bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease
Authors: Baccam Gabriel C. , Xie Jian , Jin Xin , Park Hyejung , Wang Bing , Husson Hervé , Ibraghimov-Beskrovnaya Oxana , Huang Chou-Long
Published: June 2022

A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the heart against hypertrophic growth. We have shown that sKL protects the heart by regulating the formation and function of lipid rafts by targeting the sialic acid moiety of gangliosides, GM1/GM3. Reduction in circulating sKL contributes to an increased risk of cardiac hypertrophy in mice. sKL replacement therapy has been considered but its use is limited by the inability to mass produce the protein. Therefore, alternative methods to protect the heart are proposed. Glucosylation of ceramide catalyzed by glucosylceramide synthase is the entry step for the formation of gangliosides. Here we show that oral administration of a glucosylceramide synthase inhibitor (GCSi) reduces plasma and heart tissue glycosphingolipids, including gangliosides. Administration of GCSi is protective in two mouse models of cardiac stress-induction, one with isoproterenol overstimulation and the other with 5/6 nephrectomy-induced CKD. Treatment with GCSi does not alter the severity of renal dysfunction and hypertension in CKD. These results provide proof of principle for targeting glucosylceramide synthase to decrease gangliosides as a treatment for cardiac hypertrophy. They also support the hypothesis that sKL protects the heart by targeting gangliosides.
Neoscytalidium novaehollandiae causes dieback on Pinus eldarica and its potential for infection of urban forest trees
Authors: Alizadeh Mehrdad , Safaie Naser , Shams-Bakhsh Masoud , Mehrabadi Mohammad
Published: June 2022

Neoscytalidium novaehollandiae is one of the most important pathogens on woody plants which has increasingly been reported as a pathogen in different hosts in recent years. The pine trees are widely cultured in many cities of Iran. In recent years, dieback symptoms were observed on Pinus eldarica trees in Tehran and Qazvin provinces. The aim of this study was to investigate the dieback causal agent on P. eldarica trees in Iran. The branches and cones of P. eldarica trees were sampled for fungal isolation. The morphological and molecular characterizations (ITS, LSU, and TEF1-α regions) identified N. novaehollandiae as a dieback causal agent. This is the first report of N. novaehollandiae disease of P. eldarica trees in Iran. Furthermore, disease severity was assayed on 19 urban forest trees under three different temperature and relative humidity (RHs) regimes. C regime (29 °C and 15% RH) displayed more disease severity on detached branches than B (24 °C and 80% RH) and A (19 °C and 35% RH) ones. This study presents the host range of this pathogen, and showed that these potential hosts are prone to this pathogen under high temperature and low humidity which urban forest trees experienced in recent decades.
Prenatal stress perturbs fetal iron homeostasis in a sex specific manner
Authors: Zimmermann Peter , Antonelli Marta C. , Sharma Ritika , Müller Alexander , Zelgert Camilla , Fabre Bibiana , Wenzel Natasha , Wu Hau-Tieng , Frasch Martin G. , Lobmaier Silvia M.
Published: June 2022

The adverse effects of maternal prenatal stress (PS) on child’s neurodevelopment warrant the establishment of biomarkers that enable early interventional therapeutic strategies. We performed a prospective matched double cohort study screening 2000 pregnant women in third trimester with Cohen Perceived Stress Scale-10 (PSS-10) questionnaire; 164 participants were recruited and classified as stressed and control group (SG, CG). Fetal cord blood iron parameters of 107 patients were measured at birth. Transabdominal electrocardiograms-based Fetal Stress Index (FSI) was derived. We investigated sex contribution to group differences and conducted causal inference analyses to assess the total effect of PS exposure on iron homeostasis using a directed acyclic graph (DAG) approach. Differences are reported for p < 0.05 unless noted otherwise. Transferrin saturation was lower in male stressed neonates. The minimum adjustment set of the DAG to estimate the total effect of PS exposure on fetal ferritin iron biomarkers consisted of maternal age and socioeconomic status: SG revealed a 15% decrease in fetal ferritin compared with CG. Mean FSI was higher among SG than among CG. FSI-based timely detection of fetuses affected by PS can support early individualized iron supplementation and neurodevelopmental follow-up to prevent long-term sequelae due to PS-exacerbated impairment of the iron homeostasis.
Magnetoelectrically ignited nanozyme-eel for combating bacterial biofilms
Authors: Deng Qingqing , Zhang Lu , Liu Xuemeng , You Yawen , Ren Jinsong , Qu Xiaogang
Published: June 2022

A magnetoelectrically ignited nanozyme-eel was developed, which could generate abundant surface charges upon the ignition of an alternating magnetic field, leading to the electron transport burst for bacterial biofilms eradication.
Thermally stimuli-responsive materials with transformable double channels of nonlinear optical and dielectric properties
Authors: Zhang Zhi-Cheng , Zhang Tie , Huang Pei-Zhi , Shao Ting , Fu Da-Wei , Zhang Yi
Published: June 2022

Ordered–disordered motion of cations induces phase transitions accompanying dielectric and nonlinear optical dual channels.
Observer‐based distributed model predictive control of complex systems with state coupling constraints
Authors: Du Shengli , Cao Boqi , Li Xu
Published: June 2022

