bluuebunny/crossref_metadata_2025 huggingface dataset:
Reusable Electronic Tongue Based on Transient Receptor Potential Vanilloid 1 Nanodisc‐Conjugated Graphene Field‐Effect Transistor for a Spiciness‐Related Pain Evaluation
Authors: Seo Sung Eun , Lim Seong Gi , Kim Kyung Ho , Kim Jinyeong , Shin Chan Jae , Kim Soomin , Kim Lina , Lee Seung Hwan , Jang Song Yee , Oh Hyun Woo , Lee Hyang‐Ae , Kim Woo‐Keun , Park Yoo Min , Lee Kyoung G. , Lee Sang Hun , Ha Siyoung , Kwon Oh Seok
Published: March 2023

The sense of spiciness is related to the stimulation of vanilloid compounds contained in the foods. Although, the spiciness is commonly considered as the part of taste, it is more classified to the sense of pain stimulated on a tongue, namely, pungency, which is described as a tingling or burning on the tongue. Herein, first, a reusable electronic tongue based on a transient receptor potential vanilloid 1 (TRPV1) nanodisc conjugated graphene field‐effect transistor is fabricated and spiciness‐related pain evaluation with reusable electrode is demonstrated. The pungent compound reactive receptor TRPV1 is synthesized in the form of nanodiscs to maintain stability and reusability. The newly developed platform shows highly selective and sensitive performance toward each spiciness related vanilloid compound repeatably: 1 aM capsaicin, 10 aM dihydrocapsaicin, 1 fM piperine, 10 nM allicin, and 1 pM AITC. The binding mechanism is also examined by simulation. Furthermore, the elimination of the burning sensation on the tongue after eating spicy foods is not investigated. Based on the synthesis of micelles composed of casein protein (which is contained in skim milk) that remove pungent compounds bound to TRPV1 nanodisc, the deactivation of TRPV1 is investigated, and the electrode is reusable that mimics electronic tongue.
Water‐Resistant Conductive Gels toward Underwater Wearable Sensing
Authors: Wei Junjie , Xiao Peng , Chen Tao
Published: March 2023

Conductive gels are developing vigorously as superior wearable sensing materials due to their intrinsic conductivity, softness, stretchability, and biocompatibility, showing a great potential in many aspects of lives. However, compared to their wide application on land, it is significant yet rather challenging for traditional conductive gels to realize sensing application under water. The swelling of gels and the loss of conductive components in the aqueous environment, resulted from the diffusion across the interface, lead to structural instability and sensing performance decline. Fortunately, great efforts are devoted to improving the water resistance of conductive gels and employing them in the field of underwater wearable sensing in recent years, and some exciting achievements are obtained, which are of great significance for promoting the safety and efficiency of underwater activities. However, there is no review to thoroughly summarize the underwater sensing application of conductive gels. This review presents a brief overview of the representative design strategies for developing water‐resistant conductive gels and their diversified applications in the underwater sensing field as wearable sensors. Finally, the ongoing challenges for further developing water‐resistant conductive gels for underwater wearable sensing are also discussed along with recommendations for the future.
3D Printable Hydrogel with Tunable Degradability and Mechanical Properties as a Tissue Scaffold for Pelvic Organ Prolapse Treatment
Authors: Zhu Yuxiang , Kwok Tina , Haug Joel C. , Guo Shenghan , Chen Xiangfan , Xu Weiheng , Ravichandran Dharneedar , Tchoukalova Yourka D. , Cornella Jeffrey L. , Yi Johnny , Shefi Orit , Vernon Brent L. , Lott David G. , Lancaster Jessica N. , Song Kenan
Published: March 2023

Pelvic organ prolapse (POP) is a dysfunction that affects a large proportion of women. Current support scaffolds’ lack of biocompatibility, biodegradability, and mechanical compliance are associated with surgical complications including erosion and pain, indicating the urgent need for new tissue scaffolds with customizable functions. A new material that uses polyvinyl alcohol (PVA) as the main ingredient and is chemically tuned to possess suitable mechanical properties and degradation rates for the surgical treatment of POP is developed. Specifically, the thiol‐norbornene “click” chemistry enables the sol‐gel transition of the biomaterial under UV‐light without side‐products. Meanwhile, NaOH treatment further toughens the hydrogel with a higher crosslink density. The PVA‐based biocompatible ink can be printed with UV‐facilitated direct ink writing due to the rapidly UV‐initiated chemical crosslink; in situ image analysis and machine learning methods are applied during this procedure to quantify and improve the printing quality. The cell viability results demonstrate the biocompatibility of the POP scaffolds, suggesting the potential for future animal studies and the possibility of clinical research. This study bridges polymer chemistry and manufacturing engineering with a specific tissue engineering application to solve the common disorder of POP, shedding light on individualized medicine and intelligent systems for biomedical engineering.
Graphene‐on‐Silicon Hybrid Field‐Effect Transistors
Authors: Fomin Mykola , Pasadas Francisco. , Marin Enrique G. , Medina‐Rull Alberto , Ruiz Francisco. G. , Godoy Andrés. , Zadorozhnyi Ihor , Beltramo Guillermo , Brings Fabian , Vitusevich Svetlana , Offenhaeusser Andreas , Kireev Dmitry
Published: March 2023

