bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Analytical Method for Coupled In-Plane and Out-of-Plane Vibrations of Sandwich Plates with Arbitrary Boundary Conditions
Authors: Li Wanbo , Liu Weifeng , Liang Ruihua , Li Donghai
Published: February 2024

Sandwich plates are popular in the research field of vibration damping and are widely used in numerous engineering domains. Sandwich plates have been studied extensively for their excellent performances by a large number of researchers. Due to the interaction between the out-of-plane and in-plane vibrations of the layers of sandwich plates, it is difficult to solve the displacements of each layer in all directions analytically. To deal with this problem conveniently and accurately, a novel analytical method is presented in this study for coupled out-of-plane and in-plane vibrations of sandwich plates, which can be applied to both free and forced vibrations of sandwich plates with arbitrary boundaries. In this method, the core plate is treated as a three-dimensional (3D) problem, and it is assumed that the displacement of the core plate varies linearly along the thickness. Based on the Kirchhoff hypothesis, the displacement solutions of the base and constrained plates of the sandwich plate in the [Formula: see text], [Formula: see text] and [Formula: see text] directions are expressed as a superposition of one-dimensional (1D) and two-dimensional (2D) Fourier series, respectively. By comparison to the published analytical solutions and numerical results of the finite element method, the proposed method achieves excellent accuracy and reliability. In addition, the influence of out-of-plane and in-plane vibrations of sandwich plates on each other is studied, and the effects of geometrical and material parameters on the dynamic behaviors of a sandwich plate are investigated. The result shows that the out-of-plane vibration affects the in-plane vibration significantly, which means that the coupling effect of the out-of-plane and in-plane vibrations must be taken into account when analyzing in-plane vibration.
Multimodal Resonance Response of Incompressible Hyperelastic Moderately Thick Cylindrical Shells
Authors: Zhao Zhentao , Lin Jiayan , Xu Jie , Yuan Xuegang
Published: February 2024

Based on the modified third-order shear deformation theory, the harmonic balance method, and the pseudo-arclength continuation method with two-point prediction, the nonlinear forced vibration response of incompressible hyperelastic moderately thick cylindrical shells subjected to a concentrated harmonic load at mid-span and simply supported boundary conditions at both ends is investigated. The algorithmic procedure for solving steady-state periodic solutions of strongly nonlinear systems of differential equations is presented. The structural response characteristics of shells under different excitation amplitudes and structural parameters are analyzed. The numerical results indicate that the aspect ratio of moderately thick hyperelastic cylindrical shells has a significant effect on the natural frequency ratio. Different frequency ratios lead to varying nonlinear mode coupling effects. The coupling effects among modes result in complex nonlinear behavior in the vibration response of each mode, leading to abundant multi-valued phenomena in the response curve.
Structural properties of compact stars in extended Teleparallel gravity
Authors: Ashraf Asifa , Javed Faisal , Ma Wen-Xiu , Mustafa G.
Published: February 2024

In this study, the structures of stars are examined using the Karmarkar condition (KC) to assess the metric components. The study also takes into account the anisotropic source of the matter distribution in the context of Modified Teleparallel Rastall Gravity (MTRG). Various values of the model parameter [Formula: see text] are tested by assuming different metric coefficients for the embedding spacetime. To calculate the involved model parameters, the Schwarzschild black hole solution is employed as an exterior solution. The stability and admissibility of the solutions obtained are demonstrated by analyzing some core properties of stellar objects, using observed data from established stellar models such as “PSRJ1416-2230”. It is worth noting that the results obtained in this study are physically feasible and acceptable.
A note on Schmidt’s subspace type theorems for hypersurfaces in subgeneral position
Authors: Shi Lei , Yan Qiming
Published: February 2024

In this paper, motivated by Nochka weights and the replacing hypersurfaces technique, we give an improvement of Schmidt’s subspace type theorem for hypersurfaces which are located in subgeneral position.
On the solutions of some Lebesgue–Ramanujan–Nagell type equations
Authors: Mutlu Elif Kızıldere , Soydan Gökhan
Published: February 2024

Denote by [Formula: see text] the class number of the imaginary quadratic field [Formula: see text] with [Formula: see text] prime. It is well known that [Formula: see text] for [Formula: see text]. Recently, all the solutions of the Diophantine equation [Formula: see text] with [Formula: see text] were given by Chakraborty et al. in [Complete solutions of certain Lebesgue–Ramanujan–Nagell type equations, Publ. Math. Debrecen 97(3–4) (2020) 339–352]. In this paper, we study the Diophantine equation [Formula: see text] in unknown integers [Formula: see text] where [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text]. To do this, we use the known results from the modularity of Galois representations associated with Frey–Hellegoaurch elliptic curves, the symplectic method and elementary methods of classical algebraic number theory. The aim of this paper is to extend the above results of Chakraborty et al.
Fast computation of generalized dedekind sums
Authors: Tranbarger Preston , Wang Jessica
Published: February 2024

We construct an algorithm that reduces the complexity for computing generalized Dedekind sums from exponential to polynomial time. We do so by using an efficient word rewriting process in group theory.
Multiplier systems for Siegel modular groups
Authors: Freitag Eberhard , Hauffe-Waschbüsch Adrian
Published: February 2024

