bluuebunny/crossref_metadata_2025 huggingface dataset:
Eprosartan: A closer insight into its neuroprotective activity in rats with focal cerebral ischemia–reperfusion injury
Authors: Saad Muhammad A. E. , Fahmy Mohamed I. M. , Sayed Rabab H. , El‐Yamany Muhammad F. , El‐Naggar Reham , Hegazy Ahmed A. E. , Al‐Shorbagy Muhammad
Published: May 2021

Eprosartan (EPRO), an angiotensin receptor type‐1 (AT‐1) blocker, exhibited neuroprotective activities in ischemic stroke resulting from focal cerebral ischemia in rats. The current study aimed to clarify the neuroprotective role of EPRO in middle carotid artery occlusion (MCAO)‐induced ischemic stroke in rats. Fifty‐six male Wistar rats were divided into four groups (n = 14 per group): sham‐operated group, sham receiving EPRO (60 mg/kg/day, po) group, ischemia–reperfusion (IR) group, and IR receiving EPRO (60 mg/kg/day, po) group. MCAO led to a remarkable impairment in motor function together with stimulation of inflammatory and apoptotic pathways in the hippocampus of rats. After MCAO, the AT1 receptor in the brain was stimulated, resulting in activation of Janus kinase 2/signal transducers and activators of transcription 3 signaling generating more neuroinflammatory milieu and destructive actions on the hippocampus. Augmentation of caspase‐3 level by MCAO enhanced neuronal apoptosis synchronized with neurodegenerative effects of oxidative stress biomarkers. Pretreatment with EPRO opposed motor impairment and decreased oxidative and apoptotic mediators in the hippocampus of rats. The anti‐inflammatory activity of EPRO was revealed by downregulation of nuclear factor‐kappa B and tumor necrosis factor‐β levels and (C–X–C motif) ligand 1 messenger RNA (mRNA) expression. Moreover, the study confirmed the role of EPRO against a unique pathway of hypoxia‐inducible factor‐1α and its subsequent inflammatory mediators. Furthermore, upregulation of caveolin‐1 mRNA level was also observed along with decreased oxidative stress marker levels and brain edema. Therefore, EPRO showed neuroprotective effects in MCAO‐induced cerebral ischemia in rats via attenuation of oxidative, apoptotic, and inflammatory pathways.
On the origin of BAG(3) and its consequences for an expansion of BAG3's role in protein homeostasis
Authors: Baeken Marius W. , Behl Christian
Published: May 2021

The B‐cell CLL 2‐associated athanogene (BAG) protein family in general and BAG3, in particular, are pivotal elements of cellular protein homeostasis, with BAG3 playing a major role in macroautophagy. In particular, in the contexts of senescence and degeneration, BAG3 has exhibited an essential role often related to its capabilities to organize and remove aggregated proteins. Exciting studies in different species ranging from human, murine, zebrafish, and plant samples have delivered vital insights into BAG3s' (and other BAG proteins') functions and their regulations. However, so far no studies have addressed neither BAG3's evolution nor its phylogenetic position in the BAG family.
Diagnostic and therapeutic potencies of miR‐18a‐5p in mixed‐type gastric adenocarcinoma
Authors: Wang Li , Zhang Mingxin , Wang Jiansheng , Zhang Jia
Published: May 2021

Mixed‐type gastric adenocarcinoma (by Lauren Classification) has poor clinical outcomes with few targeted treatment options. The primary objective of this study was to find the prognostic factors, accurate treatment approaches, and effective postoperative adjuvant therapy strategies for patients with mixed‐type gastric adenocarcinoma (GA). A microRNA sequencing data set and the corresponding clinical parameters of patients with gastric cancer were obtained from The Cancer Genome Atlas. Differentially expressed microRNAs (DEMs) of diffuse‐ and intestinal‐type GA were, respectively, determined. Kaplan–Meier and log‐rank tests were subsequently carried out to evaluate the prognostic relevance of each DEM. To study the common factors between diffuse‐ and intestinal‐type GA, a pathway enrichment analysis was performed on the target genes of identified DEMs using the PANTHER database. After data preprocessing, we analyzed a total of 230 samples from 210 patients with GA. Eighty‐six DEMs in diffuse‐type GA samples and 59 DEMs in intestinal‐type GA samples were, respectively, identified (p  2.0). The Kaplan–Meier survival method further screened out six prognosis‐related DEMs for diffuse‐type GA and seven prognosis‐related DEMs for intestinal‐type GA (p < 0.05). MiR‐18a‐5p was found to be the only common prognosis‐related DEM between diffuse‐ and intestinal‐type GA. The common signaling pathways further revealed that target genes of miR‐18a‐5p are involved in mixed‐type GA progression. This study suggests that miR‐18a‐5p acts as a potential target for treatment, and common signal pathways provide a rich basis to seek reliable and effective molecular targets for the diagnosis, clinical treatment, and postoperative adjuvant therapy strategy of mixed‐type GA.
Prediction of lymph node metastasis in oral tongue squamous cell carcinoma using the neutrophil‐to‐lymphocyte ratio and platelet‐to‐neutrophil ratio
Authors: Wang Bo , Liu Junwen , Zhong Zhengrong
Published: May 2021

Background

Lymph node metastasis in a variety of tumors is associated with systemic inflammatory markers. However, this association has not been reported in oral tongue squamous cell carcinoma (OTSCC). This study aimed to investigate how the preoperative neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐neutrophil ratio (PNR) in OTSCC patients correlated with the occurrence of OTSCC and lymph node metastasis.