The combination of graphene and silicon in hybrid electronic devices has attracted increasing attention over the last decade. Here, a unique technology of graphene‐on‐silicon heterostructures as solution‐gated transistors for bioelectronics applications is presented. The proposed graphene‐on‐silicon field‐effect transistors (GoSFETs) are fabricated by exploiting various conformations of channel doping and dimensions. The fabricated devices demonstrate hybrid behavior with features specific to both graphene and silicon, which are rationalized via a comprehensive physics‐based compact model which is purposely implemented and validated against measured data. The developed theory corroborates that the device hybrid behavior can be explained in terms of two independent silicon and graphene carrier transport channels, which are, however, strongly electrostatically coupled. Although GoSFET transconductance and carrier mobility are found to be lower than in conventional silicon or graphene field‐effect transistors, it is observed that the combination of both materials within the hybrid channel contributes uniquely to the electrical response. Specifically, it is found that the graphene sheet acts as a shield for the silicon channel, giving rise to a nonuniform potential distribution along it, which impacts the transport, especially at the subthreshold region, due to non‐negligible diffusion current.
An overview on AIEgen‐decorated porphyrins: Current status and applications
Authors: Bodedla Govardhana Babu , Zhu Xunjin , Wong Wai‐Yeung
Published: March 2023

One of the major obstacles of porphyrins is the aggregation‐caused quenching (ACQ) of photoluminescence due to the strong intermolecular π–π interaction of the planar porphyrin core in the solid state. However, ACQ leads to the nonradiative deactivation of the photoexcited states which results in short‐lived charge‐separated states and thus low photoluminescence and singlet quantum yields. This phenomenon would limit the utilization of porphyrins in near‐infrared fluorescent bioimaging, photodynamic therapy, photocatalytic hydrogen evolution, electrochemiluminescence, and chiroptical applications. Hence, to address the ACQ property of porphyrins and enhance the performance of the above applications, a limited number of AIEgen‐decorated porphyrins have been designed, synthesized, and tested for their applications. It has been found that the introduction of AIEgens, such as tetraphenylethylene, diphenylacrylonitrile, (3,6‐bis‐(1‐methyl‐4‐vinylpyridinium)‐carbazole diiodide, and iridium motif into the porphyrin core, transformed the porphyrins from ACQ to aggregation‐induced emission (AIE) in their solid state due to the reduced strong intermolecular π–π stacking of porphyrins. Consequently, such porphyrins containing AIE features are employed as potential candidates in the above‐mentioned applications. In this review, we summarize the AIEgen‐decorated porphyrins which have been published to date, and also discuss the benefits of converting porphyrins from ACQ to AIE for enhanced performance within each application. As far as we know, there is no review that summarizes the structures and applications of AIEgen‐decorated porphyrins to date. Therefore, we presume that this review would be helpful to design more efficient AIEgen‐decorated porphyrins for a wide range of applications in the future.
Evaluation of the clinical significance of global mRNA alternative splicing in patients with acute myeloid leukemia
Authors: Yang Yi‐Tsung , Yao Chi‐Yuan , Chiu Po‐Ju , Kao Chein‐Jun , Hou Hsin‐An , Lin Chien‐Chin , Chou Wen‐Chien , Tien Hwei‐Fang
Published: March 2023

Aberrant alternative splicing (AS) is involved in leukemogenesis. This study explored the clinical impact of alterations in global AS patterns in 341 patients with acute myeloid leukemia (AML) newly diagnosed at the National Taiwan University Hospital and validated it using The Cancer Genome Atlas (TCGA) cohort. While studying normal cord blood CD34+/CD38− cells, we found that AML cells exhibited significantly different global splicing patterns. AML with mutated TP53 had a particularly high degree of genome‐wide aberrations in the splicing patterns. Aberrance in the global splicing pattern was an independent unfavorable prognostic factor affecting the overall survival of patients with AML receiving standard intensive chemotherapy. The integration of global splicing patterns into the 2022 European LeukemiaNet risk classification could stratify AML patients into four groups with distinct prognoses in both our experimental and TCGA cohorts. We further identified four genes with AS alterations that harbored prognostic significance in both of these cohorts. Moreover, these survival‐associated AS events are involved in several important cellular processes that might be associated with poor response to intensive chemotherapy. In summary, our study demonstrated the clinical and biological implications of differential global splicing patterns in AML patients. Further studies with larger prospective cohorts are required to confirm these findings.
A review of economic issues for gene‐targeted therapies: Value, affordability, and access
Authors: Garrison Louis P. , Lo Andrew W. , Finkel Richard S. , Deverka Patricia A.
Published: March 2023

The National Center for Advancing Translational Sciences' virtual 2021 conference on gene‐targeted therapies (GTTs) encouraged multidisciplinary dialogue on a wide range of GTT topic areas. Each of three parallel working groups included social scientists and clinical scientists, and the three major sessions included a presentation on economic issues related to their focus area. These experts also coordinated their efforts across the three groups. The economics‐related presentations covered three areas with some overlap: (1) value assessment, uncertainty, and dynamic efficiency; (2) affordability, pricing, and financing; and (3) evidence generation, coverage, and access. This article provides a synopsis of three presentations, some of their key recommendations, and an update on related developments in the past year. The key high‐level findings are that GTTs present unique data and policy challenges, and that existing regulatory, health technology assessment, as well as payment and financing systems will need to adapt. But these adjustments can build on our existing foundation of regulatory and incentive systems for innovation, and much can be done to accelerate progress in GTTs. Given the substantial unmet medical need that exists for these oft‐neglected patients suffering from rare diseases, it would be a tragedy to not leverage these exciting scientific advances in GTTs.
The association of MIND diet with cognitive resilience to neuropathologies
Authors: Wagner Maude , Agarwal Puja , Leurgans Sue E. , Bennett David A. , Schneider Julie A. , Capuano Ana W. , Grodstein Francine
Published: March 2023

Introduction

Cognitive resilience (CR) can be defined as the continuum of better through worse than expected cognition, given the degree of neuropathology. The relation of healthy diet patterns to CR remains to be elucidated.

