bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein‐Templated Hit Identification through an Ugi Four‐Component Reaction**
Authors: Mancini Federica , Unver M. Yagiz , Elgaher Walid A. M. , Jumde Varsha R. , Alhayek Alaa , Lukat Peer , Herrmann Jennifer , Witte Martin D. , Köck Matthias , Blankenfeldt Wulf , Müller Rolf , Hirsch Anna K. H.
Published: May 2020

Kinetic target‐guided synthesis represents an efficient hit‐identification strategy, in which the protein assembles its own inhibitors from a pool of complementary building blocks via an irreversible reaction. Herein, we pioneered an in situ Ugi reaction for the identification of novel inhibitors of a model enzyme and binders for an important drug target, namely, the aspartic protease endothiapepsin and the bacterial β‐sliding clamp DnaN, respectively. Highly sensitive mass‐spectrometry methods enabled monitoring of the protein‐templated reaction of four complementary reaction partners, which occurred in a background‐free manner for endothiapepsin or with a clear amplification of two binders in the presence of DnaN. The Ugi products we identified show low micromolar activity on endothiapepsin or moderate affinity for the β‐sliding clamp. We succeeded in expanding the portfolio of chemical reactions and biological targets and demonstrated the efficiency and sensitivity of this approach, which can find application on any drug target.
Self‐Assembly and Biorecognition of a Spirohydantoin Derived from α‐Tetralone: Interplay between Chirality and Intermolecular Interactions
Authors: Lazić Anita M. , Đorđević Ivana S. , Radovanović Lidija D. , Popović Dragan M. , Rogan Jelena R. , Janjić Goran V. , Trišović Nemanja P.
Published: May 2020

A racemic spirohydantoin derivative with two aromatic substituents, a tetralin and a 4‐methoxybenzyl unit, was synthesized and its crystal structure was determined. To define the relationship between molecular stereochemistry and spatial association modes, development of the crystal packing was analyzed through cooperativity of intermolecular interactions. Homo and heterochiral dimeric motifs were stabilized by intermolecular N−H⋅⋅⋅O, C−H⋅⋅⋅O, C−H⋅⋅⋅π interactions and parallel interactions at large offsets (PILO), thus forming alternating double layers. The greatest contribution to the total stabilization came from a motif of opposite enantiomers linked by N−H⋅⋅⋅O bonds (interaction energy=−13.72 kcal/mol), followed by a homochiral motif where the 4‐methoxybenzyl units allowed C−H⋅⋅⋅π, C−H⋅⋅⋅O interactions and PILO (interaction energy=−11.56 kcal/mol). The number of the contact fragments in the environment of the tetralin unit was larger, but the 4‐methoxybenzyl unit had greater contribution to the total stabilization. The statistical analysis of the data from the Cambridge Structural Database (CSD) showed that this is a general trend. The compound is a potential inhibitor of kinase enzymes and antigen protein‐coupled receptors. A correlation between the docking study and the results of the CSD analysis can be drawn. Due to a greater flexibility, the 4‐methoxybenzyl unit is more adaptable for interactions with the biological targets than the tetralin unit.
A Metal‐Free Electrode: From Biomass‐Derived Carbon to Hydrogen
Authors: Ding Yuxiao , Greiner Mark , Schlögl Robert , Heumann Saskia
Published: May 2020

Hydrogen is the emission‐free fuel of the future if produced from non‐fossil sources. Biomass gasification or electrolysis of water are possible clean routes. For a global application, the material solution for the electrodes must be sustainable, scalable, and relatively inexpensive compared to the current precious metal‐based electrodes. A key requirement to sustainable and green energy systems is that all harmful or rare resources utilized in the process must be part of a closed material cycle. Here, a carbon‐based electrode for hydrogen production is presented that can be part of a closed material cycle if produced from biomass. Continuous hydrogen production takes place at the cathode through catalytic water splitting during the oxygen evolution reaction (OER), while intentionally allowing the decomposition of the electrode into CO2 analogous to the process of natural biomass decomposition. This strategy of a sacrificial electrode could provide a scalable and low‐cost material solution for hydrogen production from renewable energy sources. The theoretical and technical feasibility of using carbon to produce hydrogen is demonstrated, and it is shown that chemical modification can further improve the performance characteristics towards the catalytic process. Combined with renewable energy derived electricity, this idea offers a real option for future energy systems.
Reproductive maturity and cone abundance vary with tree size and stand basal area for two widely distributed conifers
Authors: Andrus Robert A. , Harvey Brian J. , Hoffman Ashley , Veblen Thomas T.
Published: May 2020