Deligne proved in [Extensions centrales non résiduellement finies de groupes arithmetiques, C. R. Acad. Sci. Paris 287 (1978) 203–208] (see also 7.1 in [R. Hill, Fractional weights and non-congruence subgroups, in Automorphic Forms and Representations of Algebraic Groups Over Local Fields, eds. H. Saito and T. Takahashi, Surikenkoukyuroku Series, Vol. 1338 (2003), pp. 71–80]) that the weights of Siegel modular forms on any congruence subgroup of the Siegel modular group of genus [Formula: see text] must be integral or half integral. Actually he proved that for a system [Formula: see text] of complex numbers of absolute value 1

[Formula: see text]

can be an automorphy factor only if [Formula: see text] is integral. We give a different proof for this. It uses Mennicke’s result [Zur Theorie der Siegelschen Modulgruppe, Math. Ann. 159 (1965) 115–129] that subgroups of finite index of the Siegel modular group are congruence subgroups and some techniques from [Solution of the congruence subgroup problem for [Formula: see text] and [Formula: see text], Publ. Math. Inst. Hautes Études Sci. 33 (1967) 59–137] of Bass–Milnor–Serre.
The genus of a quotient of several types of numerical semigroups
Authors: Lee Kyeongjun , Nam Hayan
Published: February 2024

Finding the Frobenius number and the genus of any numerical semigroup S is a well-known open problem. Similarly, it has been studied how to express the Frobenius number and the genus of a quotient of a numerical semigroup. In this paper, by enumerating the Hilbert series of each type of numerical semigroup, we show an expression for the genus of a quotient of numerical semigroups generated by one of the following series: arithmetic progression, geometric series, and Pythagorean triple.
Pedostratigraphic age model for Devonian red beds of NW China
Authors: Guo Xuelian , Retallack Gregory J. , Lü Bin , Ma Mingming , Cao Huairen , Wang Weibin , Liu Jinhao
Published: February 2024

Detrital zircon geochronology has been used to determine provenance, but also gives maximum depositional ages that can constrain other forms of geochronology, such as magnetostratigraphy and pedostratigraphy. Pedostratigraphy and magnetostratigraphy correlate a series of global events by spacing or intensity in a fashion comparable with a commercial barcode. The Late Devonian Shaliushui Formation of NW China is poorly fossiliferous, but shows spikes in magnetic susceptibility, Al/Si ratios, Rb/Sr ratios and the depth to carbonate nodules (Bk horizon) corresponding with the timing of named Late Devonian black shale horizons. By contrast, the Ti/Al ratios show only small variations, indicating little long-term change in the source terrain or in the hydraulic sorting of heavy minerals. Most of the detrital zircon ages are older than an age model from the pedostratigraphic correlation of deep calcic horizons corresponding to global atmospheric CO
2
spikes at times of black shale expansion, but one detrital zircon age converges with the pedostratigraphic depositional ages near the top of the section. Pedostratigraphy is widely used in Quaternary sequences, but can also be a basis for age models of rocks in deep time if supported by detrital zircon ages.

Supplementary material:
Paleosol and geochemical data, and youngest zircon ages for a section of Devonian rocks near Ciyao, Gansu, China are available at
https://doi.org/10.6084/m9.figshare.c.7008192
Optimizing Camera Motion with MCTS and Target Motion Modeling in Multi-Target Active Object Tracking
Authors: Chen Zheng , Zhao Jian , Yang Mingyu , Zhou Wengang , Li Houqiang
Published: February 2024

In this work, we are dedicated to multi-target active object tracking (AOT), where the goal is to achieve continuous tracking of targets through real-time control of camera. This form of active camera control can be applied to unmanned aerial vehicles (UAV), intelligent robots, and sports events. Our work is conducted in an environment featuring multiple cameras and targets, where our goal is to maximize target coverage. Contrasting with previous research, our work introduces additional degrees of freedom for the cameras, allowing them not only to rotate but also to move along boundary lines. In addition, we model the motion of target to predict the future position of the target in environment. With target’s future position, we use Monte Carlo Tree Search (MCTS) method to find the optimal action of camera. Since the action space is large, we propose to leverage the action selection from multi-agent reinforcement learning (MARL) network to prune the search tree of Monte Carlo Tree Search method, so as to find the optimal action more efficiently. We establish a multi-target 2D environment to simulate several sports games, and experimental results demonstrate that our method can effectively improve the target coverage. The code is available at:
http://github.com/HopeChanger/ActiveObjectTracking
.
Importance Sampling BRDF Derivatives
Authors: Belhe Yash , Xu Bing , Bangaru Sai Praveen , Ramamoorthi Ravi , Li Tzu-Mao
Published: February 2024

We propose a set of techniques to efficiently importance sample the derivatives of a wide range of Bidirectional Reflectance Distribution Function (BRDF) models. In differentiable rendering, BRDFs are replaced by their differential BRDF counterparts, which are real-valued and can have negative values. This leads to a new source of variance arising from their change in sign. Real-valued functions cannot be perfectly importance sampled by a positive-valued PDF, and the direct application of BRDF sampling leads to high variance. Previous attempts at antithetic sampling only addressed the derivative with the roughness parameter of isotropic microfacet BRDFs. Our work generalizes BRDF derivative sampling to anisotropic microfacet models, mixture BRDFs, Oren-Nayar, Hanrahan-Krueger, among other analytic BRDFs.

