bluuebunny/crossref_metadata_2025 huggingface dataset:
The efficacy and safety of ocriplasmin for patients with vitreous macular traction
Authors: Zhang Wen‐Fei , Zhao Xin‐Yu , Meng Li‐Hui , Wang Dong‐Yue , Feng Shi , Chen You‐Xin
Published: May 2021

Purpose

To estimate the efficacy and safety of ocriplasmin for patients with vitreous macular traction (VMT).

Methods

The PubMed, EMBASE and Ovid were searched up to May 2020 to identify related studies. Statistical analysis was conducted by R software version 3.6.3. Results in proportion with 95% confidence interval (CI) were calculated by means of Freeman–Tukey variant of arcsine square transformation.

Results

The pooling results indicated the overall complete release rate was 50% (95% CI [45%–54%]). For VMT patients younger than 65 years old, with smaller adhesion size of VMT (<1500 μm), phakic eyes, with macular hole (MH) and subretinal fluid (SRF), while without epiretinal membrane (ERM), ocriplasmin could achieve much higher complete release rates than those under opposite conditions. The general nonsurgical closure rate of MH was 34% (95% CI [30%–37%]), and it was positively correlated with the MH size. The visual improvement rate was 45% (95% CI [32%–59%]), and it was higher for patients with VMT resolution (59%, 95% CI [41%–75%]). The secondary pars plana vitrectomy (PPV) rate for patients without MH closure or VMT resolution was about 31% (95% CI [23%–39%]). The incidence of MH progression was 10% (95% CI [4%–18%]), and other severe adverse events such as endophthalmitis, retinal detachment and retinal tear were relatively rare.

Conclusion

Ocriplasmin is an effective, reliable and relatively safe intervention for the treatment of VMT. The most suitable candidates were patients younger than 65 years old, with smaller adhesion size (<1500 μm), phakic eyes, with MH and SRF, while without ERM.
Impact of tobacco use on corneal thickness and endothelial health: a systematic review with meta‐analyses
Authors: Frifelt Lith Elizabeth Wienholtz , Subhi Yousif , Holm Lars Morten , Singh Amardeep
Published: May 2021

Purpose

To investigate the impact of tobacco use on corneal thickness and corneal endothelial health.

Methods

We searched the PubMed/MEDLINE, EMBASE, the Cochrane Central and all affiliated databases of the Web of Science on 20 July 2020. Two authors reviewed the studies and extracted the data in an independent fashion. Studies were reviewed qualitatively in the text, and central corneal thickness (CCT) and corneal endothelial characteristics (endothelial cell density, endothelial cell variability, average of endothelial cell size and endothelial cell hexagonality) were introduced for quantitative analyses.

Results

Eighteen studies (2077 were smokers and 6429 non‐smokers) were identified, of which 17 studies provided data eligible for one or more of the quantitative analyses. When compared to non‐smokers, smokers had a higher CCT (+3.3 μm, 95% CI: +0.9 to +5.7 μm, p = 0.007) and a lower endothelial cell density (−140 cells/mm2, 95% CI: −30 to −250 cells/mm2, p = 0.01). Other corneal endothelial measures did not differ significantly.

Conclusion

Tobacco use is associated with a higher CCT and lower corneal endothelium cell density, but the clinical impact of these findings is small. Further studies are warranted on patients with a priori poor corneal health, where smoking may constitute an important risk of further progression, for example upon anterior segment surgery.
Chloride channel inhibition improves neuromuscular function under conditions mimicking neuromuscular disorders
Authors: Pedersen Thomas Holm , Macdonald William Alexander , Broch‐Lips Martin , Halldorsdottir Osk , Bækgaard Nielsen Ole
Published: May 2021

Aim

The skeletal muscle Cl− channels, the ClC‐1 channels, stabilize the resting membrane potential and dampen muscle fibre excitability. This study explored whether ClC‐1 inhibition can recover nerve‐stimulated force in isolated muscle under conditions of compromised neuromuscular transmission akin to disorders of myasthenia gravis and Lambert–Eaton syndrome.

Methods

Nerve‐muscle preparations were isolated from rats. Preparations were exposed to pre‐or post‐synaptic inhibitors (ω‐agatoxin, elevated extracellular Mg2+, α‐bungarotoxin or tubocurarine). The potential of ClC‐1 inhibition (9‐AC or reduced extracellular Cl−) to recover nerve‐stimulated force under these conditions was assessed.

Results

ClC‐1 inhibition recovered force in both slow‐twitch soleus and fast‐twitch EDL muscles exposed to 0.2 µmol/L tubocurarine or 3.5 mmol/L Mg2+. Similarly, ClC‐1 inhibition recovered force in soleus muscles exposed to α‐bungarotoxin or ω‐agatoxin. Moreover, the concentrations of tubocurarine and Mg2+ required for reducing force to 50% rose from 0.14 ± 0.02 µmol/L and 4.2 ± 0.2 mmol/L in control muscles to 0.45 ± 0.03 µmol/L and 4.7 ± 0.3 mmol/L in muscles with 9‐AC respectively (P < .05, paired T test). Inhibition of acetylcholinesterase (neostigmine) and inhibition of voltage‐gated K+ channels (4‐AP) relieve symptoms in myasthenia gravis and Lambert–Eaton syndrome, respectively. Neostigmine and 9‐AC additively increased the tubocurarine concentration required to reduce nerve‐stimulated force to 50% (0.56 ± 0.05 µmol/L with 9‐AC and neostigmine) and, similarly, 4‐AP and 9‐AC additively increased the Mg2+ concentration required to reduce nerve‐stimulated force to 50% (6.5 ± 0.2 mmol/L with 9‐AC and 4‐AP).

