bluuebunny/crossref_metadata_2025 huggingface dataset:
Soluble CD80 oral delivery by recombinant Lactococcus suppresses tumor growth by enhancing antitumor immunity
Authors: Lin Ziqing , Tang Yanqing , Chen Zerong , Li Simin , Xu Xueyan , Hou Xufeng , Chen Zhenhui , Wen Junjie , Zeng Weisen , Meng Xiaojing , Fan Hongying
Published: May 2023

CD80 is an important co‐stimulatory molecule that participates in the immune response. Soluble CD80 can induce T cell activation and overcome PDL1‐mediated immune suppression. In this study, we aimed to construct recombinant Lactococcus lactis for oral delivery of the soluble CD80 (hsCD80) protein or the fusion protein containing the cholera toxin B subunit (CTB) and hsCD80 (CTB‐hsCD80) under the control of the nisin‐inducible expression system. The recombinant L. lactis expressed and secreted hsCD80 or CTB‐hsCD80 fusion proteins after induction by nisin in vitro and in the enteric cavity. Additionally, the CTB‐hsCD80 fusion protein showed uptake by intestinal epithelial cells, was cleaved by the furin protease, and was released as free hsCD80 protein into the blood circulation. Orally administered hsCD80 and CTB‐hsCD80 containing L. lactis increased the proportion of activated T cells in the spleen and intestinal epithelium, inhibited tumor growth, and prolonged the survival of tumor‐bearing mice. The hsCD80‐containing L. lactis showed greater therapeutic effects on primary colonic adenoma in APCmin/− mice and completely suppressed tumor growth. Further, recombinant CTB‐hsCD80 in L. lactis was more efficient than hsCD80‐containing bacteria in inhibiting the growth of xenografted colon cancer and melanoma cells. hsCD80 engineered probiotics may serve as a promising new approach for antitumor immunotherapy, especially for colorectal cancer.
Biomimetic in situ tracheal microvascularization for segmental tracheal reconstruction in one‐step
Authors: Sun Fei , Shen Zhiming , Zhang Boyou , Lu Yi , Shan Yibo , Wu Qiang , Yuan Lei , Zhu Jianwei , Pan Shu , Wang Zhihao , Wu Cong , Zhang Guozhong , Yang Wenlong , Xu Xiangyu , Shi Hongcan
Published: May 2023

Formation of functional and perfusable vascular network is critical to ensure the long‐term survival and functionality of the engineered tissue tracheae after transplantation. However, the greatest challenge in tracheal‐replacement therapy is the promotion of tissue regeneration by rapid graft vascularization. Traditional prevascularization methods for tracheal grafts typically utilize omentum or muscle flap wrapping, which requires a second operation; vascularized segment tracheal orthotopic transplantation in one step remains difficult. This study proposes a method to construct a tissue‐engineered tracheal graft, which directly forms the microvascular network after orthotopic transplantation in vivo. The focus of this study was the preparation of a hybrid tracheal graft that is non‐immunogenic, has good biomechanical properties, supports cell proliferation, and quickly vascularizes. The results showed that vacuum‐assisted decellularized trachea‐polycaprolactone hybrid scaffold could match most of the above requirements as closely as possible. Furthermore, endothelial progenitor cells (EPCs) were extracted and used as vascularized seed cells and seeded on the surfaces of hybrid grafts before and during the tracheal orthotopic transplantation. The results showed that the microvascularized tracheal grafts formed maintained the survival of the recipient, showing a satisfactory therapeutic outcome. This is the first study to utilize EPCs for microvascular construction of long‐segment trachea in one‐step; the approach represents a promising method for microvascular tracheal reconstruction.
Digital therapeutics in the clinic
Authors: Phan Philana , Mitragotri Samir , Zhao Zongmin
Published: May 2023

Digital therapeutics are emerging as a new form of therapeutic interventions. Unlike conventional therapeutics, digital therapeutics deliver interventions directly to patients using an evidence‐based, clinically evaluated software to treat, manage, or prevent diseases. Digital therapeutics manifest in diverse forms such as web‐based applications, mobile applications on smart devices, virtual reality, and video games. As its own product category for FDA approval, digital therapeutics can function as stand‐alone treatments or in combination with conventional therapeutics to improve adherence and/or efficacy. Here, we review the clinical landscape of digital therapeutics. We summarize FDA‐approved products and their clinical use, overview >300 ongoing clinical trials, and discuss challenges for their clinical translation and strategies to overcome the same.
Correlation between KRAS mutation subtypes and prognosis in Chinese advanced non‐squamous non‐small cell lung cancer patients
Authors: Liu Feiwen , Wang Fang , He Jianbo , Zhou Shaozhang , Luo Min
Published: May 2023

Purpose

The relationship between mutant KRAS and the risk of disease progression and death in advanced non‐squamous non‐small cell lung cancer (NSCLC) is still controversial among current studies, and the effects of distinct KRAS mutations on prognosis may be different. This study aimed to further investigate the association between them.

Patients and Methods

Of the 184 patients eventually included in the study, 108 had KRAS wild type (WT) and 76 had KRAS mutant type (MT). Kaplan–Meier curves were plotted to describe the survival for patients among groups, while log‐rank tests were conducted to evaluate the survival differences. The univariate and multivariate Cox regression were performed to identify predictors, and subgroup analysis was used to verify the interaction effect.

Results

Similar efficacy of first‐line therapy was observed for KRAS MT and WT patients (p = 0.830). The association between KRAS mutation and progression‐free survival (PFS) was not significant in univariate analysis (hazard ratio [HR] = 0.94; 95% CI, 0.66–1.35), and no KRAS mutation subtype significantly affected PFS. However, KRAS mutation and KRAS non‐G12C were associated with increased risk of death compared to KRAS WT in univariate and multivariate analysis. Univariate and multivariate analysis also confirmed that chemotherapy combined with antiangiogenesis or immunotherapy in the KRAS mutation group was associated with decreased risk of disease progression. However, the overall survival (OS) among KRAS mutant patients received different first‐line treatments did not significantly differ.