Our method first decomposes the real-valued differential BRDF into a sum of single-signed functions, eliminating variance from a change in sign. Next, we importance sample each of the resulting single-signed functions separately. The first decomposition, positivization, partitions the real-valued function based on its sign, and is effective at variance reduction when applicable. However, it requires analytic knowledge of the roots of the differential BRDF, and for it to be analytically integrable too. Our key insight is that the single-signed functions can have overlapping support, which significantly broadens the ways we can decompose a real-valued function. Our product and mixture decompositions exploit this property, and they allow us to support several BRDF derivatives that positivization could not handle. For a wide variety of BRDF derivatives, our method significantly reduces the variance (up to 58× in some cases) at equal computation cost and enables better recovery of spatially varying textures through gradient-descent-based inverse rendering.
Recipe Generation from Unsegmented Cooking Videos
Authors: Nishimura Taichi , Hashimoto Atsushi , Ushiku Yoshitaka , Kameko Hirotaka , Mori Shinsuke
Published: February 2024

This paper tackles recipe generation from unsegmented cooking videos, a task that requires agents to (1) extract key events in completing the dish and (2) generate sentences for the extracted events. Our task is similar to dense video captioning (DVC), which aims at detecting events thoroughly and generating sentences for them. However, unlike DVC, in recipe generation, recipe story awareness is crucial, and a model should extract an appropriate number of events in the correct order and generate accurate sentences based on them. We analyze the output of the DVC model and confirm that although (1) several events are adoptable as a recipe story, (2) the generated sentences for such events are not grounded in the visual content. Based on this, we set our goal to obtain correct recipes by selecting oracle events from the output events and re-generating sentences for them. To achieve this, we propose a transformer-based multimodal recurrent approach of training an event selector and sentence generator for selecting oracle events from the DVC’s events and generating sentences for them. In addition, we extend the model by including ingredients to generate more accurate recipes. The experimental results show that the proposed method outperforms state-of-the-art DVC models. We also confirm that, by modeling the recipe in a story-aware manner, the proposed model outputs the appropriate number of events in the correct order.
Brain access of incretins and incretin receptor agonists to their central targets relevant for appetite suppression and weight loss
Authors: Buller Sophie , Blouet Clemence
Published: February 2024

New incretin-based pharmacotherapies provide efficient and safe therapeutic options to curb appetite and produce weight loss in patients with obesity. Delivered systemically, these molecules produce pleiotropic metabolic benefits, but the target sites mediating their weight-suppressive action are located within the brain. Recent research has increased our understanding of the neural circuits and behavioral mechanisms involved in the anorectic and metabolic consequences of glucagon-like peptide 1 (GLP-1)-based weight loss strategies, yet little is known about how these drugs access their functional targets in the brain to produce sustained weight loss. The majority of brain cells expressing incretin receptors are located behind the blood–brain barrier, shielded from the circulation and fluctuations in the availability of peripheral signals, which is a major challenge for the development of CNS-targeted therapeutic peptides. GLP-1 receptor (GLP-1R) agonists with increased half-life and enhanced therapeutic benefit do not cross the blood–brain barrier, yet they manage to access discrete brain sites relevant to the regulation of energy homeostasis. In this review, we give a brief overview of the different routes for peptide hormones to access the brain. We then examine the evidence informing the routes employed by incretins and incretin receptor agonists to access brain targets relevant for their appetite and weight-suppressive actions. We highlight existing controversies and suggest future directions to further establish the functionally relevant access routes for GLP-1-based weight loss compounds, which might guide the development and selection of the future generation of incretin receptor polypharmacologies.
Larsucosterol: endogenous epigenetic regulator for treating chronic and acute liver diseases
Authors: Wang Yaping , Ren Jenna , Ren Shunlin
Published: February 2024

Larsucosterol, a potent endogenous epigenetic regulator, has been reported to play a significant role in lipid metabolism, inflammatory responses, and cell survival. The administration of larsucosterol has demonstrated a reduction in lipid accumulation within hepatocytes and the attenuation of inflammatory responses induced by lipopolysaccharide (LPS) and TNFα in macrophages, alleviating LPS- and acetaminophen (ATMP)-induced multiple organ injury, and decreasing mortalities in animal models. Results from phase 1 and 2 clinical trials have shown that larsucosterol has potential as a biomedicine for the treatment of acute and chronic liver diseases. Recent evidence suggests that larsucosterol is a promising candidate for treating alcohol-associated hepatitis with positive results from a phase 2a clinical trial, and for metabolic dysfunction-associated steatohepatitis (MASH) from a phase 1b clinical trial. In this review, we present a culmination of our recent research efforts spanning two decades. We summarize the discovery, physiological and pharmacological mechanisms, and clinical applications of larsucosterol. Furthermore, we elucidate the pathophysiological pathways of metabolic dysfunction-associated steatotic liver diseases (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and acute liver injuries. A central focus of the review is the exploration of the therapeutic potential of larsucosterol in treating life-threatening conditions, including acetaminophen overdose, endotoxin shock, MASLD, MASH, hepatectomy, and alcoholic hepatitis.
Neonatal microglia transplantation at early stage but not late stage after traumatic brain injury shows protective effects in mice
Authors: Chen Maosong , Wang Hongcai , Chen Pandi , Zhu Guangyao , Li Shiwei , Li Zengpan , Liu Xuelan , Ye Gengfan , Chen Wei
Published: February 2024

