bluuebunny/crossref_metadata_2025 huggingface dataset:
FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes
Authors: Pettinato Mariateresa , Dulja Alessandro , Colucci Silvia , Furiosi Valeria , Fette Franca , Steinbicker Andrea U. , Muckenthaler Martina U. , Nai Antonella , Pagani Alessia , Silvestri Laura
Published: May 2023

The expression of the iron regulatory hormone hepcidin in hepatocytes is regulated by the BMP‐SMAD pathway through the type I receptors ALK2 and ALK3, the type II receptors ACVR2A and BMPR2, and the ligands BMP2 and BMP6. We previously identified the immunophilin FKBP12 as a new hepcidin inhibitor that acts by blocking ALK2. Both the physiologic ALK2 ligand BMP6 and the immunosuppressive drug Tacrolimus (TAC) displace FKBP12 from ALK2 and activate the signaling. However, the molecular mechanism whereby FKBP12 regulates BMP‐SMAD pathway activity and thus hepcidin expression remains unclear. Here, we show that FKBP12 acts by modulating BMP receptor interactions and ligand responsiveness. We first demonstrate that in primary murine hepatocytes TAC regulates hepcidin expression exclusively via FKBP12. Downregulation of the BMP receptors reveals that ALK2, to a lesser extent ALK3, and ACVR2A are required for hepcidin upregulation in response to both BMP6 and TAC. Mechanistically, TAC and BMP6 increase ALK2 homo‐oligomerization and ALK2–ALK3 hetero‐oligomerization and the interaction between ALK2 and the type II receptors. By acting on the same receptors, TAC and BMP6 cooperate in BMP pathway activation and hepcidin expression both in vitro and in vivo. Interestingly, the activation state of ALK3 modulates its interaction with FKBP12, which may explain the cell‐specific activity of FKBP12. Overall, our results identify the mechanism whereby FKBP12 regulates the BMP‐SMAD pathway and hepcidin expression in hepatocytes, and suggest that FKBP12–ALK2 interaction is a potential pharmacologic target in disorders caused by defective BMP‐SMAD signaling and characterized by low hepcidin and high BMP6 expression.
Changes in blood pressure, oxygen saturation, hemoglobin concentration, and heart rate among low‐altitude migrants living at high altitude (5380 m) for 360 days
Authors: Yan Yan , Mao Zhong , Jia Qian , Zhao Xiao‐jing , Yang Sheng‐hong
Published: May 2023

Background

This article aimed to study the adjustment and adaptation of resting systolic blood pressure (SBP), diastolic blood pressure (DPB), oxygen saturation (SpO2), hemoglobin concentration ([Hb]), and heart rate (HR) in low‐altitude migrants during a 1‐year stay at high altitude.

Materials and Methods

Our study enrolled 35 young migrants who were exposed to a hypoxia environment at 5380 m altitude on the Qinghai Tibetan Plateau between June 21, 2017, and June 16, 2018. We set 14‐time points (the 1st–10th, 20th, 30th, 180th, and 360th day after arriving at 5380 m) for obtaining the measurements of resting SBP, DBP, HR, SpO2, and [Hb] and compared them with the control values recorded prior to migration. Variables with continuous data were summarized as means (SD). One‐way repeated measures ANOVA without assuming sphericity was carried out to test whether the mean values (SBP, DBP, HR, SpO2, and [Hb]) on different days were different significantly. Furthermore, Dunnett's multiple comparisons test was carried out to determine the time points whose values were significantly different from the control values.

Results

SBP and DBP were continually increasing within d1‐3 and peaked on the 3rd day, then steadily declined from d3 to d30. SBP fell back to the control values on d10 (p > 0.05), and DBP fell back to the control values on d20 (p > 0.05). A significant decline occurred on d180 (p < 0.05). Both SBP and DBP were lower than the control values on d180 (p < 0.05), and this trend was maintained to d360. There were similar characteristics of HR and BP in the time course at HA. HR on d1‐3 was increasing (p < 0.05) compared to the control values, after which it fell back to the control values on d180 (p > 0.05), and this trend was maintained to d360. SpO2 was the lowest on d1 and lower than the control value throughout the study at HA (p < 0.05). [Hb] increased after long‐term exposure (180 and 360 days) to HA (p < 0.05).

Conclusions

Our study continuously monitored lowlanders at 5380 m in Tibet, and is perhaps the only longitudinal study of migrants conducted at an altitude above 5000 m during a 1‐year period. Our study provides new information on the adjustment and adaptation of [Hb], SpO2, SBP, DBP, and HR in high‐altitude plateau migrants during a 360‐day stay at an altitude of 5380 m.
Biomimetic Nanocomposites Camouflaged with Hybrid Cell Membranes for Accurate Therapy of Early‐Stage Glioma
Authors: Chi Siyu , Zhang Li , Cheng Hemei , Chang Yaran , Zhao Yaoyao , Wang Xiayan , Liu Zhihong
Published: May 2023

Glioma features high fatality rate and short survival time of patients due to its fast growth speed and high invasiveness, hence timely treatment of early‐stage glioma is extremely important. However, the blood brain barrier (BBB) severely prevents therapeutic agents from entering the brain; meanwhile, the non‐targeted distribution of agents always causes side effects to vulnerable cerebral tissues. Therefore, delivery systems that possess both BBB penetrability and precise glioma targeting ability are keenly desired. We herein proposed a hybrid cell membrane (HM) camouflage strategy to construct therapeutic nanocomposites, in which HM consisting of brain metastatic breast cancer cell membrane and glioma cell membrane was prepared with a simple membrane fusion pathway. By coating HM onto drug‐loaded nanoparticles, the as‐obtained biomimetic therapeutic agent (termed HMGINPs) inherited satisfying BBB penetrability and homologous glioma targeting ability simultaneously from the two source cells. HMGINPs exhibited good biocompatibility and superior therapeutic efficacy towards early‐stage glioma.
Multiple Helicenes Defected by Heteroatoms and Heptagons with Narrow Emissions and Superior Photoluminescence Quantum Yields**
Authors: Tan Dehui , Dong Jiaqi , Ma Tinghao , Feng Qingliang , Wang Suning , Yang Deng‐Tao
Published: May 2023

