bluuebunny/crossref_metadata_2025 huggingface dataset:
Material decomposition from photon-counting CT using a convolutional neural network and energy-integrating CT training labels
Authors: Nadkarni Rohan , Allphin Alex , Clark Darin P , Badea Cristian T
Published: June 2022

Objective. Photon-counting CT (PCCT) has better dose efficiency and spectral resolution than energy-integrating CT, which is advantageous for material decomposition. Unfortunately, the accuracy of PCCT-based material decomposition is limited due to spectral distortions in the photon-counting detector (PCD). Approach. In this work, we demonstrate a deep learning (DL) approach that compensates for spectral distortions in the PCD and improves accuracy in material decomposition by using decomposition maps provided by high-dose multi-energy-integrating detector (EID) data as training labels. We use a 3D U-net architecture and compare networks with PCD filtered back projection (FBP) reconstruction (FBP2Decomp), PCD iterative reconstruction (Iter2Decomp), and PCD decomposition (Decomp2Decomp) as the input. Main results. We found that our Iter2Decomp approach performs best, but DL outperforms matrix inversion decomposition regardless of the input. Compared to PCD matrix inversion decomposition, Iter2Decomp gives 27.50% lower root mean squared error (RMSE) in the iodine (I) map and 59.87% lower RMSE in the photoelectric effect (PE) map. In addition, it increases the structural similarity (SSIM) by 1.92%, 6.05%, and 9.33% in the I, Compton scattering (CS), and PE maps, respectively. When taking measurements from iodine and calcium vials, Iter2Decomp provides excellent agreement with multi-EID decomposition. One limitation is some blurring caused by our DL approach, with a decrease from 1.98 line pairs/mm at 50% modulation transfer function (MTF) with PCD matrix inversion decomposition to 1.75 line pairs/mm at 50% MTF when using Iter2Decomp. Significance. Overall, this work demonstrates that our DL approach with high-dose multi-EID derived decomposition labels is effective at generating more accurate material maps from PCD data. More accurate preclinical spectral PCCT imaging such as this could serve for developing nanoparticles that show promise in the field of theranostics (therapy and diagnostics).
Ferroelectric-gate tunnel field-effect transistor one-transistor ternary contents addressable memory
Authors: Kwak Been , Kim Hyunwoo , Kwon Daewoong
Published: June 2022

In the era of ‘big data’, the von Neumann architecture has significant energy consumption and latency penalties for data transfer between memory and processor. However, ternary content addressable memories (TCAMs) enable fast and energy-efficient operation by performing a parallel search for given data and returning information about whether it matches. In this study, a single transistor (1T) ferroelectric-gate tunnel FET (FeTFET) was introduced for TCAM operations, and its functionality was verified through technology computer-aided design (TCAD) simulations. The FeTFET has intrinsic directional currents due to its unique p–i–n structure. Also, the transfer curve of the FeTFET can be shifted in both directions depending on the polarization state of the ferroelectric material. By combining these properties of the FeTFET, it was confirmed that stable search operations can be performed for stored logic states. Thus, compared to conventional TCAM cell that use two or more transistors, it is expected that the proposed 1T-TCAM cell can store and search more bits in the same area.
Directed transport of a deformable particle in confined periodic structures
Authors: Li Jia-Jian , Lin Fu-Jun , Ai Bao-Quan
Published: June 2022

Directed transport of a deformable particle is numerically investigated in a two-dimensional periodic channel. Unlike the rigid particle, the deformable particle can pass through the channel bottleneck that is significantly smaller than the particle size. The deformable characteristics of the particle can greatly affect the directed transport of the particle. (i) For the case of active deformable particle, the self-propelled velocity can break thermodynamics equilibrium and induce the directed transport. The average velocity is a peak (or valley) function of the particle size for large (or small) self-propulsion speed. Particle softening (large shape parameter) facilitates the rectification of the particle for small particle, while it blocks the rectification for large particle. (ii) For the case of passive deformable particle, periodic oscillation of the particle size can also break thermodynamical equilibrium. There exists an optimal oscillating frequency at which the average velocity takes its maximal value. For low oscillating frequency, the average velocity is a peak function of the oscillating amplitude, while for high oscillating frequency the average velocity increases monotonically with the oscillating amplitude. Our results may contribute to the understanding of the transport behaviors of soft, deformable matter in confined structures.
Localization and slow-thermalization in a cluster spin model
Authors: Kuno Yoshihito , Orito Takahiro , Ichinose Ikuo
Published: June 2022

Novel cluster spin model with interactions and disorder is introduced and studied. In specific type of interactions, we find an extensive number of local integrals of motions (LIOMs), which are a modified version of the stabilizers in quantum information, i.e., mutually commuting operators specifying all quantum states in the system. These LIOMs can be defined for any strength of the interactions and disorder, and are of compact-support instead of exponentially-decaying tail. Hence, even under the presence of interactions, integrability is held, and all energy eigenstates are labeled by these LIOMs and can be explicitly obtained. Integrable dynamics is, then, expected to occur. The compact-support nature of the LIOMs crucially prevents the thermalization and entanglement spreading. We numerically investigate dynamics of the system governed by the existence of the compact-support LIOMs, and clarify the effects of additional interactions, which break the compact-support nature of the LIOMs. There, we find that the ordinary many-body localization behaviors emerge, such as the logarithmic growth of the entanglement entropy in the time evolution. Besides the ergodicity breaking dynamic, we find that symmetry protected topological order preserves for specific states even in the presence of the interactions.
Beta-decay half-lives of the isotopes close to the neutron drip line and astrophysical implications
Authors: Quyen N T T , Chae K Y , Uyen N K , Duy N N
Published: June 2022