The study demonstrated that neonatal microglia transplantation within 1 h significantly inhibited the pathogenesis of traumatic brain injury (TBI) in mouse models through inhibition of M1 polarization and promotion of M2 polarization.
Strongly Bound Frenkel Excitons on TiO2 Nanoparticles: An Evolutionary and DFT Approach
Authors: Olvera-Neria Oscar , García-Cruz Raúl , Gonzalez-Torres Julio , García-Cruz Luz María , Castillo-Sánchez Jean Luis , Poulain Enrique
Published: February 2024

An evolutionary algorithm was employed to locate the global minimum of TiO2n nanoparticles with n=2–20. More than 61,000 structures were calculated with a semiempirical method and reoptimized using density functional theory. The exciton binding energy of TiO2 nanoparticles was determined through the fundamental and optical band gap. Frenkel exciton energy scales as EB eV=8.07/n0.85, resulting in strongly bound excitons of 0.132–1.2 eV for about 1.4 nm nanoparticles. Although the exciton energy decreases with the system size, these tightly bound Frenkel excitons inhibit the separation of photogenerated charge carriers, making their application in photocatalysis and photovoltaic devices difficult, and imposing a minimum particle size. In contrast, the exciton binding energy of rutile is 4 meV, where the Wannier exciton energy scales as EB eV=13.61 μ/ε2. Moreover, the Wannier excitons in bulk TiO2 are delocalized according to the Bohr radii: 3.9 nm for anatase and 7.7 nm for rutile.
Unveiling the Influence of the Curve of Spee on Bite Force and Chewing Ability: A Comparative Study
Authors: Ali Alkhalaf Zainab , Sghaireen Mohammed Ghazi , Ganji Kiran Kumar , Alam Mohammad Khursheed , Issrani Rakhi , Mohammed Alsaleh Raghad , Almegren Sultana Zamil , Gamal Salloum Mahmoud
Published: February 2024

Aim. To investigate the impact of the curve of Spee (CS) accentuation on bite force, chewing ability, and additionally, other factors that influence chewing ability and bite force such as restorations, caries, gender, habits, and TMJ problems. Materials and Methods. 231 participants (118 male and 113 female, mean age = ±27.96 years) were recruited for this cross-section study. Participants completed a data collection sheet in which age, gender, Angle’s classification of malocclusion, overjet, overbite, TMJ problems, habits, restorations, and caries experience were recorded. Two examiners made a lower impression, chewing ability test and measured the bite force for each participant. Measurement of the CS was obtained digitally from the poured dental cast, and the categorization was as follows: flat (<1 mm), normal (1-2 mm), or deep (>2 mm). Results. The mean maximum bite force (MBF) was 468.722 N for participants with flat CS, 389.822 N for normal CS, 647.08 N for deep CS, and 384.667 N for reverse CS. The average MBF was higher for participants with deep CS (p<0.05). MBF force was higher in males. However, BMI was not significantly related to MBF values. Participants with normal and flat CS have comparable chewing capacity (p>0.05). Also, a significant difference in bite force and chewing ability was found between the three categories of CS (p<0.05). Conclusion. Bite force variations across various CS types were linked to gender and habits. Chewing ability showed no differences concerning gender, habits, TMJ problems, caries, or restorations, emphasizing CS’s significant impact on bite force while showcasing the unchanged nature of chewing ability amidst diverse factors.
PABPC1L Induces IDO1 to Promote Tryptophan Metabolism and Immune Suppression in Renal Cell Carcinoma
Authors: Shu Guannan , Chen Minyu , Liao Wuyuan , Fu Liangmin , Lin Mingjie , Gui Chengpeng , Cen Junjie , Lu Jun , Chen Zhenhua , Wei Jinhuan , Chen Wei , Wang Yinghan , Zhu Jiangquan , Zhao Tianxin , Liu Xiaonan , Jing Jiajia , Liu Guo-chang , Pan Yihui , Luo Junhang , Zhang Jiaxing
Published: February 2024

The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance despite having extensive T-cell infiltration. Elucidation of the mechanisms underlying immune evasion could help identify therapeutic strategies to boost the efficacy of immune checkpoint blockade (ICB) in RCC. This study uncovered a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine 2,3-dioxygenase 1 (IDO1), a prospective target for immunotherapy. PABPC1L was markedly upregulated in RCC, and high PABPC1L expression correlated with unfavorable prognosis and resistance to ICB. PABPC1L bolstered tryptophan metabolism by upregulating IDO1, inducing T-cell dysfunction and Treg infiltration. PABPC1L enhanced the stability of JAK2 mRNA, leading to increased JAK2-STAT1 signaling that induced IDO1 expression. Additionally, PABPC1L-induced activation of the JAK2-STAT1 axis created a positive feedback loop to promote PABPC1L transcription. Conversely, loss of PABPC1L diminished IDO1 expression, mitigated cytotoxic T-cell suppression, and enhanced responsiveness to anti-PD-1 therapy in patient-derived xenograft models. These findings reveal the crucial role of PABPC1L in facilitating immune evasion in RCC and indicate that inhibiting PABPC1L could be a potential immunotherapeutic approach in combination with ICB to improve patient outcomes.