Conclusion

KRAS mutations and their subtypes are not independent negative predictors of PFS, while KRAS mutation and KRAS non‐G12C were independent prognostic factors for OS. Chemotherapy combined with antiangiogenesis or immunotherapy conferred decreased risk of disease progression to KRAS mutation patients compared to single chemotherapy.
A case series and literature review on 98 pediatric patients of germ cell tumor developing growing teratoma syndrome
Authors: Hsieh Ming‐Yun , Chen Hsin‐Hung , Lee Chih‐Ying , Hung Giun‐Yi , Chang Tsung‐Yen , Chen Shih‐Hsiang , Lai Jin‐Yao , Jaing Tang‐Her , Cheng Chao‐Neng , Chen Jiann‐Shiuh , Tsai Hsin‐Lin , Yu Ting‐Yen , Hou Ming‐Hsin , Ho Cheng‐Yin , Yen Hsiu‐Ju
Published: May 2023

Introduction

Malignant germ cell tumors (MGCTs) can develop either extracranially or intracranially. Growing teratoma syndrome (GTS) may develop in these patients following chemotherapy. Reports on the clinical characteristics and outcomes of GTS in children with MGCTs are limited.

Methods

We retrospectively collected the data, including the clinical characteristics and outcomes of five patients in our series and 93 pediatric patients selected through a literature review of MGCTs. This study aimed to analyze survival outcomes and risk factors for subsequent events in pediatric patients with MGCTs developing GTS.

Results

The sex ratio was 1.09 (male/female). In total, 52 patients (53.1%) had intracranial MGCTs. Compared with patients with extracranial GCTs, those with intracranial GCTs were younger, predominantly boys, had shorter intervals between MGCT and GTS, and had GTS mostly occurring over the initial site (all p < 0.001). Ninety‐five patients (96.9%) were alive. However, GTS recurrence (n = 14), GTS progression (n = 9), and MGCT recurrence (n = 19) caused a substantial decrease in event‐free survival (EFS). Multivariate analyses showed that the only significant risk factors for these events were incomplete GTS resection and different locations of GCT and GTS. Patients without any risk had a 5‐year EFS of 78.8% ± 7.8%, whereas those with either risk had 41.7% ± 10.2% (p < 0.001).

Conclusion

For patients with high‐risk features, every effort should be made to closely monitor, completely remove, and pathologically prove any newly developed mass to guide relevant treatment. Further studies incorporating the risk factors into treatment strategies may be required to optimize adjuvant therapy.
Antiproliferative and Apoptotic Effects of pH‐Responsive Veratric Acid‐Loaded Polydopamine Nanoparticles in Human Triple Negative Breast Cancer Cells
Authors: Harini Ganesh , Shree Ganesh S. , Anushikaa Ramprasad , Bharathi Ramanathan , Aravind Sankaranarayanan , Vatsala Kumari , Shanmugavadivu Abinaya , Selvamurugan Nagarajan
Published: May 2023

Veratric acid (VA) is plant‐derived phenolic acid known for its therapeutic potential, but its anticancer effect on highly invasive triple‐negative breast cancer (TNBC) is yet to be evaluated. Polydopamine nanoparticles (nPDAs) were chosen as the drug carrier to overcome VA's hydrophobic nature and ensure a sustained release of VA. We prepared pH‐sensitive nano‐formulations of VA‐loaded nPDAs and subjected them to physicochemical characterization and in vitro drug release studies, followed by cell viability and apoptotic assays on TNBC cells (MDA‐MB‐231 cells). The SEM and zeta analysis revealed spherical nPDAs were uniform size distribution and good colloidal stability. In vitro drug release from VA‐nPDAs was sustained, prolonged and pH‐sensitive, which could benefit tumor cell targeting. MTT and cell viability assays showed that VA‐nPDAs (IC50=17.6 μM) are more antiproliferative towards MDA‐MB‐231 cells than free VA (IC50=437.89 μM). The induction of early and late apoptosis by VA‐nPDAs in the cancer cells was identified using annexin V and dead cell assay. Thus, the pH response and sustained release of VA from nPDAs showed the potential to enter the cell, inhibit cell proliferation, and induce apoptosis in human breast cancer cells, indicating the anticancer potential of VA.
Unimolecular Reactivity of [Cu(R)(CF3)3]−Complexes (R=Organyl): Stepwise versus Concerted Mechanism in Copper‐Mediated Trifluoromethylation
Authors: Zimmer Bastian , Auth Thomas , Koszinowski Konrad
Published: May 2023

The cuprate complexes [Cu(R)(CF3)3]−(R=organyl) offer an efficient synthetic access to valuable trifluoromethylation products RCF3. Here, electrospray‐ionization mass spectrometry is used to analyze the formation of these intermediates in solution and probe their fragmentation pathways in the gas phase. Furthermore, the potential energy surfaces of these systems are explored by quantum chemical calculations. Upon collisional activation, the [Cu(R)(CF3)3]−complexes (R=Me, Et, Bu,sBu, allyl) afford the product ions [Cu(CF3)3]⋅−and [Cu(CF3)2]−. The former obviously results from an R⋅ loss, whereas the latter originates either from the stepwise release of R⋅ and CF3⋅ radicals or a concerted reductive elimination of RCF3. The gas‐phase fragmentation experiments as well as the quantum chemical calculations indicate that the preference for the stepwise reaction toward [Cu(CF3)2]−increases with the stability of the formed organyl radical R⋅. This finding suggests that the recombination of R⋅ and CF3⋅ radicals may possibly contribute to the formation of RCF3from [Cu(R)(CF3)3]−in synthetic applications. In contrast, the [Cu(R)(CF3)3]−complexes (R=aryl) only yield [Cu(CF3)2]−when subjected to collision‐induced dissociation. These species exclusively undergo a concerted reductive elimination because the competing stepwise pathway is disfavored by the low stability of aryl radicals.
Expanding the Substrate Scope of Acyltransferase LovD9 for the Biosynthesis of Statin Analogues
Authors: García‐Marquina Guillermo , Núñez‐Franco Reyes , Grajales‐Hernández Daniel , Jiménez‐Osés Gonzalo , López‐Gallego Fernando
Published: May 2023