Conclusion

This study shows that ClC‐1 inhibition can improve neuromuscular function in pharmacological models of compromised neuromuscular transmission.
Ca2+ mishandling in heart failure: Potential targets
Authors: Val‐Blasco Almudena , Gil‐Fernández Marta , Rueda Angélica , Pereira Laetitia , Delgado Carmen , Smani Tarik , Ruiz Hurtado Gema , Fernández‐Velasco Maria
Published: May 2021

Ca2+ mishandling is a common feature in several cardiovascular diseases such as heart failure (HF). In many cases, impairment of key players in intracellular Ca2+ homeostasis has been identified as the underlying mechanism of cardiac dysfunction and cardiac arrhythmias associated with HF. In this review, we summarize primary novel findings related to Ca2+ mishandling in HF progression. HF research has increasingly focused on the identification of new targets and the contribution of their role in Ca2+ handling to the progression of the disease. Recent research studies have identified potential targets in three major emerging areas implicated in regulation of Ca2+ handling: the innate immune system, bone metabolism factors and post‐translational modification of key proteins involved in regulation of Ca2+ handling. Here, we describe their possible contributions to the progression of HF.
Kv7 channel trafficking by the microtubule network in vascular smooth muscle
Authors: Jepps Thomas A.
Published: May 2021

In arterial smooth muscle cells, changes in availability of integral membrane proteins influence the regulation of blood flow and blood pressure, which is critical for human health. However, the mechanisms that coordinate the trafficking and membrane expression of specific receptors and ion channels in vascular smooth muscle are poorly understood. In the vasculature, very little is known about microtubules, which form a road network upon which proteins can be transported to and from the cell membrane. This review article summarizes the impact of the microtubule network on arterial contractility, highlighting the importance of the network, with an emphasis on our recent findings regarding the trafficking of the voltage‐dependent Kv7 channels.
How shall we all live together?: Meta‐analytical review of the mutual intercultural relations in plural societies project
Authors: Berry John W. , Lepshokova Zarina ,   MIRIPS Collaboration, Grigoryev Dmitry
Published: May 2021

Living together in culturally plural societies poses numerous challenges for members of ethnocultural groups and for the larger society. An important goal of these societies is to achieve positive intercultural relations among all their peoples. Successful management of these relations depends on many factors including a research‐based understanding of the historical, political, economic, religious and psychological features of the groups that are in contact. The core question is ‘how we shall we all live together?’ In the project reported in this paper (Mutual Intercultural Relations in Plural Societies; MIRIPS), we seek to provide such research by reviewing three core psychological hypotheses of intercultural relations (multiculturalism, contact and integration) in 21 culturally plural societies. The main goal of the project is to evaluate these hypotheses across societies within the MIRIPS project in order to identify if there are some basic psychological principles that underlie intercultural relations panculturally. If there are, the eventual goal is to employ the findings to propose some policies and programmes that may improve the quality of intercultural relationship globally. An internal meta‐analysis using the MIRIPS project data showed that the empirical findings from these societies generally support the validity of the three hypotheses. Implications for the development of policies and programmes to enhance the quality of intercultural relations are discussed.
Expecting better: Experimental investigations of the benefits of men's access to parental leave for anticipated well‐being
Authors: Moss‐Racusin Corinne A. , Sanzari Christina M. , Bogdan Emily , Nahabedian Delia , Brown Sophie S.
Published: May 2021

We conducted the first experimental tests of the impact of men's access to paid parental leave on anticipated well‐being among heterosexual men and women in the United States. Participants read a news article reporting that paid paternity leave was either likely or unlikely in the United States in the near future, completed a future life‐brainstorming task designed to make this scenario more salient, and reported anticipated outcomes pertaining to well‐being (predicted relationship satisfaction, positive and negative emotions, and life satisfaction). Results from an online sample (Experiment 1, N = 694) revealed that both men and women predicted more positive outcomes when they believed paid paternity leave would (vs. would not) exist. In contrast, results from students (Experiment 2, N = 199) revealed that women predicted better outcomes in the leave (vs. no leave) condition, while men predicted consistently positive outcomes regardless of condition. Looking at the interaction the other way, paternity leave closed a gender gap in anticipated well‐being favoring men. Exploratory analyses revealed that students anticipated increased relationship gender equality in division of labor as a result of paternity leave, but only in gender counter‐stereotypic domains (i.e., paid work outside the home for women; unpaid childcare and housework for men).
The neuronal ceroid lipofuscinosis‐related protein CLN8 regulates endo‐lysosomal dynamics and dendritic morphology
Authors: Pesaola Favio , Quassollo Gonzalo , Venier Ana Clara , De Paul Ana Lucía , Noher Ines , Bisbal Mariano
Published: May 2021

Background Information

The endo‐lysosomal system (ELS) comprises a set of membranous organelles responsible for transporting intracellular and extracellular components within cells. Defects in lysosomal proteins usually affect a large variety of processes and underlie many diseases, most of them with a strong neuronal impact. Mutations in the endoplasmic reticulum‐resident CLN8 protein cause CLN8 disease. This condition is one of the 14 known neuronal ceroid lipofuscinoses (NCLs), a group of inherited diseases characterised by accumulation of lipofuscin‐like pigments within lysosomes. Besides mediating the transport of soluble lysosomal proteins, recent research suggested a role for CLN8 in the transport of vesicles and lipids, and autophagy. However, the consequences of CLN8 deficiency on ELS structure and activity, as well as the potential impact on neuronal development, remain poorly characterised. Therefore, we performed CLN8 knockdown in neuronal and non‐neuronal cell models to analyse structural, dynamic and functional changes in the ELS and to assess the impact of CLN8 deficiency on axodendritic development.