Significance:

PABPC1L functions as a key factor in renal cell carcinoma immune evasion, enhancing IDO1 and impeding T-cell function, and represents a potential target to enhance the efficacy of immune checkpoint blockade therapy.
Lipid-Encapsulated mRNAs Encoding Complex Fusion Proteins Potentiate Antitumor Immune Responses
Authors: Shuptrine Casey W. , Chen Yuhui , Miriyala Jayalakshmi , Lenz Karen , Moffett Danielle , Nguyen Thuy-Ai , Michaux Jenn , Campbell Kristen , Smith Connor , Morra Marc , Rivera-Molina Yisel , Murr Noah , Cooper Sarah , McGuire Ashlyn , Makani Vishruti , Oien Nathan , Zugates Jeffery T. , de Silva Suresh , Schreiber Taylor H. , de Picciotto Seymour , Fromm George
Published: February 2024

Lipid nanoparticle (LNP)–encapsulated mRNA has been used for in vivo production of several secreted protein classes, such as IgG, and has enabled the development of personalized vaccines in oncology. Establishing the feasibility of delivering complex multispecific modalities that require higher-order structures important for their function could help expand the use of mRNA/LNP biologic formulations. Here, we evaluated whether in vivo administration of mRNA/LNP formulations of SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT could achieve oligomerization and extend exposure, on-target activity, and antitumor responses comparable with that of the corresponding recombinant fusion proteins. Intravenous infusion of the formulated LNP-encapsulated mRNAs led to rapid and sustained production of functional hexameric proteins in vivo, which increased the overall exposure relative to the recombinant protein controls by ∼28 to 140 fold over 96 hours. High concentrations of the mRNA-encoded proteins were also observed in secondary lymphoid organs and within implanted tumors, with protein concentrations in tumors up to 134-fold greater than with the recombinant protein controls 24 hours after treatment. In addition, SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT mRNAs induced a greater increase in antigen-specific CD8+ T cells in the tumors. These mRNA/LNP formulations were well tolerated and led to a rapid increase in serum and intratumoral IL2, delayed tumor growth, extended survival, and outperformed the activities of benchmark mAb controls. Furthermore, the mRNA/LNPs demonstrated improved efficacy in combination with anti-PD-L1 relative to the recombinant fusion proteins. These data support the delivery of complex oligomeric biologics as mRNA/LNP formulations, where high therapeutic expression and exposure could translate into improved patient outcomes.

Significance:

Lipid nanoparticle–encapsulated mRNA can efficiently encode complex fusion proteins encompassing immune checkpoint blockers and costimulators that functionally oligomerize in vivo with extended pharmacokinetics and durable exposure to induce potent antitumor immunity.
DNA of Neutrophil Extracellular Traps Binds TMCO6 to Impair CD8+ T-cell Immunity in Hepatocellular Carcinoma
Authors: Song Mengjia , Zhang Chaoqi , Cheng Shaoyan , Ouyang Dijun , Ping Yu , Yang Jieying , Zhang YaoJun , Tang Yan , Chen Hao , Wang Qi-jing , Li Yong-qiang , He Jia , Xiang Tong , Zhang Yizhuo , Xia Jian-Chuan
Published: February 2024

Neutrophil extracellular traps (NET), formed by the extracellular release of decondensed chromatin and granules, have been shown to promote tumor progression and metastasis. Tumor-associated neutrophils in hepatocellular carcinoma (HCC) are prone to NET formation, highlighting the need for a more comprehensive understanding of the mechanisms of action of NETs in liver cancer. Here, we showed that DNA of NETs (NET-DNA) binds transmembrane and coiled-coil domains 6 (TMCO6) on CD8+ T cells to impair antitumor immunity and thereby promote HCC progression. TGFβ1 induced NET formation, which recruited CD8+ T cells. Binding to NET-DNA inhibited CD8+ T cells function while increasing apoptosis and TGFβ1 secretion, forming a positive feedback loop to further stimulate NET formation and immunosuppression. Mechanistically, the N-terminus of TMCO6 interacted with NET-DNA and suppressed T-cell receptor signaling and NFκB p65 nuclear translocation. Blocking NET formation by inhibiting PAD4 induced potent antitumor effects in wild-type mice but not TMCO6−/− mice. In clinical samples, CD8+ T cells expressing TMCO6 had an exhausted phenotype. TGFβ1 signaling inhibition or TMCO6 deficiency combined with anti-PD-1 abolished NET-driven HCC progression in vivo. Collectively, this study unveils the role of NET-DNA in impairing CD8+ T-cell immunity by binding TMCO6 and identifies targeting this axis as an immunotherapeutic strategy for blocking HCC progression.