Understanding potential limitations to tree regeneration is essential as rates of tree mortality increase in response to direct (extreme drought) and indirect (bark beetle outbreaks, wildfire) effects of a warming climate. Seed availability is increasingly recognized as an important limitation for tree regeneration. High variability in seed cone production is a trait common among many northern temperate conifers, but few studies examine the determinants of individual tree cone production and how they vary with stand structure. In subalpine forests in the southern Rocky Mountains, USA, we monitored >1600 Picea engelmannii (Engelmann spruce) and Abies lasiocarpa (subalpine fir) trees for cone presence (an indicator of reproductive maturity) and a subset of those trees for cone abundance (an indicator of seed production) from 2016 to 2018. We constructed mixed models to test how individual tree cone presence and cone abundance were affected by tree size and age as well as forest attributes at the neighborhood‐ and stand‐scales. The probability of cone presence and cone abundance increased with tree size and age for A. lasiocarpa and P. engelmannii. The youngest ages of trees with cones present were more than 100 yr later for individuals in high basal area (BA) stands (>65 m2/ha) relative to low BA stands (<25 m2/ha). P. engelmannii produced many more cones than A. lasiocarpa at similar sizes, especially in young, low BA stands. Our findings reveal how differences in tree sizes and stand structures typically associated with time since last disturbance can affect seed production patterns for decades to well over a century. The consistent regional pattern of earlier and more abundant postfire establishment of P. engelmannnii vs. the delayed postfire establishment by A. lasiocarpa may be partially explained by species’ differences in cone abundance by stand structure. The increasing loss of large, dominant cone‐producing trees will significantly reduce seed production to support future tree regeneration and maintain forest cover. However, seed availability and resilience following disturbances may be less limiting than expected for species like P. engelmannii that have the capacity to produce more cones in open‐canopy forests, such as recently disturbed areas.
Impella RP as a bridge to cardiac transplant for refractory late right ventricular failure in setting of left ventricular assist device
Authors: Randhawa Varinder Kaur , Hoffman Karlee , Bock Ashley , Bhat Pavan , Young Laura , Rossi Jeffrey , Campbell Joseph , Bott‐Silverman Corrine , Soltesz Edward G. , Tong Michael Z.Y. , Unai Shinya , Nair Ravi , Estep Jerry D. , Perez Antonio L.
Published: May 2020

Right ventricular (RV) failure remains a major complication after surgical implantation of a left ventricular assist device (LVAD). While the use of a percutaneous RV assist device has been described as a short‐term bridge to recovery in end‐stage heart failure patients with early post‐operative RV failure after index LVAD implant, management of refractory late RV failure remains challenging in these patients. We report the first successful case of extended Impella RP use as a safe and effective bridge to orthotopic heart transplant in an LVAD patient with refractory, haemodynamically significant late RV failure. The Impella RP provided support for 37 days. Haemodynamically intolerant arrhythmia precluded use of inotropic support. No adverse complications related to percutaneous Impella RP support were seen. We also review potential considerations for mechanical circulatory support strategies in this setting: central RV assist device cannulation requires sternotomy incision that can impact subsequent cardiac surgeries, while percutaneous Protek Duo insertion requires adequate vessel size and patency. With an LVAD in situ, veno‐arterial extracorporeal membrane oxygenation was not considered for isolated RV support in this case. The patient is currently over 6 months post‐orthotopic heart transplant.
Growth differentiation factor 15 in adverse cardiac remodelling: from biomarker to causal player
Authors: Wesseling Marian , de Poel Julius H.C. , de Jager Saskia C.A.
Published: May 2020

Heart failure is a growing health issue as a negative consequence of improved survival upon myocardial infarction, unhealthy lifestyle, and the ageing of our population. The large and complex pathology underlying heart failure makes diagnosis and especially treatment very difficult. There is an urgent demand for discriminative biomarkers to aid disease management of heart failure. Studying cellular pathways and pathophysiological mechanisms contributing to disease initiation and progression is crucial for understanding the disease process and will aid to identification of novel biomarkers and potential therapeutic targets. Growth differentiation factor 15 (GDF15) is a proven valuable biomarker for different pathologies, including cancer, type 2 diabetes, and cardiovascular diseases. Although the prognostic value of GDF15 in heart failure is robust, the biological function of GDF15 in adverse cardiac remodelling is not fully understood. GDF15 is a distant member of the transforming growth factor‐β family and involved in various biological processes including inflammation, cell cycle, and apoptosis. However, more research is suggesting a role in fibrosis, hypertrophy, and endothelial dysfunction. As GDF15 is a pleiotropic protein, elucidating the exact role of GDF15 in complex disease processes has proven to be a challenge. In this review, we provide an overview of the role GDF15 plays in various intracellular and extracellular processes underlying heart failure, and we touch upon crucial points that need consideration before GDF15 can be integrated as a biomarker in standard care or when considering GDF15 for therapeutic intervention.
Speckle tracking echocardiography in hypokinetic non‐dilated cardiomyopathy: comparison with dilated cardiomyopathy
Authors: Mombeini Hoda , Parsaee Mozhgan , Amin Ahmad
Published: May 2020

Aims

Hypokinetic non‐dilated cardiomyopathy (HNDC), which is determined by impaired left ventricular (LV) systolic function despite normal LV size, has been categorized as a subgroup of dilated cardiomyopathy (DCM) spectrum. Lack of data regarding advanced echocardiographic data in this population motivated us to design the present study in order to assess LV myocardial deformation properties of HNDC patients against the ones with dilated left ventricle.

Methods and results

Thirty‐one HNDC patients and 23 DCM patients were enrolled in the study consecutively. Myocardial deformation parameters including global longitudinal strain, global circumferential strain, LV basal and apical rotation, LV twist, and LV mechanical dispersion were obtained with the use of two‐dimensional speckle tracking‐based methods in all patients. Left cardiac chamber volume was also measured using three‐dimensional HeartModel application. Patients with enlarged left ventricle tend to have lower LV ejection fraction. Comparing with HNDC group, DCM patients showed worse global circumferential strain (coefficient ± standard error 3.59 ± 0.94, P < 0.001) and LV mechanical dispersion (coefficient ± standard error 16.46 ± 7.09, P = 0.02) after regression analysis, while neither the global longitudinal strain nor the LV twist was not significantly different between two study population.

