bluuebunny/crossref_metadata_2025 huggingface dataset:
Buffering Effects of Social Support and Parental Monitoring on Suicide
Authors: Kim Yi Jin , Quinn Camille R , Moon Sung Seek
Published: December 2020

A number of studies have examined the direct effects of social support, depression, and parental monitoring on suicide ideation. However, less is known about the mediation and moderation effects of social support, depression, and parental monitoring on suicide ideation among adolescents. To determine how suicide ideation is associated with an adolescent’s social support, depression, and parental monitoring, authors analyzed data drawn from the 2016 wave of the National Survey on Drug Use and Health. The total sample consisted of 14,272 participants, ages 12 to 17; 51.1 percent were male and 48.9 percent female. By using the PROCESS macro, the authors tested the mediation effect of depression between social support and suicide ideation moderated by parental monitoring. Depression mediated the correlation between social support and suicide ideation. Parental monitoring moderated the mediation effect of depression between social support and suicide ideation. These findings provide specific directions to develop and culturally tailor effective suicide intervention programs for adolescents with histories of depression to reduce their suicidal behavior.
Constitutional touchstones: Peace processes, federalism, and constitution-making in Myanmar
Authors: Crouch Melissa
Published: December 2020

A constitutional touchstone is a document that articulates alternative constitutional proposals and is a symbolic resource in discussions of constitutional reform. Such documents keep alive opposition constitutional aspirations. Constitutional touchstones enhance understanding of the influence of constitutional history on contemporary efforts at peace and constitutional reform. Through successive constitutional reform processes, constitutional touchstones articulate future visions for reform and emerge as a reference point for political dialogue on peace and constitutional change. Through the case of Myanmar, I consider the influence of constitutional touchstones on contemporary constitution-making and trace demands for federalism through four stages of peace processes in Myanmar. Constitutional touchstones are important considerations that shape the terms of a peace process and condition, though do not determine the limits of constitutional reform. Presenting an alternative view to the idea that constitution-makers and peace negotiators in a globalized age are primarily focused on best practice or the most suitable comparative models, I draw attention to the ongoing salience and social life of past constitutional debates in contemporary peace processes.
Pharmacological activation of soluble guanylate cyclase improves vascular graft function
Authors: Veres Gábor , Bai Yang , Stark Klára Aliz , Schmidt Harald , Radovits Tamás , Loganathan Sivakkanan , Korkmaz-Icöz Sevil , Szabó Gábor
Published: December 2020

OBJECTIVES

Ischaemia–reperfusion injury impairs the nitric oxide/soluble guanylate cyclase/cyclic guanosine monophosphate (cGMP) signalling pathway and leads to vascular dysfunction. We assessed the hypothesis that the soluble guanylate cyclase activator cinaciguat would protect the vascular graft against ischaemia–reperfusion injury.

METHODS

In the treatment groups, rats (n = 8/group) were pretreated with either intravenous saline or intravenous cinaciguat (10 mg/kg) 2 h before an aortic transplant. Aortic grafts were stored for 2 h in saline and transplanted into the abdominal aorta of the recipients. Two hours after the transplant, the grafts were harvested and mounted in an organ bath. Vascular function of the grafts was investigated in the organ bath. Terminal deoxynucleotidyl transferase dUTP nick end labelling, cluster of differentiation 31, caspase-3, endothelial nitric oxide synthase, cGMP, nitrotyrosine and vascular cell adhesion molecule 1 immunochemical reactions were also investigated.

RESULTS

Pretreatment with cinaciguat significantly improved endothelium-dependent maximal relaxation 2 h after reperfusion compared with the saline group (maximal relaxation control: 96.5 ± 1%, saline: 40.4 ± 3% vs cinaciguat: 54.7 ± 2%; P < 0.05). Pretreatment with cinaciguat significantly reduced DNA fragmentation and nitro-oxidative stress; decreased the caspase-3 and vascular cell adhesion molecule 1 scores; and increased endothelial nitric oxide synthase, cGMP and cluster of differentiation 31 scores.