Methods

The data of 73 patients with primary OTSCC who underwent surgical resection were retrospectively analyzed. Patients with other malignant tumors, patients who had received radiotherapy or chemotherapy before surgery, and patients with active inflammation were excluded. The enrolled patients were divided into groups N0 (no early‐stage lymph node metastasis) and N1 (early‐stage lymph node metastasis). Venous blood samples were collected before surgery and at the third week after surgery and subjected to complete blood counting in a blood analyzer. Eighty‐seven healthy people were included as a control group. In addition, the NLR and PNR in OTSCC patients were compared with those in the controls, and the postoperative NLR and PNR of group N0 were compared with those of group N1.

Results

The NLR was significantly higher in the OTSCC patients than the controls (p < 0.05). The area under the receiver operating characteristic curve was 0.595. Further comparison of the NLR and PLR between group N0 and group N1 showed that when NLR was ≤1.622, and the probability of early‐stage lymph node metastasis in OTSCC patients was 73.3%, and when PNR was >60.889, the probability was 86.7%. In re‐examination 3 weeks postoperatively, the NLR and PNR were not significantly different between groups.

Conclusion

The NLR has certain reference value for the diagnosis of OTSCC. The preoperative NLR and PNR can be used to predict early‐stage lymph node metastasis in patients with histopathologically confirmed OTSCC.
Microaggressions towards lesbian and transgender women: Biased information gathering when working alongside gender and sexual minorities
Authors: Anzani Annalisa , Sacchi Simona , Prunas Antonio
Published: May 2021

Objective

Microaggressions, a concept originally introduced for ethnic minorities, represent subtle day‐to‐day discrimination, damaging the psychological health and well‐being of lesbian, gay, bisexual, and transgender individuals as well. This study aimed to assess whether microaggressions occur in psychotherapists’ assessments of clients who identify as either lesbian or transgender woman when compared with those identifying as heterosexual woman.

Methods

The study included a sample of 135 licensed psychotherapists (110 cisgender women and 25 cisgender men). Participants were presented with an audio file of a woman introducing herself during her first therapy session. Three versions were presented: a transgender, a lesbian, and a heterosexual client. Participants were asked to assess the clinical relevance of 10 questions defined as neutral (N = 5) and microaggressive (N = 5), used to determine a clinical impression of the client. A repeated measure analysis of variance was conducted to understand the likelihood of clients of different gender identity and sexual orientation receiving microaggressions.

Results

Participants were more prone to consider microaggressive questions relevant where the client identified as either lesbian or transgender.

Conclusions

The findings highlighted a bias against lesbian and trans women in evaluating the relevance and usefulness of clinical information while making a psychological assessment of a case.
Pigeons prefer to invest early for future reinforcers
Authors: Cowie Sarah , Davison Michael
Published: May 2021

Five pigeons were trained in a series of conditions in which food was delivered after 25 responses, but only when a different (Investing) response had been made before the 25 responses had been completed. If an Investing response was not made, the 25 responses ended in blackout. In various conditions, effective Investing responses either had to be made before the first of the 25 responses, or anywhere within the 25 responses; and effective Investing responses either resulted in a stimulus change or did not. Pigeons Invested even when the consequences were temporally and spatially distant, but Investing was most likely when it produced an immediate stimulus change. When given the choice, pigeons preferred to make Investing responses at the beginning of a trial. These findings again demonstrate that behavior may be maintained by events that are separated in time and space from the present.
Pseudomelanosis coli, its relation to laxative use and association with colorectal neoplasms: A comprehensive review
Authors: Mohammed Abdul , Paranji Neethi , Singh Amandeep , Sanaka Madhusudhan R
Published: May 2021

Pseudomelanosis coli is historically associated with anthraquinone laxatives and is often used as a surrogate marker for chronic laxative use. The opioid epidemic has seen an increase in laxative use for chronic constipation. Anthraquinone laxatives have demonstrated tumorigenic potential in animal studies due to their apoptotic effects on colonic epithelial cells. Colorectal cancer is associated with significant mortality and morbidity worldwide. Human studies have not shown a significant correlation between anthraquinone laxative use, pseudomelanosis coli, and colorectal carcinoma. The characteristic pigmentation of pseudomelanosis also appears to be absent macroscopically and on histology of neoplastic epithelium. However, there appears to be a slightly higher risk of adenoma development. This has been attributed to a higher polyp detection rate during endoscopy on account of the color contrast between the polyp against a darker background of pseudomelanosis.
Gabapentin for acute pain in sickle cell disease: A randomized double‐blinded placebo‐controlled phase II clinical trial
Authors: Puri Latika , Nottage Kerri , Hankins Jane S. , Wang Winfred C. , McGregor Olivia , Gossett Jeffrey M. , Kang Guolian , Anghelescu Doralina L.
Published: May 2021

Pain in sickle cell disease (SCD) can have a neuropathic component. This randomized phase II double‐blinded placebo‐controlled study evaluated the efficacy of gabapentin in reducing pain and opioid consumption (morphine‐equivalent dose [MED]) during acute vaso‐occlusive crisis (VOC). Of 90 patients aged 1–18 years with VOC pain, 45 were randomized to a single gabapentin dose (15 mg/kg) and 45 to placebo, in addition to standard treatment; 42 and 44 patients were evaluable in the gabapentin and placebo arms, respectively. A decrease in pain of ≥33% was reported in 68% of patients in the gabapentin arm and 60% of those in the placebo arm (one‐sided p = 0.23). The median MED (mg/kg) in the gabapentin (0.12) and placebo arms (0.13) was similar (p = 0.9). However, in the subset of patients with the HbSS genotype (n = 45), the mean (SD) absolute pain score decrease by the time of discharge was significantly greater in the gabapentin arm (5.9 [3.5]) than in the placebo arm (3.6 [3.3]) (p = 0.032). Pain scores in the overall study population were not significantly reduced when gabapentin was added to standard treatment; however, gabapentin benefited individuals with the more severe genotype, HbSS, during acute VOC. Larger, prospective studies are needed to confirm these findings.
One‐Minute Multi‐contrast Echo Planar Brain MRI in Ischemic Stroke: A Retrospective Observational Study of Diagnostic Performance
Authors: Kits Annika , De Luca Francesca , Kolloch Jens , Müller Susanne , Mazya Michael V. , Skare Stefan , Falk Delgado Anna
Published: May 2021

Background

Fast multi‐contrast echo planar MRI (EPIMix) has comparable diagnostic performance to standard MRI for detecting brain pathology but its performance in detecting acute cerebral infarctions has not been determined.