Conclusions

Left ventricular enlargement has a substantial effect on the circumferential strain and mechanical dispersion more than other deformation parameters that may play a role in the assumed poor prognosis of heart failure patients with dilated left ventricle.
Gold‐Catalyzed Regioselective Synthesis of Pyrazolo[1,4]oxazepines via Intramolecular 7‐endo‐dig Cyclization
Authors: Thummala Yadagiri , Raju Chittala Emmaniel , Purnachandar Dalovai , Sreenivasulu Gottam , Doddi Venkata Ramana , Karunakar Galla V.
Published: May 2020

An efficient gold‐catalyzed intramolecular regioselective synthesis of pyrazolo[1,4]oxazepines were developed from alkynyl‐substituted pyrazoles via 7‐endo dig cyclization. In this reaction a new C–N bond was formed and substituted pyrazolo[1,4]oxazepines were obtained in moderate to very good yields. Whereas alkynyl‐substituted pyrazoles treated with sodium hydride produced the corresponding pyrazolo[1,4]oxazines regioselectively, via 6‐exo dig cyclization in one‐pot synthesis.
Local community perceptions toward livelihood and water–energy–food nexus: A perspective on food security
Authors: Wolde Zinabu , Wei Wu , Kunpeng Wang , Ketema Haile
Published: May 2020

While water–energy–food (WEF) nexus is a major livelihood sources for local community, its security issues grow continually and there is limited information on how nexus resource management is effective at delivering livelihoods and food security. These difficulties are related to the lack of local community knowledge of the use and exploitation of water, energy, and food resources; this limited awareness leads to trade‐offs, especially in local and marginalized areas. On the basis of data collected from a local community through a survey‐based approach, this study examines local community perception of nexus resources and their contribution to livelihoods. The results indicate that community perceptions of nexus resources can be understood through social, natural, economic, human, physical, and environmental livelihood indicators. According to our findings, the perception of nexus resources is based on the benefits of individual resources rather than their interlinkages. This could be the result of community perceptions of a particular nexus resource from three nexus sector, that is, food. Food is the center of nexus resources for the community in the study area. This indicates, that there is a missing link between cross‐sectorial resource utilization and management, and full‐scale adoption of the WEF nexus to enhance living conditions. Our findings suggest that there is a low understanding of WEF nexus resource use and management, and the livelihood benefit of individual nexus resources is the primary focus in the studied community. From these results, we recommend more action to be taken by the government and other stakeholders to improve the local community perception of nexus resources for their livelihoods.
Meta‐analysis of risk of occult lymph node metastasis in the irradiated, clinically N0 neck
Authors: Finegersh Andrey , Moss William J. , Saddawi‐Konefka Robert , Faraji Farhoud , Coffey Charles S. , Califano Joseph A. , Brumund Kevin T. , Orosco Ryan K.
Published: May 2020

Background

Recurrent head and neck squamous cell carcinoma (HNSCC) after radiation is associated with poor survival, and management of the clinically negative (N0) neck during salvage surgery is controversial.

Methods

Studies were selected according to preferred reporting items for systematic reviews and meta‐analyses guidelines. Inclusion criteria were patients with HNSCC, prior radiation to the lateral neck nodal basin, undergoing salvage surgery for local recurrence, persistence or second primary, and N0 at time of salvage. Eleven studies with a total of 382 patients met inclusion criteria.

Results

The rate of occult metastasis was 15.4%. The pooled rate of occult nodal metastasis was 16.2% for oral cavity, 12.9% for oropharynx, 23.7% for hypopharynx, and 27.3% for supraglottic or transglottic tumors. There was a significantly higher relative risk of occult metastasis for locally advanced tumors.

Conclusion

Elective neck dissection at time of salvage surgery should be considered based on subsite, T classification, and prior history of nodal metastasis.
Disulfide High‐Mobility Group Box 1 Drives Ischemia‐Reperfusion Injury in Human Liver Transplantation
Authors: Sosa Rebecca A. , Terry Allyson Q. , Kaldas Fady M. , Jin Yi‐Ping , Rossetti Maura , Ito Takahiro , Li Fang , Ahn Richard S. , Naini Bita V. , Groysberg Victoria M. , Zheng Ying , Aziz Antony , Nevarez‐Mejia Jessica , Zarrinpar Ali , Busuttil Ronald W. , Gjertson David W. , Kupiec‐Weglinski Jerzy W. , Reed Elaine F.
Published: May 2020

Background and Aims

Sterile inflammation is a major clinical concern during ischemia‐reperfusion injury (IRI) triggered by traumatic events, including stroke, myocardial infarction, and solid organ transplantation. Despite high‐mobility group box 1 (HMGB1) clearly being involved in sterile inflammation, its role is controversial because of a paucity of patient‐focused research.

Approach and Results

Here, we examined the role of HMGB1 oxidation states in human IRI following liver transplantation. Portal blood immediately following allograft reperfusion (liver flush; LF) had increased total HMGB1, but only LF from patients with histopathological IRI had increased disulfide‐HMGB1 and induced Toll‐like receptor 4–dependent tumor necrosis factor alpha production by macrophages. Disulfide HMGB1 levels increased concomitantly with IRI severity. IRI+ prereperfusion biopsies contained macrophages with hyperacetylated, lysosomal disulfide‐HMGB1 that increased postreperfusion at sites of injury, paralleling increased histone acetyltransferase general transcription factor IIIC subunit 4 and decreased histone deacetylase 5 expression. Purified disulfide‐HMGB1 or IRI+ blood stimulated further production of disulfide‐HMGB1 and increased proinflammatory molecule and cytokine expression in macrophages through a positive feedback loop.