Methods

Using longitudinal cognitive data and post mortem neuropathology from 578 deceased older adults, we examined associations between the Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND) diet at baseline and two standardized CR measures reflecting higher cognitive levels over time (CR), and slower decline (CRSlope), than expected given neuropathology.

Results

Compared to individuals in the lowest tertile of MIND score, those in the top tertile had higher CR (mean difference [MD] = 0.34; 95% confidence interval [CI] = 0.14, 0.55) and CRSlope (MD = 0.27; 95% CI = 0.05, 0.48), after multivariable adjustment. Overall MIND score was more strongly related to CR than the individual food components.

Discussion

The MIND diet is associated with both higher cognition and slower rates of cognitive decline, after controlling for neuropathology, indicating the MIND diet may be important to cognitive resilience.
Haloboration of o‐Alkynyl Phenols Generates Halogenated Bicyclic‐Boronates**
Authors: Yuan Kang , Ingleson Michael J.
Published: March 2023

Benzoxaborinines are intermediates en‐route to bicyclic boronates that are important active pharmaceutical ingredients (APIs). Herein, the haloboration of o‐alkynyl‐phenols using BX3 (X=Cl or Br) is disclosed as a route to form C4‐X‐benzoxaborinines with good functional group tolerance. Computational studies indicated that there are two similar in barrier mechanisms: (i) double alkyne haloboration followed by retro‐haloboration; (ii) concerted trans‐haloboration involving an exogenous chloride source. The C4‐halide in these benzoxaborinines is useful, with a one‐pot haloboration‐Negishi cross coupling protocol effective to form benzoxaborinines with an alkyl or an aryl at C4. Therefore this method is a useful addition to the toolbox for synthesising bicyclic‐boronates that are attracting increasing attention as APIs.
N‐(Morpholine‐4‐dithio)phthalimide: A Shelf‐Stable, Bilateral Platform Molecule Enabling Access to Diverse Unsymmetrical Disulfides**
Authors: Asanuma Hayato , Kanemoto Kazuya , Watanabe Tokiharu , Fukuzawa Shin‐ichi
Published: March 2023

Synthetic methods for unsymmetrical disulfides are greatly needed owing to their applications in drug discovery, linker chemistry, and materials sciences. In this study, a new shelf‐stable and easy‐to‐prepare bilateral disulfurating platform molecule,N‐(morpholine‐4‐dithio)phthalimide, has been developed for the divergent synthesis of unsymmetrical disulfides. The amino and imide leaving groups of this reagent can be orthogonally transformed. Under acidic conditions, the amino moiety undergoes selective protonation and thus can be displaced by various carbon nucleophiles, such as allyl trimethylsilanes, alkynyl silanes, and electron‐rich arenes, leaving the phthalimide moiety untouched. Meanwhile, the phthalimide leaving group is amenable to substitution under basic or neutral conditions. The combination of these transformations provides rapid access to diverse unsymmetrical disulfides through two C−S bond‐forming reactions.
Pediatric pulmonary valve replacements: Clinical challenges and emerging technologies
Authors: Crago Matthew , Winlaw David S. , Farajikhah Syamak , Dehghani Fariba , Naficy Sina
Published: March 2023

Congenital heart diseases (CHDs) frequently impact the right ventricular outflow tract, resulting in a significant incidence of pulmonary valve replacement in the pediatric population. While contemporary pediatric pulmonary valve replacements (PPVRs) allow satisfactory patient survival, their biocompatibility and durability remain suboptimal and repeat operations are commonplace, especially for very young patients. This places enormous physical, financial, and psychological burdens on patients and their parents, highlighting an urgent clinical need for better PPVRs. An important reason for the clinical failure of PPVRs is biofouling, which instigates various adverse biological responses such as thrombosis and infection, promoting research into various antifouling chemistries that may find utility in PPVR materials. Another significant contributor is the inevitability of somatic growth in pediatric patients, causing structural discrepancies between the patient and PPVR, stimulating the development of various growth‐accommodating heart valve prototypes. This review offers an interdisciplinary perspective on these challenges by exploring clinical experiences, physiological understandings, and bioengineering technologies that may contribute to device development. It thus aims to provide an insight into the design requirements of next‐generation PPVRs to advance clinical outcomes and promote patient quality of life.
Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer
Authors: Liu Chaofan , Wang Xi , Qin Wan , Tu Jingyao , Li Chunya , Zhao Weiheng , Ma Li , Liu Bo , Qiu Hong , Yuan Xianglin
Published: March 2023

Background

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) have shown a moderate response in colorectal cancer (CRC) with deficient mismatch repair (dMMR) functions and poor response in patients with proficient MMR (pMMR). pMMR tumors are generally immunogenically “cold”, emphasizing combination strategies to turn the “cold” tumor “hot” to enhance the efficacy of ICIs. ATR inhibitors (ATRi) have been proven to cooperate with radiation to promote antitumor immunity, but it is unclear whether ATRi could facilitate the efficacy of IR and ICI combinations in CRCs. This study aimed to investigate the efficacy of combining ATRi, irradiation (IR), and anti‐PD‐L1 antibodies in CRC mouse models with different microsatellite statuses.

