bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of cooling rates after annealing on the microstructure and properties of 1000 MPa grade automobile steel for cold forming
Authors: Dong Ruifeng , Zhao Qingbo , Bi Xiaohong , Deng Xiangtao , Shen Wentian , Lu Yongfa , Gele Teri , Baoxing
Published: November 2021

The effects of different cooling rates (0.05 °C s−1, 0.1 °C s−1, and 0.2 °C s−1) on the microstructure and mechanical properties of 1000 MPa grade automobile steel for cold forming after two-phase annealing were studied. The microstructure of the experimental steel was observed by SEM and TEM, and its mechanical properties were tested by a universal tensile testing machine. The results showed that by increasing the cooling rate of two-phase annealing, more massive retained austenite, more uniform and fine ferrite, better elongation and higher ultimate tensile strength of steel can be obtained, so as to obtain better production of tensile strength and total elongation (product of tensile strength and elongation, PSE). The final result shows that after the test steel is quenched at 800 °C + 10 min and annealed in the two-phase region at 690 °C + 10 min, the faster the cooling rate, the better the mechanical properties. The mechanical properties of the steel plate are the best when the cooling rate reaches 0.2 °C s−1, and PSE can reach 27.44 GPa·%.
Soft iontronic delivery devices based on an intrinsically stretchable ion selective membrane
Authors: Cherian Dennis , Lienemann Samuel , Abrahamsson Tobias , Kim Nara , Berggren Magnus , Simon Daniel T , Tybrandt Klas
Published: November 2021

Implantable electronically controlled drug delivery devices can provide precision therapeutic treatments by highly spatiotemporally controlled delivery. Iontronic delivery devices rely on the movement of ions rather than liquid, and can therefore achieve electronically controlled precision delivery in a compact setting without disturbing the microenvironment within the tissue with fluid flow. For maximum precision, the delivery device needs to be closely integrated into the tissue, which is challenging due to the mechanical mismatch between the soft tissue and the harder devices. Here we address this challenge by developing a soft and stretchable iontronic delivery device. By formulating an ink based on an in-house synthesized hyperbranched polyelectrolyte, water dispersed polyurethane, and a thickening agent, a viscous ink is developed for stencil patterning of soft ion exchange membranes (IEMs). We use this ink for developing soft and stretchable delivery devices, which are characterized both in the relaxed and stretched state. We find that their functionality is preserved up to 100% strain, with small variations in resistance due to the strain. Finally, we develop a skin patch to demonstrate the outstanding conformability of the developed device. The presented technology is attractive for future soft implantable delivery devices, and the stretchable IEMs may also find applications within wearable energy devices.
Probabilistic Machine Learning with Low-Cost Sensor Networks for Occupational Exposure Assessment and Industrial Hygiene Decision Making
Authors: Patton Andrew N , Medvedovsky Konstantin , Zuidema Christopher , Peters Thomas M , Koehler Kirsten
Published: November 2021

Occupational exposure assessments are dominated by small sample sizes and low spatial and temporal resolution with a focus on conducting Occupational Safety and Health Administration regulatory compliance sampling. However, this style of exposure assessment is likely to underestimate true exposures and their variability in sampled areas, and entirely fail to characterize exposures in unsampled areas. The American Industrial Hygiene Association (AIHA) has developed a more realistic system of exposure ratings based on estimating the 95th percentiles of the exposures that can be used to better represent exposure uncertainty and exposure variability for decision-making; however, the ratings can still fail to capture realistic exposure with small sample sizes. Therefore, low-cost sensor networks consisting of numerous lower-quality sensors have been used to measure occupational exposures at a high spatiotemporal scale. However, the sensors must be calibrated in the laboratory or field to a reference standard. Using data from carbon monoxide (CO) sensors deployed in a heavy equipment manufacturing facility for eight months from August 2017 to March 2018, we demonstrate that machine learning with probabilistic gradient boosted decision trees (GBDT) can model raw sensor readings to reference data highly accurately, entirely removing the need for laboratory calibration. Further, we indicate how the machine learning models can produce probabilistic hazard maps of the manufacturing floor, creating a visual tool for assessing facility-wide exposures. Additionally, the ability to have a fully modeled prediction distribution for each measurement enables the use of the AIHA exposure ratings, which provide an enhanced industrial decision-making framework as opposed to simply determining if a small number of measurements were above or below a pertinent occupational exposure limit. Lastly, we show how a probabilistic modeling exposure assessment with high spatiotemporal resolution data can prevent exposure misclassifications associated with traditional models that rely exclusively on mean or point predictions.
Investigating Clinician Experiences of Teleneuropsychology Service Implementation within Rural Inpatient Rehabilitation Settings: A Mixed Method Approach
Authors: Van Den Broek Sian R , Bagot Kathleen L , Arthurson Lauren , Cadilhac Dominque A , Stolwyk Renerus J
Published: November 2021

Objective

The aim of this study was to understand clinicians’ experiences of teleneuropsychology service implementation within rural inpatient rehabilitation settings and the variability of those experiences across rural settings and clinical disciplines.

Method

Clinicians (n = 56 from four rehabilitation settings) who were involved in a hub-and-spoke teleneuropsychology service completed surveys throughout service implementation. A purposive sample of 16 clinicians then completed semi-structured interviews at the conclusion of the service implementation period. Quantitative data were analyzed descriptively and qualitative data were analyzed using thematic analysis, prior to the results being converged.