Conclusions

These data identify disulfide‐HMGB1 as a mechanistic biomarker of, and therapeutic target for, minimizing sterile inflammation during human liver IRI.
Genome‐Wide Association Study of Lean Nonalcoholic Fatty Liver Disease Suggests Human Leukocyte Antigen as a Novel Candidate Locus
Authors: Yoshida Ken , Yokota Kazuha , Kutsuwada Yukinobu , Nakayama Kazuhiro , Watanabe Kazuhisa , Matsumoto Ayumi , Miyashita Hiroshi , Khor Seik‐soon , Tokunaga Katsushi , Kawai Yosuke , Nagasaki Masao , Iwamoto Sadahiko
Published: May 2020

Nonalcoholic fatty liver disease (NAFLD) is supposed to manifest its metabolic phenotype in the liver, but it is common to have lean individuals diagnosed with NAFLD, known as lean NAFLD. We conducted a two‐stage analysis to identify NAFLD‐associated loci in Japanese patients. In stage I, 275 metabolically healthy normal‐weight patients with NAFLD were compared with 1,411 non‐NAFLD controls adjusted for age, sex, and alcohol consumption by a genome‐wide association study (GWAS). In stage II, human leukocyte antigen (HLA) in chromosome 6 (chr6) (P = 6.73E‐08), microRNA (MIR) MIR548F3 in chr7 (P = 4.25E‐07), myosin light chain 2 (MYL2) in chr12 (P = 4.39E‐07), and glycoprotein precursor (GPC)6 in chr13 (P = 5.43E‐07), as suggested by the GWAS, were assessed by single nucleotide polymorphism (SNP) association analysis of whole NAFLD against non‐NAFLD in 9,726 members of the general population. A minor allele of the secondary lead SNP in chr6, rs2076529, was significantly associated (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.11‐1.28; P = 2.10E‐06) and the lead SNP in chr7 was weakly associated (OR 1.15; 95% CI, 1.04‐1.27; P = 6.19E‐03) with increased NAFLD risk. Imputation‐based typing of HLA showed a significant difference in the distribution of HLA‐B, HLA‐DR‐beta chain 1 (DRB1), and HLA‐DQ‐beta chain 1 (DQB1) alleles in lean NAFLD GWAS. Next‐generation sequence‐based typing of HLA in 5,649 members of the general population replicated the significant difference of HLA‐B allele distribution and the significant increase of the HLA‐B*54:01 allele in whole NAFLD. Fecal metagenomic analysis of 3,420 members of the general population showed significant dissimilarity in beta‐diversity analysis of rs2076529 and HLA‐B*54:01 allele carriers from noncarriers. Veillonellaceae was increased but Verrucomicrobia was decreased in rs2076529 minor allele and HLA‐B*54:01 allele carriers as in NAFLD. Conclusion: HLA was identified as a novel locus associated with NAFLD susceptibility, which might be affected by the alteration of gut microbiota.
Relationship between tRNA‐derived fragments and human cancers
Authors: Zeng Tianyu , Hua Yijia , Sun Chunxiao , Zhang Yuchen , Yang Fan , Yang Mengzhu , Yang Yiqi , Li Jun , Huang Xiang , Wu Hao , Fu Ziyi , Li Wei , Yin Yongmei
Published: May 2020

tRNA‐derived fragments, a class of small noncoding RNAs (sncRNAs), have been identified in numerous studies in recent years. tRNA‐derived fragments are classified into two main groups, including tRNA halves (tiRNAs) and tRNA‐derived small RNA fragments (tRFs), according to different cleavage positions of the precursor or mature tRNAs. Instead of random tRNA degradation debris, a growing body of evidence has shown that tRNA‐derived fragments are precise products of specific tRNA modifications and play important roles in biological activities, such as regulating protein translation, affecting gene expression, and altering immune signaling. Recently, the relations between tRNA‐derived fragments and the occurrence of human diseases, especially cancers, have generated wide interest. It has been demonstrated that tRNA‐derived fragments are involved in cancer cell proliferation, metastasis, progression and survival. In this review, we will describe the biogenesis of tRNA‐derived fragments, the distinct expression and function of tRNA‐derived fragments in the development of cancers, and their emerging roles as diagnostic and prognostic biomarkers and precise targets of future treatments.
Assessment of birth preparedness and complication readiness among pregnant women attending the Obs/Gynae wards in two teaching hospitals in Peshawar, Khyber Pakhtunkhwa, Pakistan
Authors: Qazi Umair , Latif Abdul , Irshad Gulmaskha , Malik Farhat R. , Anwar Saeed
Published: May 2020

Objective

To assess the knowledge of pregnant women receiving antenatal care at the study sites about birth preparedness and complication readiness (BPCR) and their knowledge about warning signs during pregnancy, labor, and postpartum.

Methods

A cross‐sectional study was conducted from October 2018 to April 2019 in two teaching hospitals in Peshawar, Pakistan. Pregnant women aged 15–49 years were recruited after consent. A structured questionnaire was used for data collection.

Results

Among 170 enrollees, 72.4% had not heard about BPCR. Transportation arrangements were done by 4.7%, blood donor arrangements by 10%, saving for emergency by 22.4%, and 42.4% identified a skilled provider. Prior selection of a health facility for delivery were done by 65.9%, and 71.8% received four or more antenatal visits. Vaginal bleeding (68%), placenta not delivered within 30 minutes of delivery (62.9%), and vaginal bleeding ( 51.8%) were reported as warning signs during pregnancy, delivery, and postpartum, respectively.