Results

CLN8 knockdown increased the size of the Golgi apparatus, the number of mobile vesicles and the speed of endo‐lysosomes. Using the fluorescent fusion protein mApple‐LAMP1‐pHluorin, we detected significant lysosomal alkalisation in CLN8‐deficient cells. In turn, experiments in primary rat hippocampal neurons showed that CLN8 deficiency decreased the complexity and size of the somatodendritic compartment.

Conclusions

Our results suggest the participation of CLN8 in vesicular distribution, lysosomal pH and normal development of the dendritic tree. We speculate that the defects triggered by CLN8 deficiency on ELS structure and dynamics underlie morphological alterations in neurons, which ultimately lead to the characteristic neurodegeneration observed in this NCL.

Significance

This is, to our knowledge, the first characterisation of the effects of CLN8 dysfunction on the structure and dynamics of the ELS. Moreover, our findings suggest a novel role for CLN8 in somatodendritic development, which may account at least in part for the neuropathological manifestations associated with CLN8 disease.
Specifying current physical therapy practice for paediatric trials: A survey of UK physical therapists
Authors: Duff Catherine J. , Kolehmainen Niina , McAnuff Jennifer
Published: May 2021

Background

Advancing physical therapy interventions for children and young people is a high research priority. This includes research to describe and specify the control condition, typically ‘current care’, for effectiveness trials.

This paper aims to identify physical therapy outcomes commonly targeted, and intervention techniques and approaches commonly used, by physiotherapists working with children (aged 2–19 years) with mobility limitations in the United Kingdom.

Methods

A cross‐sectional survey. Participants were recruited through the interactive Chartered Society of Physiotherapy members‐only online discussion forum, the Association of Paediatric Chartered Physiotherapists, direct emails and snowball sampling within the authors' professional networks and Twitter. Data were collected using a structured online questionnaire and analysed using descriptive statistics.

Results

We received 146 responses, 95/146 (65.1%) of which were fully complete. Therapists reported targeting 367 unique outcome constructs, of which 193 (52.6%) mapped onto activities and participation (e.g. moving around using equipment, maintaining body position and walking), 158 (43.1%) on body functions (e.g. muscle strength, joint mobility and gait functions), 11 (3.0%) on body structure (e.g. muscle length) and 3 (0.8%) on environmental factors (e.g. access home environment, access school environment and family confidence). The most commonly used interventions related to postural management (115/133 of respondents, 86.4%) and exercise therapy (116/137, 84.67%) and included techniques such as ‘use equipment’ (118/137, 86.1%), ‘instruct how to do something’ (117/137, 85.4%), ‘practice’ (105/137, 76.6%) and ‘stretch’ (99/137, 72.3%).

Conclusions

In designing trials, current care can be described as a combination of biomechanical and physiological techniques and approaches targeted at body functions and through that to activity and participation. Although some environmental behaviour change techniques and strategies were reported, the explicit use of these in current care appears limited.
Anti-JMH alloantibody in inherited JMH-negative patients leads to immunogenic destruction of JMH-positive RBCs
Authors: Yuan Zhaohu , Wei Yaming , Chen Xiaojie , He Shufei , Cai Kui , Zhong Minglu , Huang Huiying , Tong Xinxin , Liu Zhen , Yang Xuexin
Published: May 2021

The clinical significance of the specific anti-John Milton Hagen (JMH) alloantibody in inherited JMH-negative patients remains unclear. During clinical blood transfusion, it is often classified as an anti-JMH autoantibody in acquired JMH-negative patients, which might further lead to the occurrence of haemolysis events. In this study, we found that the proportion of inherited JMH-negative people in the Guangzhou population was 0.41%, based on the study of 243 blood samples by flow cytometry. Gene sequencing analysis revealed two novel variants located in exon 11 (c.1348G>A, p.Ala449Thr) and exon 14 (c.1989G>T, p.Leu663Phe). Specific antigen presentation showed that JMH-positive RBCs (red blood cells) could be internalized by SEMA7A−/− dendritic cells (DCs) and that SEMA7A−/− DCs activated by the semaphorin 7a (Sema7a) protein or JMH-positive erythrocytes further induced activation of CD4+ T cells to secrete interferon (IFN)-γ. Transfusion of JMH-positive RBCs could lead to the production of the specific anti-JMH alloantibody in Sema7a knock-out (KO) C57 mice. After erythrocyte sensitization, complement C3 was specifically fixed, causing the destruction of JMH-positive erythrocytes. The anti-JMH alloantibody caused immunological destruction of JMH-positive erythrocytes and promoted the clearance of JMH-positive RBCs. We should be cautious when making conclusions about the clinical significance of the anti-JMH alloantibody.
Prognostic factors associated with unhealed perineal wounds post‐proctectomy for perianal Crohn's disease: a two‐centre study
Authors: Grant Rebecca K. , Elosua‐González Alfonso , Bouri Sonia , Sahnan Kapil , Brindle William M. , Dilke Stella M. , Vincent Matthew L. M. , Adegbola Samuel O. A. , Warusavitarne Janindra H. , Tozer Philip J. , Arnott Ian D. R. , Hart Ailsa L.
Published: May 2021

Aim

The aim of this work was to determine the factors associated with poor wound healing in patients with perianal Crohn's disease (pCD) who had undergone proctectomy in the era of biologic therapies.