Results

Four themes characterizing clinicians’ experiences were identified. Pre- and early-implementation considerations included factors such as early collaboration and consultation, which were identified as important for service integration into rural settings. Facilitators/barriers included factors such as technology usability, which positively or negatively influenced service implementation. Benefits and outcomes included perceptions on the impact of the service, such as improved equity and quality of care in rural settings. Finally, future applications encapsulated what the clinicians envisaged for the future of teleneuropsychology services, such as hybrid teleneuropsychology/in-person services. Some differences were identified in clinicians’ experiences across rural settings and disciplines, including preferences for technology infrastructure and satisfaction with teleneuropsychology sessions.

Conclusions

Most clinicians reported positive experiences and acceptability of the teleneuropsychology service. Facilitators and barriers, which can guide the successful establishment of future teleneuropsychology services, were identified. These findings may be used to contribute to improving equity and quality of care for people living with neuropsychological impairments, especially those living in rural areas.
Delayed parenthood and its influence on offspring health: what have we learned from the mouse model
Authors: Zacchini Federica , Sampino Silvestre , Ziętek Marta , Chan Alan
Published: November 2021

Delayed parenthood is constantly increasing worldwide due to various socio-economic factors. In the last decade, a growing number of epidemiological studies have suggested a link between advanced parental age and an increased risk of diseases in the offspring. Also, poor reproductive outcome has been described in pregnancies conceived by aged parents. Similarly, animal studies showed that aging negatively affects gametes, early embryonic development, pregnancy progression, and the postnatal phenotype of resulting offspring. However, how and to what extent parental age is a risk factor for the health of future generations is still a subject of debate. Notwithstanding the limitation of an animal model, the mouse model represents a useful tool to understand not only the influence of parental age on offspring phenotype but also the biological mechanisms underlying the poor reproductive outcome and the occurrence of diseases in the descendants. The present review aims at i) providing an overview of the current knowledge from mouse model about the risks associated with conception at advanced age (e.g. neurodevelopmental and metabolic disorders), ii) highlighting the candidate biological mechanisms underlying this phenomenon, and iii) discussing on how murine-derived data can be relevant to humans.
PABPN1L assemble into “ring-like” aggregates in the cytoplasm of MII oocytes and is associated with female infertility†
Authors: Wang Ying , Feng Tianhao , Zhu Mingcong , Shi Xiaodan , Wang Zerui , Liu Siyu , Zhang Xin , Zhang Jintao , Zhao Shuqin , Zhang Junqiang , Ling Xiufeng , Liu Mingxi
Published: November 2021

Infertility affects 10–15% of families worldwide. However, the pathogenesis of female infertility caused by abnormal early embryonic development is not clear. A recent study showed that poly(A)binding protein nuclear 1-like (PABPN1L) recruited BTG anti-proliferation factor 4 (BTG4) to mRNA 3′-poly(A) tails and was essential for maternal mRNA degradation. Here, we generated a PABPN1L-antibody and found “ring-like” PABPN1L aggregates in the cytoplasm of MII oocytes. PABPN1L–EGFP proteins spontaneously formed “ring-like” aggregates in vitro. This phenomenon is similar with CCR4–NOT catalytic subunit, CCR4-NOT transcription complex subunit 7 (CNOT7), when it starts deadenylation process in vitro. We constructed two mouse model (Pabpn1l−/− and Pabpn1l  tm1a/tm1a) simulating the intron 1–exon 2 abnormality of human PABPN1L and found that the female was sterile and the male was fertile. Using RNA-Seq, we observed a large-scale up-regulation of RNA in zygotes derived from Pabpn1l−/− MII oocytes. We found that 9222 genes were up-regulated instead of being degraded in the Pabpn1l−♀/+♂zygote. Both the Btg4 and CCR4-NOT transcription complex subunit 6 like (Cnot6l) genes are necessary for the deadenylation process and Pabpn1l−/− resembled both the Btg4 and Cnot6l knockouts, where 71.2% genes stabilized in the Btg4−♀/+♂ zygote and 84.2% genes stabilized in the Cnot6l−♀/+♂zygote were also stabilized in Pabpn1l−♀/+♂ zygote. BTG4/CNOT7/CNOT6L was partially co-located with PABPN1L in MII oocytes. The above results suggest that PABPN1L is widely associated with CCR4–NOT-mediated maternal mRNA degradation and PABPN1L variants on intron 1–exon 2 could be a genetic marker of female infertility.
Effect of additive, dominant and epistatic variances on breeding and deployment strategy in Norway spruce
Authors: Nguyen Hong T H , Chen Zhi-Qiang , Fries Anders , Berlin Mats , Hallingbäck Henrik R , Wu Harry X
Published: November 2021

Genetic variances are important parameters and have a great impact on the determination of optimal breeding strategies of tree species. A large clonal testing program was conducted to estimate additive, dominant and epistatic variances for the development of breeding and deployment strategies in Norway spruce (Picea abies (L.) Karst.). The analysis results of genetic variation for growth and wood properties in two clonal trials in central Sweden indicated that the important sources of total genetic variation were both additive and non-additive genetic variances. Additive genetic variation accounted for the majority of total genetic variation for diameter at breast height (DBH) and wood quality traits, whereas non-additive genetic variation was significant only for tree height at an early age. Predicted genetic gain was the highest for clonal deployment based on best tested (replicated) clones (4.7–65.3 per cent), followed by clonal deployment of the best individual trees from a full-sib family trial (3.5–57.7 per cent), and the deployment of seedlings generated by open-pollination (1.9–48.3 per cent).
Elevated DLL3 in stomach cancer by tumor-associated macrophages enhances cancer-cell proliferation and cytokine secretion of macrophages
Authors: Ye Jian-Bin , Wen Jun-Jie , Wu Dan-Lin , Hu Bing-Xin , Luo Mei-Qun , Lin Yan-Qing , Ning Yun-Shan , Li Yan
Published: November 2021

Background

The notch signal pathway is important in the development of both tumor-associated macrophages (TAMs) and stomach cancer, but how Notch signaling affects TAMs in stomach cancer is barely understood.