The incorporation of heteroatoms and/or heptagons as the defects into helicenes expands the variety of chiroptical materials with novel properties. However, it is still challenging to construct novel boron‐doped heptagon‐containing helicenes with high photoluminescence quantum yields (PLQYs) and narrow full‐width‐at‐half‐maximum (FWHM) values. We report an efficient and scalable synthesis of a quadruple helicene 4Cz‐NBN with two nitrogen‐boron‐nitrogen (NBN) units and a double helicene 4Cz‐NBN‐P1 bearing two NBN‐doped heptagons, the latter could be formed via a two‐fold Scholl reaction of the former. The helicenes 4Cz‐NBN and 4Cz‐NBN‐P1 exhibit excellent PLQYs up to 99 % and 65 % with narrow FWHM of 24 nm and 22 nm, respectively. The emission wavelengths are tunable via stepwise titration experiments of 4Cz‐NBN‐P1 toward fluoride, enabling distinguished circularly polarized luminescence (CPL) from green, orange (4Cz‐NBN‐P1‐F1) to yellow (trans/cis‐4Cz‐NBN‐P1‐F2) with near‐unity PLQYs and broader circular dichroism (CD) ranges. The five structures of the aforementioned four helicenes were confirmed by single crystal X‐ray diffraction analysis. This work provides a novel design strategy for construction of non‐benzenoid multiple helicenes exhibiting narrow emissions with superior PLQYs.
Photochemically‐Driven CO2 Release Using a Metastable‐State Photoacid for Energy Efficient Direct Air Capture
Authors: Premadasa Uvinduni I. , Bocharova Vera , Miles Audrey R. , Stamberga Diana , Belony Stella , Bryantsev Vyacheslav S. , Elgattar Adnan , Liao Yi , Damron Joshua T. , Kidder Michelle K. , Doughty Benjamin , Custelcean Radu , Ma Ying‐Zhong
Published: May 2023

One of the grand challenges underlying current direct air capture (DAC) technologies relates to the intensive energy cost for sorbent regeneration and CO2 release, making the massive scale (GtCO2/year) deployment required to have a positive impact on climate change economically unfeasible. This challenge underscores the critical need to develop new DAC processes with substantially reduced regeneration energies. Here, we report a photochemically‐driven approach for CO2 release by exploiting the unique properties of an indazole metastable‐state photoacid (mPAH). Our measurements on simulated and amino acid‐based DAC systems revealed the potential of mPAH to be used for CO2 release cycles by regulating pH changes and associated isomers driven by light. Upon irradiating with moderate intensity light, a ≈55 % and ≈68 % to ≈78 % conversion of total inorganic carbon to CO2 was found for the simulated and amino acid‐based DAC systems, respectively. Our results confirm the feasibility of on‐demand CO2 release under ambient conditions using light instead of heat, thereby providing an energy efficient pathway for the regeneration of DAC sorbents.
Hybrid Improper Ferroelectricity in Columnar (NaY)MnMnTi4O12
Authors: Scatena Rebecca , Liu Ran , Shvartsman Vladimir V. , Khalyavin Dmitry D. , Inaguma Yoshiyuki , Yamaura Kazunari , Belik Alexei A. , Johnson Roger D.
Published: May 2023

We show that cation ordering on A site columns, oppositely displaced via coupling to B site octahedral tilts, results in a polar phase of the columnar perovskite (NaY)MnMnTi4O12. This scheme is similar to hybrid improper ferroelectricity found in layered perovskites, and can be considered a realisation of hybrid improper ferroelectricity in columnar perovskites. The cation ordering is controlled by annealing temperature and when present it also polarises the local dipoles associated with pseudo‐Jahn–Teller active Mn2+ ions to establish an additional ferroelectric order out of an otherwise disordered dipolar glass. Below TN≈12 K, Mn2+ spins order, making the columnar perovskites rare systems in which ordered electric and magnetic dipoles may reside on the same transition metal sublattice.
Comparative electroanalytical performance of poly o‐toulidine and polyaniline towards hydrazine oxidation supplemented by DFT
Authors: Liaqat Faroha , Jamil Madiha , Tariq Irsa , Haider Ali , Khan Muhammad Abdullah
Published: May 2023