CONCLUSIONS

Our results demonstrated that enhancement of cGMP signalling by pharmacological activation of the soluble guanylate cyclase activator cinaciguat might represent a beneficial therapy for treating endothelial dysfunction of arterial bypass graft during cardiac surgery.
Recovery of conduction disorders after sutureless aortic valve replacement
Authors: Lam Ka Yan , Timmermans Naomi , Akca Ferdi , Tan Erwin , Verberkmoes Niels J , de Kort Kim , Soliman-Hamad Mohamed , van Straten Albert H M
Published: December 2020

OBJECTIVES

Conduction disorders and the need for permanent pacemaker (PPM) implantation after surgical aortic valve replacement are well-recognized complications. However, in the case of sutureless valve prostheses, it remains unknown whether pacemaker (PM) dependency and conduction disturbances resolve over time. Our aim was to evaluate whether conduction disorders after Perceval sutureless valve implantation recover during follow-up.

METHODS

Patients undergoing isolated surgical aortic valve replacement or concomitant aortic valve replacement with coronary artery bypass surgery using the Perceval sutureless valve, between January 2010 and July 2018, were included. Postoperative electrocardiogram findings were analysed to determine the incidence of new-onset left bundle branch blocks (LBBBs) and the requirement for PPM implantation. During a postoperative period of 6–18 months, electrocardiogram findings during PM checks were analysed to determine PM dependency and LBBB persistence.

RESULTS

Out of 184 patients who received a Perceval prosthesis during the study period, 39 (21.2%) patients developed new-onset LBBB and 10 patients (5.4%) received a PPM postoperatively. The occurrence of conduction disorders was not associated with valve size. Follow-up was completed in 176 (95.7%) patients. In patients with a new-onset LBBB, 35.9% recovered during follow-up (P = 0.001). Seven out of 10 (70%) patients remained PM dependent.

CONCLUSIONS

After Perceval aortic valve implantation, new-onset LBBB recovers in more than one-third of patients during follow-up. In patients who needed a postoperative PPM, the majority remained PM dependent.
A bottom-up approach to creating an ontology for medication indications
Authors: Nelson Stuart J , Flynn Allen , Tuttle Mark S
Published: December 2020

Objectives

The study sought to learn if it were possible to develop an ontology that would allow the Food and Drug Administration approved indications to be expressed in a manner computable and comparable to what is expressed in an electronic health record.

Materials and Methods

A random sample of 1177 of the 3000+ extant, distinct medical products (identified by unique new drug application numbers) was selected for investigation. Close manual examination of the indication portion of the labels for these drugs led to the development of a formal model of indications.

Results

The model represents each narrative indication as a disjunct of conjuncts of assertions about an individual. A desirable attribute is that each assertion about an individual should be testable without reference to other contextual information about the situation. The logical primitives are chosen from 2 categories (context and conditions) and are linked to an enumeration of uses, such as prevention. We found that more than 99% of approved label indications for treatment or prevention could be so represented.

Discussion

While some indications are straightforward to represent, difficulties stem from the need to represent temporal or sequential references. In addition, there is a mismatch of terminologies between what is present in an electronic health record and in the label narrative.

Conclusions

A workable model for formalizing drug indications is possible. Remaining challenges include designing workflow to model narrative label indications for all approved drug products and incorporation of standard vocabularies.
Effect of storage of wet brewer’s grains with incremental levels of salt on apparent total tract nutrient digestibility and purine derivative excretion in dairy heifers
Authors: Hatungimana Eric , Stahl Tess C , Erickson Peter S
Published: December 2020