Purpose

To assess the diagnostic performance of EPIMix for the detection of acute cerebral infarctions.

Study Type

Retrospective observational cohort.

Population

One hundred and seventy‐two consecutive patients with a clinical suspicion of non‐hyperacute ischemic stroke (January 2018 to December 2019).

Field Strength and Sequence

1.5 T or 3 T. EPIMix ((echo‐planar based: diffusion weighted (DWI), T2*‐weighted, T2‐weighted, T2‐ and T1‐fluid attenuated inversion recovery (FLAIR) images) vs. standard MRI: echo‐planar DWI, echo‐planar T2*‐weighted or susceptibility weighted, turbo spin‐echo T2‐weighted, T2‐ and T1‐FLAIR turbo spin‐echo sequences.

Assessment

Three neuroradiologists rated EPIMix and standard MRI on two separate occasions. Incongruent assessments were resolved in consensus with the fourth reader. The ratings included the diagnostic category (acute infarct, normal, and other pathology). Congruent diagnoses together with consensus diagnoses served as the reference standard.

Statistical Tests

The diagnostic performance of EPIMix and standard MRI against the reference standard was calculated by the area under the receiver operating characteristic curve (AUC) and compared by DeLong's test. Sensitivity and specificity were determined. Inter‐rater agreements were evaluated by Fleiss's kappa.

Results

Of 172 patients (61 ± 16 years, 103 men), acute infarcts were present in 80/172 (47%), normal findings in 60/172 (35%), and other pathology in 32/172 (19%). Across readers, the AUCs were .94–.95 for EPIMix and .95–.99 for standard MRI, with overlapping 95% CI (P = .02–.18). Inter‐rater agreement for EPIMix was 0.90 and for standard MRI was 0.93. The sensitivity for EPIMix and standard MRI was 88–91% and 91–98%, respectively, while the specificity was 98–100% and 98–99%, both with overlapping 95% CI.

Conclusion

Multi‐contrast echo planar MRI showed a high but marginally lower diagnostic performance compared to standard MRI for the detection and characterization of acute brain infarct.

Level of Evidence

3

Technical Efficacy

Stage 2
Impact of bisoprolol transdermal patch on early recurrence during the blanking period after atrial fibrillation ablation
Authors: Suzuki Yuya , Kuroda Masaru , Fujioka Tomoo , Kintsu Masayuki , Noda Tsubasa , Matsumoto Akinori , Kawata Masahito
Published: May 2021

Background

Early recurrences of atrial arrhythmias (ERAAs) after ablation may require therapeutic intervention. The optimal medical therapy that prevents ERAAs requires clarification. This study aimed to compare the incidence of ERAAs between patients who received or did not receive bisoprolol transdermal patches (BTPs) at 3 months postablation.

Methods

This single‐center retrospective study enrolled 203 consecutive patients with paroxysmal atrial fibrillation (AF) who had undergone their first ablation, comprising 59 in the BTP group and 144 in the non‐BTP group. Follow‐up assessments were conducted monthly for 3 months. We evaluated the incidence of ERAAs.

Results

During the initial 1‐week observational period, the rate of ERAAs was lower in the BTP group (5.0%) than that in the non‐BTP group (18.8%) (P = .013). At 3 months postablation, the rate of ERAAs was lower in the BTP group (6.8%) than that in the non‐BTP group (25.7%) (P = .002). The cumulative freedom from ERAAs was significantly lower in the BTP group than in the non‐BTP group (log‐rank: P = .003). Administering BTPs was an independent factor that protected against ERAAs (odds ratio 0.181, [95% confidence interval 0.059‐0.559], P = .003).

Conclusion

BTPs may prevent ERAAs after ablation.
Divergent changes of the elevational synchronicity in vegetation spring phenology in North China from 2001 to 2017 in connection with variations in chilling
Authors: Dai Junhu , Zhu Mengyao , Mao Wei , Liu Ronggao , Wang Huanjiong , Alatalo Juha Mikael , Tao Zexing , Ge Quansheng
Published: May 2021

Mountain ecosystems are sensitive to climate change, and vegetation phenology provides one of the best signals to exemplify ecosystem responses to climate change. Vegetation phenology of mountain ecosystems is usually characterized with an elevational pattern, with the growing season starts earlier and ends later in lower versus higher elevations. With climate change, this elevational gradient of vegetation phenology is likely to shift as well. However, both the patterns and the underlying driving forces for potential changes in this elevational gradient of vegetation phenology are still unclear. Here, we used 500‐m resolutioned normalized difference vegetation index (NDVI) data from Moderate Resolution Imaging Spectroradiometer (MODIS) for the period of 2001 to 2017 to investigate changes in the start of growing season (SOS) along the elevational gradient for six mountains in northern China dominated by broadleaf deciduous forests. We found that while SOS consistently advanced for most of the pixels, the elevational lapse rate of SOS (SE) showed various trends for different mountains. Specifically, SE showed a significant (p‐value < .05) decreasing trend for the two southernmost mountains, indicating an increasing elevational synchronization in SOS. However, such phenological synchronization was not found in other temperate mountains. As warming has caused relatively consistent increases in heat forcing across different elevations and among different mountains but has led to highly various changes in chilling hours between high and low elevations, we suggested that the distinctive pattern in elevational synchronicity of spring phenology between southern and northern mountains in temperate China was primarily due to their different recent changes in chilling hours. Our work provides a novel key hypothesis for explaining the divergent changes in elevational gradients of vegetation phenology that can be tested in other regions for mountain ecosystems.
HPLC‐QTOF/MS‐based metabolomics to explore the molecular mechanisms of Yiqi Fumai Lyophilized Injection in heart failure mice
Authors: Yuan Guang‐ying , Liu Ze‐liang , Lai Qiong , Fu Fei , Zhang Lu , Kou Jun‐ping , Yu Bo‐yang , Li Fang
Published: May 2021