Conclusion

Knowledge of BPCR and warning signs during all three phases of pregnancy was low. The increased antenatal visits are an opportunity to educate the mothers about BPCR and warning signs.
Single-Cell RNA Sequencing of Calvarial and Long-Bone Endocortical Cells
Authors: Ayturk Ugur M , Scollan Joseph P , Goz Ayturk Didem , Suh Eun Sung , Vesprey Alexander , Jacobsen Christina M , Divieti Pajevic Paola , Warman Matthew L
Published: May 2020

Single-cell RNA sequencing (scRNA-Seq) is emerging as a powerful technology to examine transcriptomes of individual cells. We determined whether scRNA-Seq could be used to detect the effect of environmental and pharmacologic perturbations on osteoblasts. We began with a commonly used in vitro system in which freshly isolated neonatal mouse calvarial cells are expanded and induced to produce a mineralized matrix. We used scRNA-Seq to compare the relative cell type abundances and the transcriptomes of freshly isolated cells to those that had been cultured for 12 days in vitro. We observed that the percentage of macrophage-like cells increased from 6% in freshly isolated calvarial cells to 34% in cultured cells. We also found that Bglap transcripts were abundant in freshly isolated osteoblasts but nearly undetectable in the cultured calvarial cells. Thus, scRNA-Seq revealed significant differences between heterogeneity of cells in vivo and in vitro. We next performed scRNA-Seq on freshly recovered long bone endocortical cells from mice that received either vehicle or sclerostin-neutralizing antibody for 1 week. We were unable to detect significant changes in bone anabolism–associated transcripts in immature and mature osteoblasts recovered from mice treated with sclerostin-neutralizing antibody; this might be a consequence of being underpowered to detect modest changes in gene expression, because only 7% of the sequenced endocortical cells were osteoblasts and a limited portion of their transcriptomes were sampled. We conclude that scRNA-Seq can detect changes in cell abundance, identity, and gene expression in skeletally derived cells. In order to detect modest changes in osteoblast gene expression at the single-cell level in the appendicular skeleton, larger numbers of osteoblasts from endocortical bone are required. © 2020 American Society for Bone and Mineral Research.
RETRACTED: Coinhibition of S1PR1 and GP130 by siRNA‐loaded alginate‐conjugated trimethyl chitosan nanoparticles robustly blocks development of cancer cells
Authors: Rostami Narges , Nikkhoo Afshin , Khazaei‐poul Yalda , Farhadi Shohreh , Sadat Haeri Melika , Moghadaszadeh Ardebili Sadaf , Aghaei Vanda Nasimeh , Atyabi Fatemeh , Namdar Afshin , Baghaei Masoumeh , Haghnavaz Navideh , Kazemi Tohid , Yousefi Mehdi , Ghalamfarsa Ghasem , Sabz Gholamabas , Jadidi‐Niaragh Farhad
Published: May 2020

There is an interconnected network between S1P/sphingosine‐1‐phosphate receptor 1 (S1PR1), IL‐6/glycoprotein 130 (GP130), and signal transducer and activator of transcription 3 (STAT3) signaling pathways in the tumor microenvironment, which leads to cancer progression. S1P/S1PR1 and IL‐6/GP130 signaling pathways phosphorylate and activate STAT3, and it then induces the expression of S1PR1 and interleukin‐6 (IL‐6) in a positive feedback loop leading to cancer progression. We hypothesized that blockade of this amplification loop can suppress the growth and development of cancer cells. Therefore, we silenced STAT3 upstream molecules including the S1PR1 and GP130 molecules in cancer cells using small interfering RNA (siRNA)‐loaded alginate‐conjugated trimethyl chitosan (ATMC) nanoparticles (NPs). The generated NPs had competent properties including the appropriate size, zeta potential, polydispersity index, morphology, high uptake of siRNA, high rate of capacity, high stability, and low toxicity. We evaluated the effects of siRNA loaded ATMC NPs on tumor hallmarks of three murine‐derived cancer cell lines, including 4T1 (breast cancer), B16‐F10 (melanoma), and CT26 (colon cancer). The results confirmed the tumor‐suppressive effects of combinational targeting of S1PR1 and GP130. Moreover, combination therapy could potently suppress tumor growth as assessed by the chick chorioallantoic membrane assay. In this study, we targeted this positive feedback loop for the first time and applied this novel combination therapy, which provides a promising approach for cancer treatment. The development of a potent nanocarrier system with ATMC for this combination was also another aspect of this study, which should be further investigated in cancer animal models in further studies.
Low‐dose melatonin for sleep disturbances in early‐stage cirrhosis: A randomized, placebo‐controlled, cross‐over trial
Authors: De Silva Arjuna P , Niriella Madunil A , Ediriweera Dileepa S , De Alwis Jerome P , Liyanage Isurujith K , Ettickan Ushanthani , Liyanapathirana Kasun V , Undugodage Chandimani , de Silva H. Asita , de Silva H. Janaka
Published: May 2020

Background and aim

Melatonin is used to treat sleep disturbances (SDs). The aim of this study was to investigate the safety and efficacy of low‐dose melatonin for SDs in early‐stage cirrhosis.

Methods

In a single‐center, randomized, double‐blind, placebo‐controlled, cross‐over clinical trial, patients with early‐stage (Child‐Turcotte‐Pugh [CTP] class A or B) cirrhosis with SDs, without hepatic encephalopathy, were randomized to placebo or 3 mg of melatonin for 2 weeks. After 2 weeks, the patients were given a washout period of 1 week and crossed over to melatonin or placebo for a further 2 weeks. The Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were used to measure sleep quality and daytime sleepiness, respectively. Analysis of results was based on intention to treat, and linear mixed‐effect models were used to evaluate the effect of melatonin. Analysis was conducted using R‐programming language 3.5.1.