In this paper, we examined the β
−-decay half-lives of 94 extremely neutron-rich isotopes with Z = 26 − 57 close to the neutron drip line, which are important for the r-process calculations. The half-lives were calculated using four semi-empirical models and compared to those based on the FRDM+QRPA approach and available measured data. The impact of the difference in the models on the half-life predictions was investigated. We found that theoretical calculations for the β-decay half-life have a large deviation, up to 60%, which is mostly similar to that in measurements. The half-lives of the investigated nuclei are ranging from a few to hundreds of milliseconds. The r-process abundances in various astrophysical scenarios were calculated by using the predicted half-lives. The half-life uncertainty due to different models results in a large deviation in the isotopic abundance, specially for the isotopes in the mass range of A > 210. The shell closures in 76Fe is still a doubt due to the discrepancy in the trends of the half-life and paring gap while a closed-shell at N = 82 in 127Rh is possible. The results of this study also notice that it is a challenge for measuring precisely the masses of 106Rb, 116,117Nb, 122Tc, and 128Rh because of their short half-lives.
Automatic Detection and Classification of Radio Galaxy Images by Deep Learning
Authors: Zhang Zhen , Jiang Bin , Zhang Yanxia
Published: June 2022

Surveys conducted by radio astronomy observatories, such as SKA, MeerKAT, Very Large Array, and ASKAP, have generated massive astronomical images containing radio galaxies (RGs). This generation of massive RG images has imposed strict requirements on the detection and classification of RGs and makes manual classification and detection increasingly difficult, even impossible. Rapid classification and detection of images of different types of RGs help astronomers make full use of the observed astronomical image data for further processing and analysis. The classification of FRI and FRII is relatively easy, and there are more studies and literature on them at present, but FR0 and FRI are similar, so it is difficult to distinguish them. It poses a greater challenge to image processing. At present, deep learning has made breakthrough progress in the field of image analysis and processing and has preliminary applications in astronomical data processing. Compared with classification algorithms that can only classify galaxies, object detection algorithms that can locate and classify RGs simultaneously are preferred. In target detection algorithms, YOLOv5 has outstanding advantages in the classification and positioning of small targets. Therefore, we propose a deep-learning method based on an improved YOLOv5 object detection model that makes full use of multisource data, combining FIRST radio with SDSS optical image data, and realizes the automatic detection of FR0, FRI, and FRII RGs. The innovation of our work is that on the basis of the original YOLOv5 object detection model, we introduce the SE Net attention mechanism, increase the number of preset anchors, adjust the network structure of the feature pyramid, and modify the network structure, thereby allowing our model to demonstrate galaxy classification and position detection effects. Our improved model produces satisfactory results, as evidenced by experiments. Overall, the mean average precision (mAP@0.5) of our improved model on the test set reaches 89.4%, which can determine the position (R.A. and decl.) and automatically detect and classify FR0s, FRIs, and FRIIs. Our work contributes to astronomy because it allows astronomers to locate FR0, FRI, and FRII galaxies in a relatively short time and can be further combined with other astronomically generated data to study the properties of these galaxies. The target detection model can also help astronomers find FR0s, FRIs, and FRIIs in future surveys and build a large-scale star RG catalog. Moreover, our work is also useful for the detection of other types of galaxies.
Using Non-negative Matrix Factorization to Improve Calibration of the Keck OSIRIS Integral Field Spectrograph
Authors: Horstman Katelyn , Fitzgerald Michael P. , Lyke James E. , Yeh Sherry C. C. , Chu Devin S.
Published: June 2022

Integral Field Spectrographs (IFS) often require non-trivial calibration techniques to process raw data. The OH Suppressing InfraRed Imaging Spectrograph at the W. M. Keck Observatory is a lenslet-based IFS that requires precise methods to associate the flux on the detector with both a wavelength and a position on the detector. During calibration scans, a single column lenslet mask is utilized to keep light from adjacent lenslet columns separate from the primary lenslet column, in order to uniquely determine spectral response of individual lenslets on the detector. Despite employing a single column lenslet mask, an issue associated with such calibration schemes may occur when light from adjacent masked lenslet columns leaks into the primary lenslet column. Incorrectly characterizing the flux due to additional light in the primary lenslet column results in one form of crosstalk between lenslet columns, which most clearly manifest as non-physical artifacts in the spectral dimension of the reduced data. We treat the problem of potentially blended calibration scans as a source separation problem and implement Non-negative Matrix Factorization (NMF) as a way to separate blended calibration scan spectra. After applying NMF to calibration scan data, extracted spectra from calibration scans show reduced crosstalk of up to 26.7% ± 0.5% while not adversely impacting the signal-to-noise ratio. Additionally, we determined the optimal number of calibration scans per lenslet column needed to create NMF factors, finding that greatest reduction crosstalk occurs when NMF factors are created using one calibration scan per lenslet column.
On scattering and damping of toroidal Alfvén eigenmode by drift wave turbulence
Authors: Chen Liu , Qiu Zhiyong , Zonca Fulvio
Published: June 2022