Chronic heart failure is a common and fatal disease triggered by loss of normal cardiac function. Yiqi Fumai Lyophilized Injection is widely used in the treatment of cardiovascular diseases, especially chronic heart failure. In this study, a model of chronic heart failure in mice was established with permanent coronary artery ligation followed by Yiqi Fumai Lyophilized Injection intervention for 14 days. Then, the endogenous metabolites of mice plasma and urine samples were screened through nontargeted metabolomics techniques. The results indicated that Yiqi Fumai Lyophilized Injection treatment changed the metabolic pattern of chronic heart failure and regulated valine, leucine, and isoleucine biosynthesis, taurine and hypotaurine metabolism, histidine metabolism and arginine biosynthesis, etc. Finally, the cardioprotective mechanism of Yiqi Fumai Lyophilized Injection was further verified in the mouse model of chronic heart failure and angiotensin II‐induced cardiac fibroblasts based on metabolomics. The results showed that Yiqi Fumai Lyophilized Injection could inhibit myocardial fibrosis to improve chronic heart failure. This study firstly elucidated the metabolic network and pathways regulated by Yiqi Fumai Lyophilized Injection, which might facilitate the realization of the clinically accurate application of Yiqi Fumai Lyophilized Injection in the treatment of chronic heart failure.
CircRNA ZNF609 promotes angiogenesis in nasopharyngeal carcinoma by regulating miR‐145/STMN1 axis
Authors: Wang Jin , Lin Yan , Jiang Dong‐Hui , Yang Xi , He Xiao‐Guang
Published: May 2021

Nasopharyngeal carcinoma (NPC) is the most common type of human malignant tumor in the head and neck, and tumor angiogenesis is essential for its development. Here, we showed that the circRNA ZNF609/microRNA (miR)‐145/Stathmin 1 (STMN1) axis regulated angiogenesis in NPC.Circ‐ZNF609, miR‐145, and STMN1 expression in NPC cells and NPC samples were examined using qRT‐PCR. The protein levels of STMN1, VEGFR1, and VEGFR2 were evaluated using western blotting. VEGF level was determined by ELISA. The proliferation of NPC cells and HUVECs was examined using a CCK‐8 assay. Transwell assays and wound‐healing assays were applied to assess the migration of NPC cells and HUVECs, respectively. Angiogenesis of HUVECs was evaluated by an angiogenesis assay. In addition, a dual‐luciferase reporter assay and RNA pull‐down assays were employed to verify the binding relationship between circ‐ZNF609 and miR‐145 as well as between miR‐145 and STMN1. Here, we showed that circ‐ZNF609 and STMN1 expression was increased, while miR‐145 expression was decreased in NPC cells and NPC samples. Circ‐ZNF609 may negatively regulate miR‐145 expression by acting as a ceRNA. Silencing circ‐ZNF609 suppressed cell proliferation, migration, and angiogenesis in NPC, while knockdown of miR‐145 reversed these effects. In addition, we found that STMN1 was the downstream target of miR‐145. MiR‐145 overexpression suppressed cell proliferation, migration, and angiogenesis in NPC, which was abolished by STMN1 overexpression. Our data suggested that circ‐ZNF609 promotes cell proliferation, migration, and angiogenesis in NPC by upregulating the expression of STMN1 by sponging miR‐145 in NPC.
Podocentric view of glomerular proteinuria: Focused on cytoskeletal changes and toward promising targeted therapies and challenges
Authors: Kuo Mei‐Chuan , Liang Peir‐In , Chang Jer‐Ming
Published: May 2021

Among renal cells, podocytes (glomerular epithelial cells) are the most critical to prevent plasma proteins from excessive loss by forming their sophisticated foot processes (FP) and slit diaphragms (SD). A general finding in the glomeruli of patients with nephrotic syndrome is the foot processes “effacement” resulted from dysregulated actin cytoskeleton reorganization. Ultrastructural analysis in patients with nephrotic syndrome has demonstrated that such changes tend to be dynamic and can sometimes be reversible. In a more molecular sense, injured podocytes can no longer maintain their tight regulation and “retract” their FP, but not “efface” them. Past studies have revealed multiple exquisite mechanisms and arrays of proteins participating in the regulation of cytoskeletal rearrangement, and these mechanisms serve as potential targets to treat. A major challenge to develop specific therapies is the targeted mechanism has to be crucial and specific enough for podocyte‐oriented kidney diseases, and it would be even better to manifest in most of the glomerulonephritis. Studies have shown many approaches targeting different mechanisms, but none of them has been proved to be effective in clinical medicine. Up to the present, Abatacept (Orencia) is the first (and the only) clinical targeted therapy demonstrating limited success. It inhibits the co‐stimulatory response of B7‐1 (CD80) induced in various types of glomerulonephritis. Future clinical studies have to be expanded to substantiate this highly specific targeted therapy because the Abatacept effect is not generally accepted even within the nephrology community. Nevertheless, there are ongoing searches for specific treatment targeting podocytes through various approaches.
A Rare Laryngeal Presentation of Stevens‐Johnson Syndrome
Authors: Vittetoe Kelly L. , Landeen Kelly C. , Gelbard Alexander
Published: May 2021