Methods

The efficacy of combining ATRi, IR, and anti‐PD‐L1 antibodies was evaluated in CRC tumors. The tumor microenvironment and transcriptome signatures were investigated under different treatment regimens. The mechanisms were explored via cell viability assay, flow cytometry, immunofluorescence, immunoblotting, co‐immunoprecipitation, and real‐time quantitative PCR in multiple murine and human CRC cell lines.

Results

Combining ATRi berzosertib and IR enhanced CD8+T cell infiltration and enhanced the efficacy of anti‐PD‐L1 therapy in mouse CRC models with different microsatellite statuses. The mechanistic study demonstrated that IR + ATRi could activate both the canonical cGAS‐STING‐pTBK1/pIRF3 axis by increasing cytosolic double‐stranded DNA levels and the non‐canonical STING signaling by attenuating SHP1‐mediated inhibition of the TRAF6‐STING‐p65 axis, via promoting SUMOylation of SHP1 at lysine 127. By boosting the STING signaling, IR + ATRi induced type I interferon‐related gene expression and strong innate immune activation and reinvigorated the cold tumor microenvironment, thus facilitating immunotherapy.

Conclusions

The combination of ATRi and IR could facilitate anti‐PD‐L1 therapy by promoting STING signaling in CRC models with different microsatellite statuses. The new combination strategy raised by our study is worth investigating in the management of CRC.
Cell division cycle‐associated 8 is a prognostic biomarker related to immune invasion in hepatocellular carcinoma
Authors: Wu Haomin , Liu Shiqi , Wu Di , Zhou Haonan , Sui Guoxin , Wu Gang
Published: March 2023

Background

Cell division cycle‐associated 8 (CDCA8) is involved in numerous signaling networks, and it serves a crucial modulatory function in multiple malignant tumors. However, its significance in prognosis and immune infiltration in hepatocellular carcinoma (HCC) remains unclear.

Materials and methods

Herein, we examined the CDCA8 levels in tumor tissues, as well as its associated signaling pathways and correlation with immune infiltration. Additionally, we further clarified the prognostic significance of CDCA8 among HCC patients. HCC patient information was recruited from The Cancer Genome Atlas (TCGA). Using bioinformatics, the following parameters were analyzed among HCC patients: CDCA8 expression, enrichment analysis, immune infiltration, and prognosis analysis. Moreover, we employed in vitro investigations, such as, qRT‐PCR, immunohistochemistry (IHC), and cell functional experiments to validate our results.

Results

Elevated CDCA8 expression in HCC patients was markedly associated with T stage, pathological status (PS), tumor status (TS), histologic grade (HG), and AFP. Elevated CDCA8 expression HCC patients exhibited reduced overall survival (OS) (p < 0.001), disease‐specific survival (DSS) (p < 0.001), and progress free interval (PFI) H(p < 0.001). According to the ROC analysis, the area under the curve (AUC) was 0.997. Multivariate analysis revealed that CDCA8 was a stand‐alone prognostic indicator of patient OS (p = 0.009) and DSS (p = 0.006). A nomogram was then generated based on the multivariate analysis, and the C‐indexes and calibration chart revealed excellent predictive performance in determining HCC patient outcome. Based on the GSEA analysis, CDCA8 modulated the P53, Notch, PPAR, E2F networks. We observed a direct link between CDCA8 levels and Th2 and T helper cells, and a negative link between CDCA8 levels and dendritic cells (DC), neutrophils, cytotoxic cells, and CD8 T cells. Furthermore, CDCA8 deficiency inhibited liver cancer cell proliferation and invasion.

Conclusion

In conclusion, these findings indicate that CDCA8 is a new molecular bioindicator of HCC patient prognosis, and it is an excellent candidate for therapeutic target against HCC.
Network Pharmacology‐Based Approach for Investigating the Role of Xanthii Fructus in Treatment of Allergic Rhinitis
Authors: Liu Xinyue , Yang Yujuan , Li Yumei , Zhang Qiang , Wang Jianwei , Guo Jing , Song Zheying , Liu Zhen , Zhang Yu , Song Xicheng
Published: March 2023

Xanthii Fructus (XF) has been used for treatment of allergic rhinitis (AR), but its pharmacological mechanism of action remains unclear. We aimed to explore the potential mechanism of XF in treatment of AR by using a network pharmacology approach combined with in vivo verification experiments in this study. We identified 945 AR‐related pathogenic genes, 11 active components in XF and 178 targets of those active components by corresponding databases. Finally, 54 targets of active components from XF in treatment of AR were identified by the Protein‐protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, among which Tumor Necrosis Factor (TNF), Mitogen‐activated Protein Kinase 3 (MAPK3), Prostaglandin G/H Synthase 2 (PTGS2), Epidermal Growth Factor Receptor (EGFR) showed strongest interactions. The molecular docking analysis showed that moupinamide could bind to EGFR at LEU704 and LEU703, and PTGS2 at TRP387; 24‐Ethylcholest‐4‐en‐3‐one was identified to bind to MAPK3 at THR347. The validation of quantitative real‐time reverse transcription PCR (RT‐PCR) showed that XF decreased the levels of MAPK3, PTGS2, and EGFR expression in the nasal mucosa from AR mice gavaged with an XF water decoction. Meanwhile, the levels of interleukin (IL)‐4, IL‐5 and IL‐13were also decreased after the treatment of XF by Enzyme‐linked immunosorbent assay (ELISA). Our results provide the pharmacological mechanism and possible intervention targets of XF in treatment of AR.
Nano‐Biotechnology and Challenges of Drug Delivery System in Cancer Treatment Pathway: Review Article
Authors: Asadipour Erfan , Asgari Mahtab , Mousavi Parastoo , Piri‐Gharaghie Tohid , Ghajari Ghazal , Mirzaie Amir
Published: March 2023