Method

Case record review was performed on 103 patients with pCD who underwent proctectomy at St Mark's Hospital, Harrow and the Western General Hospital, Edinburgh between 2005 and 2017. Healing rates at 6 and 12 months post‐proctectomy were considered; univariate analysis was performed.

Results

Sixty out of 103 patients (58.3%) had failure of wound healing at 6 months and 41/103 (39.8%) at 12 months. In total, 63.1% (65/103) patients received biologic therapies prior to proctectomy; however, exposure to biologics was not a significant factor in predicting failure of wound healing at 12 months (infliximab p = 0.255; adalimumab p = 0.889; vedolizumab p = 0.153). Male gender was the only variable associated with poor wound healing at 12 months on univariate analysis (p = 0.017). A lower pre‐operative C‐reactive protein was associated with early wound healing at 6 months compared with at 12 months (p = 0.041) on univariate analysis. Other parameters not associated with rates of wound healing included smoking status, corticosteroid exposure, thiopurine exposure, number of previous biologics, perianal sepsis on MRI within the last 12 months, duration of CD prior to proctectomy and pre‐operative albumin.

Conclusion

More than a third of patients had unhealed wounds 12 months after proctectomy. We report that unhealed wounds are more common in male patients. Importantly, our results also suggest that exposure to biologics does not affect rates of wound healing.
FAIMCS: A fast and accurate influence maximization algorithm in social networks based on community structures
Authors: Bagheri Esmaeil , Dastghaibyfard Gholamhossein , Hamzeh Ali
Published: May 2021

Finding a number of nodes that are able to maximize the spread of influence through the social network and are called influence maximization has numerous applications in marketing. One such application is to find influential members for promoting a product across a large network. Even though numerous algorithms have been proposed, challenges such as scalability, time constraints, and low accuracy have motivated the researchers for better solutions. Some of the newly proposed algorithms are scalable, but fail to provide adequate accuracy. On the other hand, some greedy algorithms provide a good level of accuracy but are very time consuming for large networks. In this paper, an algorithm is proposed called FAIMCS that can quickly find influential nodes across large networks with high accuracy. FAIMCS, reduces computational overhead considerably by eliminating major portions of the social network graph which have little influence. FAIMCS uses community detection algorithm to determine each community's quota of influential nodes based on the structure of that community. Finally, it obtains influential nodes from the candidate nodes. Experiment results show FAIMCS is faster than current algorithms and provides a high level of accuracy for large social networks.
A novel mouse model for liver metastasis of prostate cancer reveals dynamic tumour‐immune cell communication
Authors: Liu Kaiyuan , Jing Na , Wang Deng , Xu Penghui , Wang Jinming , Chen Xinyu , Cheng Chaping , Xin Zhixiang , He Yuman , Zhao Huifang , Ji ZhongZhong , Zhang Pengcheng , Gao Wei‐Qiang , Zhu Helen He , Zhang Kai
Published: May 2021

Objectives

In contrast to extensive studies on bone metastasis in advanced prostate cancer (PCa), liver metastasis has been under‐researched so far. In order to decipher molecular and cellular mechanisms underpinning liver metastasis of advanced PCa, we develop a rapid and immune sufficient mouse model for liver metastasis of PCa via orthotopic injection of organoids from PbCre+; rb1f/f;p53f/f mice.

Materials and Methods

PbCre+;rb1f/f;p53f/f and PbCre+;ptenf/f;p53f/f mice were used to generate PCa organoid cultures in vitro. Immune sufficient liver metastasis models were established via orthotopic transplantation of organoids into the prostate of C57BL/6 mice. Immunofluorescent and immunohistochemical staining were performed to characterize the lineage profile in primary tumour and organoid‐derived tumour (ODT). The growth of niche‐labelling reporter infected ODT can be visualized by bioluminescent imaging system. Immune cells that communicated with tumour cells in the liver metastatic niche were determined by flow cytometry.

Results

A PCa liver metastasis model with full penetrance is established in immune‐intact mouse. This model reconstitutes the histological and lineage features of original tumours and reveals dynamic tumour‐immune cell communication in liver metastatic foci. Our results suggest that a lack of CD8+ T cell and an enrichment of CD163+ M2‐like macrophage as well as PD1+CD4+ T cell contribute to an immuno‐suppressive microenvironment of PCa liver metastasis.

Conclusions

Our model can be served as a reliable tool for analysis of the molecular pathogenesis and tumour‐immune cell crosstalk in liver metastasis of PCa, and might be used as a valuable in vivo model for therapy development.
Genome stabilization by RAD51‐stimulatory compound 1 enhances efficiency of somatic cell nuclear transfer‐mediated reprogramming and full‐term development of cloned mouse embryos
Authors: Lee Ah Reum , Park Ji‐Hoon , Shim Sung Han , Hong Kwonho , La Hyeonwoo , Park Kyung‐Soon , Lee Dong Ryul
Published: May 2021

Objectives

The genetic instability and DNA damage arise during transcription factor‐mediated reprogramming of somatic cells, and its efficiency may be reduced due to abnormal chromatin remodelling. The efficiency in somatic cell nuclear transfer (SCNT)‐mediated reprogramming is also very low, and it is caused by development arrest of most reconstituted embryos.