Stevens‐Johnson syndrome (SJS) is a rare but severe mucocutaneous epidermolysis commonly triggered by medications. SJS is characterized by mucocutaneous lesions of the trunk, face, and limbs, as well as the oral cavity, gastrointestinal tract, and respiratory tract. Although uncommon, laryngeal involvement in SJS can lead to severe respiratory, phonatory and deglutitive complications. Providers caring for patients with SJS should maintain a high index of suspicion for laryngeal involvement and low threshold to solicit Otolaryngology consultation. Laryngeal complications can be more expediently managed when anticipated early in the course of disease. Laryngoscope, 131:2519–2522, 2021
Has IMRD become IMRDi in management journals? Implications as an independent structural component of research articles
Authors: S. Plakhotnik Maria
Published: May 2021

The purpose of this study was to understand the practice of separating implications into separate sections or sub‐sections in scholarly articles that report empirical research in social sciences. Using a stratified random sampling strategy, I selected 120 articles from 40 journals in the field of management available via the Social Sciences Citation Index. I analysed the articles using qualitative content analysis that was guided by two research questions: (1) do journal articles include implications as an independent component? and (2) What guidance do journal editors provide about the presentation of implications in article submissions? The results show that 72% of articles separated implications into a section or sub‐section whilst the remaining 28% integrated them into other main sections. Of the first group, three quarters of authors separated implications into sub‐sections of the Discussion section and one quarter presented them as independent main sections that followed the Discussion. Several patterns related to the range, length, order, and type of implications sections and sub‐sections emerged. The results also showed that only 4% of journals mention implications in their guidelines for authors. Journal editors could use the results of this study to discuss the importance of implications to the journal strategic development, articulate their position on the article structure, and audit their guidelines. Researchers might use the study results to improve their article structure and, hence, increase chances of receiving positive editorial decision.
Testing miniaturized extraction chromatography protocols for combined 87Sr/86Sr and δ88/86Sr analyses of pore water by MC‐ICP‐MS
Authors: Argentino Claudio , Lugli Federico , Cipriani Anna , Panieri Giuliana
Published: May 2021

We tested two miniaturized extraction chromatography protocols for strontium isolation based on 300 μL (Protocol 1) and 30 μL (Protocol 2) column volumes of Sr‐Spec resin, for the simultaneous determination of 87Sr/86Sr and δ88/86Sr by MC‐ICP‐MS. The accuracy and precision of the Sr isotope ratios have been evaluated by analyzing JCt‐1 and SRM 1640a reference materials, resulting in a reproducibility of 87Sr/86Sr and δ88/86Sr values of 0.000026 and 0.04‰ (Protocol 1) (2SD, n = 3), and of 0.000074 and 0.13‰ (Protocol 2) (2SD, n = 4), respectively. The Sr isotopic composition of SRM 1640a, presented here for the first time, is 87Sr/86Sr = 0.708790 ± 0.000062 and δ88/86Sr = 0.07 ± 0.10‰ (2SD, n = 6). Protocols 1 and 2 were successfully applied to pore waters extracted from marine sediment cores from the northern Barents Sea. Our results demonstrate that both protocols attain accurate 87Sr/86Sr ratios and allow the detection of natural variations in δ88/86Sr in marine pore waters. Compared to previous Sr/matrix separation methods, Protocol 2 is significantly less costly, making it particularly suitable for large‐scale oceanological and limnological studies.
The Vibrant Interplay of Light and Self‐Reporting Macromolecular Architectures
Authors: Geiselhart Christina M. , Mutlu Hatice
Published: May 2021

Inspired by nature, notable efforts have been made towards the exploration of self‐reporting polymers within the last decades. Whereas the majority of the previously reported self‐reporting polymers deliberately relies on a diverse set of mechanisms triggered via different stimuli (e.g., mechanical, thermal, pH, solvation, light, and chemical amongst others), light plays a ubiquitous role not only as a remote trigger, but also as non‐destructive readout signal for the practical applications of self‐reporting polymers. Due to the ever‐growing interest within the respective field (e.g., load bearing materials, nanotechnology, biomedicine, or theranostics), herein a synthetic overview is presented with the aim to provide an informative perspective on challenges facing the vibrant interplay of light and self‐reporting macromolecular architectures.
Overcoming challenges of HERG potassium channel liability through rational design: Eag1 inhibitors for cancer treatment
Authors: Toplak Žan , Hendrickx Louise A. , Abdelaziz Reham , Shi Xiaoyi , Peigneur Steve , Tomašič Tihomir , Tytgat Jan , Peterlin‐Mašič Lucija , Pardo Luis A.
Published: May 2021

Two decades of research have proven the relevance of ion channel expression for tumor progression in virtually every indication, and it has become clear that inhibition of specific ion channels will eventually become part of the oncology therapeutic arsenal. However, ion channels play relevant roles in all aspects of physiology, and specificity for the tumor tissue remains a challenge to avoid undesired effects. Eag1 (KV10.1) is a voltage‐gated potassium channel whose expression is very restricted in healthy tissues outside of the brain, while it is overexpressed in 70% of human tumors. Inhibition of Eag1 reduces tumor growth, but the search for potent inhibitors for tumor therapy suffers from the structural similarities with the cardiac HERG channel, a major off‐target. Existing inhibitors show low specificity between the two channels, and screenings for Eag1 binders are prone to enrichment in compounds that also bind HERG. Rational drug design requires knowledge of the structure of the target and the understanding of structure–function relationships. Recent studies have shown subtle structural differences between Eag1 and HERG channels with profound functional impact. Thus, although both targets' structure is likely too similar to identify leads that exclusively bind to one of the channels, the structural information combined with the new knowledge of the functional relevance of particular residues or areas suggests the possibility of selective targeting of Eag1 in cancer therapies. Further development of selective Eag1 inhibitors can lead to first‐in‐class compounds for the treatment of different cancers.
Theory of continuous inverseclass‐Epower amplifier modes andcontinuous‐mode self‐distortion
Authors: de Almeida Jorge Virgilio , Wu Ke
Published: May 2021