We demonstrate analytically that, in toroidal plasmas, scattering by drift wave turbulence could lead to appreciable damping of toroidal Alfvén eigenmodes via generation of short-wavelength electron Landau damped kinetic Alfvén waves. A corresponding analytic expression of the damping rate is derived, and found to be, typically, comparable to the linear drive by energetic particles. The implications of this novel mechanism on the transport and heating processes in burning plasmas are also discussed.
Research with African Adolescents: Critical Epistemologies and Methodological Considerations
Authors: Manful Kuukuwa O
Published: June 2022

Whereas much research with adolescents in Africa engages them mainly with respect to issues limited and explicitly related to youth, this research note makes epistemic and methodological arguments for engaging adolescents more broadly in our research about Africa. I present a practical application of research design and methods based on these arguments through a study with adolescents in a secondary school in Ghana in which I engendered their enthusiastic participation in the research process. Through this, I demonstrate how taking a critical approach to epistemologies and methodologies in research with young participants can expand and enrich our knowledge of and about the continent.
Cervical immune activation during the luteal phase may compromise subsequent trans-cervical ram sperm transport
Authors: Abril-Parreño Laura , Krogenæs Anette Kristine , Druart Xavier , Cormican Paul , Fair Sean , Meade Kieran G
Published: June 2022

Worldwide, cervical artificial insemination using frozen–thawed semen yields low pregnancy rates. The only exception to this is in Norway, where vaginal insemination with frozen–thawed semen yields pregnancy rates in excess of 60% and which has been attributed to the specific ewe breed used. Our previous work demonstrated differences in cervical gene expression at the follicular phase of the estrous cycle in ewe breeds with known differences in pregnancy rates. In this study, we characterized the cervical transcriptome of the same ewe breeds [Suffolk, Belclare, Fur, and Norwegian White Sheep (NWS)] during the luteal phase, as an optimal environment at the luteal phase could better prepare the cervix for sperm migration through the cervix at the subsequent follicular phase. High-quality RNA extracted from postmortem cervical tissue was analyzed by RNA sequencing. After stringent filtering, 1051, 1924, and 611 differentially expressed genes (DEGs) were detected in the low-fertility Suffolk breed compared with Belclare, Fur, and NWS, respectively. Gene ontology analysis identified increased humoral adaptive immune response pathways in Suffolk. Increased expression of multiple immune genes supports the presence of an active immune response in the cervix of Suffolk ewes, which differentiates them significantly from the other three ewe breeds. Inflammatory pathways were upregulated in the Suffolk, resulting in higher expression of the potent pro-inflammatory cytokines. Therefore, higher levels of pro-inflammatory cytokines indicate unresolved inflammation in the cervix of the low-fertility Suffolk breed that could contribute to reduced cervical sperm transport in the next follicular phase.
Expression patterns and the roles of phosphatidylinositol phosphatases in testis
Authors: Ceyhan Yasemin , Zhang Manqi , Sandoval Carlos G , Agoulnik Alexander I , Agoulnik Irina U
Published: June 2022

Phosphoinositides (PIs) are relatively rare lipid components of the cellular membranes. Their homeostasis is tightly controlled by specific PI kinases and PI phosphatases. PIs play essential roles in cellular signaling, cytoskeletal organization, and secretory processes in various diseases and normal physiology. Gene targeting experiments strongly suggest that in mice with deficiency of several PI phosphatases, such as Pten, Mtmrs, Inpp4b, and Inpp5b, spermatogenesis is affected, resulting in partial or complete infertility. Similarly, in men, loss of several of the PI phosphatases is observed in infertility characterized by the lack of mature sperm. Using available gene expression databases, we compare the expression of known PI phosphatases in various testicular cell types, infertility patients, and mouse age-dependent testicular gene expression, and discuss their potential roles in testis physiology and spermatogenesis.
Perioperative care bundles for the prevention of surgical-site infections: meta-analysis
Authors: Wolfhagen Niels , Boldingh Quirine J J , Boermeester Marja A , de Jonge Stijn W
Published: June 2022

Background

Care bundles are used widely to prevent surgical-site infections (SSIs). Recent systematic reviews suggested larger effects from bundles with more interventions. These reviews were largely based on uncontrolled before–after studies and did not consider their biases. The aim of this meta-analysis was to determine the effectiveness of care bundles to prevent SSIs and explore characteristics of effective care bundles.

Methods

A systematic review, reanalysis, and meta-analysis of available evidence were undertaken. RCTs, controlled before–after studies, and uncontrolled before–after studies with sufficient data for reanalysis as interrupted time series studies (ITS) were eligible. Studies investigating the use of a care bundle, with at least one intraoperative intervention, compared with standard care were included.

Results

Four RCTs, 1 controlled before–after study, and 13 ITS were included. Pooled data from RCTs were heterogeneous. Meta-analysis of ITS resulted in a level change of −1.16 (95 per cent c.i.−1.78 to −0.53), indicating a reduction in SSI. The effect was larger when the care bundle comprised a higher proportion of evidence-based interventions. Meta-regression analyses did not show statistically significant associations between effect estimates and number of interventions, number of evidence-based interventions, or proportion of evidence-based interventions.