In this paper, the cooperative distributed model predictive control (DMPC) problem of a class of complex systems consisting of several subsystems is studied. The states of these subsystems are coupled with each other, and thus bring challenges for the model predictive control algorithm. Moreover, though the subsystems can communicate with each other, they only can access to the output information of their neighboring subsystems. In this case, Luenberger observers are used to estimate the unknown states and a distributed prediction strategy is established for the studied system. Then, the optimal control of the closed‐loop system is realized by designing distributed model predictive controller on the basis of the estimated states. The terminal constraints are introduced in the proposed DMPC algorithm to ensure the iterative feasibility and also the stability of the closed‐loop. Finally, the effectiveness of the proposed method is verified by a numerical simulation.
A construction for girth‐8 QC‐LDPC codes using Golomb rulers
Authors: Kim Inseon , Song Hong‐Yeop
Published: June 2022

In this paper, an algebraic construction of regular QC‐LDPC codes by using the modular multiplication table mod P and Golomb rulers are proposed. It is proved that the proposed QC‐LDPC codes based on a Golomb ruler of length L have girth at least 8 if . The error performance of the proposed QC‐LDPC codes are simulated with various Golomb rulers. The proposed codes of length around 300 from the optimal 6‐mark Golomb ruler have an additional coding gain of at least 0.1 dB over 5G NR LDPC codes, 0.5 dB over those given earlier by others, both at FER 10−3. Some non‐trivial techniques to increase the length of a given Golomb ruler with and without an additional mark for improving the performance of the codes from Golomb rulers up to 0.7 dB are also found.
A single watermark based scheme for both protection and authentication of identities
Authors: Sharma S. , Zou J.J. , Fang G.
Published: June 2022

The security of a watermarking scheme is mainly categorised as either robust or fragile. The former can withstand an authorised alteration/attack, primarily used in copyright protection. The latter follows a zero tolerance towards any modification, used primarily in content authentication processes. The existing literature in the field projects that two separate watermarks are required to make a watermarking scheme robust and fragile, thus making the overall process cumbersome and complex. A novel image watermarking scheme that uses only one watermark while achieving both goals of copyright protection and authentication of identities is presented. An unconventional concept of checkpointing is introduced, which equips the proposed scheme to be either robust or fragile, making it superior in its application versatility. First, watermark embedding within the host/original image is achieved by a combination of transform domain techniques along with a novel median‐based embedding block selection procedure. Second, checkpointing is performed in the spatial domain. The watermarked image in the absence of an attack is correlated to the one that is being attacked, using the template energy comparison‐based approach. In the case of the robust watermark, such checkpointing can establish whether the carried out attack is authorised or not, determining the successful recovery of the watermark or vice‐versa. Moreover, in the case of the fragile watermark, a sole confirmation of the occurrence of an attack is sufficient to make the watermark recovery impossible. Finally, the experimental analysis of the proposed scheme illustrates its excellent performance and superiority over state‐of‐the‐art methods within the field.
Dynamic event‐triggered model predictive control of Vienna rectifiers in DC charging system
Authors: Du Yudong , Zhang Aimin , Huang Jingjing , Zhou Yunhong , Zhang Hang
Published: June 2022

Here, a dynamic event‐triggered model predictive control (DETMPC) of Vienna rectifiers in the DC charging system is proposed to solve the excessive calculation burden of the conventional MPC method while maintaining the system performance. The status of the system is constantly updated, and the next model predictive control calculation is performed only when the system state meets the event‐triggered condition. Otherwise, the original switch state signal is maintained, which can greatly reduce the computational burden. A dynamic variable is introduced into the trigger condition to holdover the steady‐state performance as the system state changes. An experimental comparative analysis is carried out to verify the correctness and effectiveness of the proposed DETMPC method. The results demonstrate that the proposed method can effectively reduce calculation burden and switching loss while maintaining satisfactory system performance at the same time.
An improved wide ZVS soft‐switching range PWM bidirectional forward converter for low power applications with simple control circuit
Authors: Bahrami Hamid , Allahyari Hesamodin , Adib Ehsan
Published: June 2022

This paper presents a new PWM (Pulse Width Modulation) ZVS (Zero Voltage Switching) bidirectional forward DC‐DC converter. The proposed bidirectional forward converter uses two main switches and employs the leakage inductance of the transformer to transfer the power. Two auxiliary capacitors are paralleled with the main switches to provide the ZVS soft‐switching condition and to reset the transformer core. Having two main switches, one transformer, and two auxiliary capacitors makes the proposed converter simple and low cost. Compared with the main counterpart, the proposed converter uses PWM which is really simple relative to the phase shift voltage matching control approach. Moreover, to provide the ZVS soft switching conditions, the magnetizing inductance value should be large which decreases the circulating current and increases the efficiency significantly in both boost and buck directions especially at the low power. The ZVS soft‐switching conditions can be maintained from low power to full load. The operating modes of the proposed converter along with the design approach and the stress analysis are completely considered. To verify the theoretical results, a prototype is constructed and the theoretical results are compared with the experimental results.
Blockchain mediated virtual power plant: From concept to demonstration
Authors: Mnatsakanyan Ashot , Albeshr Hamad , Almarzooqi Ali , Iraklis Christos , Bilbao Endika
Published: June 2022