This work presents a comparative experimental and theoretical study on the use of polyaniline and its derivative, poly o‐toluidine, as effective electrochemical sensor for the detection of hydrazine. Hydrazine is a toxic analytic with numerous adverse health effects on the human brain, liver and nervous system. The conducting polymers polyaniline (PANI) and poly o‐toluidine (POT) were synthesized by oxidative polymerization and characterized through x‐ray Diffraction, FT‐IR, and UV–Visible Spectroscopy. Electrochemical studies performed on the polymer modified glassy carbon electrode (GCE) using cyclic voltammetry and differential pulse voltammetry reveal strong interaction between hydrazine and the polymer through irreversible charge transfer. The oxidation current was seen to increase with increasing hydrazine concentration. The diffusion coefficients were found to be 1.89 × 10−5 cm2/s and 2.89 × 10−6 cm2/s for PANI and POT, respectively. PANI and POT based sensors show a limit of detection of 1 μM and 5.13 mM, respectively in the linear concentration range of 1–9 mM. Density functional studies on the PANI‐hydrazine and POT‐hydrazine complexes show enhanced intermolecular charge transfer from nitrogen lone pairs in hydrazine to the polymer backbone clearly identifying the donor and acceptor moieties. PANI based electrochemical sensor is shown to have a higher sensitivity for hydrazine compared to POT, where the sensing interaction is hindered by the bulky methyl group in ortho position.
Synthesis and antimicrobial testing of 5‐fluorouracil derivatives
Authors: Patil Mrunal , Serhii Krykun , Garzino Frédéric , Gobert Quentin , Giorgio Suzanne , Raimundo Jean‐Manuel , Bolla Jean‐Michel , Camplo Michel
Published: May 2023

Antibiotic resistance has increased the demand for novel treatments against multidrug‐resistant microorganisms. In the research literature, 5‐fluorouracil (5‐FU) was proposed as an alternative due to its intrinsic antibacterial property. However, given its toxicity profile at high doses, its use in antibacterial therapy is dubious. In the quest for improving the efficacy of 5‐FU, the present study intends to synthesise 5‐FU derivatives and assess their susceptibility and mechanism against pathogenic bacteria. It was found that the compounds having tri‐hexylphosphonium substitution on both nitrogen groups of 5‐FU (6a, 6b and 6c) had considerable activity against both Gram‐positive and Gram‐negative bacteria. Among the active compounds, those with an asymmetric linker group 6c were found to have higher antibacterial efficacy. However, no conclusive efflux inhibition activity was found. As elucidated by electron microscopy studies, these self‐assembling active phosphonium‐based 5‐FU derivatives caused considerable septal damage and cytosolic alterations in Staphylococcus aureus cells. In Escherichia coli, these compounds triggered plasmolysis. Interestingly, the minimal inhibitory concentration (MIC) of the most potent 5‐FU derivative 6c remained constant, regardless of the bacteria's resistance profile. Further analysis revealed that compound 6c generated significant alterations in membrane permeabilization and depolarization in S. aureus and E. coli cells at the MIC. Compound 6c was found to substantially impede bacterial motility, suggesting its importance in regulating bacterial pathogenicity. Additionally, the nonhaemolytic activity of 6c suggested that it could be a potential therapeutic option for treating multidrug‐resistant bacterial infections.
Data analysis for accelerated life tests via Weibull‐gamma frailty regression models
Authors: Zhou Xiao‐Dong , Wang Yun‐Juan , Wu Lin , Yue Rong‐Xian
Published: May 2023

In this article, we study data analysis methods for accelerated life test (ALT) with blocking. Unlike the previous assumption of normal distribution for random block effects, we advocate the use of Weibull regression model with gamma random effects for making statistical inference of ALT data. To estimate the unknown parameters in the proposed model, maximum likelihood estimation and Bayesian estimation methods are provided. We illustrate the proposed methods using real data examples and simulation examples. Numerical results suggest that distribution of random effects has minimal impact on the estimation of fixed effects in the Weibull regression models. Furthermore, to demonstrate the advantage of our proposed model, we also provide methods to compare ALT plans and thus identify the optimal ALT plans.
Recognizing CRISPR as the new age disease‐modifying drug: Strategies to bioengineer CRISPR/Cas for direct in vivo delivery
Authors: Thevendran Ramesh , Maheswaran Solayappan
Published: May 2023

Clustered regularly interspaced short palindromic repeats (CRISPR) have established itself as a frontier technology in genetic engineering. Researchers have successfully used the CRISPR/Cas system as precise gene editing tools and have further expanded their scope beyond both imaging and diagnostic applications. The most prominent utility of CRISPR is its capacity for gene therapy, serving as the contemporary, disease‐modifying drug at the genetic level of human medical disorders. Correcting these diseases using CRISPR‐based gene editing has developed to the extent of preclinical trials and possible patient treatments. A major impediment in actualizing this is the complications associated with in vivo delivery of the CRISPR/Cas complex. Currently, only the viral vectors (e.g., lentivirus) and non‐viral encapsulation (e.g., lipid particles, polymer‐based, and gold nanoparticles) techniques have been extensively reviewed, neglecting the efficiency of direct delivery. However, the direct delivery of CRISPR/Cas for in vivo gene editing therapies is an intricate process with numerous drawbacks. Hence, this paper discusses in detail both the need and the strategies that can potentially improve the direct delivery aspects of CRISPR/Cas biomolecules for gene therapy of human diseases. Here, we focus on enhancing the molecular and functional features of the CRISPR/Cas system for targeted in vivo delivery such as on‐site localization, internalization, reduced immunogenicity, and better in vivo stability. We additionally emphasize the CRISPR/Cas complex as a multifaceted, biomolecular vehicle for co‐delivery with therapeutic agents in targeted disease treatments. The delivery formats of efficient CRISPR/Cas systems for human gene editing are also briefly elaborated.
Reexamining the Emergence and Stability of the Square Cylinder Phase in Block Copolymers
Authors: Yuan Kangrui , Xu Zhanwen , Huang Xianbo , Li Weihua
Published: May 2023