A closed‐form solution for the continuous inverse class E (class E−1) design space is presented for the first time1. Analogous to the class‐E power amplifier (PA) modes, the zero current and its derivative conditions needed for the class E−1switching action can also be shown to be satisfied with any second harmonic susceptance. The complementary relationship between the continuous PA modes for class E and class E−1are analytically proven. Signal integrity limitations on the continuous class E and class E−1PA modes are demonstrated to exist and to limit the useful range of solutions of the design space.2Consequently, the maximum achievable bandwidth using the continuum of solutions in both class E/E−1is not 2 octaves as previously reported but only 1 octave.
Micro‐electrodes for in situ temperature and bio‐impedance measurement
Authors: Leung Timothy Ka Wai , Ji Xudong , Peng Boyu , Chik Gary Kwok Ki , Dai Derek Shui Hong Siddhartha , Fang Ge , Zhang Tengfei , Cheng Xing , Kwok Ka Wai , Tsang Anderson Chun On , Leung Gilberto Ka Kit , Chan Paddy Kwok Leung
Published: May 2021

With fast recovery time and effective in situ tumor tissue killing ability, thermal ablation has become a popular treatment for tumors compared with chemotherapy and radiation. The thermal dose measurement of current technology is usually accompanied by monitoring a large area impedance across two ablation catheters and the localized impedance measurement is difficult to achieve. In this work, thermal‐resistive sensor and impedance sensor are fabricated on the curved surface of a capillary tube with 1 mm outer diameter. The device is applied for real‐time in situ tissue impedance monitoring during thermal ablation. The calibrated thermal‐resistive sensors have an average temperature coefficient of resistance (TCR) of 0.00161 ± 5.9% °C‐1 with an accuracy of ±0.7 °C. By adding electro‐polymerized PEDOT:PSS (poly(3,4‐ethylenedioxythiophene)‐poly(styrenesulfonate)) on the 300 µm diameter gold electrodes, the interface impedance reduces two orders from 408 to 3.7 kΩ at 100 Hz. The Randles equivalent circuit model fittings show a two‐order improvement in the electrode capacitance from 7.29 to 753 nF. In the ex vivo porcine liver laser ablation test, the temperature of the porcine liver tissue can reach 70°C and the impedance would drop by 50% in less than 5 minutes. The integration of laser ablation fiber with the impedance and temperature sensors can further expand the laser ablation technique to smaller scale and for precise therapeutics.
Dynamically scheduling and maintaining a flexible server
Authors: Huang Jefferson , Down Douglas G. , Lewis Mark E. , Wu Cheng‐Hung
Published: May 2021

Deciding how to jointly schedule jobs and perform preventive maintenance is a fundamental problem in flexible manufacturing systems, particularly those arising in semiconductor manufacturing. At the same time, past work in this area shows that, even when there is only one station and one type of job, identifying policies that minimize the amount of work‐in‐process (WIP) is a difficult problem. In this paper, we study a single‐station version of this problem with an arbitrary number of job classes, with the objective of minimizing average maintenance costs plus the weighted average amount of WIP. We identify conditions under which it suffices to schedule jobs according to both a server‐state‐dependent version of the cμ‐rule, and a static cμ‐rule where the average service rates are used. One of these conditions states that the ratio between the service rates should remain constant as the server deteriorates. When this assumption does not hold, scheduling with the cμ‐rule can in fact lead to an unstable system; we illustrate this using a simple example. On the other hand, we also present numerical evidence that cμ‐based scheduling performs well compared to other scheduling rules, and relative to a policy based on solving a Markov decision process.
Phase I Trial of Cemiplimab, Radiotherapy, Cyclophosphamide, and Granulocyte Macrophage Colony-Stimulating Factor in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Authors: Babiker Hani , Brana Irene , Mahadevan Daruka , Owonikoko Taofeek , Calvo Emiliano , Rischin Danny , Moreno Victor , Papadopoulos Kyriakos P. , Crittenden Marka , Formenti Silvia , Giralt Jordi , Garrido Pilar , Soria Ainara , Hervás-Morón Asunción , Mohan Kosalai Kal , Fury Matthew , Lowy Israel , Mathias Melissa , Feng Minjie , Li Jingjin , Stankevich Elizabeth
Published: May 2021

Lessons Learned

Background

Refractory and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) generally does not respond to PD-1 inhibitor monotherapy. Cemiplimab is a human anti–PD-1 monoclonal antibody. An expansion cohort enrolled patients with R/M HNSCC in a phase I study combining cemiplimab plus radiation therapy (RT), cyclophosphamide, and granulocyte macrophage colony-stimulating factor (GM-CSF).

Methods

Patients with R/M HNSCC refractory to at least first-line therapy and for whom palliative RT is clinically indicated received cemiplimab plus RT, cyclophosphamide, and GM-CSF. The co-primary objectives were the safety, tolerability, and efficacy of cemiplimab plus RT, cyclophosphamide, and GM-CSF in 15 patients with R/M HNSCC.

Results

Fifteen patients were enrolled. Patients discontinued treatment due to progression of disease. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (40.0%), constipation (26.7%), and asthenia, dyspnea, maculo-papular rash, and pneumonia (each 20%). The only grade ≥3 TEAE that occurred in two patients was pneumonia (13.3%). By investigator assessment, there was one partial response (6.7%); disease control rate was 40.0% (95% confidence interval [CI], 16.3–67.7; five patients with stable disease); seven patients had progressive disease, and two were not evaluable. Median progression-free survival by investigator assessment was 1.8 months (95% CI, 1.7–4.7).