Conclusion

Meta-analysis of ITS indicated that perioperative care bundles prevent SSI. This effect is inconsistent across RCTs. Larger bundles were not associated with a larger effect, but the effect may be larger if the care bundle contains a high proportion of evidence-based interventions. No strong evidence for characteristics of effective care bundles was identified.
Axillary surgery after neoadjuvant therapy in initially node-positive breast cancer: international EUBREAST survey
Authors: Gasparri Maria Luisa , de Boniface Jana , Poortmans Philip , Gentilini Oreste D , Kaidar-Person Orit , Banys-Paluchowski Maggie , Di Micco Rosa , Niinikoski Laura , Murawa David , Bonci Eduard Alexandru , Pasca Andrei , Rubio Isabel T , Karadeniz Cakmak Guldeniz , Kontos Michalis , Kühn Thorsten
Published: June 2022

Background

There is no consensus on axillary management after neoadjuvant therapy (NAT) in patients with clinically node-positive (cN+) breast cancer. To investigate current clinical practice, an international survey was conducted among breast surgeons and radiation oncologists. The aim of the first part of the survey was to provide a snapshot of international discrepancies regarding axillary surgery in this context.

Methods

The European Breast Cancer Research Association of Surgical Trialists (EUBREAST) developed a web-based survey containing 39 questions describing clinical scenarios in the setting of axillary management in patients with cN1 disease converting to ycN0 after NAT. The survey was then distributed to breast surgeons and radiation oncologists via 14 breast cancer societies between April and October 2021.

Results

Responses from 349 physicians in 45 countries were recorded. The most common post-NAT axillary surgery in patients with cN1 disease converting to ycN0 was targeted axillary dissection (54.2 per cent), followed by sentinel lymph node biopsy (SLNB) alone (20.9 per cent), level 1–2 axillary lymph node dissection (ALND) (18.4 per cent), level 1–3 ALND (4 per cent), and targeted lymph node biopsy (2.5 per cent). For SLNB alone, dual tracers were most commonly used (62.3 per cent). Management varied widely in patients with ambiguous axillary status before initiation of treatment or a residual metastatic burden in the axilla after NAT. In patients with ycN+ tumours, ALND was the preferred surgical approach for 66.8 per cent of respondents.

Conclusion

These results highlight the wide heterogeneity in surgical approaches to the axilla after NAT. To standardize the guidelines, further data from clinical research are urgently needed, which underlines the importance of the ongoing AXSANA (EUBREAST-3) study.
Bicuspidization of a unicuspid valve using sliding plasty of a rudimentary right coronary cusp
Authors: Shraer Nathanael , Berrebi Alain , Biondi Raoul , Lansac Emmanuel
Published: June 2022

Unicuspid aortic valve repair relies on the principles of bicuspidization by creating a neo-commissure at 180° from the existing commissure, with pericardial patch interposition. We report a case of a 26-year-old patient with cor triatriatum and a severely regurgitating unicuspid valve. The left atrium membrane was resected. Aortic valve repair was performed creating a neo-commissure using a sliding plasty of the rudimentary right coronary cusp and patch reconstruction of the anterior part of the non-coronary cusp, protected by external subvalvular annuloplasty and hemi-root remodelling. We detail a repair technique of a partial autologous reconstruction approach for bicuspidization.
Development and psychometric testing of the Heart-Healthy Information Questionnaire
Authors: Choo Jina , Noh Songwhi , Moon Jihyun , Shin Yura
Published: June 2022

Aims

This study aimed to develop a reliable and valid scale, i.e. the Heart-Healthy Information Questionnaire (HHIQ).

Methods and results

The HHIQ was developed in three phases: (i) creating the item pool, (ii) conducting a preliminary evaluating the items, and (iii) refining the scale and evaluating psychometric properties. An initial item pool of 77 items with a 3-point True/False format with a ‘Don’t know’ option was extracted from the literature review and 54 items reached content validity. The psychometric properties of HHIQ were tested with 1315 individuals without cardiovascular disease. By using the exclusion criteria of the difficulty index (>0.95), discrimination index (<10.0), and item-total correlation (tetrachoric coefficient <0.2), 50 items were finally selected. The construct validity was determined by using the known-groups validation: Individuals (n = 107) who were educated with heart-healthy education sessions showed significantly higher scores of the HHIQ than those (n = 107) who were not educated (P = 0.015). The Kuder–Richardson formula 20 coefficient indicated good internal consistency (0.85), and the test–retest reliability coefficient with a 15-day interval also indicated good stability (0.78). A total score of the HHIQ was significantly correlated with a total score of the Evaluation Tool for Metabolic Syndrome Modification Lifestyles (ρ = 0.23, P < 0.001).

Conclusion

The HHIQ showed good psychometric properties of validity and reliability and may be useful to evaluate the knowledge levels of heart-healthy information in the areas of cardiovascular disease prevention.
A Decade of GigaScience: Women in Science: Past, Present, and Future
Authors: Liu Lijun , Jovic Dragomirka , Goodman Laurie
Published: June 2022

