bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitigating non-genetic resistance to checkpoint inhibition based on multiple states of immune exhaustion
Authors: Kareva Irina , Gevertz Jana L. 
Published: February 2024

AbstractDespite the revolutionary impact of immune checkpoint inhibition on cancer therapy, the lack of response in a subset of patients, as well as the emergence of resistance, remain significant challenges. Here we explore the theoretical consequences of the existence of multiple states of immune cell exhaustion on response to checkpoint inhibition therapy. In particular, we consider the emerging understanding that T cells can exist in various states: fully functioning cytotoxic cells, reversibly exhausted cells with minimal cytotoxicity, and terminally exhausted cells. We hypothesize that inflammation augmented by drug activity triggers transitions between these phenotypes, which can lead to non-genetic resistance to checkpoint inhibitors. We introduce a conceptual mathematical model, coupled with a standard 2-compartment pharmacometric (PK) model, that incorporates these mechanisms. Simulations of the model reveal that, within this framework, the emergence of resistance to checkpoint inhibitors can be mitigated through altering the dose and the frequency of administration. Our analysis also reveals that standard PK metrics do not correlate with treatment outcome. However, we do find that levels of inflammation that we assume trigger the transition from the reversibly to terminally exhausted states play a critical role in therapeutic outcome. A simulation of a population that has different values of this transition threshold reveals that while the standard high-dose, low-frequency dosing strategy can be an effective therapeutic design for some, it is likely to fail a significant fraction of the population. Conversely, a metronomic-like strategy that distributes a fixed amount of drug over many doses given close together is predicted to be effective across the entire simulated population, even at a relatively low cumulative drug dose. We also demonstrate that these predictions hold if the transitions between different states of immune cell exhaustion are triggered by prolonged antigen exposure, an alternative mechanism that has been implicated in this process. Our theoretical analyses demonstrate the potential of mitigating resistance to checkpoint inhibitors via dose modulation.
Quantizing reconstruction losses for improving weather data synthesis
Authors: Szwarcman Daniela , Guevara Jorge , Macedo Maysa M. G. , Zadrozny Bianca , Watson Campbell , Rosa Laura , Oliveira Dario A. B. 
Published: February 2024

AbstractThe stochastic synthesis of extreme, rare climate scenarios is vital for risk and resilience models aware of climate change, directly impacting society in different sectors. However, creating high-quality variations of under-represented samples remains a challenge for several generative models. This paper investigates quantizing reconstruction losses for helping variational autoencoders (VAE) better synthesize extreme weather fields from conventional historical training sets. Building on the classical VAE formulation using reconstruction and latent space regularization losses, we propose various histogram-based penalties to the reconstruction loss that explicitly reinforces the model to synthesize under-represented values better. We evaluate our work using precipitation weather fields, where models usually strive to synthesize well extreme precipitation samples. We demonstrate that bringing histogram awareness to the reconstruction loss improves standard VAE performance substantially, especially for extreme weather events.
A Kpna1-deficient psychotropic drug-induced schizophrenia model mouse for studying gene–environment interactions
Authors: Nomiya Hirotaka , Sakurai Koki , Miyamoto Yoichi , Oka Masahiro , Yoneda Yoshihiro , Hikida Takatoshi , Yamada Masami 
Published: February 2024

AbstractKPNA1 is a mediator of nucleocytoplasmic transport that is abundantly expressed in the mammalian brain and regulates neuronal differentiation and synaptic function. De novo mutations in Kpna1 have been identified using genome-wide association studies in humans with schizophrenia; however, it remains unclear how KPNA1 contributes to schizophrenia pathogenesis. Recent studies have suggested a complex combination of genetic and environmental factors that are closely related to psychiatric disorders. Here, we found that subchronic administration of phencyclidine, a psychotropic drug, induced vulnerability and behavioral abnormalities consistent with the symptoms of schizophrenia in Kpna1-deficient mice. Microarray assessment revealed that the expression levels of dopamine d1/d2 receptors, an RNA editing enzyme, and a cytoplasmic dynein component were significantly altered in the nucleus accumbens brain region in a gene-environment (G × E) interaction-dependent manner. Our findings demonstrate that Kpna1-deficient mice may be useful as a G × E interaction mouse model for psychiatric disorders and for further investigation into the pathogenesis of such diseases and disorders.
A TME-activated nano-catalyst for triple synergistic therapy of colorectal cancer
Authors: Liu Qiang , Xiang Yurong , Yu Qiang , Lv Quan , Xiang Zheng 
Published: February 2024