Conclusion

The regimen demonstrated tolerability but not efficacy above that which can be achieved with anti–PD-1 inhibitor monotherapy for R/M HNSCC.
Switching the Inhibitor‐Enzyme Recognition Profile via Chimeric Carbonic Anhydrase XII
Authors: Smirnovienė Joana , Smirnov Alexey , Zakšauskas Audrius , Zubrienė Asta , Petrauskas Vytautas , Mickevičiūtė Aurelija , Michailovienė Vilma , Čapkauskaitė Edita , Manakova Elena , Gražulis Saulius , Baranauskienė Lina , Chen Wen‐Yih , Ladbury John E. , Matulis Daumantas
Published: May 2021

A key part of the optimization of small molecules in pharmaceutical inhibitor development is to vary the molecular design to enhance complementarity of chemical features of the compound with the positioning of amino acids in the active site of a target enzyme. Typically this involves iterations of synthesis, to modify the compound, and biophysical assay, to assess the outcomes. Selective targeting of the anti‐cancer carbonic anhydrase isoform XII (CA XII), this process is challenging because the overall fold is very similar across the twelve CA isoforms. To enhance drug development for CA XII we used a reverse engineering approach where mutation of the key six amino acids in the active site of human CA XII into the CA II isoform was performed to provide a protein chimera (chCA XII) which is amenable to structure‐based compound optimization. Through determination of structural detail and affinity measurement of the interaction with over 60 compounds we observed that the compounds that bound CA XII more strongly than CA II, switched their preference and bound more strongly to the engineered chimera, chCA XII, based on CA II, but containing the 6 key amino acids from CA XII, behaved as CA XII in its compound recognition profile. The structures of the compounds in the chimeric active site also resembled those determined for complexes with CA XII, hence validating this protein engineering approach in the development of new inhibitors.
Porous polyelectrolyte materials with controlled luminescence properties based on aromatic‐aromatic interactions with rhodamine B
Authors: Flores Mario E. , Ancalaf Daniel , Rolleri Aldo , Nishide Hiroyuki , Lisoni Judit G. , Moreno‐Villoslada Ignacio
Published: May 2021

A series of porous materials made of sodium alginate have been synthesized by freeze‐drying including rhodamine B as pigment complexed or not with the aromatic polymer poly(sodium 4‐styrenesulfonate). By means of aromatic‐aromatic interactions between the aromatic polymer and the dye, the luminescent properties of the final materials can be controlled. This is mainly produced by avoiding the dye self‐aggregation in the solid state in a higher extent as the excess of the aromatic polyelectrolyte over the dye increases. The solid materials present a structure made of microsheets and microfibers of alginate, density ranging between 17 and 26 mg/cm3, porosity higher than 97%, and Young's modulus ranging between 8 and 24 kPa. This work highlights the role or aromatic polyelectrolytes to control properties of both the polymer and its aromatic counterions in the solid state, making use of aromatic‐aromatic interactions.
Development and optimization of high‐performance PEEK/CF/Nanosilica hybrid composites
Authors: Lin Leyu , Schlarb Alois K.
Published: May 2021

In the present study, tribological properties of PEEK/CF/nanosilica composites with distinct amounts of silica nanoparticles against steel were studied by using a block‐on‐ring tribometer followed by the characterizations of associated transfer films and polymer worn surfaces. The results demonstrate that the content of silica nanoparticles exerts an obvious influence on the friction and wear properties of PEEK/CF/nanosilica composites. Under low‐load conditions, the friction coefficient and specific wear rate exhibit opposite dependence on the nanosilica content. The friction coefficient decreases with increasing nanofiller content, while the specific wear rate increases with enhancing nanosilica loading. When the load conditions were changed toward high values, the divergence of the tribological properties becomes insignificant, which show less dependence on the nanosilica loading. Taking into account the practical applications of such composites, the composite containing 2 wt.% silica nanoparticles can serve as an excellent candidate for manufacturing tribological components in the practical applications.
Diurnal variations in the thickness of the inner bark of tree trunks in relation to xylem water potential and phloem turgor
Authors: Epron Daniel , Kamakura Mai , Azuma Wakana , Dannoura Masako , Kosugi Yoshiko
Published: May 2021

Why this research Matters

The inner bark plays important roles in tree stems, including radial exchange of water with the xylem and translocation of carbohydrates. Both processes affect the water content and the thickness of the inner bark on a diurnal basis. For the first time, we simultaneously measured the diurnal variations in the inner bark thickness of hinoki cypress (Chamaecyparis obtusa) by using point dendrometers and those of local xylem potential by using stem psychrometers located next to the dendrometers to determine how these variations were related to each other, to phloem turgor and carbohydrate transport. We also estimated the axial hydrostatic pressure gradient by measuring the osmolality of the sap extracted from the inner bark. The inner bark shrunk during the day and swelled during the night with an amplitude related to day‐to‐day and seasonal variations in climate. The relationship between changes in xylem water potential and inner bark thickness exhibited a hysteresis loop during the day with a median lag of 2 h. A phloem turgor‐related signal can be retrieved from the diurnal variations in the inner bark thickness, which was higher at the upper than at the lower position along the trunk. However, a downward hydrostatic pressure gradient was only observed at dawn, suggesting diurnal variations in the phloem sap flow velocity.
TT genotype of the MMP‐9‐1562C/T polymorphism may be a risk factor for thrombolytic therapy‐induced hemorrhagic complications after acute ischemic stroke
Authors: Dusanovic Pjevic Marija , Jekic Biljana , Beslac Bumbasirevic Ljiljana , Vojvodic Ljubica , Damnjanovic Tatjana , Grk Milka , Maksimovic Nela , Pesic Milica , Gulic Milica , Trickovic Jelena , Kacar Katarina
Published: May 2021

Introduction

Levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) influence recombinant tissue plasminogen activator (rtPA) therapy response in patients with acute ischemic stroke (AIS). Serum levels of MMPs and TIMPs along with the expression of genes coding these proteins are related to the recovery and appearance of adverse effects (AE) after AIS. Consequently, it is important to explore whether polymorphisms in regulatory sequences of MMPs and TIMPs are associated with rtPA response in AIS patients.