Results

Seventy one patients were recruited (mean age: 61.9 ± 8.7 years, males: 46 [64.8%], and CTP Class A = 52 [73.2%] and Class B = 19 [26.8%]). Sixty patients completed the study (mean age: 61.7 ± 8.8 years, males: 40 [66.6%], and CTP Class A = 45 [75.0%] and Class‐B = 15 [25.0%]). Two patients dropped out due to adverse events. Nine patients were lost to follow up. Patients given melatonin had a significantly lower PSQI and ESS compared to both pretreatment (P < 0.001) and postplacebo scores (P < 0.001). Incidence of adverse events was similar (two each of abdominal pain, one each of headache, one each of dizziness) in both groups.

Conclusion

Melatonin seems safe and effective for use in patients with SDs in early‐stage cirrhosis in the short term. However, larger and longer‐term studies to assess efficacy and safety are required before its clinical use can be recommended.
Identity is About us: Leadership Lessons Learned During an Accreditation Journey
Authors: Thwaite Sapna V.
Published: May 2020

The current paper describes a university administrator and her academic unit's professional journey through a first time accreditation process. Drawing upon her professional background as an educational psychologist, the author uses the lens of identity to draw parallels between the experience of a young organization undergoing processes of change in response to accreditation and an individual undergoing the typical developmental issues and challenges we commonly associate with adolescent identity development. The current article details multiple ways that identity can serve as a useful lens for studying the development and growth of an organization, and offers practical suggestions that might benefit individuals in leadership roles whose units are undergoing similar external accountability processes.
Age‐related changes in ACL morphology during skeletal growth and maturation are different between females and males
Authors: Hosseinzadeh Shayan , Kiapour Ata M.
Published: May 2020

Despite a well‐established role of anterior cruciate ligament (ACL) anatomy on its biomechanics, little is known on how ACL anatomy develops and changes during skeletal growth. We hypothesized that ACL size and orientation will change by age during skeletal growth and maturation with different trends in males vs females. Magnetic resonance images of 269 unique knees (3‐18 years old; 51% female) were used to measure ACL length, cross‐sectional area, length‐to‐cross‐sectional area ratio, and elevation angles. In both males and females, ACLs became longer, thicker, and more vertical in sagittal and coronal planes by increasing age (R2 > 0.2; P < .001 for all associations). ACL cross‐sectional area‐to‐length ratio increased by age only in males (R2 = 0.06; P = .003). Despite similar ACL sizes between males and females at early age, adolescent males had significantly longer and thicker ACLs compared to the age‐matched females (P < .05). There were no sex differences in ACL elevation angles (P > .2) except for larger coronal elevation in 7 to 10 years old females compared to age‐matched males (P = .012). Observed changes in ACL cross‐sectional area‐to‐length ratio indicate that age‐ and sex‐dependent changes in ACL size are not homogenous. The trends seen in normalized ACL size measurements suggest that unlike ACL cross‐sectional area, ACL length is primarily controlled by body size. Smaller ACLs and lower cross‐sectional growth rates observed in females may be contributing factors to the higher risk of ACL injuries in females. Further investigations are required to identify the intrinsic and extrinsic factors responsible for these discrepancies.
Higher knee contact forces might underlie increased osteoarthritis rates in high functioning amputees: A pilot study
Authors: Ding Ziyun , Jarvis Hannah L. , Bennett Alexander N. , Baker Richard , Bull Anthony M. J.
Published: May 2020

High functioning military transtibial amputees (TTAs) with well‐fitted state of the art prosthetics have gait that is indistinguishable from healthy individuals, yet they are more likely to develop knee osteoarthritis (OA) of their intact limbs. This contrasts with the information at the knees of the amputated limbs that have been shown to be at a significantly reduced risk of pain and OA. The hypothesis of this study is that biomechanics can explain the difference in knee OA risk. Eleven military unilateral TTAs and eleven matched healthy controls underwent gait analysis. Muscle forces and joint contact forces at the knee were quantified using musculoskeletal modeling, validated using electromyography measurements. Peak knee contact forces for the intact limbs on both the medial and lateral compartments were significantly greater than the healthy controls (P ≤ .006). Additionally, the intact limbs had greater peak semimembranosus (P = .001) and gastrocnemius (P ≤ .001) muscle forces compared to the controls. This study has for the first time provided robust evidence of increased force on the non‐affected knees of high functioning TTAs that supports the mechanically based hypothesis to explain the documented higher risk of knee OA in this patient group. The results suggest several protentional strategies to mitigate knee OA of the intact limbs, which may include the improvements of the prosthetic foot control, socket design, and strengthening of the amputated muscles.
A proposal of an updated classification for pelvic relapses of rectal cancer to guide surgical decision‐making
Authors: Belli Filiberto , Sorrentino Luca , Gallino Gianfrancesco , Gronchi Alessandro , Scaramuzza Davide , Valvo Francesca , Cattaneo Laura , Cosimelli Maurizio
Published: May 2020

Background and Objectives

Selection of patients affected by pelvic recurrence of rectal cancer (PRRC) who are likely to achieve a R0 resection is mandatory. The aim of this study was to propose a classification for PRRC to predict both radical surgery and disease‐free survival (DFS).

Methods

PRRC patients treated at the National Cancer Institute of Milan (Italy) were included in the study. PRRC were classified as S1, if located centrally (S1a‐S1b) or anteriorly (S1c) within the pelvis; S2, in case of sacral involvement below (S2a) or above (S2b) the second sacral vertebra; S3, in case of lateral pelvic involvement.