AbstractColorectal cancer cells are highly heterogeneous and exhibit various drug resistances, making personalized treatment necessary. This typically involves a combination of different treatment modalities such as surgery, radiation, and chemotherapy to increase patient survival. Inspired by this, synergistic therapy, which combines multiple modalities into a single nanotherapeutic drug, shows promise in treating cancer. In this study, a nano-catalyst based on calcium peroxide (CaO2) and the chemotherapeutic drug doxorubicin hydrochloride (DOX) co-loaded into HPB nanoparticles (HPB@CaO2/DOX-PAA) was developed to achieve synergistic cancer treatment through chemodynamic/chemo/photothermal (CDT/CT/PTT) mechanisms. After being endocytosed by cancer cells, the nano-catalyst decomposes, releasing cargo. During near-infrared light irradiation, HPB induces a photothermal effect, DOX exhibits significant RNA and DNA destruction capabilities, meanwhile CaO2 produces a large amount of H2O2 in the moderately acidic TME, which combines with Fe2+ ions derived from HPB to form the highly toxic •OH in a Fenton-like reaction, enhancing the chemodynamic treatment. Assays conducted ex vivo and in vivo have exhibited the efficacy of this triple synergistic therapeutic regimen, indicating its potential clinical application.
Sex differences and individual variability in the captive Jamaican fruit bat (Artibeus jamaicensis) intestinal microbiome and metabolome
Authors: Riopelle Jade C. , Shamsaddini Amirhossein , Holbrook Myndi G. , Bohrnsen Eric , Zhang Yue , Lovaglio Jamie , Cordova Kathleen , Hanley Patrick , Kendall Lon V. , Bosio Catharine M. , Schountz Tony , Schwarz Benjamin , Munster Vincent J. , Port Julia R. 
Published: February 2024

AbstractThe intestinal microbiome plays an important role in mammalian health, disease, and immune function. In light of this function, recent studies have aimed to characterize the microbiomes of various bat species, which are noteworthy for their roles as reservoir hosts for several viruses known to be highly pathogenic in other mammals. Despite ongoing bat microbiome research, its role in immune function and disease, especially the effects of changes in the microbiome on host health, remains nebulous. Here, we describe a novel methodology to investigate the intestinal microbiome of captive Jamaican fruit bats (Artibeus jamaicensis). We observed a high degree of individual variation in addition to sex- and cohort-linked differences. The intestinal microbiome was correlated with intestinal metabolite composition, possibly contributing to differences in immune status. This work provides a basis for future infection and field studies to examine in detail the role of the intestinal microbiome in antiviral immunity.
Assessment of toxicity and antimicrobial performance of polymeric inorganic coagulant and evaluation for eutrophication reduction
Authors: Youssef Marwa , El-Tanany Sara S. , Moatasim Yassmin , Moniem Shimaa M. Abdel , Hemdan Bahaa A. , Ammar Nabila S. , El-Taweel Gamila E. , Ashmawy Azza M. , Badawy Mohamed I. , Lasheen Mohamed R. , Ibrahim Hanan S. , Ali Mohamed Eid M. 
Published: February 2024