Objectives

To determine whether selected polymorphic variants within MMP‐2, MMP‐9, and TIMP‐2 genes may influence rtPA therapy response with regard to outcomes in patients with AIS and the occurrence of AE.

Methods

Our study included 166 patients suffering AIS, treated with rtPA. Patients’ recovery was estimated using the Modified Rankin Scale (mRS) 3 months after the AIS occurred. Favorable outcome was defined with scores 0–1 and poor outcome with scores 2–6. Genotyping was performed using real‐time PCR (rs243866, rs243865, rs243864, rs2277698, and rs8179090) and PCR‐RFLP (rs2285053, rs3918242) methods. Additionally, rtPA AE were followed during the hospitalization.

Results

There was no significant association between genotypes and alleles of selected polymorphisms and rtPA therapy response measured through the decrease of the mRS score in patients with AIS. Intracranial hemorrhage, as well as parenchymal hematoma type 2, was significantly more frequent in patients with TT genotype of the MMP‐9‐1562C/T polymorphism (p = 0.047, p = 0.011, respectively). Patients with intracranial hemorrhages after rtPA were significantly more likely to have the TT genotype of TIMP‐2‐303C/T polymorphism and the TT genotype of MMP‐9‐1562C/T polymorphism (p < 0.001).

Conclusion

TT genotype of the MMP‐9‐1562C/T polymorphism may be a risk factor for rtPA‐induced hemorrhagic complications after AIS.
Von der LED bis zur laserbasierten Lichtquelle
Authors: Brümmer Mathias , Hartwig Ulrich
Published: May 2021

Projektionssysteme erfordern Lichtquellen mit kleiner Étendue und hoher Leuchtdichte. Diese Anforderungen werden von Hochdruck‐Entladungslampen, LEDs und laserbasierten Lichtquellen erfüllt. Hochdruck‐Entladungslampen erzielen höchste Leuchtdichten. Sie sind preiswert und finden noch immer in lichtstarken Videoprojektoren verbreitet Anwendung. Die Leuchtdichte moderner Dünnfilm‐LEDs ist ausreichend, um kleinere Endoskope, Bühnenscheinwerfer oder Kleinprojektoren effizient zu betreiben. Lichtquellen mit Laserdioden überschreiten die Leuchtdichte von Entladungslampen, können aber aus Sicherheitsgründen direkt nur bei geringer Strahlungsleistung betrieben werden. LARP‐Lichtquellen wandeln das Laserlicht über einen Leuchtstoff in normales Licht um. Damit sind sie hell genug, um Hochdruck‐Entladungslampen zu ersetzen. Sie sind allerdings noch sehr teuer. Deshalb finden sie zurzeit vor allem in High‐End‐Geräten und Autoscheinwerfern im Premiumbereich Anwendung.
Bose‐Einstein‐Kondensat aus Exzitonen?
Authors: Wurstbauer Ursula , Holleitner Alexander W.
Published: May 2021

Zweidimensionale (2D) Kristalle zeigen verstärkt Vielteilchenphänomene, was sie für Forschung und Anwendungen interessant macht. Dafür sorgt die viel geringere Abschirmung der Ladungsträger im Vergleich zum dreidimensionalen Fall. Verantwortlich dafür sind die Flachheit des Materials, die dieelektrische Umgebung und mit der reduzierten Dimensionalität verbundene Quanteneinschränkungen. 2D‐Kristalle können zudem aufeinander gestapelt werden, wobei die einzelnen Schichten nur durch Van‐der‐Waals‐Kräfte verbunden sind. Solche künstlichen Van‐der‐Waals‐Kristalle erlauben die Realisierung einer Fülle von neuartigen physikalischen Systemen. In halbleitenden Heterostrukturen gelang es nun, erste Hinweise für ein optisch generiertes Bose‐Einstein‐Kondensat von Exzitonen zu finden.
Das hölzerne Gelächter
Authors: Mathelitsch Leopold , Verovnik Ivo
Published: May 2021

Ein Spielzeug‐Xylophon ist meist das erste Instrument unserer Kindheit – wenn auch mit Metallplättchen als Klangerzeuger. Dabei bedeutet das Wort Xylophon im Griechischen „Holzklang“. Xylophone und Marimbas gab es bereits in der Antike. Instrumente mit Metallplättchen zeigen ein signifikant anderes Schwingungsverhalten als solche mit Holzplättchen. Deren Klang lässt sich durch Feilen an den richtigen Stellen in einem weiten Bereich abstimmen.
Physik Schwarzer Löcher mit Trapped in Gravity
Authors: Becker Sebastian , Kuhn Jochen , Wilhelm Thomas
Published: May 2021

Wie entstehen Gravitationswellen und was haben Schwarze Löcher damit zu tun? Welche Erkenntnisse kann die Gravitationswellen‐Astronomie liefern? Die kostenlose App Trapped in Gravity, entwickelt im Exzellenzcluster Quantum Universe der Universität Hamburg, eröffnet einen spielerischen Zugang zur Physik dahinter. Die App soll auch jüngere Physikinteressierte begeistern.