In this review, we discuss Nanotechnology models, which have been developed recently in cancer treatment. Nanotechnology manipulates matter at the atomic and molecular scale to create materials with new and advanced properties. Nano‐biotechnology consists of the branches of nanotechnology that have been applied in biology (molecular and cellular genetics) and biotechnology. Nano‐biotechnology allows us to put components and compounds into cells and build new materials using new methods like assembly. Cancer is a disease caused by an uncontrolled division of abnormal cells in a part of the body. Its therapeutic methods include chemotherapy, radiation, or surgery, but the effects of these techniques are not only on tumor tissue and may affect healthy tissues. Nano‐Biotech applications regarding cancer include drug delivery, treatment, and foresight therapy. This review article aims to obtain a proper mentality of the current technologies of Nano‐biotechnology for cancer treatment.
Type II Polyketide Synthases: A Bioinformatics‐Driven Approach
Authors: Xie Shengling , Zhang Lihan
Published: March 2023

Bioinformatics has become an indispensable tool for natural products research in the genomic era. One of the key challenges is to accurately convert sequence data of a biosynthetic gene cluster into chemical information such as the enzymatic function or the biosynthetic product structure. Type II polyketide synthase is the most bioinformatically well‐studied class of non‐modular biosynthetic machinery and represents a model system to showcase bioinformatic applications in natural products research. This review takes a bioinformatics‐centered perspective and summarizes the past advances and future opportunities of bioinformatics‐guided research on type II polyketide synthases. How bioinformatics has contributed to deepen the chemical understanding of type II PKSs will be discussed with the focus on enzymology, evolution, structural prediction of the biosynthetic products, genome mining, and the global analyses of their polyketide products.
Popularity bias in personality perspective: An analysis of how personality traits expose individuals to the unfair recommendation
Authors: Yalcin Emre , Bilge Alper
Published: March 2023

Recommender systems are subject to well‐known popularity bias issues, that is, they expose frequently rated items more in recommendation lists than less‐rated ones. Such a problem could also have varying effects on users with different gender, age, or rating behavior, which significantly diminishes the users' overall satisfaction with recommendations. In this paper, we approach the problem from the view of user personalities for the first time and discover how users are inclined toward popular items based on their personality traits. More importantly, we analyze the potential unfairness concerns for users with different personalities, which the popularity bias of the recommenders might cause. To this end, we split users into groups of high, moderate, and low clusters in terms of each personality trait in the big‐five factor model and investigate how the popularity bias impacts such groups differently by considering several criteria. The experiments conducted with 10 well‐known algorithms of different kinds have concluded that less‐extroverted people and users avoiding new experiences are exposed to more unfair recommendations regarding popularity, despite being the most significant contributors to the system. However, discrepancies in other qualities of the recommendations for these user characteristics, such as accuracy, diversity, and novelty, vary depending on the utilized algorithm.
Symmetric searchable encryption with supporting search pattern and access pattern protection in multi‐cloud
Authors: Xu Wanshan , Zhang Jianbiao , Yuan Yilin , Wang Xiao
Published: March 2023

Symmetric searchable encryption (SSE) enables users to search the ciphertext stored on the untrusted cloud without revealing the search keywords, effectively protecting users' privacy. However, most of the existing SSE schemes reveal the search or access pattern during the keyword query, which can be used by the adversary to infer the sensitive information in ciphertext, thus posing a great threat to users' privacy. To address this, we propose an SSE scheme supporting search pattern and access pattern protection in multi‐cloud, called SAPM‐SSE. In our scheme, an index shuffle protocol is proposed to change the content and location of the index after each query, which helps to achieve the protection of search and access pattern. Furthermore, with the purpose of improving the efficiency of shuffling, we construct a shuffling algorithm based on index cache, the number of index entries for shuffling reduced from γ to γ/n (n≥1). Besides, our scheme supports the dynamic update of documents and achieves the forward security in update. Finally, security analysis and experimental results show that our scheme can achieve the protection of search pattern and access pattern with high efficiency.
SCF‐FBXL8 contributes to liver metastasis and stem‐cell‐like features in colorectal cancer cells by mediating ubiquitination and degradation of TP53
Authors: Yao Jing , Wang Xin‐Ping , Yang Jun , Yang Zhe , Zhang Zheng‐Yun
Published: March 2023

Background

FBXL8 is a conserved F‐box protein, belonging to the ubiquitin ligase complex, which promotes the development and progression of tumours. However, the regulation function and mechanism of FBXL8's involvement in colorectal cancer (CRC) remain unclear.

Methods

RT–PCR is used to detect gene expression levels. Protein levels were determined by western blotting and flow cytometry. The bindings of FBXL8 and p53 and ubiquitination levels were detected by cell transfection and immunoprecipitation. The transwell assay was used to measure the ability of cells to migrate and invade. Animal studies were used to verify the function of FBXL8 in vivo.