Materials and Methods

Whether the repair of genetic instability or double‐strand breaks (DSBs) during SCNT reprogramming may play an important role in embryonic development, we observed and analysed the effect of Rad 51, a key modulator of DNA damage response (DDR) in SCNT‐derived embryos.

Results

Here, we observed that the activity of Rad 51 is lower in SCNT eggs than in conventional IVF and found a significantly lower level of DSBs in SCNT embryos during reprogramming. To address this difference, supplementation with RS‐1, an activator of Rad51, during the activation of SCNT embryos can increase RAD51 expression and DSB foci and thereby increased the efficiency of SCNT reprogramming. Through subsequent single‐cell RNA‐seq analysis, we observed the reactivation of a large number of genes that were not expressed in SCNT‐2‐cell embryos by the upregulation of DDR, which may be related to overcoming the developmental block. Additionally, there may be an independent pathway involving histone demethylase that can reduce reprograming‐resistance regions.

Conclusions

This technology can contribute to the production of comparable cell sources for regenerative medicine.
A call to assess the impacts of electromagnetic fields from subsea cables on the movement ecology of marine migrants
Authors: Klimley A. Peter , Putman Nathan F. , Keller Bryan, A. , Noakes David
Published: May 2021

The number of subsea cables in the marine environment is likely to grow substantially in the near future. Arrays of energy‐generating windmills or wave power generators are planned for installation in the coastal waters of many countries worldwide. The electricity generated by these and other marine energy sources will be transported to shore through cables with the current and voltage creating electromagnetic fields (EMFs). Furthermore, there are also plans for the installation of undersea cables to interconnect countries and islands for the purpose of sharing power and communications. These also will generate EMFs in the marine environment. While shielding can negate the presence of direct electric fields, induced electric and magnetic fields readily penetrate into the water column. Cables carrying electric current produce anomalies in the earth's main field, which could have the potential for disrupting the migrations of fishes and diverse marine animals that rely on magnetic cues for orientation or navigation. Studies designed to test how these anthropogenic magnetic fields disrupt magnetic orientation have only recently started to be conducted. Given the cultural, economic, and conservation value of many of the species potentially at risk, such work should be immediately prioritized.
Identifying gaps in protected areas to expand integrated riverine ecosystem conservation
Authors: Major James , Perry Denielle , Aslan Clare , McManamay Ryan
Published: May 2021

As demand for water in the arid southwest increases, pressure is mounting on many aquatic and riparian species that rely on riverine habitat for survival. Some of these riverine areas are managed as private, state, or federal lands with differing levels of mandated protections; however, few efforts have explored the potential of filling gaps in riverine protection afforded by designation under the protection of the Wild and Scenic Rivers Act (WSRA) of 1968. Here, we examine how inclusion of eligible rivers, specifically the Nationwide Rivers Inventory (NRI), could fill gaps in protection for a species of high conservation need. A gap analysis overlapping the predicted species range with human disturbances and the level of protection identifies where sufficient protections for a species exist and where there are shortcomings, that is, gaps, potentially addressed by elevating NRI reaches to WSRA protection. This study uses the narrow‐headed garter snake as an indicator species for riverine ecosystem health of free‐flowing perennial reaches within the Arizona/New Mexico Mountains EPA Level III ecoregion. Over a quarter of NRI‐eligible reaches within the ecoregion are within the protection gap for the narrow‐headed garter snake. If designated Wild and Scenic, these reaches could offer needed protection for this species.
Aberrant cytoplasmic connexin43 expression as a helpful marker in vascular neoplasms
Authors: Frings Verena Gerlinde , Goebeler Matthias , Schilling Bastian , Kneitz Hermann
Published: May 2021

Background

Gap junctions consisting of connexins (Cx) are fundamental in controlling cell proliferation, differentiation, and cell death. Cx43 is the most broadly expressed Cx in humans and is attributed an important role in skin tumor development. Its role in cutaneous vascular neoplasms is yet unknown.

Methods

Fifteen cases each of cutaneous angiosarcoma (cAS), Kaposi sarcoma (KS), and cherry hemangioma (CH) were assessed by immunohistochemistry for expression of Cx43. Expression pattern, intensity, and percentage of positively stained cells were analyzed. Solid basal cell carcinomas served as positive and healthy skin as negative controls.

Results

Most cases of cAS presented with a strong Cx43 staining of almost all tumor cells, whereas endothelia of KS showed medium expression and CH showed mostly weak expression. In comparison with KS or cAS, the staining intensity of CH was significantly lower (P ≤ 0.001). All tissue sections of both cAS and KS were characterized by a mostly diffuse, cytoplasmic staining pattern of the vascular endothelia. None of those showed nuclear staining.

Conclusion

The high‐to‐intermediate expression of Cx43 observed in all cases of cAS and KS suggests that this Cx may play a role in the development of malignant vascular neoplasms and serve as a helpful diagnostic marker.
Uncertainty in the modelled mortality of two tree species (Fraxinus) under novel climatic regimes
Authors: Steiner Kim C. , Graboski Lake E. , Berkebile Jennifer L. , Fei Songlin , Leites Laura P.
Published: May 2021

Aim

Based upon species distribution models (SDMs), many studies have predicted that climate change will cause regional extinctions of tree species within the next 50–100 years. SDM‐based predictions have been challenged on procedural and theoretical grounds, but for tree species they are largely beyond the practical reach of direct experimental validation. Here we report the experimental consequences of moving seedlings from ~50 natural populations of each of two ash (Fraxinus) species to experimental sites spanning a range of 10°C colder to 10°C warmer (mean annual temperature) than home environments.