Objectives of this study were to evaluate apparent total tract nutrient digestibility and purine derivative (PD) excretion in dairy heifers limit-fed diets containing wet brewer’s grains (WBG) treated with salt. A 12-wk replicated 4 × 4 Latin square was conducted using 8 Holstein heifers of 224.5 ± 19.4 d of age, and body weight (BW) of 219.2 ± 28.1 kg (mean ± SD). Fresh WBG were treated with 0%, 0.8%, 1.6%, and 2.4% salt and stored for 4 d before being fed. Salt was added either to the WBG or separately to equalize the amount of salt in the diet. The diet contained 9% grass silage, 47% corn silage, 19% corn meal, 17.6% WBG and salt, 2% soybean meal, and 3% mineral mix. Diets were formulated to be limit-fed at 2.15% of BW, provide 14% crude protein (CP) and 2.27 Mcal metabolizable energy (ME)/kg of dry matter (DM). Heifers were adapted to diets for 14 d followed by a 7-d collection period. Dry matter intake (DMI) was recorded daily during the collection week while BW was recorded once a week. Urine and fecal samples were collected during the last 4 d of the collection period. Acid insoluble ash was used as an internal marker to determine apparent nutrient digestibility. Weight loss of WBG during storage was determined from days 1 to 11 and initial and final yeast and mold counts were determined. Final yeast counts were similar among treatments while final mold counts tended to be lesser (P = 0.07) for the 0.8% and 1.6% salt treatments. Urinary volume was similar among treatments while allantoin (P = 0.14), and uric acid (P < 0.01) and total PD excretion tended to increase (P = 0.13) quadratically. DMI was varied by treatment (linear, quadratic, and cubic effects P < 0.01). Heifers fed the 0.8% treatment had the least DMI. Nonfiber carbohydrate (NFC) digestibility linearly decreased (P < 0.04) as salt increased. Digestibilities of DM, and organic matter (OM), tended to decrease (P < 0.10) with increasing levels of salt added to WBG. Fat digestibility was quadratic with the greatest value for the 1.6% treatment. Treating WBG with salt reduced its deterioration based on lesser mold counts for the 0.8% and 1.6% treatments. These treatments had resulted in greater fat digestibility and tended to have increased PD excretion suggesting improved microbial protein synthesis.
An Assessment of Research Priorities to Dampen the Pendulum Swing of Burn Resuscitation
Authors: Burmeister David M , Smith Susan L , Muthumalaiappan Kuzhali , Hill David M , Moffatt Lauren T , Carlson Deborah L , Kubasiak John C , Chung Kevin K , Wade Charles E , Cancio Leopoldo C , Shupp Jeffrey W
Published: December 2020

On June 17 to 18, 2019, the American Burn Association, in conjunction with Underwriters Laboratories, convened a group of experts on burn resuscitation in Washington, DC. The goal of the meeting was to identify and discuss novel research and strategies to optimize the process of burn resuscitation. Patients who sustain a large thermal injury (involving >20% of the total body surface area [TBSA]) face a sequence of challenges, beginning with burn shock. Over the last century, research has helped elucidate much of the underlying pathophysiology of burn shock, which places multiple organ systems at risk of damage or dysfunction. These studies advanced the understanding of the need for fluids for resuscitation. The resultant practice of judicious and timely infusion of crystalloids has improved mortality after major thermal injury. However, much remains unclear about how to further improve and customize resuscitation practice to limit the morbidities associated with edema and volume overload. Herein, we review the history and pathophysiology of shock following thermal injury, and propose some of the priorities for resuscitation research. Recommendations include: studying the utility of alternative endpoints to resuscitation, reexamining plasma as a primary or adjunctive resuscitation fluid, and applying information about inflammation and endotheliopathy to target the underlying causes of burn shock. Undoubtedly, these future research efforts will require a concerted effort from the burn and research communities.
Dispersal patterns of a recovering brown bear (Ursus arctos) population in a human-dominated landscape
Authors: Karamanlidis Alexandros A , Kopatz Alexander , de Gabriel Hernando Miguel
Published: December 2020

Despite increasing habitat fragmentation, large carnivore populations in parts of Europe have been recovering and expanding into human-dominated areas. Knowledge of animal dispersal patterns in such areas is important for their conservation, management, and coexistence with humans. We used genetic data based on 15 microsatellite markers from 312 individuals (98 females, 214 males) to assess kinship and dispersal patterns during the recovery and spatial expansion of a wild brown bear (Ursus arctos) population (2003–2010) in the human-dominated landscape of Greece. We hypothesized that bear dispersal in Greece was sex-biased, with females being more philopatric and males dispersing more frequently and over greater distances. Dispersal indeed was sex-biased, with males dispersing more frequently and farther than females. Overall, females were found to be philopatric; males also appeared to be philopatric, but to a lesser degree. However, a high proportion of females displayed dispersal behavior, which may be indicative of a pre-saturation stage of the population in that part of the country. Our results indicate that dispersal may be due to evading competition and avoiding inbreeding. We also documented long-distance dispersal of bears, which is considered to be indicative of a spatially expanding population. Our results highlight the value of using noninvasive genetic monitoring data to assess kinship among individuals and study dispersal patterns in human-dominated landscapes. Brown bears remain threatened in Greece; we therefore recommend systematic genetic monitoring of the species in combination with careful habitat management to protect suitable habitat (i.e., dispersal corridors) and ultimately ensure co-existence with humans and survival of brown bears in the country.
Associations Between Amplification (1q) and Prior Cancer in a Real-World De Novo Myeloma Cohort
Authors: Lamont Elizabeth B , Yee Andrew J , Goldberg Stuart L , Siegel David S , Norden Andrew D
Published: December 2020