Results

The expression of FBXL8 was up‐regulated in CRC tissues, and its overexpression was associated with poor prognosis in CRC patients. The up‐regulation of FBXL8 promoted the proliferation, invasion and migration of CRC tumour cells and maintained the stem‐cell characteristics of colorectal tumour cells. Further analysis demonstrated that FBXL8 targeted p53 and reduced its stability through ubiquitination. Knockout of FBXL8 down‐regulated the proliferation, migration and stem‐like properties of tumour cells. CRC mouse xenograft tumour model confirmed that FBXL8 gene knockout inhibited tumour formation and liver metastasis.

Conclusion

FBXL8 was highly expressed in CRC. Mechanism studies have shown that FBXL8 degraded tumour suppressor gene p53 by ubiquitination. FBXL8 knockout inhibited the proliferation and stem characteristics of CRC cells, so SCF‐FBXL8‐TP53 has potential to be used as a therapeutic target for CRC in subsequent studies.
Effectiveness of lenvatinib plus immune checkpoint inhibitors in primary advanced hepatocellular carcinoma beyond oligometastasis
Authors: Wang Xiao‐Hui , Liu Chang‐Jun , Wen Hao‐Quan , Duan Xiao‐Hui , Jiao Yu‐Qing , Liu Yu‐Jiang , Chen Min‐Shan , Zhu Kang‐Shun , Mao Xian‐Hai , Zhou Qun‐Fang
Published: March 2023

Background

Targeted therapy combined with immune checkpoint inhibitors is considered a promising treatment for primary advanced hepatocellular carcinoma (HCC). Nevertheless, the difference between synchronous and asynchronous treatment of lenvatinib with programmed death receptor‐1 (PD‐1) inhibitor in advanced HCC is still unclear. The aim of this investigation is to evaluate the effectiveness of synchronous and asynchronous of lenvatinib and PD‐1 inhibitor on the advanced HCC beyond oligometastasis.

Methods

In this study, 213 patients from four institutions in China were involved. Patients were split into two collections: (1) lenvatinib plus PD‐1 inhibitor were used synchronously (synchronous treatment group); (2) patients in asynchronous treatment group received PD‐1 inhibitor after 3 months of lenvatinib treatment prior to tumour progression. To analyse progression‐free survival (PFS), overall survival (OS), efficacy and safety of patients in both groups, we employed propensity score matching (PSM).

Results

The 6‐, 12‐ and 24‐month OS rates were 100%, 93.4% and 58.1% in the synchronous treatment group and 100%, 71.5% and 25.3% in the asynchronous treatment group, respectively. In contrast to the asynchronous treatment group, the group treated synchronously exhibited a substantially enhanced OS (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.30–0.66; p < .001). The 6‐, 12‐ and 18‐month PFS rates were 82.6%, 42.6% and 10.8% in the synchronous treatment group and 63.3%, 14.2% and 0% in the asynchronous treatment group, respectively. A significant difference was observed in the PFS rate (HR, 0.46; 95% CI, 0.33–0.63; p < .001) between the two collections.

Conclusions

Patients with advanced HCC beyond oligometastasis, simultaneous administration of lenvatinib and PD‐1 inhibitor led to significant improvements in survival.
Difficulties with positive emotion regulation in anorexia nervosa
Authors: Santos Bolade M. , Haynos Ann F.
Published: March 2023

Individuals with anorexia nervosa (AN) have well‐documented difficulties regulating negative emotions, but less is known about positive emotion regulation in this population. To address this gap, we compared responses on the Difficulties in Emotion Regulation Scale‐Positive questionnaire and the traditional DERS questionnaire (measuring negative affect dysregulation) between females with AN (n = 30) and demographically‐matched controls without an eating disorder history (NC; n = 30) and examined relations between positive emotion regulation and clinical symptoms. Results indicated that individuals with AN demonstrated greater difficulty regulating negative (p < 0.001, d = 2.75) and positive (p < 0.001, d = 1.08) emotions compared to NC participants. Specifically, the AN group reported heightened positive emotion nonacceptance (p = 0.004, d = 0.78) and impulsivity (p = 0.003, d = 0.81). Greater positive emotion nonacceptance was associated with higher anxiety (p = 0.015) and depression (p = 0.022) among individuals with AN. Unexpectedly, more positive emotion impulsivity was associated with less restrictive eating in AN (p < 0.001). Findings were largely maintained even after controlling for negative emotion dysregulation and psychotropic medication use. The results suggest that reducing shame related to positive emotions could improve mood in AN; alternatively, relinquishing control when experiencing positive emotion could reduce restriction. More research is warranted on positive emotion regulation as a treatment target for AN.
A flexible copula regression model with Bernoulli and Tweedie margins for estimating the effect of spending on mental health
Authors: Marra Giampiero , Fasiolo Matteo , Radice Rosalba , Winkelmann Rainer
Published: March 2023

We develop a flexible two‐equation copula model to address endogeneity of medical expenditures in a distribution regression for health. The expenditure margin uses the compound gamma distribution, a special case of the Tweedie family of distributions, to account for a spike at zero and a highly skewed continuous part. An efficient estimation algorithm offers flexible choices of copulae and link functions, including logit, probit and cloglog for the health margin. Our empirical application revisits data from the Rand Health Insurance Experiment. In the joint model, using random insurance plan assignment as instrument for spending, a $1000 increase is estimated to reduce the probability of a low post‐program mental health index by 1.9 percentage points. The effect is not statistically significant. Ignoring endogeneity leads to a spurious positive effect estimate.
Introduction to the Special Series “Environmental Monitoring on Global and Local Scales”
Authors: Zotina Tatiana A. , Kudryasheva Nadezhda S. , Soukhovolsky Vladislav G.
Published: March 2023