Significance:

TMCO6 is a receptor for DNA of NETs that mediates CD8+ T-cell dysfunction in HCC, indicating that the NET-TMCO6 axis is a promising target for overcoming immunosuppression in liver cancer.
Exploiting Tertiary Lymphoid Structures to Stimulate Antitumor Immunity and Improve Immunotherapy Efficacy
Authors: Petroni Giulia , Pillozzi Serena , Antonuzzo Lorenzo
Published: February 2024

Tumor-associated tertiary lymphoid structures (TLS) have been associated with favorable clinical outcomes and response to immune checkpoint inhibitors in many cancer types, including non–small cell lung cancer. Although the detailed cellular and molecular mechanisms underlying these clinical associations have not been fully elucidated, growing preclinical and clinical studies are helping to elucidate the mechanisms at the basis of TLS formation, composition, and regulation of immune responses. However, a major challenge remains how to exploit TLS to enhance naïve and treatment-mediated antitumor immune responses. Here, we discuss the current understanding of tumor-associated TLS, preclinical models that can be used to study them, and potential therapeutic interventions to boost TLS formation, with a particular focus on lung cancer research.
Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-resistant Estrogen Receptor–positive Breast Cancer
Authors: Guarducci Cristina , Nardone Agostina , Russo Douglas , Nagy Zsuzsanna , Heraud Capucine , Grinshpun Albert , Zhang Qi , Freelander Allegra , Leventhal Mathew Joseph , Feit Avery , Cohen Feit Gabriella , Feiglin Ariel , Liu Weihan , Hermida-Prado Francisco , Kesten Nikolas , Ma Wen , De Angelis Carmine , Morlando Antonio , O'Donnell Madison , Naumenko Sergey , Huang Shixia , Nguyen Quang-Dé , Huang Ying , Malorni Luca , Bergholz Johann S. , Zhao Jean J. , Fraenkel Ernest , Lim Elgene , Schiff Rachel , Shapiro Geoffrey I. , Jeselsohn Rinath
Published: February 2024

Purpose:

Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive. Herein, we sought to unravel these mechanisms.

Experimental Design:

We conducted multi-omic analyses in ER+ breast cancer models in vitro and in vivo, including models with different genetic backgrounds. We also performed genome-wide CRISPR/Cas9 knockout screens to identify potential therapeutic vulnerabilities in CDK4/6i-resistant models.

Results:

We found that the on-target antitumor effects of CDK7 inhibition in ER+ breast cancer are in part p53 dependent, and involve cell cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ET and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118; however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Finally, genome-wide CRISPR/Cas9 knockout screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i-resistant models.

Conclusions:

Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ breast cancer. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors of sensitivity to CDK7i-based treatments.
Serotonin Receptor HTR2B Facilitates Colorectal Cancer Metastasis via CREB1–ZEB1 Axis–Mediated Epithelial–Mesenchymal Transition
Authors: Li Tao , Wei Lei , Zhang Xin , Fu Bin , Zhou Yunjiang , Yang Mengdi , Cao Mengran , Chen Yaxin , Tan Yingying , Shi Yongwei , Wu Leyin , Xuan Chenyuan , Du Qianming , Hu Rong
Published: February 2024

A number of neurotransmitters have been detected in tumor microenvironment and proved to modulate cancer oncogenesis and progression. We previously found that biosynthesis and secretion of neurotransmitter 5-hydroxytryptamine (5-HT) was elevated in colorectal cancer cells. In this study, we discovered that the HTR2B receptor of 5-HT was highly expressed in colorectal cancer tumor tissues, which was further identified as a strong risk factor for colorectal cancer prognostic outcomes. Both pharmacological blocking and genetic knocking down HTR2B impaired migration of colorectal cancer cell, as well as the epithelial–mesenchymal transition (EMT) process. Mechanistically, HTR2B signaling induced ribosomal protein S6 kinase B1 (S6K1) activation via the Akt/mTOR pathway, which triggered cAMP-responsive element-binding protein 1 (CREB1) phosphorylation (Ser 133) and translocation into the nucleus, then the phosphorylated CREB1 acts as an activator for ZEB1 transcription after binding to CREB1 half-site (GTCA) at ZEB1 promoter. As a key regulator of EMT, ZEB1, therefore, enhances migration and EMT process in colorectal cancer cells. We also found that HTR2B-specific antagonist (RS127445) treatment significantly ameliorated metastasis and reversed EMT process in both HCT116 cell tail-vein–injected pulmonary metastasis and CT26 cell intrasplenic-injected hepatic metastasis mouse models.

Implications:

These findings uncover a novel regulatory role of HTR2B signaling on colorectal cancer metastasis, which provide experimental evidences for potential HTR2B-targeted anti-colorectal cancer metastasis therapy.
Table S2 from NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma
Authors: Hamad Samera H. , Sellers Rani S. , Wamsley Nathan , Zolkind Paul , Schrank Travis P. , Major Michael B. , Weissman Bernard E.
Published: February 2024

Table S2 shows TCGA data used to analyze mutations in TP53, CDKN2A, and NRF2 pathways.
Figure S5 from NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma
Authors: Hamad Samera H. , Sellers Rani S. , Wamsley Nathan , Zolkind Paul , Schrank Travis P. , Major Michael B. , Weissman Bernard E.
Published: February 2024

Figure S5 shows box-and-whisker plots of protein abundance as measured by targeted protein mass spectrometry CP and CPN oral cavity tissues.
Figure S3 from NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma
Authors: Hamad Samera H. , Sellers Rani S. , Wamsley Nathan , Zolkind Paul , Schrank Travis P. , Major Michael B. , Weissman Bernard E.
Published: February 2024

Figure S3 shows examples of abdominal tumors from CP and CPN mice.
Figure S1 from NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma
Authors: Hamad Samera H. , Sellers Rani S. , Wamsley Nathan , Zolkind Paul , Schrank Travis P. , Major Michael B. , Weissman Bernard E.
Published: February 2024