Over the last decade, women have made decisive advances in increasing equality in science, technology, engineering, and medicine (STEM), but they still do not rival that of men. Many mechanisms to reduce gender discrimination have been addressed; however, little to nothing has been done to tackle the differences in the amount of time women spend on responsibilities at home. This has never been more apparent than during the COVID-19 pandemic. After a decade of advances promoting women, the last two years have seen these advances halted, and the long-term implications for women in STEM will be substantial. Moving forward, career advancement and funding mechanisms need to be adjusted to not just help women catch up, but to become a permanent support mechanism for women in the workplace. The higher amount of responsibilities at home and lack of support for women is not reserved for times of international upheaval: it has just become more apparent.
Severe acute respiratory infection surveillance in Brazil: the role of public, private and philanthropic healthcare units
Authors: Silva Amauri Duarte da , Veiga Ana Beatriz Gorini da , Cruz Oswaldo Gonçalves , Bastos Leonardo Soares , Gomes Marcelo Ferreira da Costa
Published: June 2022

Epidemiological surveillance and notification of respiratory infections are important for management and control of epidemics and pandemics. Fact-based decisions, like social distancing policies and preparation of hospital beds, are taken based on several factors, including case numbers; hence, health authorities need quick access to reliable and well-analysed data. We aimed to analyse the role of the Brazilian public health system in the notification and hospitalization of patients with severe acute respiratory infection (SARI). Data of SARI cases in Brazil (2013–20) were obtained from SIVEP-Gripe platform, and legal status of each healthcare unit (HCU) responsible for case notification and hospitalization was obtained from the National Registry of Health Facilities (CNES) database. HCUs that are part of the hospital network were classified as ‘Public Administration’, ‘Business Entities’, ‘Philanthropic Entities’ or ‘Individuals’. SARI notification data from Brazilian macro-regions (North, Northeast, Midwest, Southeast and South) were analysed and compared between administrative spheres. This study reveals that hospitalizations due to SARI increased significantly in Brazil during the coronavirus disease 2019 (COVID-19) pandemic, especially in HCUs of Public Administration. In the Southeast and South, where incidence of SARI is high, philanthropic HCUs also contribute to hospitalization of SARI cases and attend up to 7.4% of the cases notified by the Public Administration. The number of cases is usually lower in other regions, but in 2020 the Northeast showed more hospitalizations than the South. In the South, SARI season occurs later; however, in 2020, an early peak was observed because of COVID-19. Notably, the contribution of each administrative sphere that manages hospital networks in Brazil in the control and management of SARI varies between regions. Our approach will allow managers to assess the use of public resources, given that there are different profiles of healthcare in each region of Brazil and that the public health system has a major role in notifying and attending SARI cases.
Mutant VPS35-D620N induces motor dysfunction and impairs DAT-mediated dopamine recycling pathway
Authors: Huang Yi , Huang Heng , Zhou Leping , Li Jiawei , Chen Xiang , Thomas Joseph , He Xiaofei , Guo Wenyuan , Zeng Yixuan , Low Boon Chuan , Liang Fengyin , Zeng Jinsheng , Ross Christopher A , Tan Eng-King , Smith Wanli , Pei Zhong
Published: June 2022

The D620N mutation in vacuolar protein sorting protein 35 (VPS35) gene has been identified to be linked to late onset familial Parkinson disease (PD). However, the pathophysiological roles of VPS35-D620N in PD remain unclear. Here, we generated the transgenic Caenorhabditis elegans overexpressing either human wild type or PD-linked mutant VPS35-D620N in neurons. C. elegans expressing VPS35-D620N, compared with non-transgenic controls, showed movement disorders and dopaminergic neuron loss. VPS35-D620N worms displayed more swimming induced paralysis but showed no defects in BSR assays, thus indicating the disruption of dopamine (DA) recycling back inside neurons. Moreover, VPS35 formed a protein interaction complex with DA transporter (DAT), RAB5, RAB11 and FAM21. In contrast, the VPS35-D620N mutant destabilized these interactions, thus disrupting DAT transport from early endosomes to recycling endosomes, and decreasing DAT at the cell surface. These effects together increased DA in synaptic clefts, and led to dopaminergic neuron degeneration and motor dysfunction. Treatment with reserpine significantly decreased the swimming induced paralysis in VPS35-D620N worms, as compared with vehicle treated VPS35-D620N worms. Our studies not only provide novel insights into the mechanisms of VPS35-D620N-induced dopaminergic neuron degeneration and motor dysfunction via disruption of DAT function and the DA signaling pathway but also indicate a potential strategy to treat VPS35-D620N-related PD and other disorders.
Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3
Authors: Martínez-Rubio Dolores , Rodríguez-Prieto Ángela , Sancho Paula , Navarro-González Carmen , Gorría-Redondo Nerea , Miquel-Leal Javier , Marco-Marín Clara , Jenkins Alison , Soriano-Navarro Mario , Hernández Alberto , Pérez-Dueñas Belén , Fazzari Pietro , Aguilera-Albesa Sergio , Espinós Carmen
Published: June 2022