Methods

The expressions of Notch1, Notch2, Notch3, Notch4, hes family bHLH transcription factor 1 (Hes1), and delta-like canonical Notch ligand 3 (DLL3) were detected by Western blot and the expressions of interleukin (IL)-10, IL-12, and IL1-β were detected using enzyme-linked immunosorbent assay after the co-culture of macrophages and stomach-cancer cells. The proliferation and migration of cancer cells were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and scratch assay, respectively, and the cell cycle was detected using Annexin V/propidium iodide assay. The protein interactions with DLL3 were detected using co-immunoprecipitation and mass spectrometry.

Results

The co-culture of macrophages and stomach-cancer cells MKN45 and BGC823 could enhance cell proliferation accompanied by the activation of Notch1/Notch2 signaling and upregulation of DLL3. Notch signaling gamma-secretase inhibitor (DAPT) blocked this process. The overexpression of DLL3 in stomach-cancer cells could promote the proliferation of cancer cells, enhance the activation of Notch1/Notch2 signaling, induce the expression of IL-33, lead to the degradation of galectin-3–binding protein (LG3BP) and heat shock cognate 71 kDa protein (HSPA8), and result in elevated IL-1β, IL-12, and IL-10 secretion by macrophages. Higher expression of DLL3 or IL-33 could lead to a lower survival rate based on University of California, Santa Cruz Xena Functional Genomics Explorer and The Cancer Genome Atlas data set.

Conclusions

This is evidence that DLL3 regulates macrophages in stomach cancer, suggesting that DLL3 may be a novel and potential target for stomach-cancer therapy.
Neuronal KGB-1 JNK MAPK signaling regulates the dauer developmental decision in response to environmental stress in Caenorhabditis elegans
Authors: Dogra Deepshikha , Kulalert Warakorn , Schroeder Frank C , Kim Dennis H
Published: November 2021

In response to stressful growth conditions of high population density, food scarcity, and elevated temperature, young larvae of nematode Caenorhabditis elegans can enter a developmentally arrested stage called dauer that is characterized by dramatic anatomic and metabolic remodeling. Genetic analysis of dauer formation of C. elegans has served as an experimental paradigm for the identification and characterization of conserved neuroendocrine signaling pathways. Here, we report the identification and characterization of a conserved c-Jun N-terminal Kinase-like mitogen-activated protein kinase (MAPK) pathway that is required for dauer formation in response to environmental stressors. We observed that loss-of-function mutations in the MLK-1-MEK-1-KGB-1 MAPK pathway suppress dauer entry. A loss-of-function mutation in the VHP-1 MAPK phosphatase, a negative regulator of KGB-1 signaling, results in constitutive dauer formation, which is dependent on the presence of dauer pheromone but independent of diminished food levels or elevated temperatures. Our data suggest that the KGB-1 pathway acts in the sensory neurons, in parallel to established insulin and TGF-β signaling pathways, to transduce the dauer-inducing environmental cues of diminished food levels and elevated temperature.
IL-4i1 Regulation of Immune Protection During Mycobacterium tuberculosis Infection
Authors: Hlaka Lerato , Ozturk Mumin , Chia Julius E , Jones Shelby-Sara , Pillay Shandre , Poswayo Sibongiseni K L , Mpotje Thabo , Nono Justin K , Simelane Simphiwe R N , Parihar Suraj P , Roy Sugata , Suzuki Harukazu , Brombacher Frank , Guler Reto
Published: November 2021

Background

Interleukin 4 (IL-4i1)–induced gene 1 encodes L-phenylalanine oxidase that catabolizes phenylalanine into phenylpyruvate. IL-4i1 is mainly expressed by antigen-presenting cells (APCs), inhibits T-cell proliferation, regulates B-cell activation, modulates T cell responses, and drives macrophage polarization, but its role in bacterial infections is understudied.

Methods

We evaluated IL-4i1 deletion in macrophages and mice on infection with virulent H37Rv and W-Beijing lineage hypervirulent HN878 Mycobacterium tuberculosis (Mtb) strains. The bacterial growth and proinflammatory responses were measured in vitro and in vivo. Histopathological analysis, lung immune cell recruitment, and macrophage activation were assessed at the early and chronic stages of Mtb infection.

Results

IL-4i1–deficient (IL-4i1−/−) mice displayed increased protection against acute H37Rv, HN878 and chronic HN878 Mt infections, with reduced lung bacterial burdens and altered APC responses compared with wild-type mice. Moreover, “M1-like” interstitial macrophage numbers, and nitrite and Interferon-γ production were significantly increased in IL-4i1−/− mice compared with wild-type mice during acute Mtb HN878 infection.

