (SHR, 0.64; 95% CI, 0.48-0.86; P = .003) MZL and did not affect survival in extranodal disease (HR, 0.94; 95% CI, 0.97-1.02; P = .15). HGT was associated with decrease in LSS across all histologies. Upfront treatment reduced the risk of HGT only in FL but not MZL.
The wolf in sheep’s clothing: vasovagal syncope in acute aortic dissection
Authors: Donner Viviane , Beuret Hadrien , Savoy Simon , Ribordy Vincent , Sadeghi Christine D.
Published: July 2024

Background

The presentation of acute aortic dissection can pose a challenge for emergency physicians, as it may occur without pain. Atypical presentations can lead to significant delays in diagnosis and increased mortality rates.

Case description

Our case illustrates that isolated painless syncope can be a rare presenting symptom of acute aortic dissection type A. What is unique about our case is the limited extension of the dissection tear and the availability of Holter monitoring during the syncopal episode.

Conclusion

This constellation provides insight into the pathophysiological mechanism of the syncope in this patient. Mechanisms of syncope related to acute aortic dissection are diverse. We show that vasovagal activation not related to pain can be the underlying mechanism of syncope in acute aortic dissection type A. Although excessive vasovagal tone in the setting of aortic dissection has been hypothesized in the past, it has never been as clearly illustrated as in the present case. This also highlights the challenge in risk stratification of syncope in the emergency department.
The effect of air pollution on selected immune system parameters, 8-isoprostane, and alpha-1-antitrypsin of people living in environmentally distinct regions
Authors: Jiřík Vítězslav , Machaczka Ondřej , Riedlová Petra , Kramná Dagmar , Siemiatkowski Grzegorz , Ośródka Leszek , Krajny Ewa , Ambrož Antonín , Topinka Jan , Rössner Pavel
Published: July 2024

Background

Air pollution is associated with adverse health effects, especially on the respiratory and cardiovascular systems, but according to recent research, even in cognitive health, metabolic, and immune systems. The objective was to analyse the effect of long-term exposure to air pollution on selected immune system parameters, 8-isoprostane a parameter of oxidative stress, and alpha-1-antitrypsin a protease inhibitor.

Methods

The number of 381 probands aged 35–65 from two differently polluted regions was included. Lifetime exposures to PM10, PM2.5, NO2, B(a)P, and benzene for each proband were calculated based on historical pollutant concentrations observed. The selected blood parameters were analysed in relation to independent variables (air pollutants, socioeconomic factors, etc.) using multiple regression. Possible covariates were determined. In its end, the study was conceived as a case–control study, and the odds ratio was quantified, expressing the strength of the association of the monitored parameters with the region.

Results

The average lifetime exposures to air pollution were significantly different between the two regions. Significant effects of the region were observed on IgM, IL-6, 8-isoprostane, and alpha-1-antitrypsin levels. The strongest positive association was observed between 8-isoprostane levels and benzene, PM2.5, PM10 and B(a)P. Odds ratio was 3.21 (95%CI 1.61–6.38). A significant negative association between all pollutants and IgM levels was observed even with covariate adjustment. Odds ratio was 1.80 (95%CI 1.15–2.82). A significant negative association between the alpha-1-antitrypsin levels and PM10, PM2.5, and benzene was found, independent of smoking as a covariate factor. Odds ratio was 1.77 (95%CI 1.09–2.87). In the case of IL-6, a significant effect of especially sleep as a covariate was observed. After covariates adjustment, a significant positive association between the IL-6 levels and PM10 and benzene was only observed. The odds ratio was 1.95 (95%CI 1.28–2.97).