Peroxiredoxin 3 (PRDX3) encodes a mitochondrial antioxidant protein, which is essential for the control of reactive oxygen species homeostasis. So far, PRDX3 mutations are involved in mild-to-moderate progressive juvenile onset cerebellar ataxia. We aimed to unravel the molecular bases underlying the disease in an infant suffering from cerebellar ataxia that started at 19 months old and presented severe cerebellar atrophy and peripheral neuropathy early in the course of disease. By whole exome sequencing, we identified a novel homozygous mutation, PRDX3 p.D163E, which impaired the mitochondrial ROS defense system. In mouse primary cortical neurons, the exogenous expression of PRDX3 p.D163E was reduced and triggered alterations in neurite morphology and in mitochondria. Mitochondrial computational parameters showed that p.D163E led to serious mitochondrial alterations. In transfected HeLa cells expressing the mutation, mitochondria accumulation was detected by correlative light electron microscopy. Mitochondrial morphology showed severe changes, including extremely damaged outer and inner membranes with a notable cristae disorganization. Moreover, spherical structures compatible with lipid droplets were identified, which can be associated with a generalized response to stress and can be involved in the removal of unfolded proteins. In the patient’s fibroblasts, PRDX3 expression was nearly absent. The biochemical analysis suggested that the mutation p.D163E would result in an unstable structure tending to form aggregates that trigger unfolded protein responses via mitochondria and endoplasmic reticulum. Altogether, our findings broaden the clinical spectrum of the recently described PRDX3-associated neurodegeneration and provide new insight into the pathological mechanisms underlying this new form of cerebellar ataxia.
Assessing the Effects of Measles Virus Infections on Childhood Infectious Disease Mortality in Brazil
Authors: Xia Siyang , Gullickson Cricket C , Metcalf C Jessica E , Grenfell Bryan T , Mina Michael J
Published: June 2022

Background

Measles virus infection induces acute immunosuppression for weeks following infection, and also impairs preexisting immunological memory, resulting in “immune amnesia” that can last for years. Both mechanisms predispose the host to severe outcomes of subsequent infections. Therefore, measles dynamics could potentially affect the epidemiology of other infectious diseases.

Methods

To examine this hypothesis, we analyzed the annual mortality rates of children aged 1–9 years in Brazil from 1980 to 1995. We calculated the correlation between nonmeasles infectious disease mortality rates and measles mortality rates using linear and negative-binomial models, with 3 methods to control the confounding effects of time. We also estimated the duration of measles-induced immunomodulation.

Results

The mortality rates of nonmeasles infectious diseases and measles virus infection were highly correlated. This positive correlation remained significant after removing the time trends. We found no evidence of long-term measles immunomodulation beyond 1 year.

Conclusions

These results support that measles virus infection could increase the mortality of other infectious diseases. The short lag identified for measles effects (<1 year) implies that acute immunosuppression was potentially driving this effect in Brazil. Overall, our study indicates disproportionate contributions of measles to childhood infectious disease mortality, highlighting the importance of measles vaccination.
The Cytokines CXCL10 and CCL2 and the Kynurenine Metabolite Anthranilic Acid Accurately Predict Patients at Risk of Developing Dengue With Warning Signs
Authors: Jusof Felicita Fedelis , Lim Chai K , Aziz Fazidatul Nadhirah , Soe Hui Jen , Raju Chandramathi Samudi , Sekaran Shamala Devi , Guillemin Gilles J
Published: June 2022

Background

The resolution or aggravation of dengue infection depends on the patient’s immune response during the critical phase. Cytokines released by immune cells increase with the worsening severity of dengue infections. Cytokines activate the kynurenine pathway (KP) and the extent of KP activation then influences disease severity.

Methods

KP metabolites and cytokines in plasma samples of patients with dengue infection (dengue without warning signs [DWS–], dengue with warning signs [DWS+], or severe dengue) were analyzed. Cytokines (interferon gamma [IFN-ɣ], tumor necrosis factor, interleukin 6, CXCL10/interferon-inducile protein 10 [IP-10], interleukin 18 [IL-18], CCL2/monocyte chemoattractant protein-1 [MCP-1], and CCL4/macrophage inflammatory protein-1beta [MIP-1β] were assessed by a Human Luminex Screening Assay, while KP metabolites (tryptophan, kynurenine, anthranilic acid [AA], picolinic acid, and quinolinic acid) were assessed by ultra-high-performance liquid chromatography and Gas Chromatography Mass Spectrophotometry [GCMS] assays.

Results

Patients with DWS+ had increased activation of the KP where kynurenine-tryptophan ratio, anthranilic acid, and picolinic acid were elevated. These patients also had higher levels of the cytokines IFN-ɣ, CXCL10, CCL4, and IL-18 than those with DWS–. Further receiver operating characteristic analysis identified 3 prognostic biomarker candidates, CXCL10, CCL2, and AA, which predicted patients with higher risks of developing DWS+ with an accuracy of 97%.

Conclusions

The data suggest a unique biochemical signature in patients with DWS+. CXCL10 and CCL2 together with AA are potential prognostic biomarkers that discern patients with higher risk of developing DWS+ at earlier stages of infection.
Analytical Quality by Design-Based Robust RP-HPLC Method for Quantitative Estimation of Pregabalin and Etoricoxib in Fixed-Dose Combination Tablet Formulation
Authors: Shah Janvi , Kotadiya Rajendra , Patel Rashmin
Published: June 2022

Background

The Central Drugs Standard Control Organization approved a bilayered, uncoated, fixed-dosage combination tablet formulation containing pregabalin (75 mg) and etoricoxib (60 mg) in November 2019 to control prolonged back pain with neuropathic components.

Objective

This research aims to create an analytical quality by design-assisted reversed phase (RP)-HPLC method for quantifying pregabalin and etoricoxib in tablet formulation.

Methods

The best chromatographic conditions were a Phenomenex C8 column (250 × 4.6 mm, 5.6 μm) and a mobile phase of 0.35% orthophosphoric acid –acetonitrile (1 + 1, by volume). A flow rate of 1 mL/min was used with a detection wavelength of 220 nm.