Large penetration of various types of distributed energy resources and new requirements in electricity markets, have facilitated creation of sophisticated distributed energy resource aggregation systems for providing grid services. Aggregators such as Virtual Power Plants enable participation of small‐ and medium‐scale distributed energy resources in electricity markets, interacting with grid operators to collectively provide ancillary power and energy services. These interactions between grid operator, Virtual Power Plants operator and distributed energy resources are complex both in terms of contractual agreements and provision of services. On all layers, accurate tracking of distributed energy resource usage and execution of contracts is required for establishing trust between transacting participants. Digitalisation and automation of processes such as control of distributed energy resources, verification and payouts for services will add value for solving complexity of dealing with multiple parties in a Virtual Power Plants aggregation model. The authors present a blockchain‐integrated Virtual Power Plants system that enables full automation of distributed energy resource controls through smart contracts, digital trust between participants and immediate payouts for services. Effectiveness of the developed blockchain mechanism is demonstrated on a pilot Virtual Power Plants system comprising distributed energy storage systems, renewables, EV charging stations and loads with a total size of 1.8 MWs. Additionally, we propose a new mechanism for managing renewable energy curtailments through blockchain.
Central star formation in double-peak, gas-rich radio galaxies
Authors: Maschmann Daniel , Melchior Anne-Laure , Combes Francoise , Mazzilli Ciraulo Barbara , Freundlich Jonathan , Halle Anaëlle , Drabent Alexander
Published: June 2022

The respective contributions of gas accretion, galaxy interactions, and mergers to the mass assembly of galaxies, as well as the evolution of their molecular gas and star-formation activity are still not fully understood. In a recent work, a large sample of double-peak (DP) emission-line galaxies have been identified from the SDSS. While the two peaks could represent two kinematic components, they may be linked to the large bulges that their host galaxies tend to have. Star-forming DP galaxies display a central star-formation enhancement and have been discussed as compatible with a sequence of recent minor mergers. In order to probe merger-induced star-formation mechanisms, we conducted observations of the molecular-gas content of 35 star-forming DP galaxies in the upper part of the main sequence (MS) of star formation (SF) with the IRAM 30 m telescope. Including similar galaxies 0.3 dex above the MS and with existing molecular-gas observations from the literature, we finally obtained a sample of 52 such galaxies. We succeeded in fitting the same kinematic parameters to the optical ionised- and molecular-gas emission lines for ten (19%) galaxies. We find a central star-formation enhancement resulting most likely from a galaxy merger or galaxy interaction, which is indicated by an excess of gas extinction found in the centre. This SF is traced by radio continuum emissions at 150 MHz, 1.4 GHz, and 3 GHz, all three of which are linearly correlated in log with the CO luminosity with the same slope. The 52 DP galaxies are found to have a significantly larger amount of molecular gas and longer depletion times, and hence a lower star-formation efficiency, than the expected values at their distance of the MS. The large bulges in these galaxies might be stabilising the gas, hence reducing the SF efficiency. This is consistent with a scenario of minor mergers increasing the mass of bulges and driving gas to the centre. We also excluded the inwards-directed gas migration and central star-formation enhancement as the origin of a bar morphology. Hence, these 52 DP galaxies could be the result of recent minor mergers that funnelled molecular gas towards their centre, triggering SF, but with moderate efficiency.
Sensor-size-related attenuation correction of wall pressure spectra measurements
Authors: Hu Nan
Published: June 2022

A correction model is presented for sensor-size-related high-frequency attenuation when measuring the wall pressure fluctuations beneath turbulent boundary layers. The model is developed based on the wall pressure spectra measured on a flat plate model using sensors of different sizes and types. The measurement covers the range of Reynolds numbers, Reθ, based on the momentum thickness between 1500 and 11 400, including flows with adverse and favorable pressure gradients, which were produced by a National Advisory Committee for Aeronautics (NACA) 0012 airfoil installed above the flat plate. The present model follows the principle of the Corcos correction and is expressed with a simple mathematical form. Major improvements compared with the Corcos correction are made with regard to determining the effective sensing area and the convection velocity for a specific sensor. With the help of convection velocity modeling, the present correction model can be applied to flows in pressure gradients with high accuracy. To assess the generality of the assumptions, the model is used to correct the wall pressure spectra measured at different test facilities with different sensor types, covering a large range of Reynolds numbers, 1.6×103<Reθ<1.19×105.
Research on the interference characteristics of successively launched underwater projectiles
Authors: Lu Jiaxing , Bi Dianfang , Wang Cong , Wei Yingjie , Wang Wenjun , Zhang Dehua
Published: June 2022

In the successive underwater launch of two projectiles, wake vortices shed from the leading projectile have significant effects on the subsequent projectile's hydrodynamic forces, attitude, and trajectory. Herein, experimental research is conducted by successively launching two underwater projectiles at prescribed transport velocities using embedded inertial measurement units to record acceleration data simultaneous with a high-speed camera to visualize the cavity behaviors. After a trial error evaluation, the interference between two conical-nosed projectiles is shown to increase as wake vortices develop from dispersed vortex rings at low transport velocities into continuous counterrotating vortex pairs at high transport velocities. Thus, the second projectile experiences less lateral movement and rotation than the first projectile at u > 0.1 m s−1. The effect of the nose shape is also studied by conducting experiments on ellipsoidal-nosed projectiles, whose trends are similar to those of the conical-nosed projectiles. A quantitative comparison of the interference shows that the ellipsoidal-nosed projectiles experience more interference than the conical-nosed projectiles due to the absence of the shoulder cavity.
Numerical prediction of cavitation erosion risk in an axisymmetric nozzle using a multi-scale approach
Authors: Wang Ziyang , Cheng Huaiyu , Ji Bin
Published: June 2022