Genomic biomarkers inform treatment in multiple myeloma (MM), making patient clinical data a potential window into MM biology. We evaluated de novo MM patients for associations between specific MM cytogenetic patterns and prior cancer history. Analyzing a MM real-world dataset, we identified a cohort of 1769 patients with fluorescent in situ hybridization cytogenetic testing at diagnosis. Of the patients, 241 (0.14) had histories of prior cancer(s). Amplification of the long arm of chromosome 1 [amp(1q)] varied by prior cancer history (0.31 with prior cancer vs 0.24 without; 2-sided P = .02). No other MM translocations, amplifications, or deletions were associated with prior cancers. Amp(1q) and cancer history remained strongly associated in a logistic regression adjusting for patient demographic and disease attributes. The results merit follow-up regarding carcinogenic treatment effects and screening strategies for second malignancies. Broadly, the findings suggest that analyses of patient-level phenotypic-genomic real-world dataset may accelerate cancer research through hypothesis-generating studies.
Calcifying fibrous tumour—a rare cause of anaemia
Authors: Abd Kahar Nurul Nadhirah , Al-Mukhtar Ahmed
Published: December 2020

Calcifying fibrous tumour (CFT) is a rare benign tumour with non-specific anatomical distribution. We describe a case of a patient who presented with chronic generalised fatigue secondary to anaemia. Her symptoms did not improve while being on oral iron replacement therapy. Further endoscopic investigations were unremarkable. She had a computed tomography scan showing masses in the right pleural base and in the spleen. She then underwent splenic biopsy that only showed inflammatory changes. As her symptoms persisted, she was worked up for elective laparoscopic splenectomy during which she was found to have multiple peritoneal deposits. Biopsies were taken and the splenectomy was abandoned. The biopsies eventually showed changes consistent with CFT. This was conclusive for diagnosis of multifocal CFT.
Contested language in the making and unmaking of Western Sahara’s extractive economy
Authors: Irwin Randi L
Published: December 2020

This article considers the battle over resource extraction in the non-self-governing territory of Western Sahara. I analyse how the language of human rights has simultaneously been used by the Moroccan state to justify its extractive operations in the territory while Saharawi refugees use it to challenge these operations. Such competing invocations of human rights generate insight into how rights are made and re-made through configurations of populations, territory, markets, and regulations.
‘The Destiny of a Whole Race’: Identity, Race, and Politics in the Cold War Italian Performances of ‘Porgy and Bess’
Authors: Agugliaro Siel
Published: December 2020

In 1954–5, Porgy and Bess appeared for the first time in Italy in an all-Black production formally endorsed by the US State Department. Italian theatre administrators saw this production as an opportunity to sever any ideological connection with Fascism after decades of institutional support. At the same time, while Italian audiences and critics were often aware of the essentializing practices at the origins of Porgy and Bess, they relied on the stereotypical image of African American culture presented by the show to project their own experiences and political aspirations onto the opera’s subject and music. Drawing on primary sources, interviews, and the analysis of the earlier European reception of Porgy and Bess, this article argues that the success of the opera in Italy, rather than being determined by US diplomatic efforts, was a result of Italians’ need to redefine a sense of collective identity in a time of political transition.
Dose- and time-dependent tolerability and efficacy of organo-osmium complex FY26 and its tissue pharmacokinetics in hepatocarcinoma-bearing mice
Authors: Kumar Swati A , Needham Russell J , Abraham Kristin , Bridgewater Hannah E , Garbutt Lauren A , Xandri-Monje Helena , Dallmann Robert , Perrier Sebastien , Sadler Peter J , Lévi Francis
Published: December 2020