Results

The optimized reversed phase HPLC method was successfully validated by the International Conference on Hormonization guideline Q2(R1). Moreover, the percentage assay of pregabalin and etoricoxib tablet formulation was 99.05 and 100.02% w/w, respectively, using the validated RP-HPLC method.

Conclusion

The newly developed analytical quality by design-assisted RP-HPLC method has several advantages, including shortened analytical time (2.65 min and 7.45 min pregabalin and etoricoxib, respectively), efficient separation in terms of well-defined peaks, and a simple mobile phase combination.

Highlights

The use of analytical quality by design principles and the design of the experiment tool allowed the detection of influential parameters critical for achieving the most favourable chromatographic conditions for accurately quantifying individual drugs using the RP-HPLC method. The compliance of the results with the ICH criteria validated the method. As a result, adopting the analytical quality by design methodology ensured the development of a more robust method that can generate consistent, dependable, and quality data throughout the process while also saving time.
Significance of the effects of chemotherapy on programmed death-ligand 1 expression in triple-negative breast cancer
Authors: Imanishi Seiichi , Morishima Hirotaka , Gotoh Takayoshi
Published: June 2022

Background

Atezolizumab has been approved as an antibody against programmed death-ligand 1 (PD-L1)-positive immune cells in patients with advanced or recurrent triple-negative breast cancer. However, the optimal timing to examine PD-L1 expression remains controversial. We retrospectively researched PD-L1 positivity rates in biopsy, surgical and recurrent specimens from patients with triple-negative breast cancer treated with neoadjuvant chemotherapy. We also examined alterations in PD-L1 and their meaning.

Methods

In total, 35 triple-negative breast cancer biopsy specimens obtained before neoadjuvant chemotherapy, 20 corresponding specimens obtained after neoadjuvant chemotherapy and 5 corresponding recurrent specimens were obtained. We examined PD-L1 immunohistochemistry on tumor cells and tumor-infiltrating immune cells using SP142 antibody.

Results

In comparison with specimens obtained before neoadjuvant chemotherapy, PD-L1 expression randomly changed in immune cells after neoadjuvant chemotherapy, but PD-L1 expression was significantly reduced in tumor cells. Pre-neoadjuvant chemotherapy specimens with low PD-L1 expression (PD-L1 scores of ≤1 for both immune cells and tumor cells) were linked to better disease-free survival (P < 0.001) and overall survival (P < 0.001) than the other specimens.

Conclusion

This is the first study to evaluate PD-L1 expression both before and after chemotherapy in breast cancer and examine its relationship with prognosis. The results suggest that the PD-L1 level may be useful for predicting the prognosis of patients with triple-negative breast cancer who do not have pathological complete responses to neoadjuvant chemotherapy.
Phytomelatonin and plant mineral nutrition
Authors: Sun Chengliang , Sun Nan , Ou Yiqun , Gong Biao , Jin Chongwei , Shi Qinghua , Lin Xianyong
Published: June 2022

Plant mineral nutrition is critical for agricultural productivity and for human nutrition; however, the availability of mineral elements is spatially and temporally heterogeneous in many ecosystems and agricultural landscapes. Nutrient imbalances trigger intricate signalling networks that modulate plant acclimation responses. One signalling agent of particular importance in such networks is phytomelatonin, a pleiotropic molecule with multiple functions. Evidence indicates that deficiencies or excesses of nutrients generally increase phytomelatonin levels in certain tissues, and it is increasingly thought to participate in the regulation of plant mineral nutrition. Alterations in endogenous phytomelatonin levels can protect plants from oxidative stress, influence root architecture, and influence nutrient uptake and efficiency of use through transcriptional and post-transcriptional regulation; such changes optimize mineral nutrient acquisition and ion homeostasis inside plant cells and thereby help to promote growth. This review summarizes current knowledge on the regulation of plant mineral nutrition by melatonin and highlights how endogenous phytomelatonin alters plant responses to specific mineral elements. In addition, we comprehensively discuss how melatonin influences uptake and transport under conditions of nutrient shortage.
CRISPR/Cas9-mediated genetic correction reverses spinocerebellar ataxia 3 disease-associated phenotypes in differentiated cerebellar neurons
Authors: Song Guoxu , Ma Yuying , Gao Xing , Zhang Xuewen , Zhang Fei , Tian Chunhong , Hou Jiajia , Liu Zheng , Zhao Zixin , Tian Yong
Published: June 2022

The neurodegenerative disease spinocerebellar ataxia type 3 (SCA3; also called Machado-Joseph disease, MJD) is a trinucleotide repeat disorder caused by expansion of the CAG repeats in the ATXN3 gene. Here, we applied a CRISPR/Cas9-mediated approach using homologous recombination to achieve a one-step genetic correction in SCA3-specific induced pluripotent stem cells (iPSCs). The genetic correction reversed disease-associated phenotypes during cerebellar region-specific differentiation. In addition, we observed spontaneous ataxin-3 aggregates specifically in mature cerebellar neurons differentiated from SCA3 iPSCs rather than in SCA3 pan-neurons, SCA3 iPSCs or neural stem cells, suggesting that SCA3 iPSC-derived disease-specific and region-specific cerebellar neurons can provide unique cellular models for studying SCA3 pathogenesis in vitro. Importantly, the genetically corrected cerebellar neurons did not display typical SCA3 aggregates, suggesting that genetic correction can subsequently reverse SCA3 disease progression. Our strategy can be applied to other trinucleotide repeat disorders to facilitate disease modeling, mechanistic studies and drug discovery.
EDGE: the puzzling ellipticity of Eridanus II’s star cluster and its implications for dark matter at the heart of an ultra-faint dwarf
Authors: Orkney Matthew D A , Read Justin I , Agertz Oscar , Pontzen Andrew , Rey Martin P , Goater Alex , Taylor Ethan , Kim Stacy Y , Delorme Maxime
Published: June 2022