Location

Eastern North America.

Methods

We measured population‐by‐test‐site survival percentages and mean trunk diameters at an average age of 35 years. We then used linear, mixed‐effect models to develop transfer functions for each species and predict survival and mean annual growth as functions of fixed and random effects including, especially, the climatic distance (CD) between test site and home environment.

Results

Survival and growth were highest at CD ≈ 0 and declined as populations were moved to warmer or colder environments, indicating that survival and growth were optimal when populations were in home‐like climates. However, variance around the model fit was substantial, and we could not statistically detect, even at α = .50, elevated mortality following displacements into environments 3.5°C (white ash) and 4.1°C (green ash) warmer in mean annual temperature. Survival rates of 80%–100% were common even within populations subjected to warming conditions greater than those predicted to cause meso‐scale extinctions in this century. We show that within‐population genetic variance, phenotypic plasticity and idiosyncratic aspects of the non‐climatic environment and its interaction with genotype each likely contributed to these unexpected responses to climatic displacement.

Main conclusions

Results emphasize the uncertainty that underlies predictions of climate‐induced extinctions of long‐lived woody plants over time frames of 50 to perhaps 100 years into the future.
Acoustic stimulation increases implicit adaptation in sensorimotor adaptation
Authors: Leow Li‐Ann , Tresilian James R. , Uchida Aya , Koester Dirk , Spingler Tamara , Riek Stephan , Marinovic Welber
Published: May 2021

Sensorimotor adaptation is an important part of our ability to perform novel motor tasks (i.e., learning of motor skills). Efforts to improve adaptation in healthy and clinical patients using non‐invasive brain stimulation methods have been hindered by inter‐individual and intra‐individual variability in brain susceptibility to stimulation. Here, we explore unpredictable loud acoustic stimulation as an alternative method of modulating brain excitability to improve sensorimotor adaptation. In two experiments, participants moved a cursor towards targets, and adapted to a 30º rotation of cursor feedback, either with or without unpredictable acoustic stimulation. Acoustic stimulation improved initial adaptation to sensory prediction errors in Study 1, and improved overnight retention of adaptation in Study 2. Unpredictable loud acoustic stimulation might thus be a potent method of modulating sensorimotor adaptation in healthy adults.
The effects of psychosocial stress on item, cued‐pair and emotional memory
Authors: McManus Elizabeth , Talmi Deborah , Haroon Hamied , Muhlert Nils
Published: May 2021

Physical stress, such as from the cold‐pressor test, has been robustly associated with altered memory retrieval, but it is less clear whether the same happens following psychosocial stress. Studies using psychosocial stressors report mixed effects on memory, leading to uncertainty about the common cognitive impact of both forms of stress. The current study uses a series of four carefully designed experiments, each differing by only a single critical factor to determine the effects of psychosocial stress on specific aspects of episodic memory. In three experiments, we induced psychosocial stress after participants encoded words, then assessed retrieval of those words after a prolonged delay. These experiments found no effect of post‐encoding stress on recognition of neutral words or cued recall of word‐pairs, but a small effect on recollection of semantically related words. There were, however, positive relationships within the stress group between measures of stress (cortisol in experiment 1 and self‐reported‐anxiety in experiment 3) and recollection of single word stimuli. In the fourth experiment, we found that psychosocial stress immediately before retrieval did not influence word recognition. Recollection, particularly for semantically related stimuli, may therefore be more susceptible to the effects of psychosocial stress, and future studies can assess how this relates to other forms of stress. Overall, our findings suggest that the effects of psychosocial stress on episodic memory may be more subtle than expected, warranting further exploration in larger studies.
Effect of food on the single‐dose pharmacokinetics and tolerability of savolitinib in Chinese healthy volunteers
Authors: Ding Qichen , OU Meixian , Zhu Huijuan , Wang Yijun , Jia Jingying , Sai Yang , Chen Qian , Wang Jian
Published: May 2021

The aim of this study was to investigate the effect of a high‐fat and high‐calorie meal on the single‐dose pharmacokinetics (PK) and tolerability of savolitinib. The study included two phases: safety run‐in phase and food effect assessment phase. In the safety run‐in phase, 9 healthy male volunteers were divided into three groups to be administered a single oral dose of savolitinib tablets at 200, 400, and 600 mg. In the food effect assessment phase, 16 healthy male volunteers received a single 600 mg dose of savolitinib tablets following an overnight fast or a high‐fat and high‐calorie breakfast prior to dosing. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety and tolerability were assessed throughout the study by clinical assessments and adverse events (AEs). A total of 25 healthy male volunteers were enrolled in the study, including 9 in the safety run‐in phase and 16 in the food effect assessment phase. In the food effect assessment phase, the geometric mean ratios (90% confidence interval) for savolitinib dosed under the fed condition compared with that dosed under the fasting condition were 102.7% (84.9%, 124.2%) and 117.1% (103.9%, 131.9%) for Cmax and AUC0‐inf of savolitinib, respectively. The Tmax was delayed significantly (p = 0.023) under fed condition. The most common AEs possibly related to the study drug were dizziness, nausea, and emesis. The study indicated that a high‐fat and high‐calorie meal has no clinically relevant impact on the PK and bioavailability of savolitinib in healthy male volunteers.
A micromechanical loading/unloading constitutive model of fiber‐reinforced ceramic‐matrix composites considering matrix crack closure
Authors: Li Longbiao
Published: May 2021