The organo-osmium complex [OsII(ɳ6-p-cym)(PhAzPy-NMe2)I]+ (FY26) exhibits promising in vitro antitumour activity against mouse hepatocarcinoma Hepa1–6 and other mouse or human cancer cell lines. Here, we drastically enhance water solubility of FY26 through the replacement of the PF6− counter-anion with chloride using a novel synthesis method. FY26⋅PF6 and FY26⋅Cl displayed similar in vitro cytotoxicity in two cancer cell models. We then show the moderate and late anticancer efficacy of FY26⋅PF6 and FY26⋅Cl in a subcutaneous murine hepatocarcinoma mouse model. Both efficacy and tolerability varied according to FY26 circadian dosing time in hepatocarcinoma tumour-bearing mice. Tumour and liver uptake of the drug were determined over 48 h following FY26⋅Cl administration at Zeitgeber time 6 (ZT6), when the drug is least toxic (in the middle of the light span when mice are resting). Our studies suggest the need to administer protracted low doses of FY26 at ZT6 in order to optimize its delivery schedule, for example through the use of chrono-releasing nanoparticles.
Distinguishing the effects of Ce nanoparticles from their dissolution products: identification of transcriptomic biomarkers that are specific for ionic Ce inChlamydomonas reinhardtii
Authors: Morel Elise , Dozois Jessica , Slaveykova Vera I , Wilkinson Kevin J
Published: December 2020

Cerium (Ce) is a rare earth element that is incorporated in numerous consumer products, either in its cationic form or as engineered nanoparticles (ENPs). Given the propensity of small oxide particles to dissolve, it is unclear whether biological responses induced by ENPs will be due to the nanoparticles themselves or rather due to their dissolution. This study provides the foundation for the development of transcriptomic biomarkers that are specific for ionic Ce in the freshwater alga, Chlamydomonas reinhardtii, exposed either to ionic Ce or to two different types of small Ce ENPs (uncoated, ∼10 nm, or citrate-coated, ∼4 nm). Quantitative reverse transcription PCR was used to analyse mRNA levels of four ionic Ce-specific genes (Cre17g.737300, MMP6, GTR12, and HSP22E) that were previously identified by whole transcriptome analysis in addition to two oxidative stress biomarkers (APX1 and GPX5). Expression was characterized for exposures to 0.03–3 µM Ce, for 60–360 min and for pH 5.0–8.0. Near-linear concentration–response curves were obtained for the ionic Ce and as a function of exposure time. Some variability in the transcriptomic response was observed as a function of pH, which was attributed to the formation of metastable Ce species in solution. Oxidative stress biomarkers analysed at transcriptomic and cellular levels confirmed that different effects were induced for dissolved Ce in comparison to Ce ENPs. The measured expression levels confirmed that changes in Ce speciation and the dissolution of Ce ENPs greatly influence Ce bioavailability.
AUF1 ligand circPCNX reduces cell proliferation by competing with p21 mRNA to increase p21 production
Authors: Tsitsipatis Dimitrios , Grammatikakis Ioannis , Driscoll Riley K , Yang Xiaoling , Abdelmohsen Kotb , Harris Sophia C , Yang Jen-Hao , Herman Allison B , Chang Ming-Wen , Munk Rachel , Martindale Jennifer L , Mazan-Mamczarz Krystyna , De Supriyo , Lal Ashish , Gorospe Myriam
Published: December 2020

Mammalian circRNAs can influence different cellular processes by interacting with proteins and other nucleic acids. Here, we used ribonucleoprotein immunoprecipitation (RIP) analysis to identify systematically the circRNAs associated with the cancer-related protein AUF1. Among the circRNAs interacting with AUF1 in HeLa (human cervical carcinoma) cells, we focused on hsa_circ_0032434 (circPCNX), an abundant target of AUF1. Overexpression of circPCNX specifically interfered with the binding of AUF1 to p21 (CDKN1A) mRNA, thereby promoting p21 mRNA stability and elevating the production of p21, a major inhibitor of cell proliferation. Conversely, silencing circPCNX increased AUF1 binding to p21 mRNA, reducing p21 production and promoting cell division. Importantly, eliminating the AUF1-binding region of circPCNX abrogated the rise in p21 levels and rescued proliferation. Therefore, we propose that the interaction of circPCNX with AUF1 selectively prevents AUF1 binding to p21 mRNA, leading to enhanced p21 mRNA stability and p21 protein production, thereby suppressing cell growth.
Local and systemic therapy of recurrent ependymoma in children and adolescents: short- and long-term results of the E-HIT-REZ 2005 study
Authors: Adolph Jonas E , Fleischhack Gudrun , Mikasch Ruth , Zeller Julia , Warmuth-Metz Monika , Bison Brigitte , Mynarek Martin , Rutkowski Stefan , Schüller Ulrich , von Hoff Katja , Obrecht Denise , Pietsch Torsten , Pfister Stefan M , Pajtler Kristian W , Witt Olaf , Witt Hendrik , Kortmann Rolf-Dieter , Timmermann Beate , Krauß Jürgen , Frühwald Michael C , Faldum Andreas , Kwiecien Robert , Bode Udo , Tippelt Stephan
Published: December 2020

Background

Survival in recurrent ependymomas in children and adolescents mainly depends on the extent of resection. Studies on repeated radiotherapy and chemotherapy at relapse have shown conflicting results.