The ecosystems of Siberia provide valuable services to the human population and afford important climate feedback. However, they are subject to anthropogenic pressures leading to the transformation of ecosystem structure and functions such as deforestation; extraction and transportation of fossil hydrocarbons; mining, refining, and smelting industrial activities; damming of rivers by high-pressure hydroelectric plants, and other activities. The articles in this special series deal with the monitoring of natural ecosystems of Siberia that are located on vast areas of Eurasia, many of which are hard to reach and sparsely populated. The results and approaches of environmental monitoring presented in this special series offer new opportunities for developing the strategy of intelligent management and conservation of vulnerable Siberian ecosystems to meet the challenges of global climate change and unsustainable use of natural resources. Integr Environ Assess Manag 2023;19:970–971. © 2023 SETAC
Trends in best‐case, typical and worst‐case survival scenarios of patients with non‐metastatic esophagogastric cancer between 2006 and 2020: A population‐based study
Authors: Kuijper Steven C. , Pape Marieke , Vissers Pauline A. J. , Jeene Paul M. , Kouwenhoven Ewout A. , Haj Mohammad Nadia , Ruurda Jelle P. , Sosef Meindert N. , Verhoeven Rob H. A. , van Laarhoven Hanneke W. M.
Published: March 2023

New treatment options and centralization of surgery have improved survival for patients with non‐metastatic esophageal or gastric cancer. It is unknown, however, which patients benefitted the most from treatment advances. The aim of this study was to identify best‐case, typical and worst‐case scenarios in terms of survival time, and to assess if survival associated with these scenarios changed over time. Patients with non‐metastatic potentially resectable esophageal or gastric cancer diagnosed between 2006 and 2020 were selected from the Netherlands Cancer Registry. Best‐case (20th percentile), upper‐typical (40th percentile), typical (median), lower‐typical (60th percentile) and worst‐case (80th percentile) survival scenarios were defined, and regression analysis was used to investigate the change in survival time for each scenario across years. For patients with esophageal cancer (N = 24 352) survival time improved on average 12.0 (until 2011), 1.5 (until 2018), 0.7, 0.4 and 0.2 months per year for the best‐case, upper‐typical, median, lower‐typical and worst‐case scenario, respectively. For patients with gastric cancer (N = 9993) survival time of the best‐case scenario remained constant, whereas the upper‐typical, median, lower‐typical and worst‐case scenario improved on average with 1.0 (until 2018), 0.5, 0.2 and 0.2 months per year, respectively. Subgroup analyses showed that, survival scenarios improved for nearly all patients across treatment groups and for patients with squamous cell carcinomas or adenocarcinomas. Survival improved for almost all patients suggesting that in clinical practice the vast majority of patients benefitted from treatment advances. The clinically most meaningful survival advantage was observed for the best‐case scenario of esophageal cancer.
Edmond Fischer's kinase legacy: History of the protein kinase inhibitor and protein kinase A
Authors: Taylor Susan S. , Herberg Friedrich W , Veglia Gianluigi , Wu Jian
Published: March 2023

Although Fischer's extraordinary career came to focus mostly on the protein phosphatases, after his co‐discovery of Phosphorylase Kinase with Ed Krebs he was clearly intrigued not only by cAMP‐dependent protein kinase (PKA), but also by the heat‐stable, high‐affinity protein kinase inhibitor (PKI). PKI is an intrinsically disordered protein that contains at its N‐terminus a pseudo‐substrate motif that binds synergistically and with high‐affinity to the PKA catalytic (C) subunit. The sequencing and characterization of this inhibitor peptide (IP20) were validated by the structure of the PKA C‐subunit solved first as a binary complex with IP20 and then as a ternary complex with ATP and two magnesium ions. A second motif, nuclear export signal (NES), was later discovered in PKI. Both motifs correspond to amphipathic helices that convey high‐affinity binding. The dynamic features of full‐length PKI, recently captured by NMR, confirmed that the IP20 motif becomes dynamically and sequentially ordered only in the presence of the C‐subunit. The type I PKA regulatory (R) subunits also contain a pseudo‐substrate ATPMg2‐dependent high‐affinity inhibitor sequence. PKI and PKA, especially the Cβ subunit, are highly expressed in the brain, and PKI expression is also cell cycle‐dependent. In addition, PKI is now linked to several cancers. The full biological importance of PKI and PKA signaling in the brain, and their importance in cancer thus remains to be elucidated.
Elabela‐apelin‐12, 17, 36/APJ system promotes platelet aggregation and thrombosis via activating the PANX1‐P2X7 signaling pathway
Authors: Chen Zhe , Luo Xuling , Liu Meiqing , Jiang Jinyong , Li Yao , Huang Zhen , Wang Lingzhi , Cao Jiangang , He Lu , Huang Shifang , Hu Haoliang , Li Lanfang , Chen Linxi
Published: March 2023