Figure S1 shows survival curves and weight loss of CP and CPN mice after treatment with tamoxifen.
FIGURE 5 from NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma
Authors: Hamad Samera H. , Sellers Rani S. , Wamsley Nathan , Zolkind Paul , Schrank Travis P. , Major Michael B. , Weissman Bernard E.
Published: February 2024

NRF2 activity in human OSCC. TP53, CDKN2A, and NRF2 pathway mutational profiles from 268 HPV—oral cavity squamous cell carcinoma in TCGA. A, Waterfall plot—relative frequency and mutational classes. Color—mutational class. B, Kaplan–Meier plot—disease specific survival of the 254 patients with HPV—oral cavity squamous cell carcinoma with available outcomes data, stratified by NRF2 pathway alteration status. Red—Altered NRF2 pathway. Blue—wild-type NRF2 pathway. P value represents log-rank test. HR—hazard ratio with 95% confidence interval.
FIGURE 4 from NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma
Authors: Hamad Samera H. , Sellers Rani S. , Wamsley Nathan , Zolkind Paul , Schrank Travis P. , Major Michael B. , Weissman Bernard E.
Published: February 2024

Targeted proteomic analyses of oral cavity tissues from CP and CPN mice. A, Heat map of protein expression from oral tissues of CP (K14-CreERTAM2; p16−/−; p53−/−) and CPN (K14-CreERTAM2; p16−/−; p53−/−; NRF2E79Q/WT) mice, with columns normalized by Z-scores; protein abundances were measured by IS-PRM. See also Supplementary Table S5. B, PCA plot from protein abundances shown in A; the first two principal components explained 35% and 27% of the total variance respectively. C, Plot of the NRF2 score in CP and CPN mice. The score was calculated using 10 NRF2 targets within the first principal component. D, Correlation of the NQO1 protein expression with the NRF2 pathway score. E, Correlation of the SRXN1 protein expression with the NRF2 pathway score. F, Correlation of the IL36G protein expression with the NRF2 pathway score. For correlations of all proteins correlated with the NRF2 score, see Supplementary Fig. S4. G, Box-and-whisker plots of protein abundance in CP and CPN oral cavity tissues. For box-and-whisker plots of abundance for all proteins, see Supplementary Fig. S5. Adjusted P values were calculated with a Mann–Whitney U test. The normal tissue from the oral cavity of the CPN mice showed hyperplasia with hyperkeratosis as shown in Fig. 2B.
FIGURE 2 from NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma
Authors: Hamad Samera H. , Sellers Rani S. , Wamsley Nathan , Zolkind Paul , Schrank Travis P. , Major Michael B. , Weissman Bernard E.
Published: February 2024

Histologic profile of normal and epithelial lesions of the oral mucosa from CP and CPN mice. Normal epithelium (CP; A); epithelial hyperplasia with hyperkeratosis (CPN; B); CPN (C); and oral squamous cell carcinoma (CPN; D). Scale bar = 50 µm. Images were taken using an Olympus DP38 digital camera on an Olympus BX46 microscope.
Advances in the Treatment of Pulmonary Nodules
Authors: Zhang Quncheng , Wu Xuan , Yang Huizhen , Luo Peiyuan , Wei Nan , Wang Shuai , Zhao Xingru , Wang Ziqi , Herth Felix J.F. , Zhang Xiaoju
Published: February 2024

Background: Early detection and accurate diagnosis of pulmonary nodules are crucial for improving patient outcomes. While surgical resection of malignant nodules is still the preferred treatment option, it may not be feasible for all patients. We aimed to discuss the advances in the treatment of pulmonary nodules, especially stereotactic body radiotherapy (SBRT) and interventional pulmonology technologies, and provide a range of recommendations based on our expertise and experience. Summary: Interventional pulmonology is an increasingly important approach for the management of pulmonary nodules. While more studies are needed to fully evaluate its long-term outcomes and benefits, the available evidence suggests that this technique can provide a minimally invasive and effective alternative for treating small malignancies in selected patients. We conducted a systematic literature review in PubMed, designed a framework to include the advances in surgery, SBRT, and interventional pulmonology for the treatment of pulmonary nodules, and provided a range of recommendations based on our expertise and experience. Key Messages: As such, alternative therapeutic options such as SBRT and ablation are becoming increasingly important and viable. With recent advancements in bronchoscopy techniques, ablation via bronchoscopy has emerged as a promising option for treating pulmonary nodules. This study reviewed the advances of interventional pulmonology in the treatment of peripheral lung cancer patients that are not surgical candidates. We also discussed the challenges and limitations associated with ablation, such as the risk of complications and the potential for incomplete nodule eradication. These advancements hold great promise for improving the efficacy and safety of interventional pulmonology in treating pulmonary nodules.
Awareness and Knowledge of Stuttering among Malaysian School-Aged Children: An Exploratory Study
Authors: Ong Ying Qian , Hasmidi Nurul Nadia , Lee Jaehoon , Hamzah Dadang Amir , Unicomb Rachael , Chu Shin Ying
Published: February 2024