Under cyclic loading/unloading, hysteresis loops appear due to the internal slip between the fiber and the matrix in the interface debonding regions of fiber‐reinforced ceramic‐matrix composites (CMCs). Hysteresis loops can be used as an effective tool to monitor internal damage evolution inside of CMCs. Within the present study, a micromechanical loading/unloading constitutive model was designed to predict the cyclic hysteresis loops of CMCs based on the matrix crack closure. A correlation was formulated between their hysteresis loops, matrix cracking density, loading/unloading inverse tangent modulus (ITMs), and interface reverse/new slip ratio (IRSR/INSR), as well as their dependence upon the material properties. In addition, different SiC/SiC composites (i.e., mini, unidirectional, cross‐ply, and 2D plain‐woven) were predicted based on the hysteresis loops, ITMs, IRSR, and INSR experimental results. The results indicated identical hysteresis loop peak strains for the samples both with and without matrix crack closure, though those without the matrix crack closure exhibited a lower hysteresis loop residual strain. All in all, the theoretical predicted results with regard to matrix crack closure were in correlation with the experimental data.
Improving fatigue life of 7N01 Al alloy weld by surface spinning strengthening
Authors: Wang Dongqiqiong , Wang Suhuan , Wang Qiang , Hou Jiapeng , Li Xiaowu , Zhang Zhefeng
Published: May 2021

The purpose of this study is to improve the surface microstructure and mechanical properties of 7N01 Al alloy welded joints by surface spinning strengthening (3S), so as to improve the fatigue life at certain stress. Results show that after the 3S treatment, the microhardness of the welded joint increases significantly due to the introduction of some nanoprecipitates and dislocations, and the strength and elongation increase simultaneously. The minimum fatigue life of the welded specimen under the condition of maximum stress of 150 MPa and stress ratio of 0.1 is increased from less than 106 cycles to more than 3 × 106 cycles after the 3S treatment. Fracture surface analysis shows that the crack initiation site of the sample with welded joint is turned from the surface to the subsurface after 3S treatment, which is beneficial to the elimination of surface defect and the improvement of surface strength.
A portfolio of climate‐tailored approaches to advance the design of marine protected areas in the Red Sea
Authors: Gajdzik Laura , DeCarlo Thomas M. , Aylagas Eva , Coker Darren J. , Green Alison L. , Majoris John E. , Saderne Vincent F. , Carvalho Susana , Berumen Michael L.
Published: May 2021

Intensified coastal development is compromising the health and functioning of marine ecosystems. A key example of this is the Red Sea, a biodiversity hotspot subjected to increasing local human pressures. While some marine‐protected areas (MPAs) were placed to alleviate these stressors, it is unclear whether these MPAs are managed or enforced, thus providing limited protection. Yet, most importantly, MPAs in the Red Sea were not designed using climate considerations, likely diminishing their effectiveness against global stressors. Here, we propose to tailor the design of MPAs in the Red Sea by integrating approaches to enhance climate change mitigation and adaptation. First, including coral bleaching susceptibility could produce a more resilient network of MPAs by safeguarding reefs from different thermal regions that vary in spatiotemporal bleaching responses, reducing the risk that all protected reefs will bleach simultaneously. Second, preserving the basin‐wide genetic connectivity patterns that are assisted by mesoscale eddies could further ensure recovery of sensitive populations and maintain species potential to adapt to environmental changes. Finally, protecting mangrove forests in the northern and southern Red Sea that act as major carbon sinks could help offset greenhouse gas emissions. If implemented with multinational cooperation and concerted effort among stakeholders, our portfolio of climate‐tailored approaches may help build a network of MPAs in the Red Sea that protects more effectively its coastal resources against escalating coastal development and climate instability. Beyond the Red Sea, we anticipate this study to serve as an example of how to improve the utility of tropical MPAs as climate‐informed conservation tools.
Matching‐adjusted indirect comparisons of oral rimegepant versus placebo, erenumab, and galcanezumab examining monthly migraine days and health‐related quality of life in the treatment of migraine
Authors: Popoff Evan , Johnston Karissa , Croop Robert , Thiry Alexandra , Harris Linda , Powell Lauren , Coric Vladimir , L’Italien Gilbert , Moren James
Published: May 2021

Objective

Rimegepant is an orally administered small‐molecule calcitonin gene‐related peptide (CGRP) receptor antagonist, with demonstrated efficacy in the acute treatment of migraine. Recent estimates from a single‐arm trial (BHV3000‐201) have also shown evidence of long‐term preventive effects in monthly migraine days (MMDs) and health‐related quality of life (HRQoL). This study aimed to compare MMDs and HRQoL data for oral rimegepant to those obtained in placebo‐controlled trials for injectable anti‐CGRP monoclonal antibodies (mAbs) galcanezumab and erenumab.

Methods

Matching‐adjusted indirect comparisons (MAICs) were conducted using rimegepant subject‐level data and published aggregate‐level results from mAb trials. Rimegepant baseline characteristics were matched to the pooled subject characteristics from EVOLVE‐I/II (galcanezumab vs. placebo;n = 1773) and STRIVE (ereumab vs. placebo;n = 955) by reweighting the rimegepant subjects to more closely match the distributions observed in these trials. To align with inclusion criteria of the mAb trials, only the subset of rimegepant subjects with a history of 4–14 MMDs were included (n = 257). Weighted mean differences were used to calculate adjusted change in MMDs, Migraine Disability Assessment Test (MIDAS) score, and Migraine‐Specific Quality of Life Questionnaire version 2 (MSQv2) scores from baseline to week 12.