Recently, a few AB‐type multiblock copolymers have been successfully designed to form stable square cylinder phase based on self‐consistent field theory (SCFT) calculations. The previous works only identify the stability region of the square phase but not analyzing its stability, which is closely related to the free‐energy landscape. In this work, we have reexamined the stability of the square phase in
linear pentablock and
star triblock copolymers by drawing the free‐energy landscape with respect to the two dimensions of a rectangular unit cell. Our results demonstrate that the square phase continuously transfers to the rectangular phase as the degree of packing frustration is gradually released. Moreover, the prolate contour lines of the free‐energy landscape indicate the weak stability of the square phase in the
copolymer. In contrast, the stability of the square phase is notably improved in the
copolymer due to its enhanced concentration of bridging configurations. Our work sheds light on the understanding of the stability of the square cylinder phase in block copolymers. Accordingly, we propose some possible strategies for further designing new AB‐type block copolymer systems to obtain more stable square phase.
Construction of Five Tryptophan Isomers and Application of the Isomers to Solid‐Phase Total Syntheses of Lysocin E Derivatives
Authors: Nakata Yosuke , Fu Junhao , Itoh Hiroaki , Panthee Suresh , Hamamoto Hiroshi , Sekimizu Kazuhisa , Inoue Masayuki
Published: May 2023

Tryptophan (Trp) plays a unique role in peptides and proteins as its indole ring possesses an electron‐rich character and an N1−H hydrogen‐bond donor. Because of its non‐rotationally symmetric structure, synthetic alterations of the orientation of the indole ring would modulate the intrinsic structures and functions of peptides and proteins. Here we developed synthetic routes to the five Trp isomers in which the C3‐substitution of the indole ring was changed to the C2/4/5/6/7‐substitutions, and applied the five monomers to Fmoc‐based solid‐phase peptide synthesis. Specifically, the five monomers were prepared via Negishi cross‐coupling reactions of C2/4/5/6/7‐iodoindoles. To demonstrate the applicability of the monomers to the solid‐phase synthesis, the five Trp isomers of macrocyclic antibiotic lysocin E were selected as target molecules and synthesized through peptide elongation, on‐resin macrocyclization, and global deprotection. The Trp isomers displayed markedly weaker antibacterial activity than the parent natural product, revealing the biological importance of the precise three‐dimensional shape of the original Trp residue of lysocin E. The present methods for the preparation and application of these five Trp isomers provide a new strategy for analyzing and modifying the specific functions of numerous Trp‐containing peptides and proteins beyond this study.
Vibrational Predissociation Spectra of C2N− and C3N−: Bending and Stretching Vibrations
Authors: Dahlmann Franziska , Dinu Dennis F. , Jusko Pavol , Lochmann Christine , Gstir Thomas , Marimuthu Aravindh N. , Liedl Klaus R. , Brünken Sandra , Wester Roland
Published: May 2023

We present infrared predissociation spectra of C2N−(H2) and C 3N−(H2) in the 300–1850 cm−1 range. Measurements were performed using the FELion cryogenic ion trap end user station at the Free Electron Lasers for Infrared eXperiments (FELIX) laboratory. For C2N−(H2), we detected the CCN bending and CC−N stretching vibrations. For the C3N−(H2) system, we detected the CCN bending, the CC−CN stretching, and multiple overtones and/or combination bands. The assignment and interpretation of the presented experimental spectra is validated by calculations of anharmonic spectra within the vibrational configuration interaction (VCI) approach, based on potential energy surfaces calculated at explicitly correlated coupled cluster theory (CCSD(T)‐F12/cc‐pVTZ−F12). The H2 tag acts as an innocent spectator, not significantly affecting the C2,3N− bending and stretching mode positions. The recorded infrared predissociation spectra can thus be used as a proxy for the vibrational spectra of the bare anions.
The Function of Hydrotalcite as a Support Material in the Alcohol‐Assisted Catalytic CO2 Hydrogenation Reaction
Authors: Ye Linlin , Xiao Penny , Webley Paul , Singh Ranjeet , Li Gang Kevin
Published: May 2023

The traditional CO2 hydrogenation reaction in gas phase always requires harsh reaction conditions to activate CO2, resulting in huge energy consumption. However, with the assistance of 1‐butanol solvent, catalytic CO2 hydrogenation can be proceeded at a mild condition of 170 °C and 30 bars. To further improve the catalytic performance of the widely studied Cu‐ZnO‐ZrO2 catalyst (CZZ), the catalysts were modified by incorporating hydrotalcite (HTC) as a support material. The addition of HTC significantly improved the copper dispersion and surface area of the catalyst. The performance of CZZ‐HTC catalysts was investigated at varying weight percentages of HTC, and all showed higher space‐time yield of methanol (STYMeOH) compared to the commercial catalyst. Notably, CZZ‐6HTC exhibited the highest methanol selectivity, further highlighting the beneficial role of HTC as a support material.
Design of a high‐efficiency bandwidth‐enhanced power amplifier based on dual‐paths impedance matching techniques
Authors: Xuan Xuefei , Cheng Zhiqun , Zhang Zhiwei , Gong Tingwei , Liu Guohua , Le Chao
Published: May 2023

In this brief, we propose a bandwidth‐enhanced dual‐paths impedance matching technique that can effectively match the four preset design frequency points in the operating frequency band to the optimal impedance region provided by a series of inverse continuous modes (SICMs), thus realizing the bandwidth expansion and efficiency improvement of the power amplifier (PA). To verify the proposed design theory, a multi‐octave PA component was designed, fabricated, and measured with a 10‐W GaN HEMT device. The implemented PA exhibits superior performance, with a relative bandwidth of 142.9% in the bandwidth range of 0.55–3.3 GHz. Moreover, the 39.1–42 dBm output power, 60.1%–76.2% drain efficiency (DE), and 9.1–12 dB gain are also achieved in the target band. Based on the simulated and measured results, the effectiveness of the proposed design theory is further confirmed.
Individual variation in spawning migration timing in a salmonid fish—Exploring roles of environmental and social cues
Authors: Fukushima Michio , Rand Peter S.
Published: May 2023