This study identifies new acyl donors for manufacturing statin analogues through the acylation of monacolin J acid by the laboratory evolved acyltransferase LovD9. Vinyl and p‐nitrophenyl esters have emerged as alternate substrates for LovD9‐catalyzed acylation. While vinyl esters can reach product yields as high as the ones obtained by α‐dimethyl butyryl‐S‐methyl‐3‐mercaptopropionate (DMB‐SMMP), the thioester for which LovD9 was evolved, p‐nitrophenyl esters display a reactivity even higher than DMB‐SMMP for the first acylation step yet the acylation product yield is lower. The reaction mechanisms were elucidated through quantum mechanics (QM) calculations.
Linguistic Framing of Artificial Intelligence: What Language to Use When Talking about Artificial Intelligence
Authors: Lammers Svenja , Lasch Alexander
Published: May 2023

A psycholinguistic study was conducted to assess the level of trust in different fictional products with varying framing. It was found that the product type has the greatest influence on the level of acceptance, while the expert or layperson status of the participants has the least influence. The second most relevant influencing factor is framing. The level of trust is estimated higher by all groups when a product description using the frame SUPPORTING rather than the frames DECIDING or CONTROL is presented.
Interleaved boost converter open switch fault detection and reconfiguration using harmonic selection calculation
Authors: Badaoui Yacine , Gouichiche Abdelmadjid , Safa Ahmed , Messlem Youcef , Chibani Abdelilah , Chedjara Zakaria
Published: May 2023

In this paper, a new technique for open‐circuit switch fault (OCF) detection and reconfiguration of an interleaved boost converter (IBC) is proposed. Harmonic selection calculation (HSC) is elaborated from the frequency domain analysis using the Fourier transformer of the input current. The symmetric phase shifting of the inductor currents has induced some characteristics in the input current that make the HSC an interesting tool for the fault detection process of an OCF. The HSC consists of selecting the adequate harmonic for detecting and isolating an OCF with a thresholding strategy. The proposed approach can handle different operation modes such as CCM, DCM, load change, and parameter change. Besides the short‐time detection (less than one cycle), this technique is based on the measurement of the only used inductor currents, which means that it does not require any additional hardware. The effectiveness of the proposed HSC technique is verified by simulation and experimental tests for three interleaved boost converters under different situations, such as load change, conduction mode change, and OCF mode. The obtained results show the validity of the proposed technique.
Non‐coding RNAs and colitis‐associated cancer: Mechanisms and clinical applications
Authors: Gu Yijie , Zhao Haizhou , Zheng Lu , Zhou Chentao , Han Ye , Wu Airong , Jia Zhenyu , Xia Tingting , Zhi Qiaoming
Published: May 2023

Background

Colitis‐associated cancer (CAC) is one of the most severe complications of inflammatory bowel disease (IBD), which has caused a worse survival rate in IBD patients. Although the exact aetiology and pathogenesis of CAC are not completely elucidated, evidence indicates that non‐coding RNAs are closely involved and play a key role.

Methods

This review aims to summarise the major findings of non‐coding RNAs in the development of CAC and present the potential mechanistic links between non‐coding RNAs and CAC pathogenesis. The results show that non‐coding RNAs can hinder DNA mismatch repair proteins and obstruct chromosome passenger complexes to increase microsatellite instability and accumulate chromosomal instability, respectively. The data also suggest that DNA promoter methylation or RNA methylation modifications of non‐coding RNA are the main mechanisms to regulate oncogene or tumour suppressor expression during the CAC progression. Other factors, including gut microbiota perturbations, immune dysregulation and barrier dysfunction, are also regulated and influenced by non‐coding RNAs. Besides, non‐coding RNAs as molecular managers are associated with multiple critical signalling pathways governing the initiation, progression and metastasis of CAC, including the janus kinase/signal transducer and activator of transcription (JAK/STAT), nuclear factor‐kappa B (NF‐κB), extracellular signal‐regulated kinase (ERK), Toll‐like receptor 4 (TLR4), Wnt/β‐catenin and phosphatidylinositol 3‐Kinase/Protein Kinase B (PI3K/AKT) pathways. In addition, non‐coding RNAs can be detected in colon tissues or blood, and their aberrant expressions and diagnostic and prognostic roles are also discussed and confirmed in CAC patients.