Conclusions

Together, these data suggest that IL-4i1 regulates APC-mediated inflammatory responses during acute and chronic Mtb infection. Hence, IL-4i1 targeting has potential as an immunomodulatory target for host-directed therapy.
Forum: Conflict Delegation in Civil Wars
Authors: Karlén Niklas , Rauta Vladimir , Salehyan Idean , Mumford Andrew , San-Akca Belgin , Stark Alexandra , Wyss Michel , Moghadam Assaf , Duursma Allard , Tamm Henning , Jenne Erin K , Popovic Milos , Siroky David S , Meier Vanessa , Chinchilla Alexandra , Rickard Kit , Spatafora Giuseppe
Published: November 2021

This forum provides an outlet for an assessment of research on the delegation of war to non-state armed groups in civil wars. Given the significant growth of studies concerned with this phenomenon over the last decade, this forum critically engages with the present state of the field. First, we canvass some of the most important theoretical developments to demonstrate the heterogeneity of the debate. Second, we expand on the theme of complexity and investigate its multiple facets as a window into pushing the debate forward. Third, we draw the contours of a future research agenda by highlighting some contemporary problems, puzzles, and challenges to empirical data collection. In essence, we seek to connect two main literatures that have been talking past each other: external support in civil wars and proxy warfare. The forum bridges this gap at a critical juncture in this new and emerging scholarship by offering space for scholarly dialogue across conceptual labels.
Axillary Imaging Following a New Invasive Breast Cancer Diagnosis—A Radiologist’s Dilemma
Authors: Dialani Vandana , Dogan Basak , Dodelzon Katerina , Dontchos Brian N , Modi Neha , Grimm Lars
Published: November 2021

Traditionally, patients with newly diagnosed invasive breast cancer underwent axillary US to assess for suspicious axillary lymph nodes (LNs), which were then targeted for image-guided needle biopsy to determine the presence of metastasis. Over the past decade, there has been a shift towards axillary preservation. For patients with palpable lymphadenopathy, the decision to perform axillary imaging with documentation of the number and location of abnormal LNs in preparation for image-guided LN sampling is straightforward. Since LN involvement correlates with cancer size, it is reasonable to image the axilla in patients with tumors larger than 5 cm; however, for tumors smaller than 5 cm, axillary imaging is often deferred until after the tumor molecular subtype and treatment plan are established. Over the last decade, neoadjuvant chemotherapy (NACT) is increasingly used for smaller cancers with more aggressive molecular subtypes. In most cases, detecting axillary metastasis is critical when deciding whether the patient would benefit from NACT. There is increasing evidence that abnormal axillary US findings correlates with LN metastases and reliably establishes a baseline to monitor response to NACT. Depending on hormone receptor status, practices may choose to image the axilla in the setting of clinical stage T1 and T2 cancers to evaluate nodal status and help determine further steps in care. Radiologists should understand the nuances of axillary management and the scope and challenges of LN marking techniques that significantly increase the precision of limited axillary surgery.
Deep carbonate reservoir characterisation using multi-seismic attributes via machine learning with physical constraints
Authors: Chen Yuanyuan , Zhao Luanxiao , Pan Jianguo , Li Chuang , Xu Minghui , Li Kejian , Zhang Fengshou , Geng Jianhua
Published: November 2021

Seismic characterisation of deep carbonate reservoirs is of considerable interest for reservoir distribution prediction, reservoir quality evaluation and reservoir structure delineation. However, it is challenging to use the traditional methodology to predict a deep-buried carbonate reservoir because of the highly nonlinear mapping relationship between heterogeneous reservoir features and seismic responses. We propose a machine-learning-based method (random forest) with physical constraints to enhance deep carbonate reservoir prediction performance from multi-seismic attributes. We demonstrate the effectiveness of this method on a real data application in the deep carbonate reservoir of Tarim Basin, Western China. We first perform feature selection on multi-seismic attributes, then four kinds of physical constraint (continuity, boundary, spatial and category constraint) transferred from domain knowledge are imposed on the process of model building. Using the physical constraints, the F1 score of reservoir quality and reservoir type can be significantly improved and the combination of the effective physical constraints gives the best prediction of performance. We also apply the proposed strategy on 2D seismic data to predict the spatial distribution of reservoir quality and type. The seismic prediction results provide a reasonable description of the strong heterogeneity of the reservoir, offering insights into sweet spot detection and reservoir development.
Acoustic wave propagation with new spatial implicit and temporal high-order staggered-grid finite-difference schemes
Authors: Wang Jing , Liu Yang , Zhou Hongyu
Published: November 2021

The implicit staggered-grid (SG) finite-difference (FD) method can obtain significant improvement in spatial accuracy for performing numerical simulations of wave equations. Normally, the second-order central grid FD formulas are used to approximate the temporal derivatives, and a relatively fine time step has to be used to reduce the temporal dispersion. To obtain high accuracy both in space and time, we propose a new spatial implicit and temporal high-order SG FD stencil in the time–space domain by incorporating some additional grid points to the conventional implicit FD one. Instead of attaining the implicit FD coefficients by approximating spatial derivatives only, we calculate the coefficients by approximating the temporal and spatial derivatives simultaneously through matching the dispersion formula of the seismic wave equation and compute the FD coefficients of our new stencil by two schemes. The first one is adopting a variable substitution-based Taylor-series expansion (TE) to derive the FD coefficients, which can attain (2M + 2)th-order spatial accuracy and (2N)th-order temporal accuracy. Note that the dispersion formula of our new stencil is non-linear with respect to the axial and off-axial FD coefficients, it is complicated to obtain the optimal spatial and temporal FD coefficients simultaneously. To tackle the issue, we further develop a linear optimisation strategy by minimising the L2-norm errors of the dispersion formula to further improve the accuracy. Dispersion analysis, stability analysis and modelling examples demonstrate the accuracy, stability and efficiency advantages of our two new schemes.
Observational measures of halo properties beyond mass
Authors: Behroozi Peter , Hearin Andrew , Moster Benjamin P
Published: November 2021