Results

When matched to the EVOLVE trials, rimegepant was superior to placebo with a mean difference in MMD change from baseline [95% confidence interval] of −1.16 [−1.80, −0.52] and was not statistically significantly different from galcanezumab 0.59 [−0.13, 1.32]. When matched to the STRIVE trial, rimegepant was superior to placebo −1.59 [−2.15, −1.03] and was not statistically significantly different from erenumab −0.06 [−0.61, 0.50]. Rimegepant showed superior MIDAS and MSQv2 results compared with placebo in both EVOLVE trials and in the STRIVE trial, no statistically significant differences from galcanezumab and erenumab regarding MIDAS, and favorable results compared with erenumab across all MSQv2 domains, while being generally similar to galcanezumab across all MSQv2 domains.

Conclusions

When adjustments were made to reflect baseline characteristics in published literature, supporting data from BHV3000‐201 suggest that rimegepant every other day is an effective therapy in reducing disability and MMDs and enhancing migraine‐specific HRQoL. These data support the preventive benefit observed in randomized trials of rimegepant and further validate its efficacy for both acute and preventive treatment of migraine.
Post‐rift stress history of Southwest Japan inferred from early to middle Miocene intrusions and meso‐scale faults in the Tajima–Myokensan area
Authors: Haji Toshiki , Yamaji Atsushi
Published: May 2021

Miocene igneous dikes older and younger than 15 Ma in Southwest Japan are thought to be oriented parallel and perpendicular to the arc, respectively. This difference of orientations was referred to as significant evidence for termination of the opening of the Japan Sea at 15 Ma. The tightest constraint comes from ~60 dikes in the Tajima–Myokensan area, northern Hyogo Prefecture. Here we present orientations of 716 planar intrusive bodies and the directions of 143 meso‐scale faults, obtained using the latest stress inversion techniques from the lower to middle Miocene Hokutan Group in the Tajima–Myokensan area. The results contradict the 15 Ma hypothesis for the end of the opening of the Japan Sea. We find that intrusive bodies cannot be separated into two groups by their orientations as reported previously. Rather, the orientations of their poles comprise a horizontal girdle and a vertical cluster. The former indicates NE‐SW extensional stress, and the latter NW‐SE compression. However, the latter are interpreted as not representative of regional stress, based on common sill intrusions (the formation of which was not influenced by regional stress) in the well‐stratified Muraoka Formation resulting in the vertical cluster of pole orientations from which compression was recognized. The results of fault‐slip analysis are consistent with the extensional stress. Fission‐track and U–Pb ages of zircons were obtained from seven intrusive bodies. These and previously published ages suggest that the area underwent NW‐SE extension both before and after 15 Ma. In the main part of Southwest Japan, the weak extension was kept after 16 Ma when intra‐arc rifting was terminated. This is consistent with the hypothesis that the Japan Sea continued to open until 13.5 Ma.
Apical pressures generated by several canal irrigation methods: A laboratory study in a maxillary central incisor with an open apex
Authors: Magni Eva , Jäggi Marco , Eggmann Florin , Weiger Roland , Connert Thomas
Published: May 2021

Aim

A laboratory study to determine the apical pressure generated by seven canal irrigation methods in an anterior tooth with an open apex.

Methodology

Canal irrigation was performed on a 3D‐printed central maxillary incisor with an open apex (maximum diameter of 2.1 mm). Ultrasonically activated irrigation (UAI), sonic activation (EDDY), negative pressure irrigation (EndoVac), the self‐adjusting file (SAF) and the XP‐endo Finisher were employed at tooth length (TL), TL—1 mm, TL—2 mm and TL—3 mm. UAI was tested at three intensity levels additionally. Hydrodynamic irrigation with RinsEndo was performed in the pulp chamber, at the canal orifice, the coronal third, the middle of the canal and at TL. Er:YAG laser activation, at four frequency settings, was performed in the pulp chamber and at the orifice of the canal. The pressure of the fluid towards the canal terminus generated by activation was directly transferred to a pressure sensor with a range of 0 to 120 mmHg and a response time of ≤0.5 ms. The critical threshold for apical extrusion of the irrigant was set at 5.73 mmHg (lower limit of the central venous pressure: 5.88 ± 0.15 mmHg). Each experiment was repeated ten times. The tests were followed by descriptive analyses (maximum, mean, standard deviation, 95% confidence interval).

Results

EndoVac, the SAF, the XP‐endo Finisher, and UAI never exceeded the critical threshold at any insertion depth or intensity level. Er:YAG laser activation exceeded the critical threshold exclusively at frequency settings that varied from the manufacturer's recommendation. EDDY at TL and RinsEndo at any insertion depth exceeded the critical threshold in 100% of the measurements. EDDY at TL—1,—2, and—3 mm crossed the critical threshold in 30%, 10%, and 20% of the measurements, respectively.

Conclusions

In a simulated maxillary central incisor with an open apex, irrigation with EndoVac, Er:YAG laser activation, UAI, the SAF, and the XP‐endo Finisher generated apical pressures below the critical threshold of 5.73 mmHg. By contrast, using EDDY and RinsEndo for irrigation produced higher apical pressures that exceeded the critical threshold.