Conclusions

The study confirmed that long-term exposure to air pollutants is associated with reduced levels of the protease inhibitor alpha-1-antitrypsin and decreased immune system performance by IgM. Furthermore, long-term exposure to air pollutants was associated with increased oxidative stress in humans, measured by 8-isoprostane levels. Residents who live in an industrial, environmentally polluted region showed elevated levels of IL-6.
Differences in virus and immune dynamics for SARS-CoV-2 Delta and Omicron infections by age and vaccination histories
Authors: Tan Maxine W , Anelone Anet J.N. , Tay An Ting , Tan Ren Ying , Zeng Kangwei , Tan Kelvin Bryan , Clapham Hannah Eleanor
Published: July 2024

Vaccination against COVID-19 was integral to controlling the pandemic that persisted with the continuous emergence of SARS-CoV-2 variants. Using a mathematical model describing SARS-CoV-2 within-host infection dynamics, we estimate differences in virus and immunity due to factors of infecting variant, age, and vaccination history (vaccination brand, number of doses and time since vaccination). We fit our model in a Bayesian framework to upper respiratory tract viral load measurements obtained from cases of Delta and Omicron infections in Singapore, of whom the majority only had one nasopharyngeal swab measurement. With this dataset, we are able to recreate similar trends in URT virus dynamics observed in past within-host modelling studies fitted to longitudinal patient data.

We found that Omicron had higher R0,within values than Delta, indicating greater initial cell-to-cell spread of infection within the host. Moreover, heterogeneities in infection dynamics across patient subgroups could be recreated by fitting immunity-related parameters as vaccination history-specific, with or without age modification. Our model results are consistent with the notion of immunosenescence in SARS-CoV-2 infection in elderly individuals, and the issue of waning immunity with increased time since last vaccination. Lastly, vaccination was not found to subdue virus dynamics in Omicron infections as well as it had for Delta infections.

This study provides insight into the influence of vaccine-elicited immunity on SARS-CoV-2 within-host dynamics, and the interplay between age and vaccination history. Furthermore, it demonstrates the need to disentangle host factors and changes in pathogen to discern factors influencing virus dynamics. Finally, this work demonstrates a way forward in the study of within-host virus dynamics, by use of viral load datasets including a large number of patients without repeated measurements.
Prevalence and related factors of nephrolithiasis among medical staff in Qingdao, China: a retrospective cross-sectional study
Authors: Guo Lei , Liu Lijun , Sun Ying , Xue Li , Gong Xingji , Wang Yue , Jiao Wei , Niu Haitao
Published: July 2024

Background

Certain occupations may predispose individuals to urolithiasis, a multi-factorial disease. The study aimed to evaluate the prevalence and related factors of nephrolithiasis in medical staff in Qingdao, China.

Methods

Physical examination results of 5115 in-service medical staff aged 22–60 years old were retrospectively analyzed. Multivariable logistic regression analysis and stratified analyses by age and gender were applied to explore the related factors of nephrolithiasis in these medical staff.

Results

The overall nephrolithiasis prevalence in medical staff in Qingdao, China was 4.65%. Doctors were more prone to nephrolithiasis than nurses (5.63% vs. 3.96%, P = 0.013) and the peak prevalence (6.69%) was observed in medical staff working in the emergency department (ED). Male gender (OR = 1.615, 95% CI = 1.123–2.323, P = 0.010), overweight or obesity (OR = 1.674, 95% CI = 1.266–2.214, P < 0.001), work seniority ≥ 10 years (OR = 2.489, 95%CI = 1.675–3.699, P < 0.001) and working in the ED (OR = 1.815, 95% CI = 1.202–2.742, P = 0.005) were independent predictors for nephrolithiasis in medical staff based on the results of multivariate logistic regression analysis. The associations between overweight or obesity and nephrolithiasis risk as well as between work seniority ≥ 10 years and nephrolithiasis risk in medical staff were independent of age or gender in stratified analysis.

Conclusions

Nephrolithiasis prevalence in medical staff in Qingdao, China seemed not to be higher than that in the general population. Medical staff with work seniority ≥ 10 years and working in the ED should pay abundant attention to take measures to modify their nephrolithiasis risk.