Different properties of dark matter haloes, including growth rate, concentration, interaction history, and spin, correlate with environment in unique, scale-dependent ways. While these halo properties are not directly observable, galaxies will inherit their host haloes’ correlations with environment. In this paper, we show how these characteristic environmental signatures allow using measurements of galaxy environment to constrain which dark matter halo properties are most tightly connected to observable galaxy properties. We show that different halo properties beyond mass imprint distinct scale-dependent signatures in both the galaxy two-point correlation function and the distribution of distances to galaxies’ kth nearest neighbours, with features strong enough to be accessible even with low-resolution (e.g. grism) spectroscopy at higher redshifts. As an application, we compute observed two-point correlation functions for galaxies binned by half-mass radius at $z$ = 0 from the Sloan Digital Sky Survey, showing that classic galaxy size models (i.e. galaxy size being proportional to halo spin) as well as other recent proposals show significant tensions with observational data. We show that the agreement with observed clustering can be improved with a simple empirical model in which galaxy size correlates with halo growth.
Heart function in juvenile idiopathic arthritis patients: A biventricular two-dimensional speckle-tracking echocardiography study
Authors: Lianza Alessandro C , Leal Gabriela N , Aikawa Nádia E , Kozu Katia T , Diniz Maria De Fátima R , Sawamura Karen S S , Menezes Carolina R B , Martins Camila Lino , Campos Lucia M , Elias Adriana M , Silva Clovis A
Published: November 2021

Objectives

We evaluated cardiac function in juvenile idiopathic arthritis (JIA) patients by 2D speckle-tracking echocardiography (2DSTE) and to assess possible associations with clinical, laboratorial, and treatment data.

Methods

A group of 42 JIA patients and 42 healthy controls were evaluated using both conventional echocardiography and 2DSTE. JIA patients underwent clinical and laboratory assessment.

Results

Conventional echocardiography data demonstrated normal left ventricular (LV) ejection fraction in both groups (71 vs. 71%; p = .69). 2DSTE analysis demonstrated that JIA patients presented significantly lower LV global systolic longitudinal strain (LVGLS) (−18.76 vs. −22%; p < .0001), LV systolic strain rate (LVSSR) (1.06 vs. 1.32 s−1; p < .0001), LV diastolic strain rate (LVDSR) (1.58 vs. 1.8 s−1; p < .0137), right ventricular global systolic strain (RVGLS) (−24.1% vs. −27.7%; p = .0002), and right ventricular systolic strain rate (RVSSR) (1.4 vs. 1.8 s−1; p = .0035). JIA patients under biological agents presented higher LVGLS (p = .02) and RVLS (p = .01). We also detected an association between LVGLS and C-reactive protein [CRP; −20% in normal CRP (10/42) vs. −18% in elevated CRP patients (32/42), p = .03].

Conclusions

JIA patients present different echocardiographic status from healthy patients. Moreover, our data suggest that JIA patients under biological agents present association with better cardiac function as shown by strain analysis.
Wound-inducible WUSCHEL-RELATED HOMEOBOX 13 is required for callus growth and organ reconnection
Authors: Ikeuchi Momoko , Iwase Akira , Ito Tasuku , Tanaka Hayato , Favero David S , Kawamura Ayako , Sakamoto Shingo , Wakazaki Mayumi , Tameshige Toshiaki , Fujii Haruki , Hashimoto Naoki , Suzuki Takamasa , Hotta Kazuhiro , Toyooka Kiminori , Mitsuda Nobutaka , Sugimoto Keiko
Published: November 2021

Highly efficient tissue repair is pivotal for surviving damage-associated stress. Plants generate callus upon injury to heal wound sites, yet regulatory mechanisms of tissue repair remain elusive. Here, we identified WUSCHEL-RELATED HOMEOBOX 13 (WOX13) as a key regulator of callus formation and organ adhesion in Arabidopsis (Arabidopsis thaliana). WOX13 belongs to an ancient subclade of the WOX family, and a previous study shows that WOX13 orthologs in the moss Physcomitrium patens (PpWOX13L) are involved in cellular reprogramming at wound sites. We found that the Arabidopsis wox13 mutant is totally defective in establishing organ reconnection upon grafting, suggesting that WOX13 is crucial for tissue repair in seed plants. WOX13 expression rapidly induced upon wounding, which was partly dependent on the activity of an AP2/ERF transcription factor, WOUND-INDUCED DEDIFFERENTIATION 1 (WIND1). WOX13 in turn directly upregulated WIND2 and WIND3 to further promote cellular reprogramming and organ regeneration. We also found that WOX13 orchestrates the transcriptional induction of cell wall-modifying enzyme genes, such as GLYCOSYL HYDROLASE 9Bs, PECTATE LYASE LIKEs and EXPANSINs. Furthermore, the chemical composition of cell wall monosaccharides was markedly different in the wox13 mutant. These data together suggest that WOX13 modifies cell wall properties, which may facilitate efficient callus formation and organ reconnection. Furthermore, we found that PpWOX13L complements the Arabidopsis wox13 mutant, suggesting that the molecular function of WOX13 is partly conserved between mosses and seed plants. This study provides key insights into the conservation and functional diversification of the WOX gene family during land plant evolution.
Mechanical characterization of rose bengal and green light crosslinked collagen scaffolds for regenerative medicine
Authors: Braun Joy , Eckes Stefanie , Kilb Michelle Fiona , Fischer Dirk , Eßbach Claudia , Rommens Pol Maria , Drees Philipp , Schmitz Katja , Nickel Daniela , Ritz Ulrike
Published: November 2021