In the present study, a two-way coupling Eulerian–Lagrangian approach is developed to assess the cavitation erosion risk in an axisymmetric nozzle. Macroscopic cavitation structures are simulated using the large eddy simulation along with the volume of fluid method. The compressible Rayleigh–Plesset equation and the bubble motion equation are introduced to resolve the microscopic bubble dynamics. The calculated results agree favorably with the experimental data and can capture more flow details, which is associated with the potential erosion risk. Based on the bubble information in multi-scale cavitating flow, a new asymmetric bubble collapse model is proposed to calculate the impact pressure, which is then used to quantitatively assess the cavitation erosion risk in the nozzle. The results show that, compared with the traditional Euler method, the location and value of the potential maximum cavitation erosion risk predicted by this new method are closer to the experimental measurement. The advantages of the newly proposed method are further elaborated systematically. The study found that the high environmental pressure triggered by the collapse of shedding clouds can cause the near-wall bubbles to shrink and even collapse, releasing impulsive pressure, which directly damages the material surface. This phenomenon is considered to be closer to the actual cavitation erosion process. Finally, analyzing the relationship between multi-scale cavitation structures and erosion risk reveals that the high risk of cavitation erosion is mainly due to the oscillation and collapse of near-wall bubbles which are generated near the attached cavity closure line or surrounding the shedding clouds.
Theoretical investigation of droplet splitting due to electrowetting on dielectric in a Hele–Shaw cell
Authors: Katoh Kenji , Wakimoto Tatsuro , Ito Takahiro , Matsuura Jyobu
Published: June 2022

In this study, we investigated electrowetting on the dielectric-induced splitting behavior of droplets placed in a Hele–Shaw cell. The deformation behavior of the droplet was experimentally observed under various applied voltages. A theoretical model was proposed to express the droplet behavior by balancing the surface tension, viscous force, and pressure acting on the droplet. The effect of the dynamic contact angle was considered and used to estimate the capillary force along the moving contact line. The results obtained from the theoretical model showed a qualitative agreement with the deformation behavior of the observed droplets. An approximate model was proposed to verify the observations that demonstrated that the contact line widths at the boundary between the positive and negative electrodes remain almost constant during the splitting process. The behavior of the contact linewidth was explained using the model based on the minimum work required for droplet deformation during the splitting process.
Effects of exercise training on glycaemic control in youths with type 1 diabetes: A systematic review and meta‐analysis of randomised controlled trials
Authors: García‐Hermoso Antonio , Ezzatvar Yasmin , Huerta‐Uribe Nidia , Alonso‐Martínez Alicia M. , Chueca‐Guindulain Maria J. , Berrade‐Zubiri Sara , Izquierdo Mikel , Ramírez‐Vélez Robinson
Published: June 2022

The aim of the study is to evaluate whether exercise interventions are associated with improved glycaemic control in children and adolescents with type 1 diabetes mellitus (T1DM), and to examine its relationship with the characteristics of the intervention (i.e. type, intensity, length, and duration of the sessions). Eligible criteria were randomised controlled trials of youth aged 6–18 years with T1DM, participating in an exercise‐based intervention where glycaemic control is measured (i.e. glycated haemoglobin [HbA1c]). Pooled effect sizes (Hedges'g) were calculated using random‐effects inverse‐variance analyses. Fourteen studies enrolling 509 patients were analysed. Effect size was expressed as Hedges’ g to correct for possible small sample bias. Overall, HbA1c levels in the exercise group (g = –0.38 95% confidence interval [CI], –0.66 to –0.11; mean difference [MD] = –0.62%) were reduced compared with the control group. Concurrent training (g = –0.63 95%CI, –1.05 to –0.21), high‐intensity exercise (g = –0.43 95%CI, –0.83 to –0.03), interventions ≥24 weeks (g = –0.92 95%CI, –1.44 to –0.40), and sessions ≥60 minutes (g = –0.71 95%CI, –1.05 to –0.08) showed larger changes (MD = –0.66% to 1.30%). In conclusion, our study suggests that programmes longer than 24 weeks with at least 60 min/session of high‐intensity concurrent exercise may serve as a supportive therapy to metabolic control in youth with T1DM.

Highlights

Exercise training has a moderate effect on the reduction of glycated haemoglobin (HbA1c) and insulin dose per day in youths with type 1 diabetes.

Exercise training moderately increases cardiorespiratory fitness youths with type 1 diabetes.

Reductions in HbA1c are stronger with high‐intensity and concurrent training (i.e. aerobic and strength) interventions, and longer programmes.
Reformulating provider profiling by grouping providers treating similar patients prior to evaluating performance
Authors: Silva Gabriella C , Gutman Roee
Published: June 2022

Standard approaches to comparing health providers’ performance rely on hierarchical logistic regression models that adjust for patient characteristics at admission. Estimates from these models may be misleading when providers treat different patient populations and the models are misspecified. To address this limitation, we propose a novel profiling approach that identifies groups of providers treating similar populations of patients and then evaluates providers’ performance within each group. The groups of providers are identified using a Bayesian multilevel finite mixture of general location models. To compare the performance of our proposed profiling approach to standard methods, we use patient-level data from 119 skilled nursing facilities in Massachusetts. We use simulated and observed outcome data to explore the performance of these profiling methods in different settings. In simulations, our proposed method classifies providers to groups with similar patients’ admission characteristics. In addition, in the presence of limited overlap in patient characteristics across providers and misspecifications of the outcome model, the provider-level estimates obtained using our approach identified providers that under- and overperformed compared to the standard regression-based approaches more accurately.
Altered functional coupling between the cerebellum and cerebrum in patients with amnestic mild cognitive impairment
Authors: Li Hehui , Guan Qing , Huang Rong , Lei Mengmeng , Luo Yue-Jia , Zhang Zhanjun , Tao Wuhai
Published: June 2022