Results

Of 280 reviewed PRRC patients, 152 (54.3%) were evaluated for curative surgery. The strongest predictor of R+ resection was the S3 category (OR, 6.37; P = .011). Abdominosacral resection (P = .012), anterior exenteration (P = .012) and extended rectal re‐excision (P = .003) were predictive of R0 resection. S3 category was highly predictive of poor DFS (HR 2.53; P = .038). DFS was significantly improved after R0 surgery for S1 (P < .0001) and S2 (P = .015) patients but not for S3 cases (P = .525).

Conclusions

The proposed classification allows selection of subjects candidates to curative surgery, emphasizing that lateral pelvic involvement is the main predictor of R+ resection and independently affects the DFS.
Methane production in oxic seawater of the western North Pacific and its marginal seas
Authors: Ye Wang‐Wang , Wang Xiao‐Lei , Zhang Xiao‐Hua , Zhang Gui‐Ling
Published: May 2020

The oceans are natural sources of atmospheric methane (CH4), but the origin of excess CH4 at the surface remains enigmatic. Incubation experiments were conducted in the western North Pacific (WNP) and its marginal seas (i.e., Yellow Sea and South China Sea [SCS]) to identify the degradation of methylphosphonate (MPn) to CH4 in the oceans and the microbes associated with MPn‐driven CH4 production. In the coastal seawater of the Yellow Sea, CH4 was observed to accumulate after MPn enrichment with a high MPn to CH4 conversion efficiency (approximately 60%). Dissolved inorganic phosphorus (Pi) did not effectively restrict the microbial utilization of MPn in the eutrophic coastal waters. The results of 16S rRNA gene sequencing showed that Vibrio spp. were the dominant bacteria in the MPn‐amended treatments. Moreover, several Vibrio isolates isolated from the coastal waters were found to produce CH4 while growing in culture using MPn as the sole P source, thereby indicating that Vibrio spp. might be the major contributors to MPn‐dependent CH4 production. In oligotrophic areas, such as the SCS and WNP, CH4 production from MPn metabolism was also observed in the surface seawater. In contrast to coastal waters, this pathway in oligotrophic areas is regulated by dissolved Pi availability. This work confirms that aerobic CH4 formation from MPn degradation can occur both in eutrophic coastal waters and oligotrophic oceans driven by MPn‐utilizing microorganisms (especially heterotrophic bacteria), which may have a significant impact on our understanding of the CH4 and P cycles in global oceans.
Use of Artificial Intelligence as an Innovative Method for Liver Graft Macrosteatosis Assessment
Authors: Cesaretti Manuela , Brustia Raffaele , Goumard Claire , Cauchy François , Poté Nicolas , Dondero Federica , Paugam‐Burtz Catherine , Durand François , Paradis Valerie , Diaspro Alberto , Mattos Leonardo , Scatton Olivier , Soubrane Olivier , Moccia Sara
Published: May 2020

The worldwide implementation of a liver graft pool using marginal livers (ie, grafts with a high risk of technical complications and impaired function or with a risk of transmitting infection or malignancy to the recipient) has led to a growing interest in developing methods for accurate evaluation of graft quality. Liver steatosis is associated with a higher risk of primary nonfunction, early graft dysfunction, and poor graft survival rate. The present study aimed to analyze the value of artificial intelligence (AI) in the assessment of liver steatosis during procurement compared with liver biopsy evaluation. A total of 117 consecutive liver grafts from brain‐dead donors were included and classified into 2 cohorts: ≥30 versus <30% hepatic steatosis. AI analysis required the presence of an intraoperative smartphone liver picture as well as a graft biopsy and donor data. First, a new algorithm arising from current visual recognition methods was developed, trained, and validated to obtain automatic liver graft segmentation from smartphone images. Second, a fully automated texture analysis and classification of the liver graft was performed by machine‐learning algorithms. Automatic liver graft segmentation from smartphone images achieved an accuracy (Acc) of 98%, whereas the analysis of the liver graft features (cropped picture and donor data) showed an Acc of 89% in graft classification (≥30 versus <30%). This study demonstrates that AI has the potential to assess steatosis in a handy and noninvasive way to reliably identify potential nontransplantable liver grafts and to avoid improper graft utilization.
Comparison of high spatiotemporal‐resolution soil moisture observations with CLM4.0 simulations
Authors: Shao Changliang , Wu Dongli , Guo Yakai
Published: May 2020

Automatic soil moisture data with a temporal resolution of 1 hr, a spatial resolution of 30 km, from the period June 1–September 1, 2017, and from Henan province in China, and simulation results from the Community Land Model (CLM4.0) were first compared, and a calibration study was further conducted and investigated. The operational status of the instruments was confirmed, and the data passed quality control. The corresponding simulation was performed using the CLM4.0. Small spatial scale variations in observed soil moisture contents were found, but relatively large spatial variations were observed in the simulated soil moisture contents. Since a relatively large bias and weak correlation were found between the simulation and observations, it is necessary to bias‐correct the model outputs in order to improve the prediction capability of the numerical models. After bias correction was conducted, the outliers accounting for around 10% of the actual samples were identified and removed for each layer. The observed and simulated data were found to be linearly distributed, and the probability density distribution of deviations between observed and simulated values showed a normal distribution. The mean bias (BIAS) and root mean square error (RMSE) decreased by 100% and 50%, respectively, and the correlation co‐efficient (CORR) increased by about 10 times. These improvements showed that the bias‐corrected data met the requirements for the evaluation and application of soil moisture data, which can be of great significance in improving future land simulation and assimilation.
Segmentation of pulmonary nodules in CT images based on 3D‐UNET combined with three‐dimensional conditional random field optimization
Authors: Wu Wenhao , Gao Lei , Duan Huihong , Huang Gang , Ye Xiaodan , Nie Shengdong
Published: May 2020