Collagen is one of the most important biomaterials for tissue engineering approaches. Despite its excellent biocompatibility, it shows the non-negligible disadvantage of poor mechanical stability. Photochemical crosslinking with rose bengal and green light (RGX) is an appropriate method to improve this property. The development of collagen laminates is helpful for further adjustment of the mechanical properties as well as the controlled release of incorporated substances. In this study, we investigate the impact of crosslinking and layering of two different collagen scaffolds on the swelling behavior and mechanical behavior in micro tensile tests to obtain information on its wearing comfort (stiffness, strength and ductility). The mechanical stability of the collagen material after degradation due to cell contact is examined using thickness measurements. There is no linear increase or decrease due to layering homologous laminates. Unexpectedly, a decrease in elongation at break, Young’s modulus and ultimate tensile strength are measured when the untreated monolayer is compared to the crosslinked one. Furthermore, we can detect a connection between stability and cell proliferation. The results show that with variation in number and type of layers, collagen scaffolds with tailored mechanical properties can be produced. Such a multi-layered structure enables the release of biomolecules into inner or outer layers for biomedical applications.
Neratinib causes non-recoverable gut injury and reduces intestinal cytochrome P450 3A enzyme in mice
Authors: Tao Gabriel , Dagher Fatima , Ghose Romi
Published: November 2021

Neratinib is a pan-HER tyrosine kinase inhibitor newly approved by FDA in 2017 to treat HER2-positive breast cancer, but the phase III trial of neratinib showed that 96% of the patients taking neratinib experienced diarrhea. So far very few mechanistic studies explore neratinib-induced gastrointestinal (GI) toxicity. Hereby, we performed toxicity studies in mice to characterize the potential mechanism underlying this adverse effect. C57BL/6 J mice were separated into three groups A, B, C. Group A received vehicle; group B was orally dosed with 100 mg/kg neratinib once daily for 18 days. Group C was dosed with 100 mg/kg neratinib for 12 days and switched to vehicle for 6 days. Intestine and liver were collected for further analysis. Human intestine-derived cells were treated with neratinib in vitro. Our results showed that 12 days treatment of neratinib caused persistent histological damage in mouse GI tract. Both gene expression and activity of Cyp3a11, the major enzyme metabolizing neratinib in mice was reduced in small intestine. The gene expression of proinflammatory cytokines increased throughout the GI tract. Such damages were not recovered after 6 days without neratinib treatment. In addition, in vitro data showed that neratinib was potent in killing human intestine-derived cell lines. Based on such findings, we hypothesized that neratinib downregulates intestinal CYP3A enzyme to cause excessive drug disposition, eventually leading to gut injury.
Association between SLCO1B1 polymorphism and methotrexate-induced hepatotoxicity: a systematic review and meta-analysis
Authors: Han Ji Min , Choi Kyung Hee , Lee Hong Hyun , Gwak Hye Sun
Published: November 2021

Reports on the association between the solute carrier organic anion transporter 1B1 (SLCO1B1) T521C polymorphism and methotrexate-induced hepatotoxicity in patients with malignancies are inconsistent. This meta-analysis evaluated the association between the SLCO1B1 T521C polymorphism and methotrexate-induced hepatotoxicity. We performed a systematic review of previous reports from the PubMed, Web of Science, and EMBASE databases, and a meta-analysis was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated to evaluate the effect of the SLCO1B1 T521C polymorphism on the occurrence of methotrexate-induced hepatotoxicity. In total, data from five studies including 465 patients were analyzed. Patients had received a high-dose methotrexate regimen (1–5 g/m2). The SLCO1B1 variant allele (C allele) carriers had a 1.9-fold higher risk of hepatotoxicity than wild-type homozygote carriers (TT; OR, 1.94; 95% CI, 1.14–3.31). This meta-analysis demonstrated that C allele carriers of the SLCO1B1 polymorphism had a higher risk of hepatotoxicity than patients with the TT genotype. The SLCO1B1 T521C polymorphism may be a useful predictor for methotrexate-induced hepatotoxicity in patients with malignancies.
Eruptive melanocytic nevi in a patient with amelanotic melanoma: a paraneoplastic phenomenon?
Authors: De Giorgi Vincenzo , Gemignani Andrea , Scarfì Federica , Trane Luciana , Silvestri Flavia , Venturi Federico , Zuccaro Biancamaria , Urso Carmelo
Published: November 2021

Eruptive melanocytic nevi (EMN) describes the sudden onset of cutaneous nevi over weeks or months. Such a clinical event is generally seen in young adult patients and may be related to several possible causes. We report here a case of EMN in an old male patient followed up for a thick amelanotic cutaneous melanoma. A few months after the eruption, multiple hepatic masses, diagnosed as melanoma metastasis, were detected. The presented case may suggest that EMN may be a paraneoplastic phenomenon of alert in patients being followed for melanoma or other malignancies.
Bilateral Hand Metastases From a Pleomorphic/Dedifferentiated Leiomyosarcoma: A Case Report
Authors: Bubau Marina , Georgiu Carmen , Fodor Lucian
Published: November 2021