Methods

Using data from the German multi-center E-HIT-REZ-2005 study, we examined the role of local therapy and the efficacy of chemotherapy with blockwise temozolomide (TMZ) in children and adolescents with recurrent ependymomas.

Results

Fifty-three patients with a median age of 6.9 years (1.25–25.4) at first recurrence and a median follow-up time of 36 months (2–115) were recruited. Gross- and near-total resection (GTR/NTR) were achieved in 34 (64.2%) patients and associated with a markedly improved 5-year overall survival (OS) of 48.7% vs. 5.3% in less than GTR/NTR. Radiotherapy showed no improvement in OS following complete resection (OS: 70 (CI: 19.9–120.1) vs. 95 (CI: 20.7–169.4) months), but an advantage was found in less than GTR/NTR (OS: 22 (CI: 12.7–31.3) vs. 7 (CI: 0–15.8) months). Following the application of TMZ, disease progression was observed in most evaluable cases (18/21). A subsequent change to oral etoposide and trofosfamide showed no improved response. PF-A EPN were most abundant in relapses (n = 27). RELA-positive EPN (n = 5) had a 5-year OS of 0%.

Conclusion

The extent of resection is the most important predictor of survival at relapse. Focal re-irradiation is a useful approach if complete resection cannot be achieved, but no additional benefit was seen after GTR/NTR. Longer-term disease stabilization (>6 months) mediated by TMZ occurred in a small number of cases (14.3%).
Rolling-translated EGFR variants sustain EGFR signaling and promote glioblastoma tumorigenicity
Authors: Liu Yi , Li Zhongjun , Zhang Maolei , Zhou Huangkai , Wu Xujia , Zhong Jian , Xiao Feizhe , Huang Nunu , Yang Xuesong , Zeng Rong , Yang Lixuan , Xia Zhibo , Zhang Nu
Published: December 2020

Background

Aberrant epidermal growth factor receptor (EGFR) activation is observed in over 50% of cases of adult glioblastoma (GBM). Nevertheless, EGFR antibodies are ineffective in clinical GBM treatment, suggesting the existence of redundant EGFR activation mechanisms. Whether circular RNA (circRNA) encodes a protein involved in EGFR-driven GBM remains unclear. We reported an unexpected mechanism in which circular EGFR RNA (circ-EGFR) encodes a novel EGFR variant to sustained EGFR activation.

Method

We used RNA-seq, Northern blot, and Sanger sequencing to confirm the existence of circ-EGFR. Antibodies and a liquid chromatograph tandem mass spectrometer were used to identify circ-EGFR protein products. Lentivirus-transfected stable cell lines were used to assess the biological functions of the novel protein in vitro and in vivo. Clinical implications of circ-EGFR were assessed using 97 pathologically diagnosed GBM patient samples.

Results

The infinite open reading frame (iORF) in circ-EGFR translated repeating amino acid sequences via rolling translation and programmed −1 ribosomal frameshifting (-1PRF) induced out-of-frame stop codon (OSC), forming a polymetric novel protein-complex, which we termed rolling-translated EGFR (rtEGFR). rtEGFR directly interacted with EGFR, maintained EGFR membrane localization and attenuated EGFR endocytosis and degradation. Importantly, circ-EGFR levels correlated with the EGFR signature and predicted the poor prognosis of GBM patients. Deprivation of rtEGFR in brain tumor-initiating cells (BTICs) attenuated tumorigenicity and enhanced the anti-GBM effect.