Cognitive processing relies on the functional coupling between the cerebrum and cerebellum. However, it remains unclear how the 2 collaborate in amnestic mild cognitive impairment (aMCI) patients. With functional magnetic resonance imaging techniques, we compared cerebrocerebellar functional connectivity during the resting state (rsFC) between the aMCI and healthy control (HC) groups. Additionally, we distinguished coupling between functionally corresponding and noncorresponding areas across the cerebrum and cerebellum. The results demonstrated decreased rsFC between both functionally corresponding and noncorresponding areas, suggesting distributed deficits of cerebrocerebellar connections in aMCI patients. Increased rsFC was also observed, which were between functionally noncorresponding areas. Moreover, the increased rsFC was positively correlated with attentional scores in the aMCI group, and this effect was absent in the HC group, supporting that there exists a compensatory mechanism in patients. The current study contributes to illustrating how the cerebellum adjusts its coupling with the cerebrum in individuals with cognitive impairment.
Risk perception, farmer−herder conflicts and production decisions: evidence from Nigeria
Authors: Nnaji Amaka , Ratna Nazmun , Renwick Alan , Ma Wanglin
Published: June 2022

This paper investigates the influence of the risk perception of farmer−herder (FH) conflicts on rural households’ production decisions. Extending the farm household model to include the risk perception of farmer−herder conflicts, we test hypotheses derived using primary data from 401 rural households in Nigeria. Results indicate that higher risk perception of FH conflict reduces fertiliser use and increases the time allocated for farm work. Dividing households based on their risk aversion, we find that risk-averse households rent-in significantly less cropland compared to risk-taking households. Findings highlight the need for policies that sustainably tackle FH conflicts for improved agricultural production.
The association of HpDof1.7 and HpDof5.4 with soluble sugar accumulation in pitaya fruit by transcriptionally activating sugar metabolic genes
Authors: Mou Zhenliang , Zeng Runxi , Chen Nanhui , Liu Zongli , Zeng Zexiang , Qin Yonghua , Shan Wei , Kuang Jianfei , Lu Wangjin , Chen Jianye , Zhao Yating
Published: June 2022

Soluble sugar is one of the most important factors affecting fruit flavor and quality. Here, we report the identification of two Dof (DNA-binding with one finger) transcription factors termed HpDof1.7 and HpDof5.4 and their roles in influencing sugar accumulation in pitayas. HpDof1.7 and HpDof5.4 share a similar expression pattern with sugar metabolism-related genes HpSuSy1 and HpINV2, and sugar transporter genes HpTMT2 and HpSWEET14 during pitayas maturation, and their expression pattern was also consistent with the accumulation of glucose and fructose, which were the predominant sugars in pitayas. HpDof1.7 and HpDof5.4 were both typical nucleus-localized proteins with trans-activation ability. Gel mobility shift assay revealed that HpDof1.7 and HpDof5.4 were bound to promoters of HpSuSy1, HpINV2, HpTMT2 and HpSWEET14. Finally, transient expression assays in tobacco leaves showed that HpDof1.7 and HpDof5.4 increased the activities of HpSuSy1, HpINV2, HpTMT2 and HpSWEET14 promoters, thus facilitating sugar accumulation by transcriptionally enhancing sugar metabolic pathway genes. Our findings provide a new perspective on the regulatory mechanisms of Dof transcription factors in sugar accumulation and pitaya fruit quality formation.
The primary pharmacology of ceftazidime/avibactam: in vitro translational biology
Authors: Nichols Wright W , Bradford Patricia A , Lahiri Sushmita D , Stone Gregory G
Published: June 2022

Previous reviews of ceftazidime/avibactam have focused on in vitro molecular enzymology and microbiology or the clinically associated properties of the combination. Here we take a different approach. We initiate a series of linked reviews that analyse research on the combination that built the primary pharmacology data required to support the clinical and business risk decisions to perform randomized controlled Phase 3 clinical trials, and the additional microbiological research that was added to the above, and the safety and chemical manufacturing and controls data, that constituted successful regulatory licensing applications for ceftazidime/avibactam in multiple countries, including the USA and the EU. The aim of the series is to provide both a source of reference for clinicians and microbiologists to be able to use ceftazidime/avibactam to its best advantage for patients, but also a case study of bringing a novel β-lactamase inhibitor (in combination with an established β-lactam) through the microbiological aspects of clinical development and regulatory applications, updated finally with a review of resistance occurring in patients under treatment. This first article reviews the biochemistry, structural biology and basic microbiology of the combination, showing that avibactam inhibits the great majority of serine-dependent β-lactamases in Enterobacterales and Pseudomonas aeruginosa to restore the in vitro antibacterial activity of ceftazidime. Translation to efficacy against infections in vivo is reviewed in the second co-published article, Nichols et al. (J Antimicrob Chemother 2022; 77: 2341–52).
The primary pharmacology of ceftazidime/avibactam: in vivo translational biology and pharmacokinetics/pharmacodynamics (PK/PD)
Authors: Nichols Wright W , Bradford Patricia A , Stone Gregory G
Published: June 2022