The elabela‐apelin/angiotensin domain type 1 receptor‐associated protein (APJ) system is an important regulator in certain thrombosis‐related diseases such as atherosclerosis, myocardial infarction, and cerebral infarction. Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela‐apelin/APJ system and platelet aggregation and atherothrombosis is unclear. The results of the present study demonstrate that elabela and other endogenous ligands such as apelin‐12, ‐17, and ‐36 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)‐P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela‐ and apelin isoforms‐induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti‐HIV ancillary drug cobicistat and the traditional Chinese medicine monomer Schisandrin A. Both cobicistat and Schisandrin A abolished the effects of elabela and apelin isoforms on platelet aggregation, thrombosis, and cerebral infarction. In addition, cobicistat significantly attenuated thrombosis in a ponatinib‐induced zebrafish trunk model. Overall, the elabela–apelin/APJ axis mediated platelet aggregation and thrombosis via the PANX1‐P2X7 signaling pathway in vitro and in vivo. Blocking the APJ receptor with cobicistat/Schisandrin A or inhibiting PANX1 with spironolactone may provide novel therapeutic strategies against thrombosis.
EPISOL: A software package with expanded functions to perform 3D‐RISM calculations for the solvation of chemical and biological molecules
Authors: Cao Siqin , Kalin Michael L. , Huang Xuhui
Published: March 2023

Integral equation theory (IET) provides an effective solvation model for chemical and biological systems that balances computational efficiency and accuracy. We present a new software package, the expanded package for IET‐based solvation (EPISOL), that performs 3D‐reference interaction site model (3D‐RISM) calculations to obtain the solvation structure and free energies of solute molecules in different solvents. In EPISOL, we have implemented 22 different closures, multiple free energy functionals, and new variations of 3D‐RISM theory, including the recent hydrophobicity‐induced density inhomogeneity (HI) theory for hydrophobic solutes and ion‐dipole correction (IDC) theory for negatively charged solutes. To speed up the convergence and enhance the stability of the self‐consistent iterations, we have introduced several numerical schemes in EPISOL, including a newly developed dynamic mixing approach. We show that these schemes have significantly reduced the failure rate of 3D‐RISM calculations compared to AMBER‐RISM software. EPISOL consists of both a user‐friendly graphic interface and a kernel library that allows users to call its routines and adapt them to other programs. EPISOL is compatible with the force‐field and coordinate files from both AMBER and GROMACS simulation packages. Moreover, EPISOL is equipped with an internal memory control to efficiently manage the use of physical memory, making it suitable for performing calculations on large biomolecules. We demonstrate that EPISOL can efficiently and accurately calculate solvation density distributions around various solute molecules (including a protein chaperone consisting of 120,715 atoms) and obtain solvent free energy for a wide range of organic compounds. We expect that EPISOL can be widely applied as a solvation model for chemical and biological systems. EPISOL is available at https://github.com/EPISOLrelease/EPISOL.
Characterization of eyes, photoreceptors, and opsins in developmental stages of the arrow wormSpadella cephaloptera(Chaetognatha)
Authors: Wollesen Tim , Rodriguez Monje Sonia V. , Oel Adam P. , Arendt Detlev
Published: March 2023

The phylogenetic position of chaetognaths, or arrow worms, has been debated for decades, however recently they have been grouped into the Gnathifera, a sister clade to all other Spiralia. Chaetognath photoreceptor cells are anatomically unique by exhibiting a highly modified cilium and are arranged differently in the eyes of the various species. Studies investigating eye development and underlying gene regulatory networks are so far missing. To gain insights into the development and the molecular toolkit of chaetognath photoreceptors and eyes a new transcriptome of the epibenthic speciesSpadella cephalopterawas searched for opsins. Our screen revealed two copies ofxenopsinand a single copy ofperopsin. Gene expression analyses demonstrated that onlyxenopsin1is expressed in photoreceptor cells of the developing lateral eyes. Adults likewise exhibit twoxenopsin1 + photoreceptor cells in each of their lateral eyes. Beyond that, a singlecryptochromegene was uncovered and found to be expressed in photoreceptor cells of the lateral developing eye. In addition,cryptochromeis also expressed in the cerebral ganglia in a region in which alsoperopsinexpression was observed. This condition is reminiscent of a nonvisual photoreceptive zone in the apical nervous system of the annelidPlatynereis dumeriliithat performs circadian entrainment and melatonin release.Cryptochromeis also expressed in cells of the corona ciliata, an organ in the posterior dorsal head region, indicating a role in circadian entrainment. Our study highlights the importance of the Gnathifera for unraveling the evolution of photoreceptors and eyes in Spiralia and Bilateria.
Automatic design of microwave filters by using relational induction neural networks
Authors: Dai Xi Wang , Hu Wen Hao , Fu Yang Hui , Liu Jie , Chen Zhi Xi
Published: March 2023

Automatic design of microwave filter based on artificial intelligence is recognized as an alternative to conventional approach, due to the complexity of the structure parameters and the need of enormous solution space. In this paper, an unsupervised, end‐to‐end training framework, which is named Relational Induction Neural Network (RINN) is proposed. RINN discretizes the model, and makes cluster analysis on each action of geometrical parameters. Deep reinforcement learning (DRL) neural network is applied to design the filter according to reward function. Several second‐order filters with different performance and one sixth‐order filter are designed with RINN. The results show that RINN can automatically induce the relationship between microwave device structures without any prior knowledge through training or learning. This research crosses the gap between DRL and microwave filter, and can also be extended to other microwave device, antenna and other related fields.