Conclusion

Our findings identified the endogenous rolling-translated protein and provided strong clinical evidence that targeting rtEGFR could improve the efficiency of EGFR-targeting therapies in GBM.
Extracting Money from Causal Decision Theorists
Authors: Oesterheld Caspar , Conitzer Vincent
Published: December 2020

Newcomb’s problem has spawned a debate about which variant of expected utility maximisation (if any) should guide rational choice. In this paper, we provide a new argument against what is probably the most popular variant: causal decision theory (CDT). In particular, we provide two scenarios in which CDT voluntarily loses money. In the first, an agent faces a single choice and following CDT’s recommendation yields a loss of money in expectation. The second scenario extends the first to a diachronic Dutch book against CDT.
The effect of LyPRP/collagen composite hydrogel on osteogenic differentiation of rBMSCs
Authors: Chen Manyu , Liu Quanying , Xu Yang , Wang Yuxiang , Han Xiaowen , Wang Zhe , Liang Jie , Sun Yong , Fan Yujiang , Zhang Xingdong
Published: December 2020

Although platelet-rich plasma (PRP) plays a significant role in the orthopedic clinical application, it still faces two major problems, namely, uncontrollable factors release, frequent preparation and extraction processes as well as the inconvenient form of usage. To overcome these shortcomings, freeze-dried PRP (LyPRP) was encapsulated into bioactive Col I hydrogel to induce osteogenic differentiation of rabbit bone marrow mesenchymal stem cells (rBMSCs). And PRP/Col І composite hydrogel was prepared as a control. Compared with Col І hydrogel, the introduction of platelets significantly improved the mechanical properties of hydrogels. Meanwhile, platelets were evenly distributed in the composite hydrogels network. The sustainable release of related factors in the composite hydrogels could last for more than 14 days to maintain its long-term biological activity. Further cell experiments confirmed that PRP and LyPRP could effectively alleviate the contraction of collagen hydrogel in vitro, and promote the adhesion, proliferation and osteogenesis differentiation of rBMSCs. The results of osteogenic gene expression indicated that the 10% LyPRP/Col І composite hydrogel could facilitate the early expression of BMP-2 and late osteogenic associated protein formation with higher expression of alkaline phosphatase and Osteocalcin (OCN). These results might provide new insights for the clinical application of 10% LyPRP/Col І composite hydrogel as practical bone repair injection.
Effects of multilevel policy mix of public R&D subsidies: Empirical evidence from Japanese local SMEs
Authors: Okamuro Hiroyuki , Nishimura Junichi
Published: December 2020

Regional innovation policies have been implemented in several countries. In Japan, controlled decentralization of traditionally centralized innovation policy is ongoing, so that we can observe multilevel policy mix of public R&D (research and development) subsidies by national, prefecture, and city governments. However, empirical studies on multilevel R&D support using panel data and considering municipality level have been scarce. Based on original survey data and financial data of manufacturing small and medium enterprises (SMEs), we estimate their total factor productivity (TFP) and empirically investigate the effects of public R&D subsidies by national, prefecture, and city governments. We employ firm-level fixed-effect panel estimation in order to control for the effects of any unobservable time-invariant factors. We find that multilevel subsidies (especially those involving city subsidies) complementarily and persistently increase recipients’ TFP. These results suggest significant advantages of multilevel policy mix, especially those involving city subsidies.
Effect of the new dual orexin receptor antagonist daridorexant on nighttime respiratory function and sleep in patients with mild and moderate obstructive sleep apnea
Authors: Boof Marie-Laure , Dingemanse Jasper , Lederer Katharina , Fietze Ingo , Ufer Mike
Published: December 2020

In this randomized, double-blind, placebo-controlled, two-period crossover study, the effect of the dual orexin receptor antagonist daridorexant was evaluated on nighttime respiratory function and sleep in 28 patients with mild and moderate obstructive sleep apnea (OSA). In each period, 50 mg daridorexant or placebo was administered every evening for 5 days. The primary endpoint was apnea/hypopnea index (AHI) during total sleep time (TST) after the last dosing. Other endpoints included peripheral oxygen saturation (SpO2), sleep duration, latency to persistent sleep (LPS), wake after sleep onset (WASO), and sleep efficiency index (SEI). Pharmacokinetics, safety, and tolerability were also assessed. The mean treatment difference for AHI during TST (i.e. daridorexant − placebo) after the last dosing was 0.74 events/hour (90% confidence interval [CI]: –1.43, 2.92). The corresponding treatment difference for SpO2 during TST was 0.16% [90% CI: –0.21, 0.53]. Overall, there was no clinically relevant effect of daridorexant on AHI or SpO2-related data after single and repeated dosing irrespective of sleep phase (i.e. rapid eye movement [REM] vs non-REM). Moreover, after single and repeated dosing, daridorexant prolonged TST by 39.6 minutes (90% CI: 16.9, 62.3) and 38.8 minutes (19.7, 57.9), respectively, compared with placebo and favorably modulated other sleep-related endpoints (i.e. increased SEI, decreased WASO, and shortened LPS). It attained expected plasma concentrations and was well tolerated in patients with mild and moderate OSA.