Conclusions

It is believed that a deepening understanding of non‐coding RNAs in CAC pathogenesis may prevent the progression to carcinogenesis, and will offer new effective therapies for CAC patients.
Anthocyanin and proanthocyanidin from Aronia melanocarpa (Michx.) Ell.: Purification, fractionation, and enzyme inhibition
Authors: Chen Limei , Chen Wuxi , Li Demao , Liu Xiumin
Published: May 2023

Aronia melanocarpa (Michx.) Ell. is a rich source of anthocyanins and proanthocyanidins with confirmed health benefits. Individual cyanidin glucosides (cyanidin 3‐galactoside, cyanidin 3‐arabinoside, cyanidin 3‐xyloside, and cyanidin 3‐glucoside) of anthocyanins (calculated by individual cyanin glycoside fractions was 419.9 mg/100 g FW) were isolated by Sephadex LH‐20 column and different parts of proanthocyanidins with a different mean degree of polymerization (mDP) were fractionated by the solubility differences in different solvents. The composition of different mDP of proanthocyanidins was as follows: monomers (1.51%), oligomer (mDP of 4.2 ± 0.9, 20.57%), CPP‐50 (mDP of 78.9 ± 4.1, 22.17%), CPP‐60 (mDP of 66.1 ± 1.2, 27.94%), CPP‐70 (mDP of 36.8 ± 3.9, 36.8%), CPP‐75 (mDP of 25.2 ± 1.3, 6.14%), CPP‐L (mDP of 10.2 ± 2.6, 6.95%), and there were recycling loss of 0.34%. Cyanidin 3‐glucoside showed the strongest inhibition effects on α‐amylase and lipase and cyanidin 3‐arabinoside showed the strongest inhibition effect on α‐glucosidase, while cyanidin 3‐xyloside has no inhibition effect on the α‐amylase, and cyanidin 3‐galactoside, cyanidin 3‐arabinoside, and cyanidin 3‐xyloside have no inhibition effects on lipase. The inhibition effect of proanthocyanidins with different mDP to the enzymes all showed high negative correlations between the mDP and IC50 (half‐maximal inhibitory concentration). This study suggests that A. melanocarpa (Michx.) Ell. can have beneficial effects due to inhibition of the digestion enzyme.
Effects of free and encapsulated Siah‐e‐Samarghandi grape seed extract on the physicochemical, textural, microbial, and sensorial properties of UF‐Feta cheese
Authors: Sekhavatizadeh Seyed Saeed , Abadariyan Nasim , Ebrahimi Laya , Hasanzadeh Mahboobeh
Published: May 2023

The current study was conducted to elucidate the impact of grape seed extract (SE) and microencapsulated seed extract (MSE) addition to UF‐Feta cheese. The SE was encapsulated in maize starch, alginate, and canola oil using the emulsion technique. The SE and MSE characteristics were evaluated. The products were subjected to physicochemical (pH, titrable acidity, color, texture, and sensory properties), microbiological analysis (starter count), and lipid oxidation test (proxide, acid degree, and ansidine value) during 60 days of storage. The main phenol component in the SE was catechin (419.04 mg/L), gallic acid (319.63 mg/L), and chlorogenic acid (4.19 ± 0.002 mg/L). The antioxidant value was 157.80 mg/L. The MSE was elliptical in shape with a 24.29 μm diameter. The efficiency of microencapsulation was 53.86%. The addition of SE and MSE had no significant effect on pH and acidity, but lipolysis decreased based on acid degree value (0.7%; p > .05). The increasing trend of peroxide values was 172.54%, 145.68%, and 118.75% for C, SE, and MSE samples, respectively, and 35.68%, 32.28%, and 17.24% for the P‐anisidine values during the storage time. Therefore, fat oxidation was reduced in the supplemented cheese. Nevertheless, the supplemented cheese had limited color alterations. The MSE and SE did not affect the survival rates of the starter count. The SE and MSE had a less rigid structure. The hardness (2748.0 g) and chewiness (57.45 mJ) values in SE cheese had the greatest value among the samples. All sensory parameters were lowest in MSE cheese. In short, encapsulation showed suitable properties for SE to apply in UF‐Feta cheese.
Fates of Emitted Particles Depending on Mask Wearing Using an Approach Validated Across Spatial Scales
Authors: Baumann André , Hoch Dennis , Niessner Jennifer
Published: May 2023

The spread of emitted potentially virus‐laden aerosol particles is known to be highly dependent on whether a mask is worn by an infected person and on the emission scenario, i.e., whether the person is coughing, speaking, or breathing. The aim of this work is to investigate in detail the fates of particles emitted by a person wearing a perfectly fitting, a naturally fitted mask with leakage, and no mask depending on the emission scenario. Therefore, a two‐scale numerical workflow is proposed where parameters are carried through from a micro‐scale where the fibers of the mask filter medium and the aerosol particles are resolved to a macro‐scale and validated by comparison to experimental measurements of fractional filtration efficiency and pressure drop of the filter medium as well as pressure drop of the mask. It turns out that masks reduce the number of both emitted and inhaled particles significantly even with leakage. While without a mask, the person opposite of an infected person is generally at the highest risk of being infected, a mask worn by an infected person speaking or coughing will deflect the flow leading to the fact that the person behind the infected person might inhale the largest number of aerosol particles.
Deoxyhypusine hydroxylase: A novel therapeutic target differentially expressed in short‐term vs long‐term survivors of glioblastoma
Authors: Ofek Paula , Yeini Eilam , Arad Gali , Danilevsky Artem , Pozzi Sabina , Luna Christian Burgos , Dangoor Sahar Israeli , Grossman Rachel , Ram Zvi , Shomron Noam , Brem Henry , Hyde Thomas M. , Geiger Tamar , Satchi‐Fainaro Ronit
Published: May 2023