This review describes the translational in vivo and non-clinical pharmacokinetics/pharmacodynamics (PK/PD) research that supported clinical trialling and subsequently licensing approval of ceftazidime/avibactam, a new β-lactam/β-lactamase inhibitor combination aimed at the treatment of infections by Enterobacterales and Pseudomonas aeruginosa. The review thematically follows on from the co-published article, Nichols et al. (J Antimicrob Chemother 2022; 77: 2321–40). Avibactam protected ceftazidime in animal models of infection with ceftazidime-resistant, β-lactamase-producing bacteria. For example, a single subcutaneous dose of ceftazidime at 1024 mg/kg yielded little effect on the growth of ceftazidime-resistant, blaKPC-2-carrying Klebsiella pneumoniae in the thighs of neutropenic mice (final counts of 4 × 108 to 8 × 108 cfu/thigh). In contrast, co-administration of avibactam in a 4:1 ratio (ceftazidime:avibactam) was bactericidal in the same model (final counts of 2 × 104 to 3 × 104 cfu/thigh). In a rat abdominal abscess model, therapy with ceftazidime or ceftazidime/avibactam (4:1 w/w) against blaKPC-2-positive K. pneumoniae resulted in 9.3 versus 3.3 log cfu/abscess, respectively, after 52 h. With respect to PK/PD, in Monte Carlo simulations, attainment of unbound drug exposure targets (ceftazidime fT>8 mg/L and avibactam fT>1 mg/L, each for 50% of the dosing interval) for the labelled dose of ceftazidime/avibactam (2 and 0.5 g, respectively, q8h by 2 h IV infusion), including dose adjustments for patients with impaired renal function, ranged between 94.8% and 99.6% of patients, depending on the infection modelled.
Population pharmacokinetics and dosing optimization of mezlocillin in neonates and young infants
Authors: Zhou Jing , Jiang Li , Zhang Zhi Ling , Wang Zhao Rui , Zhang Yan Xiu , Lin Xu , Tang Bo Hao , Yao Bu Fan , Guo Zi Xuan , Yang Jing Jing , Van Den Anker John , Wu Yue E , Zhao Wei
Published: June 2022

Objectives

Mezlocillin is used in the treatment of neonatal infectious diseases. However, due to the absence of population pharmacokinetic studies in neonates and young infants, dosing regimens differ considerably in clinical practice. Hence, this study aimed to describe the pharmacokinetic characteristics of mezlocillin in neonates and young infants, and propose the optimal dosing regimen based on the population pharmacokinetic model of mezlocillin.

Methods

A prospective, open-label pharmacokinetic study of mezlocillin was carried out in newborns. Blood samples were collected using an opportunistic sampling method. HPLC was used to measure the plasma drug concentrations. A population pharmacokinetic model was developed using NONMEM software.

Results

Ninety-five blood samples from 48 neonates and young infants were included. The ranges of postmenstrual age and birth weight were 29–40 weeks and 1200–4000 g, respectively, including term and preterm infants. A two-compartment model with first-order elimination was developed to describe the population pharmacokinetics of mezlocillin. Postmenstrual age, current weight and serum creatinine concentration were the most important covariates. Monte Carlo simulation results indicated that the current dose of 50 mg/kg q12h resulted in 89.2% of patients achieving the therapeutic target, when the MIC of 4 mg/L was used as the breakpoint. When increasing the dosing frequency to q8h, a dose of 20 mg/kg resulted in 74.3% of patients achieving the therapeutic target.

Conclusions

A population pharmacokinetic model of mezlocillin in neonates and young infants was established. Optimal dosing regimens based on this model were provided for use in neonatal infections.
Manufacturer Signal-to-Cutoff Threshold Underestimates Cumulative Incidence of SARS-CoV-2 Infection: Evidence from the Los Angeles Firefighters Study
Authors: Toubat Omar , Berg Anders H , Sobhani Kimia , Mulligan Karen , Hori Acacia M , Bhattacharya Jay , Sood Neeraj
Published: June 2022

Background

The objective of this analysis was to compare the performance sensitivity and specificity of manufacturer-recommended signal-to-cutoff (S/Co) thresholds with modified S/Co values to estimate the prevalence of SARS-CoV-2-specific antibodies in a cohort of firefighters with a known infection history.

Methods

Plasma venipuncture samples were used for serologic analysis of firefighters in Los Angeles, CA, USA, in October 2020. Seropositivity was assessed using the manufacturer’s recommended S/Co (≥1.4 IgG) and modified S/Co thresholds based on measured antibody levels in 178 negative control patients who had blood drawn prior to the emergence of COVID-19. Optimal S/Co threshold was determined by receiver operating characteristic (ROC) curve analysis.

Results

Of 585 firefighters included in the study, 52 (8.9%) reported having a PCR-positive test history prior to antibody testing. Thirty-five (67.3%) firefighters with a previous PCR-positive test were seropositive based on the manufacturer S/Co thresholds, consistent with an estimated 67.3% sensitivity and 100% specificity. After evaluating multiple modified S/Co thresholds based on pre-pandemic negative samples, a modified S/Co of 0.36 was found to yield optimal sensitivity (88.5%) and specificity (99.4%) by ROC curve analysis. This modified threshold improved serostatus classification accuracy by 21.2%.