Describing and explaining patterns of individual animal behaviors in situ, and their repeatability over the annual cycle, is an emerging field in ecology owing largely to advances in tagging technology. We describe individual movements of adult Sakhalin taimen Parahucho perryi, an endangered salmonid fish, in the headwaters of a river in northern Japan during the spring spawning season over 2 years. Migration timing, separated into stages prior to, during, and following the spawning period, was found to be more consistent and repeatable for females than males. We hypothesized that the observed coordinated movement within seasons, and repeatability in migration timing across seasons, could result from (1) individual‐specific responsiveness resulting from endogenous, biological traits that are mediated by environmental factors, or (2) social interactions among comigrating individuals. We found that water temperature and water level experienced by fish near the river mouth approximately a week before arrival at the spawning ground explained variability in run timing between years for females but not males. We found no evidence of conspecific attraction or repulsion resulting from social interactions among the spawners and post‐spawners. We conclude that individual‐specific responsiveness to environmental cues was the likely mechanism underpinning the observed migration timing and movement patterns.
Tofacitinib treatment of rheumatoid arthritis increases senescent T cell frequency in patients and limits T cell function in vitro
Authors: Alamino Vanina A. , Onofrio Luisina I. , Acosta Cristina del Valle , Ferrero Paola V. , Zacca Estefanía R. , Cadile Isaac I. , Mussano Eduardo D. , Onetti Laura B. , Montes Carolina L. , Gruppi Adriana , Acosta Rodriguez Eva V.
Published: May 2023

Unraveling the immune signatures in rheumatoid arthritis (RA) patients receiving various treatment regimens can aid in comprehending the immune mechanisms’ role in treatment efficacy and side effects. Given the critical role of cellular immunity in RA pathogenesis, we sought to identify T‐cell profiles characterizing RA patients under specific treatments.

We compared 75 immunophenotypic and biochemical variables in healthy donors (HD) and RA patients, including those receiving different treatments as well as treatment‐free patients. Additionally, we conducted in vitro experiments to evaluate the direct effect of tofacitinib on purified naïve and memory CD4+ and CD8+ T cells.

Multivariate analysis revealed that tofacitinib‐treated patients segregated from HD at the expense of T‐cell activation, differentiation, and effector function‐related variables. Additionally, tofacitinib led to an accumulation of peripheral senescent memory CD4+ and CD8+ T cells. In vitro, tofacitinib impaired the activation, proliferation, and effector molecules expression and triggered senescence pathways in T‐cell subsets upon TCR‐engagement, with the most significant impact on memory CD8+ T cells.

Our findings suggest that tofacitinib may activate immunosenescence pathways while simultaneously inhibiting effector functions in T cells, both effects likely contributing to the high clinical success and reported side effects of this JAK inhibitor in RA.
MHC I tetramer staining tends to overestimate the number of functionally relevant self‐reactive CD8 T cells in the preimmune repertoire
Authors: Pircher Hanspeter , Pinschewer Daniel D. , Boehm Thomas
Published: May 2023

Previous studies that used peptide‐MHC (pMHC) tetramers (tet) to identify self‐specific T cells have questioned the effectiveness of thymic‐negative selection. Here, we used pMHCI tet to enumerate CD8 T cells specific for the immunodominant gp33 epitope of lymphocytic choriomeningitis virus glycoprotein (GP) in mice transgenically engineered to express high levels of GP as a self‐antigen in the thymus. In GP‐transgenic mice (GP+), monoclonal P14 TCR+ CD8 T cells that express a GP‐specific TCR could not be detected by gp33/Db‐tet staining, indicative of their complete intrathymic deletion. By contrast, in the same GP+ mice, substantial numbers of polyclonal CD8 T cells identifiable by gp33/Db‐tet were present. The gp33‐tet staining profiles of polyclonal T cells from GP+ and GP‐negative (GP−) mice were overlapping, but mean fluorescence intensities were ∼15% lower in cells from GP+ mice. Remarkably, the gp33‐tet+ T cells in GP+ mice failed to clonally expand after lymphocytic choriomeningitis virus infection, whereas those of GP− mice did so. In Nur77GFP‐reporter mice, dose‐dependent responses to gp33 peptide‐induced TCR stimulation revealed that gp33‐tet+ T cells with high ligand sensitivity are lacking in GP+ mice. Hence, pMHCI tet staining identifies self‐specific CD8 T cells but tends to overestimate the number of truly self‐reactive cells.
Interferon‐α regulates abnormally increased expression of RSAD2 in Th17 and Tfh cells in systemic lupus erythematosus patients
Authors: Xin Yue , He Zhenghao , Mei Yang , Li Xi , Zhao Zhidan , Zhao Mingming , Yang Ming , Wu Haijing
Published: May 2023

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that often involves abnormal activation of regulatory IFN genes and regulation of B cells by CD4+ T cells. Radical S‐adenosyl methionine domain containing 2 (RSAD2) is a viral suppressor protein regulated by type I IFN, and it has been proven to play an important regulatory role in SLE. However, the mechanism by which RSAD2 participates in the pathogenesis of SLE is unclear. In this study, we observed higher expression levels of RSAD2 in CD4+ T‐cell subsets from the peripheral blood of SLE patients than in those from healthy controls by bioinformatics analysis and validation experiments. We analyzed the expression of RSAD2 in CD4+ T cells of patients with SLE and other autoimmune diseases. In addition, we found that the expression of RSAD2 in CD4+ T cells might be regulated by IFN‐α, and RSAD2 significantly affected the differentiation of Th17 cells and T follicular helper (Tfh) cells. Our findings underlined that RSAD2 may promote B‐cell activation by promoting the differentiation of Th17 and Tfh cells in SLE patients, a process that is regulated by IFN‐α.
High Stearic High Oleic Sunflower Oil Extraction: Influence of Temperature, Moisture, and Dehulling on Kinetic Parameters
Authors: de Figueiredo Ana K. , Fernández María B. , Nolasco Susana M.
Published: May 2023