Glioblastoma (GB) is the most aggressive neoplasm of the brain. Poor prognosis is mainly attributed to tumor heterogeneity, invasiveness and drug resistance. Only a small fraction of GB patients survives longer than 24 months from the time of diagnosis (ie, long‐term survivors [LTS]). In our study, we aimed to identify molecular markers associated with favorable GB prognosis as a basis to develop therapeutic applications to improve patients' outcome. We have recently assembled a proteogenomic dataset of 87 GB clinical samples of varying survival rates. Following RNA‐seq and mass spectrometry (MS)‐based proteomics analysis, we identified several differentially expressed genes and proteins, including some known cancer‐related pathways and some less established that showed higher expression in short‐term (<6 months) survivors (STS) compared to LTS. One such target found was deoxyhypusine hydroxylase (DOHH), which is known to be involved in the biosynthesis of hypusine, an unusual amino acid essential for the function of the eukaryotic translation initiation factor 5A (eIF5A), which promotes tumor growth. We consequently validated DOHH overexpression in STS samples by quantitative polymerase chain reaction (qPCR) and immunohistochemistry. We further showed robust inhibition of proliferation, migration and invasion of GB cells following silencing of DOHH with short hairpin RNA (shRNA) or inhibition of its activity with small molecules, ciclopirox and deferiprone. Moreover, DOHH silencing led to significant inhibition of tumor progression and prolonged survival in GB mouse models. Searching for a potential mechanism by which DOHH promotes tumor aggressiveness, we found that it supports the transition of GB cells to a more invasive phenotype via epithelial‐mesenchymal transition (EMT)‐related pathways.
The social drama of digital multimodal composing: A case study with emergent bi/multilingual newcomer students
Authors: Michalovich Amir
Published: May 2023

This multi‐year, ethnographic, qualitative case study in English Language Learning classrooms contributes a unique analysis of nine adolescent newcomer students' investment in a digital multimodal composing (DMC) project as a social drama. Using reflexive thematic analysis, it explores the following possibilities afforded by in‐school, dramaturgically structured DMC processes for the students' investment in classroom learning: (1) changing the definition of the situation, (2) supporting students' impression management to gain social and cultural capital, and (3) creating bonds of reciprocal dependence and familiarity. The study helps language and literacy researchers, educators, and teacher educators better understand emergent bi/multilingual newcomer students' investment in DMC processes through the sociological perspective of dramaturgy, suggesting how DMC might deepen learning while valuing the assets of culturally, linguistically, and racially diverse newcomer students.
The generalist CEO pay premium and CEO risk aversion
Authors: Zbib Leila , Asare Kwadwo
Published: May 2023

We investigate whether and how managerial risk aversion influences the structuring of the generalist pay premium. We use three candidate variables for managerial risk aversion: the CEO's equity portfolio vega, decision horizon, and wealth. We find that equity‐based pay differs between generalist CEOs (who have broader experience spanning several industries) and non‐generalist CEOs (who tend to have narrower, specialized industry‐specific experience) based on their risk appetite. Further, how the generalist pay premium is structured depends on the risk aversion measure. Because generalist CEOs tend to be better paid than their counterparts, understanding their risk aversion level will help companies improve the structure of these CEOs’ compensation packages, and ultimately those of all CEOs. When vega is the risk aversion measure, CEOs get compensated for bearing risk. However, generalist CEOs with high vegas suffer a “risk discount” in their compensation. These generalist CEOs are associated with lower cash, equity, and total pay. CEOs with longer decision horizons get more equity and less cash, but this structuring does not extend to the generalist CEOs. Finally, wealthier CEOs get more cash and total pay. However, generalist CEOs who are wealthier get less cash pay.
Acceleration of generalized replica exchange with solute tempering simulations of large biological systems on massively parallel supercomputer
Authors: Jung Jaewoon , Kobayashi Chigusa , Sugita Yuji
Published: May 2023

Generalized replica exchange with solute tempering (gREST) is one of the enhanced sampling algorithms for proteins or other systems with rugged energy landscapes. Unlike the replica‐exchange molecular dynamics (REMD) method, solvent temperatures are the same in all replicas, while solute temperatures are different and are exchanged frequently between replicas for exploring various solute structures. Here, we apply the gREST scheme to large biological systems containing over one million atoms using a large number of processors in a supercomputer. First, communication time on a multi‐dimensional torus network is reduced by matching each replica to MPI processors optimally. This is applicable not only to gREST but also to other multi‐copy algorithms. Second, energy evaluations, which are necessary for the multistate bennet acceptance ratio (MBAR) method for free energy estimations, are performed on‐the‐fly during the gREST simulations. Using these two advanced schemes, we observed 57.72 ns/day performance in 128‐replica gREST calculations with 1.5 million atoms system using 16,384 nodes in Fugaku. These schemes implemented in the latest version of GENESIS software could open new possibilities to answer unresolved questions on large biomolecular complex systems with slow conformational dynamics.
Neurodevelopmental dimensional assessment of young children at high genomic risk of neuropsychiatric conditions
Authors: Chawner Samuel J. R. A. , Paine Amy L. , Dunn Matt J. , Walsh Alice , Sloane Poppy , Thomas Megan , Evans Alexandra , Hopkins‐Jones Lucinda , Struik Siske ,   IMAGINE‐ID consortium, Hall Jeremy , Erichsen Jonathan T. , Leekam Susan R. , Owen Michael J. , Hay Dale , van den Bree Marianne B. M.
Published: May 2023

Background

Individuals with 22q11.2 deletion are at considerably increased risk of neurodevelopmental and psychiatric conditions. There have been very few studies investigating how this risk manifests in early childhood and what factors may underlie developmental variability. Insights into this can elucidate transdiagnostic markers of risk that may underlie later development of neuropsychiatric outcomes.

Methods

Thirty two children with 22q11.2 Deletion Syndrome (22q11.2DS) (mean age = 4.1 [SD = 1.2] years) and 12 sibling controls (mean age = 4.1 [SD = 1.5] years) underwent in‐depth dimensional phenotyping across several developmental domains selected as being potential early indicators of neurodevelopmental and psychiatric liability. Comparisons were conducted of the dimensional developmental phenotype of 22q11.2DS and sibling controls. For autistic traits, both parents and children were phenotyped using the Social Responsiveness Scale.