The Eridanus II (EriII) ‘ultra-faint’ dwarf has a large (15 pc) and low-mass (4.3 × 103 M⊙) star cluster (SC) offset from its centre by 23 ± 3 pc in projection. Its size and offset are naturally explained if EriII has a central dark matter core, but such a core may be challenging to explain in a ΛCDM cosmology. In this paper, we revisit the survival and evolution of EriII’s SC, focusing for the first time on its puzzlingly large ellipticity ($0.31^{+0.05}_{-0.06}$). We perform a suite of 960 direct N-body simulations of SCs, orbiting within a range of spherical background potentials fit to ultra-faint dwarf (UFD) galaxy simulations. We find only two scenarios that come close to explaining EriII’s SC. In the first scenario, EriII has a low-density dark matter core (of size ${\sim}70\, \text{pc}$ and density $\lesssim 2\times 10^8\, \text{M}_{\odot }\, \text{kpc}^{-3}$). In this model, the high ellipticity of EriII’s SC is set at birth, with the lack of tidal forces in the core allowing its ellipticity to remain frozen for long times. In the second scenario, EriII’s SC orbits in a partial core, with its high ellipticity owing to its imminent tidal destruction. However, this latter model struggles to reproduce the large size of EriII’s SC, and it predicts substantial tidal tails around EriII’s SC that should have already been seen in the data. This leads us to favour the cored model. We discuss potential caveats to these findings, and the implications of the cored model for galaxy formation and the nature of dark matter.
Non-thermal emission from the plunging region: a model for the high-energy tail of black hole X-ray binary soft states
Authors: Hankla Amelia M , Scepi Nicolas , Dexter Jason
Published: June 2022

X-ray binaries exhibit a soft spectral state comprising thermal blackbody emission at 1 keV and a power-law tail above 10 keV. Empirical models fit the high-energy power-law tail to radiation from a non-thermal electron distribution, but the physical location of the non-thermal electrons and the reason for their power-law index and high-energy cut-off are still largely unknown. Here, we propose that the non-thermal electrons originate from within the black hole’s innermost stable circular orbit (the ‘plunging region’). Using an analytic model for the plunging region dynamics and electron distribution function properties from particle-in-cell simulations, we outline a steady-state model that can reproduce the observed spectral features. In particular, our model reproduces photon indices of Γ ≳ 2 and power-law luminosities of the order of a few per cent of the disc luminosity for strong magnetic fields, consistent with observations of the soft state. Because the emission originates so close to the black hole, we predict that the power-law luminosity should strongly depend on the system inclination angle and black hole spin. This model could be extended to the power-law tails observed above 400 keV in the hard state of X-ray binaries.
The role of dendrin in IgA nephropathy
Authors: Levin Anna , Schwarz Angelina , Hulkko Jenny , He Liqun , Sun Ying , Barany Peter , Bruchfeld Annette , Herthelius Maria , Wennberg Lars , Ebefors Kerstin , Patrakka Jaakko , Betsholtz Christer , Nyström Jenny , Mölne Johan , Hultenby Kjell , Witasp Anna , Wernerson Annika
Published: June 2022

Background

Immunoglobulin A nephropathy (IgAN) and its systemic variant IgA vasculitis (IgAV) damage the glomeruli, resulting in proteinuria, hematuria and kidney impairment. Dendrin is a podocyte-specific protein suggested to be involved in the pathogenesis of IgAN. Upon cell injury, dendrin translocates from the slit diaphragm to the nucleus, where it is suggested to induce apoptosis and cytoskeletal changes, resulting in proteinuria and accelerated disease progression in mice. Here we investigated gene and protein expression of dendrin in relation to clinical and histopathological findings to further elucidate its role in IgAN/IgAV.

Methods

Glomerular gene expression was measured using microarray on 30 IgAN/IgAV patients, 5 patients with membranous nephropathy (MN) and 20 deceased kidney donors. Dendrin was spatially evaluated on kidney tissue sections by immunofluorescence (IF) staining (IgAN patients, n = 4; nephrectomized kidneys, n = 3) and semi-quantified by immunogold electron microscopy (IgAN/IgAV patients, n = 21; MN, n = 5; living kidney donors, n = 6). Histopathological grading was performed according to the Oxford and Banff classifications. Clinical data were collected at the time of biopsy and follow-up.

Results

Dendrin mRNA levels were higher (P = .01) in IgAN patients compared with MN patients and controls and most prominently in patients with preserved kidney function and fewer chronic histopathological changes. Whereas IF staining did not differ between groups, immunoelectron microscopy revealed that a higher relative nuclear dendrin concentration in IgAN patients was associated with a slower annual progression rate and milder histopathological changes.

Conclusion

Dendrin messenger RNA levels and relative nuclear protein concentrations are increased and associated with a more benign phenotype and progression in IgAN/IgAV patients.