In the present work, the influence of temperature, moisture content, and dehulling on the kinetic parameters of the oil extraction of high stearic high oleic (HSHO) sunflower seeds is analyzed. A modified Fick's diffusion model that considers extraction as the sum of two components (diffusion and washing) is used. The washing fraction (M0/M∞) and diffusion coefficients (Deff) are calculated taking into account the number of terms appropriate to each case. The statistical analysis shows a dependence of the washing fraction on temperature in the 40–50 °C range, while no statistical differences are detected in the 50–60 °C range. Although there are changes in the model parameters with the moisture content of the seeds (7.8%, 6.9%, and 4.8% dry basis), no specific trend is evidenced. The effective diffusion coefficient for the dehulled sample (1.48 ± 0.13 × 10−12 m2 s−1) is 60% higher than that of the unshelled sample (0.95 ± 0.05 × 10−12 m2 s−1). The extraction kinetics of tocopherols at 50 °C is also analyzed.

Practical Applications: The manuscript performs an analysis of different factors that influence the extraction of oil from high stearic high oleic (HSHO) sunflower seeds, which directly affect the efficiency of the oil extraction process. The results of this study provide useful information for a joint evaluation of oil extraction yields and costs resulting from the processing of a non‐conventional sunflower hybrid, promoting, in addition, the development of healthy high value‐added oils.
VEGF sticky‐trap: the first report of a non‐systemically acting angiogenesis inhibitor
Authors: Favara David M , Harris Adrian L
Published: May 2023

Current therapeutic anti‐angiogenic biologics used for the treatment of pathological ocular angiogenesis such as in diabetic retinopathy and wet macular degeneration often lead to detrimental side effects due to their interference with normal blood vessel physiology. In this issue of EMBO Molecular Medicine, Michael et al report on a novel angiogenesis inhibitor with unique properties that allow for local inhibition of angiogenesis without detectable systemic side effects.
Microglia‐specific knock‐out of NF‐κB/IKK2 increases the accumulation of misfolded α‐synuclein through the inhibition of p62/sequestosome‐1‐dependent autophagy in the rotenone model of Parkinson's disease
Authors: Rocha Savannah M. , Kirkley Kelly S. , Chatterjee Debotri , Aboellail Tawfik A. , Smeyne Richard J. , Tjalkens Ronald B.
Published: May 2023

Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide, with a greater prevalence in men than women. The etiology of PD is largely unknown, although environmental exposures and neuroinflammation are linked to protein misfolding and disease progression. Activated microglia are known to promote neuroinflammation in PD, but how environmental agents interact with specific innate immune signaling pathways in microglia to stimulate conversion to a neurotoxic phenotype is not well understood. To determine how nuclear factor kappa B (NF‐κB) signaling dynamics in microglia modulate neuroinflammation and dopaminergic neurodegeneration, we generated mice deficient in NF‐κB activation in microglia (CX3CR1‐Cre::IKK2fl/fl) and exposed them to 2.5 mg/kg/day of rotenone for 14 days, followed by a 14‐day post‐lesioning incubation period. We postulated that inhibition of NF‐κB signaling in microglia would reduce overall inflammatory injury in lesioned mice. Subsequent analysis indicated decreased expression of the NF‐κB‐regulated autophagy gene, sequestosome 1 (p62), in microglia, which is required for targeting ubiquitinated α‐synuclein (α‐syn) for lysosomal degradation. Knock‐out animals had increased accumulation of misfolded α‐syn within microglia, despite an overall reduction in neurodegeneration. Interestingly, this occurred more prominently in males. These data suggest that microglia play key biological roles in the degradation and clearance of misfolded α‐syn and this process works in concert with the innate immune response associated with neuroinflammation. Importantly, the accumulation of misfolded α‐syn protein aggregates alone did not increase neurodegeneration following exposure to rotenone but required the NF‐κB‐dependent inflammatory response in microglia.
The highly educated live longer: The role of time preference, cognitive ability, and educational plans
Authors: Norrgren Lisa Josefin
Published: May 2023

Using Swedish data on a cohort born in 1953, interviewed in 1966 (age 13), and followed with register data until 2018 (age 65), this study shows that one more year of schooling predicts a 17% lower risk of early mortality. Addressing concerns of potential selection bias, the mortality inequality by educational attainment persists when extensive controls are included in the regression. Adding information on background health, gender, socioeconomic variables, as well as adolescents' early educational plans, cognitive ability, and time preferences, only result in a 2‐percentage point change in the mortality risk by years of education. Even when adolescents' applications to upper‐secondary school and years 6 and 9 grades are controlled for, completion of upper‐secondary and university education remain strong predictors of future health. Yet, the study also finds that the measure of future health matters for the stability of the results.
Excess deaths by cause and place of death in England and Wales during the first year of COVID‐19
Authors: Laliotis Ioannis , Stavropoulou Charitini , Ceely Greg , Brett Georgia , Rushton Rachel
Published: May 2023