AbstractIn this study, the efficacy of the promising iron—based polymeric inorganic coagulant (POFC) was assessed for the reduction of eutrophication effect (freshwater toxicity) and the microbial loads from wastewater. Toxicity assessment for POFC was conducted on mice and skin cell lines. The results confirm the lower toxicity level of POFC. The POFC showed excellent antibacterial efficacy against Gram-positive and Gram-negative bacteria. Moreover, it demonstrated a remarkable effectiveness against black fungus such as Aspergillus niger and Rhizopus oryzae. Additionally, POFC showed antiviral effectiveness against the highly pathogenic H5N1 influenza virus as well as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). POFC-based treatment gives excellent removal percentages for phosphate, and phosphorus at doses below 60 ppm with a low produced sludge volume that leads to 84% decrease in the rate of eutrophication and freshwater toxicity. At a POFC concentration of 60 ppm, remarkable reduction rates for total coliforms, fecal coliforms, and E. coli were achieved. After POFC-based coagulation, the produced sludge retains a lower bacterial density due to the antibacterial activity of POFC. Furthermore, it revealed that the observed removal efficiencies for fungi and yeasts in the produced sludge reached 85% at a POFC dose of 60 ppm. Overall, our research indicates that POFC has potential for application in pre-treatment of wastewater and serves as an antimicrobial agent.
Preparation and research of new black zirconia ceramics
Authors: Ding Yuxuan , Wang Qingchun 
Published: February 2024

AbstractThe existing black zirconia has problems such as uneven color development, poor stability, expensive raw materials, and harm to the human body and the environment. In order to solve the above problems, this paper intends to use NiAl2O4, NiTiO3, Fe2O3 as chromophore, zirconia as a matrix, and a solid-phase method is used to prepare high-performance black zirconia ceramics. The method avoids the introduction of toxic elements, and at the same time, it is more economical in the selection of color-developing pigments. The experimental results show that black zirconia ceramics with uniform color, continuous adjustment and high temperature stability can be obtained. When the sintering temperature is lower than 1450 °C and the color material mixing ratio is 10 wt.%, the mechanical properties and optical properties of the obtained samples optimum, the overall reflectance of the sample is less than 10 wt.%, which meets the conditions for market application. These black ceramics can be widely used in high-tech fields such as mobile phone backplanes, photovoltaic industry and high-end decorative materials, and have broad application prospects.
Type III secretion system effector YfiD inhibits the activation of host poly(ADP-ribose) polymerase-1 to promote bacterial infection
Authors: Zhou Mengqing , Liu Yabo , Zhang Yibei , Ma Yue , Zhang Yuanxing , Choi Sang Ho , Shao Shuai , Wang Qiyao 
Published: February 2024

AbstractModulation of cell death is a powerful strategy employed by pathogenic bacteria to evade host immune clearance and occupy profitable replication niches during infection. Intracellular pathogens employ the type III secretion system (T3SS) to deliver effectors, which interfere with regulated cell death pathways to evade immune defenses. Here, we reveal that poly(ADP-ribose) polymerase-1 (PARP1)-dependent cell death restrains Edwardsiella piscicida’s proliferation in mouse monocyte macrophages J774A.1, of which PARP1 activation results in the accumulation of poly(ADP-ribose) (PAR) and enhanced inflammatory response. Moreover, E. piscicida, an important intracellular pathogen, leverages a T3SS effector YfiD to impair PARP1’s activity and inhibit PAR accumulation. Once translocated into the host nucleus, YfiD binds to the ADP-ribosyl transferase (ART) domain of PARP1 to suppress its PARylation ability as the pharmacological inhibitor of PARP1 behaves. Furthermore, the interaction between YfiD and ART mainly relies on the complete unfolding of the helical domain, which releases the inhibitory effect on ART. In addition, YfiD impairs the inflammatory response and cell death in macrophages and promotes in vivo colonization and virulence of E. piscicida. Collectively, our results establish the functional mechanism of YfiD as a potential PARP1 inhibitor and provide more insights into host defense against bacterial infection.
Stability analysis of discrete‐time systems with a time‐varying delay via improved methods
Authors: Sha Hongjia , Park Ju H. , Chen Jun , Zhu Mingbo , Nan Chengjie 
Published: February 2024

AbstractThis paper is concerned with the stability analysis of discrete‐time systems with a time‐varying delay. The conservatism and computation burden are two important factors to evaluate a stability condition. By taking the relationship of two reciprocally convex parts into consideration, a new combined matrix‐separation‐based inequality is proposed that involves only a few free matrices. Moreover, an improved matrix‐injection‐based transformation lemma with the parameter varying within a closed interval is proposed by introducing only one free matrix. By constructing an appropriate Lyapunov–Krasovskii functional and applying the improved methods, a relaxed stability condition is consequently obtained with a small number of decision variables. Two numerical examples are given to show the merits of the proposed methods.
Combination of Vertical Electrical Sounding (VES) and Electrical Resistivity Tomography (ERT) techniques for hydrogeological reconnaissance in the Guigou plain, Tabular Middle Atlas, Morocco
Authors: El Makrini Saïd , El Bouhaddioui Mohamed , Fatah-Allah Nouredine , Chariki Yassine , Boualoul Mustapha 
Published: February 2024