Leiomyosarcomas of the lower extremity are heterogeneous tumors with high recurrence and metastasizing rates, which, rarely, can suffer a dedifferentiation process, making them extremely aggressive and unpredictable. We report the case of a 72-year-old female patient who presented the clinical and histopathological features of a rare leiomyosarcoma of the foot that was completely excised, but because of the interruption of adjuvant oncological treatment and lack of compliance for the follow-up, the patient suffered a dedifferentiation process and the tumor metastasized in the fingers—an unprecedented site for this type. The present case proves the fact that there is still a lot we do not know about the behavior of this disease, and there is always room to learn. Also, through this report, we are emphasizing a frequently encountered and never-ending problem in our country—that of difficult and resource-consuming cases derived from disconsidering medical advice by noncompliant patients when faced with a malignant diagnosis, making all attempts to offer them a better quality of life futile.
Multifocal Cutaneous Granular Cell Tumor in Children: A Rare Entity
Authors: El-Khalawany Mohamed , Rageh Mahmoud A. , Hassab-El-Naby Hussein M. M.
Published: November 2021

Granular cell tumors (GCTs) are rare soft tissue tumors of Schwann cell origin that manifest as papulonodular lesions and occur mainly in adults. The diagnosis is usually confirmed by histopathology. Most of GCTs are benign, but some lesions may exhibit malignant criteria. This study is a retrospective case series including all children with histopathologically documented multiple GCTs who attended the dermatology department of the university hospitals between February 2008 and March 2021. The objective of our study was to raise awareness to this unrecognized and rare entity in such age group. The study included 9 patients (6 girls and 3 boys) with multiple GCTs. Their age ranged between 5 and 13 years. The lesions were skin-colored to light brown, firm, smooth-surfaced nodules. Most of the lesions were on the extremities, and their mean diameter was 160.5 mm2. None of the lesions exhibited any malignant criteria on histopathology. No extracutaneous or mucosal lesions were detected. Dermatologists should be aware of this rare condition in children because early recognition allows more conservative resection of the tumor and less invasive reconstruction of the defect. Our study highlights that multifocality does not necessarily indicate malignancy or other systemic comorbidities.
Estrogen modulates metabolic risk profile after resistance training in early postmenopausal women: a randomized controlled trial
Authors: Dam Tine Vrist , Dalgaard Line Barner , Thomsen Christian Bejlegaard , Hjortebjerg Rikke , Ringgaard Steffen , Johansen Frank Ted , Bengtsen Mads Bisgaard , Mose Maike , Lauritsen Katrine Meyer , Søndergaard Esben , Gravholt Claus H. , Hansen Mette
Published: November 2021

Objective:

Women experience an unhealthy change in metabolic risk profile at menopause. The purpose of the present study was to determine effects of resistance training with or without transdermal estrogen therapy (ET) on adipose tissue mass and metabolic risk profile in early postmenopausal women.

Methods:

A double-blinded randomized controlled trial, where healthy, untrained postmenopausal women were allocated to supervised resistance training with placebo (PLC, n = 16) or transdermal ET (n = 15) for 12 weeks. Endpoints with prespecified hypotheses were the change in total fat mass (FM) (main endpoint) and the change in visceral FM (secondary endpoint) from before to after the intervention. Additionally, prespecified endpoints of body composition, metabolic health-related blood markers, fat%, fat cell size, and lipogenic markers in subcutaneous adipose tissue (SAT) from abdominal and femoral region were explored.

Results:

Compared with the ET group, the PLC group experienced a greater reduction (time × treatment interaction P < 0.05) in total FM (PLC vs ET: −5.6% vs −1.1%) and visceral FM (−18.6% vs −6.8%), and femoral SAT (−5.6% vs 1.0%), but not abdominal SAT mass (−8.5% vs −2.8%, P = 0.15).

The ET group improved their metabolic blood profile by reduced low-density lipoprotein, glucose and hemoglobin A1c compared with PLC (time × treatment interaction P < 0.05). The intervention induced changes in lipolytic markers of abdominal SAT, whereas no changes were detected in femoral SAT.

Conclusion:

Use of transdermal ET reduced adipose tissue loss, but improved metabolic blood markers when combined with 12 weeks of progressive resistance training in early postmenopausal women.
Cardiovascular mortality after bilateral oophorectomy: a prospective cohort study
Authors: Olesen Cathrine S. , Koch Trine , Uldbjerg Cecilie S. , Gregersen Laura S. , Christensen Jane , Dehlendorff Christian , Priskorn Lærke , Wilson Louise F. , Lim Youn-Hee , Jørgensen Jeanette T. , Andersen Zorana J. , Juul Anders , Abildgaard Julie , Hickey Martha , Bräuner Elvira V.
Published: November 2021

Objectives:

Bilateral oophorectomy permanently reduces endogenous estrogen exposure and may increase cardiovascular mortality in women. This study aimed to investigate the association between bilateral oophorectomy and cardiovascular mortality and whether this association was conditional on hysterectomy or on the use of hormone therapy at the time of study entry.

Methods:

A prospective cohort study of 25,338 female nurses aged ≥ 45 years within the Danish Nurse Cohort. Nurses were enrolled in 1993 or 1999 and followed until death, emigration, or end of follow-up on December 31, 2018, whichever came first. Exposure was bilateral oophorectomy. Outcome was cardiovascular mortality. Associations were estimated using Poisson regression models with log person-years as the offset.