Using officially registered weekly mortality data, we estimate a counterfactual death count in the absence of the pandemic and we calculate the number of excess deaths in England and Wales during 2020 after the pandemic onset. We also break down those figures by region, age, gender, place of death, and cause of death. Our results suggest that there were 82,428 (95% Confidence interval [CI]: 78,402 to 86,415) excess deaths, and 88.9% (95% CI: 84.8%–93.5%) of them was due to COVID‐19, suggesting that non‐COVID‐19 excess mortality may have been slightly higher that what has been previously estimated. Regarding deaths not due to COVID‐19, persons older than 45 years old who died at their homes, mainly from heart diseases and cancer, were the most affected group. Across all causes of death, there was increased excess mortality from dementia and Alzheimer's disease, diabetes, Parkinson's disease and heart‐related disease, while at the same period there was a reduction in deaths from pneumonia and influenza, stroke as well as infectious diseases and accidents. Supported by regional panel event estimates, our results highlight how measures to mitigate the pandemic spread and ease the pressure on healthcare service systems may adversely affect out‐of‐hospital mortality from other causes.
A retrospective study for association between post‐transfusion hemoglobin S level and pre‐transfusion hemoglobin S level at the next scheduled transfusion
Authors: Wu Ding Wen , Jacobson Jessica , Lifshitz Mark , Li Yanhua , Lyu Chen , Friedmann Rachel , Walsh Ronald , Himchak Evan , Mohandas Kala , Karim Sadiqa , Marks Etan , Himchak Sang Hwa , Hilbert Timothy
Published: May 2023

Background

Patients with sickle cell disease (SCD) frequently undergo prophylactic red blood cell (RBC) exchange transfusion and simple transfusion (RCE/T) to prevent complications of disease, such as stroke. These treatment procedures are performed with a target hemoglobin S (HbS) of ≤30%, or a goal of maintaining an HbS level of <30% immediately prior to the next transfusion. However, there is a lack of evidence‐based instructions for how to perform RCE/T in a way that will result in an HbS value <30% between treatments.

Principal objective

To determine whether targets for post‐treatment HbS (post‐HbS) or post‐treatment HCT (post‐HCT) can help to maintain an HbS <30% or <40% between treatments.

Materials and methods

We performed a retrospective study of patients with SCD treated with RCE/T at Montefiore Medical Center from June 2014 to June 2016. The analysis included patients of all ages, and data including 3 documented parameters for each RCE/T event: post‐HbS, post‐HCT, and follow‐up HbS (F/u‐HbS), which is the pre‐treatment HbS prior to the next RCE/T. Generalized linear mixed model was used for estimating the association between post‐HbS or post‐HCT levels and F/u‐HbS <30%.

Results

Based on our results, targeting post‐HbS ≤10% was associated with higher odds of having events of F/u‐HbS <30% between monthly treatments. Targeting post‐HbS ≤15% was associated with higher odds of events of F/u‐HbS < 40%. As compared to post‐HCT ≤30%, a post‐HCT >30%‐36% did not contribute to more F/u‐HbS <30% or HbS <40% events.

Conclusions

For patients with SCD undergoing regular RCE/T for stroke prevention, a post‐HbS ≤10% can be used as a goal to help maintain an HbS <30% for 1 month, and a post‐HbS ≤15% allowed patients to maintain HbS <40%.
The association of genetic polymorphisms in protocadherin 15 with sudden sensorineural hearing loss in a Chinese population
Authors: Lan Ying , Hou Tao , Peng Lu , Li Yongpeng , Yin Shihua
Published: May 2023

Background

Sudden sensorineural hearing loss (SSNHL) is a multifactorial disease, and its etiology is still unknown. SSNHL may be caused by environmental factors and genetic changes. PCDH15 is associated with susceptibility to hearing loss. The relationship between PCDH15 and SSNHL remains unknown.

Methods

In this study, the potential association between PCDH15 polymorphism and SSNHL in Chinese population was evaluated. Two single nucleotide polymorphisms PCDH15‐rs7095441 and rs11004085 in 195 SSNHL patients and 182 healthy controls were determined by TaqMan technology.

Results

In Chinese population, the TT genotype and T allele of rs7095441 are associated with increased susceptibility to SSNHL. The relationships between rs7095441 and the degree of hearing loss were analyzed, and TT genotype increased the risk of hearing loss. Among SSNHL patients, patients with TT genotype of rs7095441 have an increased risk of vertigo.

Conclusion

This study found that the TT genotype of SNP rs7095441 can increase the risk of SSNHL in Chinese population.
Evolutionary traces of miniaturization in a giant—Comparative anatomy of brain and brain nerves inBathochordaeus stygius(Tunicata, Appendicularia)
Authors: Zemann Berit , Le Mai‐Lee Van , Sherlock Rob E. , Baum Daniel , Katija Kakani , Stach Thomas
Published: May 2023

Appendicularia comprises 70 marine, invertebrate, chordate species. Appendicularians play important ecological and evolutionary roles, yet their morphological disparity remains understudied. Most appendicularians are small, develop rapidly, and with a stereotyped cell lineage, leading to the hypothesis that Appendicularia derived progenetically from an ascidian‐like ancestor. Here, we describe the detailed anatomy of the central nervous system ofBathochordaeus stygius, a giant appendicularian from the mesopelagic. We show that the brain consists of a forebrain with on average smaller and more uniform cells and a hindbrain, in which cell shapes and sizes vary to a greater extent. Cell count for the brain was 102. We demonstrate the presence of three paired brain nerves. Brain nerve 1 traces into the epidermis of the upper lip region and consists of several fibers with some supportive bulb cells in its course. Brain nerve 2 innervates oral sensory organs and brain nerve 3 innervates the ciliary ring of the gill slits and lateral epidermis. Brain nerve 3 is asymmetric, with the right nerve consisting of two neurites originating posterior to the left one that contains three neurites. Similarities and differences to the anatomy of the brain of the model speciesOikopleura dioicaare discussed. We interpret the small number of cells in the brain ofB. stygiusas an evolutionary trace of miniaturization and conclude that giant appendicularians evolved from a small, progenetic ancestor that secondarily increased in size within Appendicularia.
Intra‐ and Peritumoral Based Radiomics for Assessment of Lymphovascular Invasion in Invasive Breast Cancer
Authors: Jiang Wenyan , Meng Ruiqing , Cheng Yuan , Wang Haotian , Han Tingting , Qu Ning , Yu Tao , Hou Yang , Xu Shu
Published: May 2023