Results

Young children with 22q11.2DS exhibited large impairments (Hedge's g ≥ 0.8) across a range of developmental domains relative to sibling controls, as well as high rates of transdiagnostic neurodevelopmental and psychiatric traits. Cluster analysis revealed a subgroup of children with 22q11.2DS (n = 16; 53%) in whom neurodevelopmental and psychiatric liability was particularly increased and who differed from other children with 22q11.2DS and non‐carrier siblings. Exploratory analyses revealed that early motor and sleep impairments indexed liability for neurodevelopmental and psychiatric outcomes. Maternal autism trait scores were predictive of autism traits in children with 22q11.2DS (intraclass correlation coefficients = 0.47, p = 0.046, n = 31).

Conclusions

Although psychiatric conditions typically emerge later in adolescence and adulthood in 22q11.2DS, our exploratory study was able to identify a range of early risk indicators. Furthermore, findings indicate the presence of a subgroup who appeared to have increased neurodevelopmental and psychiatric liability. Our findings highlight the scope for future studies of early risk mechanisms and early intervention within this high genetic risk patient group.
Evaluation of an automated response‐independent schedule on the behavioral welfare of shelter dogs
Authors: Fernandez Eduardo J. , Anderson Wes , Kowalski Amanda
Published: May 2023

Response‐independent schedules involve the delivery of an item independent of a response requirement. Often described in the applied behavior analytic literature as “noncontingent reinforcement,” they have also frequently been used to reduce undesired or problematic behaviors. The current study examined the use of an automated response‐independent food schedule on the behaviors and sound levels of shelter dogs. Several dogs were included in a 6‐week reversal design, where a fixed‐time 1 min schedule was compared with a baseline condition. Eleven behaviors were measured, as were two areas of each kennel and the overall and session sound intensity (dB) that occurred during the study. The results demonstrated that the fixed‐time schedule increased overall activity while decreasing inactivity and led to a reduction in the overall sound intensity measured. Session and hour‐to‐hour sound‐intensity data were less clear, suggesting a potential contextual conditioning effect as well as a need for adjusted methods to study shelter sound. The above are discussed in terms of their potential welfare benefits for shelter dogs as well as the translational approach that this and similar research could contribute to the application and functional understanding of response‐independent schedules.
Effect of Ca2+ on 3D printing accuracy and antioxidant efficacy of nano starch‐lutein surimi: mechanical properties, chemical bonds and release rate
Authors: Li Gaoshang , Zhan Junqi , Hu Zhiheng , Huang Jiayin , Xu Enbo , Yuan Chunhong , Chen Jianchu , Yao Qian , Hu Yaqin
Published: May 2023

BACKGROUND

Nano starch‐lutein (NS‐L) can be used in three‐dimensional (3D) printed functional surimi. However, the lutein release and printing effect are not ideal. The purpose of this study was to facilitate the function and printing properties of surimi by adding the combination of calcium ion (Ca2+) and NS‐L.

RESULTS

Printing properties, lutein release and antioxidation of printed Ca2+‐NS‐L‐surimi were determined. The NS‐L‐surimi with 20 mM kg−1 Ca2+ had the best printing effects (fine accuracy, 99 ± 1%). Compared to NS‐L‐surimi, the structure became denser after adding Ca2+, the gel strength, hardness, elasticity, yield stress (τ), water holding capacity of Ca2+‐NS‐L‐surimi increased by about 17 ± 4%, 3 ± 1%, 9 ± 2%, 20 ± 4%, 40 ± 5% respectively. These enhanced mechanical strength and self‐supporting ability to resist binding deformation and improve printing accuracy. Moreover, salt dissolution and increased hydrophobic force by Ca2+ stimulated protein stretching and aggregation, leading to enhancement of gel formation. Decreased printing effects of NS‐L‐surimi with excessive Ca2+ (> 20 mM kg−1) caused by excessive gel strength and τ, leading to strong extrusion force and low extrudability. Additionally, Ca2+‐NS‐L‐surimi had higher digestibility and lutein release rate (increased from 55 ± 2% to 73 ± 3%), because Ca2+ made NS‐L‐surimi structure porous, which promoted contact of enzyme‐protein. Furthermore, weakened ionic bonds reduced electron binding bondage that combined with released lutein to provide more electrons for enhancing antioxidation.

CONCLUSION

Collectively, 20 mM kg−1 Ca2+ could better promote printing process and function exertion of NS‐L‐surimi, facilitating the application of 3D printed functional surimi. © 2023 Society of Chemical Industry.
An efficient method for improving the stability of Monascus pigments using ionic gelation
Authors: Wei Mengru , Zhu Jingjing , Gao Hongshuai , Yao Huanhuan , Zhai Cuiping , Nie Yi
Published: May 2023

BACKGROUND

Monascus pigments (Mps) are easily impacted by heating, pH and light, resulting in degradation. In this study, Mps were encapsulated by the ionic gelation method with sodium alginate (SA) and sodium caseinate (SC), as well as CaCl2 as a crosslinker. The encapsulated Mps SA/SC in four proportions (SA/SC: 1/4, 2/3, 3/2, 4/1, w/w). Then, the encapsulation efficiency and particle size of the SA/SC‐Mps system were evaluated to obtain the optimal embedding conditions. Finally, the effects of heating, pH, light and storage on the stability of non‐capsulated Mps and encapsulated Mps were assessed.