Conclusions

S/Co thresholds based on known negative samples significantly increase seropositivity and more accurately estimate cumulative incidence of disease compared to manufacturer-based thresholds.
TT-pocket/HIRAN: binding to 3′-terminus of DNA for recognition and processing of stalled replication forks
Authors: Masai Hisao
Published: June 2022

Stalled replication forks need to be swiftly detected and protected from collapse and the cause for fork stall be removed to restore the active replication fork. In bacteria, stalled forks are recognized and stabilized by PriA, a DEXH-type helicase, which also facilitates reassembly of an active replication fork. A TT-pocket (three-prime terminus binding pocket) present in the N-terminal segment of PriA plays a crucial role in stabilization of the stalled forks by specifically binding to the 3$^\prime$-terminus of the nascent leading strand. Eukaryotic proteins, Rad5/HLTF, contain a TT-pocket related domain, HIRAN, that specifically binds to 3′-terminus of DNA and play a role in stalled fork processing. While the TT-pocket of PriA facilitates the formation of an apparently stable and immobile complex on a fork with a 3′-terminus at the fork junction, HIRAN of Rad5/HLTF facilitates fork regression by itself. A recent report shows that HIRAN can displace 3 nucleotides at the end of the duplex DNA, providing mechanistic insight into how stalled forks are reversed in eukaryotes. In this article, I will compare the roles of 3′-terminus binding domains in stalled fork processing in prokaryotes and in eukaryotes.
Parenting Stress over the First Year of Inflammatory Bowel Disease Diagnosis
Authors: Rea Kelly E , Cushman Grace K , Westbrook Adrianna L , Reed Bonney
Published: June 2022

Objective

A diagnosis of inflammatory bowel disease (IBD) in children can disrupt the family, including altered routines and increased medical responsibilities. This may increase parenting stress; however, little is known about parenting stress changes over the first year following an IBD diagnosis, including what demographic, disease, or psychosocial factors may be associated with parenting stress over time.

Methods

Fifty-three caregivers of children newly diagnosed with IBD (Mage = 14.17 years; Mdays since diagnosis = 26.15) completed parenting stress (Pediatric Inventory for Parents), child anxiety (Screen for Child Anxiety-Related Disorders), and child health-related quality of life (HRQOL; IMPACT) measures within 1 month of diagnosis and 6-month and 1-year follow-ups. Multilevel longitudinal models assessed change and predictors of parenting stress.

Results

Parenting stress was significantly associated with greater child anxiety and lower HRQOL at diagnosis (rs = 0.27 to −0.53). Caregivers of color and caregivers of female youth reported higher parenting stress at diagnosis (ts = 2.02–3.01). Significant variability and declines in parenting stress were observed across time (ts = −2.28 and −3.50). In final models, caregiver race/ethnicity and child HRQOL were significantly related to parenting stress over the first year of diagnosis (ts = −2.98 and −5.97).

Conclusion

Caregivers’ parenting stress decreases across 1 year of diagnosis. However, caregivers of color and those rating their child’s HRQOL as lower may be at risk for greater parenting stress. More research is needed to understand why caregivers of color reported greater parenting stress compared to White caregivers. Results highlight the importance of providing whole-family care when a child is diagnosed with IBD.
The therapeutic efficacy and safety of intravenous immunoglobulin in dermatomyositis and polymyositis: A systematic review and meta-analysis
Authors: Xiong Anji , Qiang Yiying , Cao Yuzi , Shuai Yu , Chen Huini , Xiang Qilang , Hu Ziyi , Song Zhuoyao , Zhou Shifeng , Zhang Yan , Cui Hongxu , Wang Ye , Luo Jie , Shuai Shiquan , Yang Yuan
Published: June 2022

Objectives

To evaluate the efficacy and safety of intravenous immunoglobulin (IVIG) in the treatment of dermatomyositis (DM) and polymyositis (PM).

Methods

We searched PubMed, Embase, and the China National Knowledge Infrastructure for relevant studies from July 1919 to May 2021.

Results

Seventeen papers pertinent to our questions were found: In a meta-analysis, we found that IVIG significantly improved the level of CK (SMD (STD. Mean Difference) = −0.69; 95%CI −0.93, −0.46; P < 0.0001), Manual Muscle Test (SMD = 1.12; 95%CI 0.77, 1.47; P < 0.00001), Medical Research Council (SMD = 1.59; 95%CI 0.86, 2.33; P < 0.00001), Activities of Daily Living (SMD = 1.07; 95%CI 0.59, 1.56; P < 0.0001). The CK levels in DM and PM were also significantly improved after IVIG (SMD = −0.73; 95%CI −1.12, −0.34; P = 0.0002 and SMD = −3.29; 95%CI −5.82, −0.76; P < 0.0001, respectively). The meta-analysis of three RCTs showed that there was a statistically significant improvement after IVIG (SMD = 0.63; 95%CI 0.22, 1.03; P = 0.002). In a random effects model, pooled muscle power improvement rate was 77% (95% CI: 66.0–87.0%). Meta-analyses of IVIG as first-line therapy showed a significant improvement of the CK level (SMD = −0.71; 95%CI −1.12, −0.30; P = 0.0007). The polled improvement rate of oesophageal disorders was 88% (95% CI: 80.0–95.0%). There was no statistically significant difference in the rate of improvement between the number of courses <2 and ≥2 (0.80% vs. 0.80%, P = 0.9). The proportion of corticosteroid-sparing success reached 81.8%. Adverse reactions following IVIG administration are usually mild and transient. Seven patients developed serious adverse events.