The study site is located in the Guigou plain, which is situated on the south-eastern edge of the Tabular Middle Atlas and is characterised by a particular geology within the mountainous region. Unlike the Tabular Middle Atlas, which is generally covered by Lias carbonate formations, the Guigou plain is characterised by the presence of a different type of cover formed by basaltic flows of plioquaternary age, forming a surface layer that is used extensively for agricultural activities. The main objective of our study is to detect the different geoelectric levels both at the surface and at depth, thus providing indications of the specific aquifer formations in the region studied.
The analysis of the results obtained highlighted the presence of a superficial resistant level, attributed to basalts of Plio-Quaternary age, with an estimated thickness of between 30 and 100 m, forming the superficial aquifer of the plain. Next, a conductive level was identified, associated with alternating marl and marl-limestone of Pliocene age, in keeping with the local geology. Finally, at a depth of 225 m, a very resistant level was identified, corresponding to Lias limestone, which becomes a deep aquifer on the Guigou plain.
This study provides essential vertical hydrogeological reconnaissance and highlights the need to carry out numerous tomographic profiles as well as electrical boreholes. These combined approaches are crucial to enriching our understanding of the particular geological and hydrogeological characteristics of this region, which forms a transition zone between the MAT and the MAP.
What is the best fixation method in medial patellofemoral ligament reconstruction? A biomechanical comparison of common methods for femoral graft attachment
Authors: Vezole Léonard , Gunst Stanislas , Gras Laure-Lise , Shatrov Jobe , Mertbakan Ozgur , Lustig Sébastien , Servien Elvire 
Published: February 2024

Introduction: A variety of techniques have been described for femoral fixation in medial patellofemoral ligament reconstruction (MPFLr). The aim of this study was to compare the biomechanical performance of the most used methods for graft fixation in the femur using human cadaveric tissue. We wondered what is the best fixation method for femoral fixation in MPFL reconstruction?Hypothesis: A suspensory fixation device provides the best femoral fixation.Material and method: Twenty cadaveric knees were tested. Four femoral fixation methods were compared (5 knees per group): interference fixation with a Biosure© RG 5 mm and a 7 mm, suture anchor (Healicoil Regenesorb 4.75 mm ©) and suspensory fixation with the Ultrabutton©. The testing was divided in preconditioning, cyclic loading and load to failure. Load to failure, elongation, stiffness and mode of failure were recorded and compared.Results: The Ultrabutton© had the highest mean ultimate load (427 ± 215 N (p = 0.5)), followed by Healicoil anchor © (308 ± 44 N (p > 0.05)) and the interference screw of 7 mm (255 ± 170 N (p > 0.05)). Mean stiffness was similar in the Ultrabutton© and 4.75 mm. Healicoil anchor © groups (111 ± 21 N/mm and 119 ± 20 N/mm respectively), and lowest in 7 mm Biosure© screw fixation group (90 ± 5 N/mm). The Biosure© 5 mm RG screw presented 100% of premature rupture because of tendon slippage. The Ultrabutton© presented the lowest premature rupture (40%).Discussion: A suspensory fixation for the femur had the lowest number of graft failures and highest load to failure. This study has implications for surgeons’ choice of graft fixation in MPFLr. It is the first study to test the most commonly femoral used fixation methods, allowing direct comparisons between each method.
Surgical Treatment of Scaphoid Fractures: Recommendations for Management
Authors: Samade Richard , Awan Hisham M. 
Published: February 2024