Purpose

Pulmonary nodules are a potential manifestation of lung cancer. In computer‐aided diagnosis (CAD) of lung cancer, it is of great significance to extract the complete boundary of the pulmonary nodules in the computed tomography (CT) scans accurately. It can provide doctors with important information such as tumor size and density, which assist doctors in subsequent diagnosis and treatment. In addition to this, in the molecular subtype and radiomics of lung cancer, segmentation of lung nodules also plays a pivotal role. Existing methods are difficult to use only one model to simultaneously treat the boundaries of multiple types of lung nodules in CT images.

Method

In order to solve the problem, this paper proposed a three‐dimensional (3D)‐UNET network model optimized by a 3D conditional random field (3D‐CRF) to segment pulmonary nodules. On the basis of 3D‐UNET, the 3D‐CRF is used to optimize the sample output of the training set, so as to update the network weights in training process, reduce the model training time, and reduce the loss rate of the model. We selected 936 sets of pulmonary nodule data for the lung image database consortium and image database resource initiative (LIDC‐IDRI)1 database to train and test the model. What’s more, we used clinical data from partner hospitals for additional validation.

Results and conclusions

The results show that our method is accurate and effective. Particularly, it shows more significance for the optimization of the segmentation of adhesive pulmonary nodules (the juxta‐pleural and juxta‐vascular nodules) and ground glass pulmonary nodules (GGNs).
Pixel‐wise assessment of cardiovascular magnetic resonance first‐pass perfusion using a cardiac phantom mimicking transmural myocardial perfusion gradients
Authors: Milidonis Xenios , Nazir Muhummad Sohaib , Schneider Torben , Capstick Myles , Drost Sita , Kok Gertjan , Pelevic Nikola , Poelma Christian , Schaeffter Tobias , Chiribiri Amedeo
Published: May 2020

Purpose

Cardiovascular magnetic resonance first‐pass perfusion for the pixel‐wise detection of coronary artery disease is rapidly becoming the clinical standard, yet no widely available method exists for its assessment and validation. This study introduces a novel phantom capable of generating spatially dependent flow values to enable assessment of new perfusion imaging methods at the pixel level.

Methods

A synthetic multicapillary myocardial phantom mimicking transmural myocardial perfusion gradients was designed and manufactured with high‐precision 3D printing. The phantom was used in a stationary flow setup providing reference myocardial perfusion rates and was scanned on a 3T system. Repeated first‐pass perfusion MRI for physiological perfusion rates between 1 and 4 mL/g/min was performed using a clinical dual‐sequence technique. Fermi function‐constrained deconvolution was used to estimate pixel‐wise perfusion rate maps. Phase contrast (PC)‐MRI was used to obtain velocity measurements that were converted to perfusion rates for validation of reference values and cross‐method comparison. The accuracy of pixel‐wise maps was assessed against simulated reference maps.

Results

PC‐MRI indicated excellent reproducibility in perfusion rate (coefficient of variation [CoV] 2.4‐3.5%) and correlation with reference values (R2 = 0.985) across the full physiological range. Similar results were found for first‐pass perfusion MRI (CoV 3.7‐6.2%, R2 = 0.987). Pixel‐wise maps indicated a transmural perfusion difference of 28.8‐33.7% for PC‐MRI and 23.8‐37.7% for first‐pass perfusion, matching the reference values (30.2‐31.4%).

Conclusion

The unique transmural perfusion pattern in the phantom allows effective pixel‐wise assessment of first‐pass perfusion acquisition protocols and quantification algorithms before their introduction into routine clinical use.
Supporting measurements or more averages? How to quantify cerebral blood flow most reliably in 5 minutes by arterial spin labeling
Authors: Bladt Piet , van Osch Matthias J. P. , Clement Patricia , Achten Eric , Sijbers Jan , den Dekker Arnold J.
Published: May 2020

Purpose

To determine whether sacrificing part of the scan time of pseudo‐continuous arterial spin labeling (PCASL) for measurement of the labeling efficiency and blood
is beneficial in terms of CBF quantification reliability.

Methods

In a simulation framework, 5‐minute scan protocols with different scan time divisions between PCASL data acquisition and supporting measurements were evaluated in terms of CBF estimation variability across both noise and ground truth parameter realizations taken from the general population distribution. The entire simulation experiment was repeated for a single‐post‐labeling delay (PLD), multi‐PLD, and free‐lunch time‐encoded (te‐FL) PCASL acquisition strategy. Furthermore, a real data study was designed for preliminary validation.

Results

For the considered population statistics, measuring the labeling efficiency and the blood
proved beneficial in terms of CBF estimation variability for any distribution of the 5‐minute scan time compared to only acquiring ASL data. Compared to single‐PLD PCASL without support measurements as recommended in the consensus statement, a 26%, 33%, and 42% reduction in relative CBF estimation variability was found for optimal combinations of supporting measurements with single‐PLD, free‐lunch, and multi‐PLD PCASL data acquisition, respectively. The benefit of taking the individual variation of blood
into account was also demonstrated in the real data experiment.

Conclusions

Spending time to measure the labeling efficiency and the blood
instead of acquiring more averages of the PCASL data proves to be advisable for robust CBF quantification in the general population.