RESULTS

SA/SC = 2/3 (AC2) had higher encapsulation efficiency (74.30%) of Mps and relatively small particle size (2.02 mm). The AC2 gel beads were chosen for further investigating the stability of encapsulated Mps to heating, pH, light and storage. Heat stability experiments showed that the degradation of Mps followed first‐order kinetics, and the encapsulated Mps had lower degradation rates than non‐capsulated Mps. Encapsulation could reduce the effect of pH on Mps. The effects of ultraviolet light on the stability of Mps were considered, and showed that the retention efficiency of encapsulated Mps was 22.01% higher than that of non‐capsulated Mps on the seventh day. Finally, storage stability was also evaluated under dark refrigerated conditions for 30 days, and the results indicated that encapsulation could reduce the degradation of Mps.

CONCLUSION

This study has proved that AC2 gel beads can improve the stability of Mps. Thus, the ionic gelation method is a promising encapsulation method to improve the stability of Mps. © 2023 Society of Chemical Industry.
Near‐Infrared Autofluorescence Identification of Ectopic Parathyroid Lesions
Authors: Abe Kanako , Takahashi Takeshi , Yokoyama Yusuke , Shodo Ryusuke , Ueki Yushi , Yamazaki Keisuke , Horii Arata
Published: May 2023

Ectopic parathyroid lesions can be difficult to detect. In the present study, we used near‐infrared autofluorescence imaging (NIFI) in three cases of ectopic parathyroid lesions. Our results suggest that NIFI may be a confirmation tool for parathyroid pathology and an intraoperative navigation tool in vivo and ex vivo. Laryngoscope, 134:496–500, 2024
Nanocomposite Hydrogels in Regenerative Medicine: Applications and Challenges
Authors: Chen Weixing , Ming Yue , Wang Min , Huang Mingshu , Liu Hongyu , Huang Yisheng , Huang Zhijie , Qing Ling , Wang Qin , Jia Bo
Published: May 2023

Regenerative medicine is a highly regarded multidisciplinary field that aims to transform the future of clinical medicine through curative strategies rather than palliative therapies. As an emerging field, the development of regenerative medicine cannot be achieved without multifunctional biomaterials. Among the various bioscaffold materials, hydrogels are one of the materials of interest in bioengineering and medical research because of their similarity to the natural extracellular matrix and good biocompatibility. However, conventional hydrogels have simple internal structures and single cross‐linking modes, which require improvement in a single function and structural stability. Introducing multifunctional nanomaterials into 3D hydrogel networks physically or chemically avoids their disadvantages. Nanomaterials (NMs) are materials in the size range of 1–100 nm with distinct physical and chemical properties that differ from that of the macroscopic size and enable hydrogels to exhibit multifunctionality. Although regenerative medicine and hydrogels have been well researched in their respective fields, the connection between nanocomposite hydrogels (NCHs) and regenerative medicine has not been elaborated. Therefore, this review briefly describes the preparation and design requirements of NCHs and discusses their applications and challenges in regenerative medicine, hoping to clarify the relationship between the two.
Jain's operator: A new construction and applications in approximation theory
Authors: Ansari Khursheed J. , Civelek Muhammet , Usta Fuat
Published: May 2023

The new and more comprehensive Jain‐type operators based on a function
and two sequences of functions
and
have been introduced. This newly defined operator has an important place in which these three functions can create both existing and new operators with special selections. In order to show their approximation properties, we present direct approximation results and Voronovkskaya‐type results for these operators. Finally, we provide a series of numerical examples to show their performance visually.
Stability analysis for singular random impulsive control system: A novel neutral impulsive delay system approach
Authors: Senthilkumar T. , Vinodkumar A.
Published: May 2023

The paper studies stability analysis for an uncertain singular time varying delay system (USTDS) under random impulsive control (RIC). It also proves the stability results for a singular impulsive time delay system in terms of neutral impulsive time delay system approach. Besides, we derive the new sufficient conditions for stability results like exponential stability (ES) and robust exponential stability (RES) of the proposed system via linear matrix inequality (LMI) by employing the Lyapunov–Krasovskii functional (LKF) approach. In addition, two numerical examples, along with graphical simulations, are provided to illustrate the validity and effectiveness of the proposed results.
The experiences and preferences of individuals living with a musculoskeletal disorder regarding prognosis: A qualitative study
Authors: Mullen Nicholas , Ashby Samantha , Haskins Robin , Osmotherly Peter
Published: May 2023

Question(s)

What are the experiences and preferences of individuals living with a musculoskeletal disorder regarding prognosis?

Design

Exploratory phenomenological study.

Participants

Individuals aged 18‐year or older currently experiencing a musculoskeletal disorder and receiving treatment from a physiotherapist.

Data Analysis

Data were collected through semi‐structured interviews and analysed using inductive coding and thematic analysis.

Results

Five themes were identified. First, participants described seeking a cause for their pain. This influenced their experience of prognosis as they perceived a diagnosis was required to inform their prognosis. Second, whilst participants wished to receive a prognosis from their physiotherapist, this was often not their experience. Third, participants perceived that physiotherapists have the potential to impact prognosis through exercise prescription, management of conditions, and improving function. Fourth, receiving a prognosis can have both a positive and negative impact on the individual. Positive impacts include planning for the future, motivation, knowledge acquisition, and instilling hope. However, receiving a prognosis can be disheartening if a patient's expectations are unmet. Finally, participants have several preferences regarding receiving a prognosis including when and how often the prognosis is discussed, what prognostic information is provided, how the prognosis is presented, and what prognosis based on.