Results:

A total of 2,040 (8.1%) participants underwent bilateral oophorectomy. During a mean follow-up of 21.2 (SD: 5.6) years, 772 (3.0%) nurses died from cardiovascular disease. In adjusted analyses, a 31% higher rate of cardiovascular mortality was observed after bilateral oophorectomy (aMRR 1.31; 95% CI, 0.88-1.96) compared with women who retained their ovaries. No evidence of effect modification by use of hormone therapy at baseline or by hysterectomy on the association between bilateral oophorectomy and cardiovascular mortality was observed.

Conclusion:

Bilateral oophorectomy may be associated with cardiovascular mortality in women, but the estimate was not statistically significant. Additionally, we were unable to make firm conclusions regarding the possible modifying role of hormone therapy and hysterectomy on this potential association. Additional studies are needed to replicate this work.
Conduit-assisted Allograft Neurorrhaphy for the Treatment of Intractable Lower Extremity Pain Due to Neuromas-in-continuity
Authors: Rodriguez-Collazo Edgardo , Laube Ward Kaitlyn
Published: November 2021

Background:

We present a novel technique for the management of intractable lower extremity pain, due to neuromas-in-continuity of two peripheral nerves, through combined neurectomies proximal to the zone of initial injury and subsequent bridging utilizing an allograft-coupled conduit construct.

Methodology:

A retrospective chart review of 36 patients (18 women and 18 men) with recalcitrant nerve pain secondary to neuromas-in-continuity of two peripheral nerves following lower extremity trauma was conducted. Subjects underwent superficial peroneal nerve (SPN) to deep peroneal nerve neurorrhaphy (19 patients) or SPN to sural nerve neurorrhaphy (17 patients) proximal to the zone of initial injury. Patient demographics, comorbidities, procedure details, complications, and preoperative and postoperative pain assessments using a visual analog scale were evaluated.

Results:

Residual nerve pain from previous lower extremity trauma was included. Analysis of preprocedure and postprocedure visual analog scale scores demonstrated a mean decrease of 7.45 points (mean: pre 8.89, mean: post 1.44). All patients voiced satisfaction with postoperative ambulatory tolerance and pain relief at last follow-up (mean: 30.86 months).

Conclusions:

The sequelae of neuromas-in-continuity of the SPN, deep peroneal nerve, and sural nerves were noted to have significantly improved with proximal neurectomy and subsequent bridging utilizing a nerve allograft and conduit construct. We present this coaptation technique as a viable treatment option for reduction in neurogenic pain involving peripheral nerve injury of two dermatome distributions.
IMPAIRMENTS IN CONE PIGMENT REGENERATION AND ABSOLUTE THRESHOLD IN MACULAR TELANGIECTASIA TYPE 2
Authors: Simunovic Matthew P. , Hess Kristina , Gillies Mark C.
Published: November 2021

Purpose:

To test the hypothesis that Müller cell dysfunction in macular telangiectasia type 2 (MacTel) results in delayed cone adaptation kinetics and to assess absolute cone and rod thresholds in this condition.

Methods:

Adaptation after an approximate 63.5% full-field cone photopigment bleach was assessed for Goldmann size V (1.7° diameter) 640 nm (red) and 480 nm (blue) targets presented at a retinal locus corresponding to 2° temporal to fixation. The cone time constant of adaptation and absolute cone and rod thresholds were calculated from exponential functions fitted to the resultant dark adaptation curves.

Results:

Eighteen eyes with MacTel (from 11 patients) were compared with 19 control eyes (from 16 normal subjects). Cone adaptation kinetics were significantly impaired in MacTel, as was the absolute cone threshold. Final thresholds for blue targets were also significantly elevated in MacTel, consistent with impaired rod absolute threshold. Losses in sensitivity observed in MacTel were consistent with a so-called d1/2 mechanism (i.e., receptoral) site of sensitivity loss.

Conclusion:

In addition to previously documented impairments in rod dark adaptation, MacTel results in a significant elevation in cone thresholds because of pathology at the level of the photoreceptors. The delays in cone adaptation that we found in eyes with MacTel may reflect impairment of the Müller cell–mediated cone-specific visual cycle.
Barriers to Transition to Home From the Neonatal Intensive Care Unit
Authors: Hebballi Nutan B. , Kerl Cameron G. , Garcia Elisa I. , Ottosen Madelene J. , Kelly Katherine C. , Bartz-Kurycki Marisa A. , Tang Brian , Hillman Elizabeth A. , Aneji Chiamaka U. , Tsao KuoJen , Austin Mary T.
Published: November 2021

The objective of this study was to explore the challenges faced by parents of former neonatal intensive care unit (NICU) patients in transitioning home from parents' and healthcare providers' perspective. We conducted semistructured individual and group interviews with parents of former NICU patients and healthcare providers. Themes from the individual interviews framed the group interviews' contents. The group interviews were recorded and transcribed, and thematic analysis was performed to identify themes. We conducted individual and group interviews with 16 parents and 33 inpatient and outpatient providers from November 2017 to June 2018. Individual interview participants identified several barriers experienced by parents when transitioning their infant home from the NICU including parental involvement and engagement during NICU stay and during the discharge process. Further exploration within group interviews revealed opportunities to improve discharge communication and processes, standardization of parental education that was lacking due to NICU resource constraints, support for parents' emotional state, and use of technology for infant care in the home. Parents of NICU patients face serious emotional, logistical, and knowledge challenges when transitioning their infant home from the NICU. Understanding and mitigating the challenges of transitioning infants from NICU to home require multistakeholder input from both parents and providers.