Background

Radiomics has been applied for assessing lymphovascular invasion (LVI) in patients with breast cancer. However, associations between features from peritumoral regions and the LVI status were not investigated.

Purpose

To investigate the value of intra‐ and peritumoral radiomics for assessing LVI, and to develop a nomogram to assist in making treatment decisions.

Study Type

Retrospective.

Population

Three hundred and sixteen patients were enrolled from two centers and divided into training (N = 165), internal validation (N = 83), and external validation (N = 68) cohorts.

Field Strength/Sequence

1.5 T and 3.0 T/dynamic contrast‐enhanced (DCE) and diffusion‐weighted imaging (DWI).

Assessment

Radiomics features were extracted and selected based on intra‐ and peritumoral breast regions in two magnetic resonance imaging (MRI) sequences to create the multiparametric MRI combined radiomics signature (RS‐DCE plus DWI). The clinical model was built with MRI‐axillary lymph nodes (MRI ALN), MRI‐reported peritumoral edema (MPE), and apparent diffusion coefficient (ADC). The nomogram was constructed with RS‐DCE plus DWI, MRI ALN, MPE, and ADC.

Statistical Tests

Intra‐ and interclass correlation coefficient analysis, Mann–Whitney U test, and least absolute shrinkage and selection operator regression were used for feature selection. Receiver operating characteristic and decision curve analyses were applied to compare performance of the RS‐DCE plus DWI, clinical model, and nomogram.

Results

A total of 10 features were found to be associated with LVI, 3 from intra‐ and 7 from peritumoral areas. The nomogram showed good performance in the training (AUCs, nomogram vs. clinical model vs. RS‐DCE plus DWI, 0.884 vs. 0.695 vs. 0.870), internal validation (AUCs, nomogram vs. clinical model vs. RS‐DCE plus DWI, 0.813 vs. 0.695 vs. 0.794), and external validation (AUCs, nomogram vs. clinical model vs. RS‐DCE plus DWI, 0.862 vs. 0.601 vs. 0.849) cohorts.

Data Conclusion

The constructed preoperative nomogram might effectively assess LVI.

Level of Evidence

3

Technical Efficacy

Stage 2
Dispersive solid‐phase extraction of risperidone from plasma samples using graphene oxide aerogels and determination with liquid chromatography
Authors: Feyzi Faez , Soleymani Jafar , Dastmalchi Siavoush , Ranjbar Fatemeh , Jouyban Abolghasem
Published: May 2023

A graphene oxide‐based aerogel was synthesized and applied to the extraction and the determinations with the high‐performance liquid chromatography‐ultraviolet detector. After the characterization of the produced graphene‐aerogel, it was utilized as a dispersive solid‐phase extraction sorbent for risperidone extraction from plasma samples. Aerogels are materials with a large surface area‐to‐mass ratio and plenty of core with functional groups which can easily attach to the analytes to extract them to the second phase. The suggested method determined risperidone in plasma samples in the wide dynamic range from 20 ng/ml to 3 μg/ml. The limits of detection and quantification of the developed method were calculated as 2.4 and 8.2 ng/ml, respectively. As a novel feature, the developed method has no need to precipitate plasma proteins, improving the analytical performance of the analysis. Also, for the first time, the produced materials were utilized for the extraction of risperidone from the plasma samples. The obtained results revealed that the developed approach could be employed as an accurate method for the quantification of risperidone in real plasma samples.
A multidimensional assessment and analysis of farmland fragmentation in the southeast coastal area of China
Authors: Zou Lilin , Liang Yifan , Hu Xuedong , Bai Mengdi , Wen Qi
Published: May 2023

Farmland fragmentation is a typical feature of arable land use in the economies dominated by smallholder production mode, and scientific evaluation of farmland fragmentation is an effective and crucial process to find and solve problems. Farmland fragmentation, as a kind of long‐standing physiographic landscape and agricultural economic phenomenon under the comprehensive effect of “human‐land‐property rights”, not only contains the scale status and spatial distribution of cultivated patches but also is featured with farming and tenure right. However, the theoretical interpretation of the multidimensional characteristics of farmland fragmentation was insufficient, and it was rare to evaluate the farmland fragmentation based on plot scale. To this end, an evaluation framework of farmland fragmentation with four dimensions and 12 indicators was constructed in this paper. Moreover, regarding Minqing County located in China's southeast coast as a case, empirical research was thus conducted. The findings indicated that the physical properties of farmland patches were depicted through scale fragmentation. Spatial fragmentation represented the spatial distribution of farmland patches. Farming fragmentation revealed agricultural production and management differences while tenure fragmentation embodied the tenure rights segmentation induced by the land distribution system. Farmland fragmentation consolidation was an effective way to solve these issues, and some differential tactics should be conducted in accordance with the path of “zoning types–obstacle factors–consolidation directions–treatment measures”.