Abstract
Background: Several operative treatments exist for scaphoid fractures, varying by approach (e.g., ercutaneous, volar, or dorsal), implant type (e.g., screw or Kirschner wire), and bone raft choice (e.g., none, nonvascularized, or vascularized). Many previous systematic eviews and meta-analyses have investigated outcomes following different surgicalÚpproaches, the use of vascularized versus nonvascularized bone graft for scaphoidßracture nonunions, and treatment for specific fracture patterns. However, given the advancements n scaphoid fracture treatment in recent years, there is a need for updated treatment recommendations hat would be beneficial to hand surgeons.
Purpose: We present a comprehensive review of the operative treatment of scaphoid fractures based on recent literature and propose a unified treatment algorithm for managing these fractures.
Methods: The English-language literature was searched from 2002 to 2023 for high evidence level (e.g., randomized trials), review, and meta-analysis articles with the following search terms: “scaphoid, ”u8220“scaphoid” AND “nonunion, ” and “scaphoid” AND “malunion. ” Each article was creened by the authors to determine the scaphoid fracture scenario addressed and ubsequent treatment recommendations. The findings from article reviews were then rganized by scaphoid fracture types in this manuscript.
Results: A total of 95 pertinent articles were ultimately selected and used as the basis for reviewing different scaphoid fracture scenarios. A treatment algorithm was then proposed based on literature review.
Conclusion: This summary of the recent literature can guide hand surgeons in addressing scaphoidßractures. Future research in scaphoid fracture treatment, particularly for nonunions, would be most beneficial n the form of systematic review, meta-analysis, or multicenter prospective randomized clinical trials.
Level of Evidence: IV
Effect of Phonological Awareness-Focused Interventions on Phonological Errors and Phonemic Awareness in Young School-Age Children
Authors: Alvis Jewel E. , Brumbaugh Klaire M. , Tambyraja Sherine R. 
Published: February 2024

AbstractThis study aimed to explore the effects of an integrated phonological awareness intervention on phonological errors and phonemic awareness among young school-age children. Three children with at least one phonological error pattern and below-average phonological awareness skills participated in a non-concurrent multiple baseline single-subject design across participants' investigation. The integrated phonological awareness intervention consisted of completing blending and segmenting activities using 20 trained words, with a dose of 70 to 100 productions of the targeted phonological error pattern for 10, 30-minute sessions. All participants showed improvement in the primary dependent variable of percent consonants correct for their targeted error pattern for trained words. Results for percent phonemes correct showed gains for both blending and segmenting for all participants. All the participants transferred targeted skills to untrained words with their error pattern and generalized blending and segmenting to consonant–vowel–consonant words that did not contain their target error pattern in a pretest/posttest. Integrated phonological awareness intervention was an effective method of simultaneously improving speech production and phonemic awareness skills for young school-age children across 5 hours of treatment. The intervention was designed to be replicable by school-based speech-language pathologists seeking to efficiently support students with phonological errors and phonological awareness deficits.
Are Hospital Admissions (Costs) and Mortality Rate Impacted by Guideline-driven Treatment of Heart Failure?: A Comparison between Participants in the “CorBene” CMP and Standard-care Patients on the Basis of Propensity Score Matching
Authors: Ehling Josef , Noblé Hans Jürgen , Gysan Detlef , Möller Mareike , Goss Franz , Haerer Winfried , Glück Simon , Bansmann Paul Martin 
Published: February 2024

AbstractHeart failure (HF) is one of the most common diagnoses on admission to hospital in Germany, and one which incurs high costs. Integrated care in case management programs (CMPs) aims to improve treatment quality in the sense of guideline-driven treatment, while reducing hospital admissions, hospital costs, and mortality. A total of 1,844 patient data records from 11 German statutory health insurance companies enrolled in the CMP (intervention group [IG]) were compared with 1,844 standard-care patients (control group) using propensity score matching. The two groups were assessed over three follow-up observation periods regarding the endpoints' treatment costs, hospitalization rate, indicators for treatment quality (diagnostics, physician contact), and mortality. The evaluation revealed no significant differences regarding overall costs. The IG incurred significantly higher outpatient costs, but the medication costs and inpatient costs were not significantly different. There were also no significant differences in the number of hospital admissions. Patients within the CMP had significantly more frequent contact with a cardiologist, and underwent echocardiographic examination significantly more frequently. Mortality during the first follow-up observation year was considerably more favorable for the IG. There are indications that treatment quality is improved in HF patients.