Conclusion

IVIG seems to be an effective drug for DM/PM, improving muscle strength, CK levels, and oesophageal involvement, and it is well tolerated by patients.
The role of ultrasound and FDG-PET/CT to detect extracranial artery involvement in patients with suspected large vessel vasculitis
Authors: Molina-Collada Juan , Castrejón Isabel , Rivera Javier , Martínez-Barrio Julia , Nieto-González Juan Carlos , López Katerine , Montero Fernando , Trives Laura , González Carlos , Álvaro-Gracia José María
Published: June 2022

Objective

To assess the accuracy of ultrasound (US) versus fluorodeoxyglucose—positron emission tomography/computed tomography (FDG-PET/CT) to identify extracranial involvement in large vessel vasculitis (LVV).

Methods

A retrospective observational study of patients with suspected LVV. All patients underwent US exam within 24 h per protocol. FDG-PET/CT was performed according to clinician criteria. The gold standard for LVV diagnosis was clinical confirmation after 6 months.

Results

Of the 113 patients included (74.3% female, mean age 74 years), 37 (32.7%) were diagnosed with LVV after 6 months. The sensitivity and specificity of US were 86.5% and 96.1%, respectively. Only 12 (42.9%) of 28 patients undergoing a FDG-PET/CT per clinician criteria showed positive findings. The sensitivity and specificity of FDG-PET/CT for LVV were 61.1% and 90%, respectively. Taking FDG-PET/CT as the reference, US showed extracranial inflammation in 10/12 (83.3%) and detected 2 (12.5%) additional cases of extracranial involvement with negative FDG-PET/CT. Conversely, FDG-PET/CT was positive in two patients with negative US (one isolated aortitis and one aortoiliac involvement).

Conclusions

US and FDG-PET/CT are both valid tools to detect extracranial involvement. The presence of US extracranial artery inflammation is consistent with FDG-PET/CT examination, although a negative US scan does not rule out extracranial involvement.
Stemness and clinical features in relation to the subventricular zone in diffuse lower-grade glioma: an exploratory study
Authors: Corell Alba , Gómez Vecchio Tomás , Ferreyra Vega Sandra , Dénes Anna , Neimantaite Alice , Hagerius Alexander , Barchéus Hanna , Solheim Ole , Lindskog Cecilia , Bontell Thomas Olsson , Carén Helena , Jakola Asgeir S , Smits Anja
Published: June 2022

Background

The subventricular zone (SVZ) of the human brain is a site of adult stem cell proliferation and a microenvironment for neural stem cells (NSCs). It has been suggested that NSCs in the SVZ are potential cells of origin containing driver mutations of glioblastoma, but their role in the origin of diffuse lower-grade gliomas (dLGGs) is not much studied.

Methods

We included 188 patients ≥18 years with IDH-mutated dLGG (WHO grades 2–3) histologically diagnosed between 2007 and 2020. Tissue microarrays of tumor samples for patients between 2007 and 2016 were used for immunodetection of Nestin, SOX2, SOX9, KLF4, NANOG, CD133 cMYC, and Ki67. DNA methylation profile was used for stemness index (mDNAsi). Tumor contact with the SVZ was assessed and the distance was computed.

Results

Overall, 70.2% of the dLGG had SVZ contact. Tumors with SVZ contact were larger (102.4 vs 30.9 mL, P < .01), the patients were older (44.3 vs 40.4 years, P = .04) and more often had symptoms related to increased intracranial pressure (31.8% vs 7.1%, P < .01). The expression of SOX2, SOX9, Nestin, and Ki67 showed intersample variability, but no difference was found between tumors with or without SVZ contact, nor with the actual distance to the SVZ. mDNAsi was similar between groups (P = .42).

Conclusions

We found no statistical relationship between proximity with the SVZ and mDNAsi or expression of SOX2, SOX9, Nestin, and Ki67 in IDH-mutated dLGG. Our data suggest that the potential impact of SVZ on IDH-mutated dLGG is probably not associated with a more stemness-like tumor profile.
Root Cap to Soil Interface: A Driving Force Toward Plant Adaptation and Development
Authors: Ganesh Alagarasan , Shukla Vishnu , Mohapatra Ankita , George Abin Panackal , Bhukya Durga Prasad Naik , Das Krishna Kodappully , Kola Vijaya Sudhakara Rao , Suresh Aparna , Ramireddy Eswarayya
Published: June 2022

Land plants have developed robust roots to grow in diverse soil ecosystems. The distal end of the root tip has a specialized organ called the ‘root cap’. The root cap assists the roots in penetrating the ground, absorbing water and minerals, avoiding heavy metals and regulating the rhizosphere microbiota. Furthermore, root-cap-derived auxin governs the lateral root patterning and directs root growth under varying soil conditions. The root cap formation is hypothesized as one of the key innovations during root evolution. Morphologically diversified root caps in early land plant lineage and later in angiosperms aid in improving the adaptation of roots and, thereby, plants in diverse soil environments. This review article presents a retrospective view of the root cap’s important morphological and physiological characteristics for the root–soil interaction and their response toward various abiotic and biotic stimuli. Recent single-cell RNAseq data shed light on root cap cell-type-enriched genes. We compiled root cap cell-type-enriched genes from Arabidopsis, rice, maize and tomato and analyzed their transcription factor (TF) binding site enrichment. Further, the putative gene regulatory networks derived from root-cap-enriched genes and their TF regulators highlight the species-specific biological functions of root cap genes across the four plant species.