Introduction: Knowledge and awareness of stuttering are closely associated with attitudes toward stuttering. Few studies have been conducted on the knowledge and awareness of school-aged children, and none have been conducted in Malaysia. This study aimed to: (a) determine knowledge and awareness of stuttering among Malaysian school-aged children, and (b) determine whether there are differences between age group, gender, and people who stutter (PWS) exposure groups. Methods: A cross-sectional study was conducted among 192 Malay school-aged children (mean age = 9.47, SD = 1.781) recruited via email and social media platforms. They completed a Malay version of the questionnaire devised by van Borsel et al. (1999) on various aspects of stuttering, including prevalence, onset, gender distribution, occurrence in different cultures, cause, treatment, intelligence, and heredity of stuttering. The χ2 test of independence was performed to compare the distributions of survey responses by age group, gender, and PWS exposure group. Results: Around half of the school-aged children had met a person who stutters, but certain aspects of their knowledge were limited. Knowledge also differed according to age and gender. Girls were more knowledgeable about stuttering than boys. Regarding stuttering treatment, younger children had more positive attitudes than older children. Participants who did not know a PWS were more likely to consult their family doctor rather than a speech-language pathologist in relation to stuttering. Conclusion: Knowledge and awareness of stuttering among Malaysian school-aged children were limited. Findings of this study could be used to develop a stuttering awareness program specific to children to increase their knowledge and awareness about stuttering.
Regulasi Diri Pasien Kanker Payudara
Authors: Supriati Lilik , Astari Asti Melani , Sunarto Muhammad
Published: February 2024

Buku ini merupakan buku yang berisi konsep dan praktik yang memberikan pemahaman dan panduan kepada petugas kesehatan seperti perawat, bidan, mahasiswa keperawatan, relawan paliatif sebagai panduan membantu pasien kanker payudara dalam melakukan manajemen diri. Buku ini disertai dengan berbagai konsep teori seperti konsep teori regulasi diri, teori uncertainty in illness theory (teori ketidakpastian dalam perjalanan penyakit kronik), konsep pencarian makna hidup walau menderita kanker payudara dan juga disertai kaitan stres dengan imunitas yang sangat dibutuhkan dalam melawan sel kanker. Penulis menggunakan pendekatan yang lebih komprehensif dengan melibatkan konsep teori dan pendekatan aspek psikologis dengan menggunakan bahasa yang lebih sederhana sehingga bisa diterima oleh banyak kalangan termasuk relawan, kader, dan pemerhati kanker payudara di masyarakat.
Tissue Factor and COVID-19 Associated Thrombosis
Authors: Mackman Nigel
Published: February 2024

Microbial infections activate the innate and adaptive immune systems.

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Pathogen-associated molecular patterns produced by microbes, such as double-stranded RNA, are detected by PRRs (pattern-recognition receptors), such as toll-like receptor 3, and this leads to the expression of interferons and cytokines.

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AI, Machine Learning, and ChatGPT in Hypertension
Authors: Layton Anita T.
Published: February 2024

Hypertension, a leading cause of cardiovascular disease and premature death, remains incompletely understood despite extensive research. Indeed, even though numerous drugs are available, achieving adequate blood pressure control remains a challenge, prompting recent interest in artificial intelligence. To promote the use of machine learning in cardiovascular medicine, this review provides a brief introduction to machine learning and reviews its notable applications in hypertension management and research, such as disease diagnosis and prognosis, treatment decisions, and omics data analysis. The challenges and limitations associated with data-driven predictive techniques are also discussed. The goal of this review is to raise awareness and encourage the hypertension research community to consider machine learning as a key component in developing innovative diagnostic and therapeutic tools for hypertension. By integrating traditional cardiovascular risk factors with genomics, socioeconomic, behavioral, and environmental factors, machine learning may aid in the development of precise risk prediction models and personalized treatment approaches for patients with hypertension.
Indigenous Clockmakers, Schedules, and Quantitative Time in the Spanish Colonies (16th Century)
Authors: Uribe Ricardo
Published: February 2024

During the 16th century, the term “Cemilhuitlapohualtepoztli” meant “clock” to the indigenous peoples of Mexico. They had formed this neologism out of three words from the Nahual language: “cemilhui” (the passing of a day); “tlapoaliztli” (to count); and “tepoztli” (bell or iron). This linguistic evidence, in conjunction with other documents found in Spanish and Latin American archives, show that autochthonous people came into early contact with these mechanisms and promptly assimilated quantified time. Historiography often claims that the Catholic Church imposed this kind of time among indigenous societies, however, this paper demonstrates that indigenous peoples appropriated a more precise and quantified time in the offices of the colonial administration, either by working as clockmakers or by producing “timetables” and calendars. This process allowed, on the one hand, the global synchrony between the Old and the New World, and on the other hand, the coordination of collective temporalities and local calendars.
Time Experiencing in Men Serving the Term of Imprisonment – a Semantic Differential Study
Authors: Tucholska Kinga , Gulla Bożena , Wysocka-Pleczyk Małgorzata , Piotrowski Przemysław , Florek Stefan , Sekulak Martyna , Głomb Kaja
Published: February 2024

This paper proposes a semantic differential-based research method called Prison Time. The study with this tool was conducted on a group (N = 161) of men serving time in Polish prisons. The analysis revealed a two-factor structure accounting for 49.1% of the variance, with Cronbach’s alpha greater than 0.74. The Perceptual-Formal factor reflects formal aspects of perceiving time – pace, dynamics, and changeability. The Emotional-Valence factor captures both the emotional load and assessment related to experiencing imprisonment time. The measure is likely to be used by both academics and practitioners interested in assessing the subjective attitude to time as experienced in prison.