Conclusion

Individuals wish to receive a prognosis, although this is not always their experience. Individuals perceive that physiotherapists have the ability to provide a prognosis and impact their prognosis. Furthermore, receiving a prognosis has an impact on itself. To ensure patient‐centred care, physiotherapists should explicitly discuss the prognosis with patients and consider their preferences when providing a prognosis.
Developing and testing inter‐rater reliability of a data collection tool for patient health records on end‐of‐life care of neurological patients in an acute hospital ward
Authors: Jonsdottir Gudrun , Haraldsdottir Erna , Sigurdardottir Valgerdur , Thoroddsen Asta , Vilhjalmsson Runar , Tryggvadottir Gudny Bergthora , Jonsdottir Helga
Published: May 2023

Aim

Develop and test a data collection tool—Neurological End‐Of‐Life Care Assessment Tool (NEOLCAT)—for extracting data from patient health records (PHRs) on end‐of‐life care of neurological patients in an acute hospital ward.

Design

Instrument development and inter‐rater reliability (IRR) assessment.

Method

NEOLCAT was constructed from patient care items obtained from clinical guidelines and literature on end‐of‐life care. Expert clinicians reviewed the items. Using percentage agreement and Fleiss' kappa we calculated IRR on 32 nominal items, out of 76 items.

Results

IRR of NEOLCAT showed 89% (range 83%–95%) overall categorical percentage agreement. The Fleiss' kappa categorical coefficient was 0.84 (range 0.71–0.91). There was fair or moderate agreement on six items, and moderate or almost perfect agreement on 26 items.

Conclusion

The NEOLCAT shows promising psychometric properties for studying clinical components of care of neurological patients at the end‐of‐life on an acute hospital ward but could be further developed in future studies.
Fusion with type 2 macrophages induces melanoma cell heterogeneity that potentiates immunological escape from cytotoxic T lymphocytes
Authors: Minowa Tomoyuki , Hirohashi Yoshihiko , Murata Kenji , Sasaki Kenta , Handa Toshiya , Nakatsugawa Munehide , Mizue Yuka , Murai Aiko , Kubo Terufumi , Kanaseki Takayuki , Tsukahara Tomohide , Iwabuchi Sadahiro , Hashimoto Shinichi , Ishida‐Yamamoto Akemi , Uhara Hisashi , Torigoe Toshihiko
Published: May 2023

Evasion from immunity is a major obstacle to the achievement of successful cancer immunotherapy. Hybrids derived from cell–cell fusion are theoretically associated with tumor heterogeneity and progression by conferring novel properties on tumor cells, including drug resistance and metastatic capacity; however, their impact on immune evasion remains unknown. Here, we investigated the potency of tumor–macrophage hybrids in immune evasion. Hybrids were established by co‐culture of a melanoma cell line (A375 cells) and type 2 macrophages. The hybrids showed greater migration ability and greater tumorigenicity than the parental melanoma cells. The hybrids showed heterogeneous sensitivity to New York esophageal squamous cell carcinoma‐1 (NY‐ESO‐1)‐specific T‐cell receptor‐transduced T (TCR‐T) cells and two out of four hybrid clones showed less sensitivity to TCR‐T compared with the parental cells. An in vitro tumor heterogeneity model revealed that the TCR‐T cells preferentially killed the parental cells compared with the hybrids and the survival rate of the hybrids was higher than that of the parental cells, indicating that the hybrids evade killing by TCR‐T cells efficiently. Analysis of a single‐cell RNA sequencing dataset of patients with melanoma revealed that a few macrophages expressed RNA encoding melanoma differentiation antigens including melan A, tyrosinase, and premelanosome protein, which indicated the presence of hybrids in primary melanoma. In addition, the number of potential hybrids was correlated with a poorer response to immune checkpoint blockade. These results provide evidence that melanoma–macrophage fusion has a role in tumor heterogeneity and immune evasion. © 2023 The Pathological Society of Great Britain and Ireland.
In vivo activity of the dual PI3Kδ and PI3Kγ inhibitor duvelisib against pediatric acute lymphoblastic leukemia xenografts
Authors: Randall Joanna , Evans Kathryn , Watts Ben , Smith Christopher M. , Hughes Keira , Earley Eric J. , Erickson Stephen W. , Pachter Jonathan A. , Teicher Beverly A. , Smith Malcolm A. , Lock Richard B.
Published: May 2023

Background

Acute lymphoblastic leukemia (ALL) remains one of the most common causes of cancer‐related mortality in children. Phosphoinositide 3‐kinases (PI3Ks) are a family of lipid kinases, and aberrations in the PI3K pathway are associated with several hematological malignancies, including ALL. Duvelisib (Copiktra) is an orally available, small molecule dual inhibitor of PI3Kδ and PI3Kγ, that is Food and Drug Administration (FDA) approved for the treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Here, we report the efficacy of duvelisib against a panel of pediatric ALL patient‐derived xenografts (PDXs).

Procedures

Thirty PDXs were selected for a single mouse trial based on PI3Kδ (PIK3CD) and PI3Kγ (PIK3CG) expression and mutational status. PDXs were grown orthotopically in NSG (NOD.Cg‐PrkdcscidIL2rgtm1Wjl/SzJAusb) mice, and engraftment was evaluated by enumerating the proportion of human versus mouse CD45+ cells (%huCD45+) in the peripheral blood. Treatment commenced when the %huCD45+ reached greater than or equal to 1%, and events were predefined as %huCD45+ greater than or equal to 25% or leukemia‐related morbidity. Duvelisib was administered per oral (50 mg/kg, twice daily for 28 days). Drug efficacy was assessed by event‐free survival and stringent objective response measures.

Results

PI3Kδ and PI3Kγ mRNA expression was significantly higher in B‐lineage than T‐lineage ALL PDXs (p‐values <.0001). Duvelisib was well‐tolerated and reduced leukemia cells in the peripheral blood in four PDXs, but with only one objective response. There was no obvious relationship between duvelisib efficacy and PI3Kδ or PI3Kγ expression or mutation status, nor was the in vivo response to duvelisib subtype dependent.

Conclusions

Duvelisib demonstrated limited in vivo activity against ALL PDXs.