These results indicate that single and repeated doses of 50 mg daridorexant do not impair nighttime respiratory function and improve sleep in patients with mild and moderate OSA.

Clinical Trial Registration: ClinicalTrials.gov NCT03765294. A study to investigate the effects of ACT-541468 on nighttime respiratory function in patients with mild to moderate obstructive sleep apnea. https://clinicaltrials.gov/ct2/show/ NCT03765294.
Memory performance following napping in habitual and non-habitual nappers
Authors: Leong Ruth L F , Yu Nicole , Ong Ju Lynn , Ng Alyssa S C , Jamaluddin S Azrin , Cousins James N , Chee Nicholas I Y N , Chee Michael W L
Published: December 2020

Study Objectives

Afternoon naps benefit memory but this may depend on whether one is a habitual napper (HN; ≥1 nap/week) or non-habitual napper (NN). Here, we investigated whether a nap would benefit HN and NN differently, as well as whether HN would be more adversely affected by nap restriction compared to NN.

Methods

Forty-six participants in the nap condition (HN-nap: n = 25, NN-nap: n = 21) took a 90-min nap (14:00–15:30 pm) on experimental days while 46 participants in the Wake condition (HN-wake: n = 24, NN-wake: n = 22) remained awake in the afternoon. Memory tasks were administered after the nap to assess short-term topographical memory and long-term memory in the form of picture encoding and factual knowledge learning respectively.

Results

An afternoon nap boosted picture encoding and factual knowledge learning irrespective of whether one habitually napped (main effects of condition (nap/wake): ps < 0.037). However, we found a significant interaction for the hippocampal-dependent topographical memory task (p = 0.039) wherein a nap, relative to wake, benefitted habitual nappers (HN-nap vs HN-wake: p = 0.003) compared to non-habitual nappers (NN-nap vs. NN-wake: p = 0.918). Notably for this task, habitual nappers’ performance significantly declined if they were not allowed to nap (HN-wake vs NN-wake: p = 0.037).

Conclusions

Contrary to concerns that napping may be disadvantageous for non-habitual nappers, we found that an afternoon nap was beneficial for long-term memory tasks even if one did not habitually nap. Naps were especially beneficial for habitual nappers performing a short-term topographical memory task, as it restored the decline that would otherwise have been incurred without a nap.

Clinical Trial Information

NCT04044885.
Role of Respiratory Buffering in the Relationship Between Recovery and Performance Fatigability After Aerobic Exercise Training
Authors: Wooten Liana C. , Neville Brian T. , Guccione Andrew A. , Chin Lisa M.K. , Keyser Randall E.
Published: December 2020

Purpose:

This study characterized the influence of excess expired carbon dioxide (excess V̇co
2) in the relationship between recovery and fatigability.

Methods:

Twenty healthy adults completed peak cardiopulmonary exercise tests (CPXs) and constant work rate tests before and after a vigorous, 4-week aerobic exercise training (AET) regimen. Each test was followed by 10 minutes of recovery and an endurance test at 70% of peak watts attained during CPX. Fatigability was assessed by measures of time to exhaustion and power output. Metabolic and recovery capacity indices were obtained. Data were analyzed using correlations and regressions and compared pre/post AET using paired t tests.

Results:

Significant improvements in recovery and fatigability were observed after AET, along with significant increases in total and excess V̇co
2. Relationships between measures of recovery and fatigability were observed, although strengths of the relationships were diminished after controlling analyses for the effect of excess V̇co
2.

Conclusions:

This study suggests that the ionic buffering capacity may moderate the relationship between recovery and fatigability. These results could have implications regarding AET-induced buffering dynamics, and its role in fatigue resistance when performing activities above moderate intensities. This may be of particular importance in patients with cardiopulmonary complications, unable to improve peak aerobic capacity.
A feature-based network analysis and fMRI meta-analysis reveal three distinct types of prosocial decisions
Authors: Rhoads Shawn A. , Cutler Jo , Marsh Abigail A.
Published: December 2020

Tasks that measure correlates of prosocial decision-making share one common feature: agents can make choices that increase the welfare of a beneficiary. However, prosocial decisions vary widely as a function of other task features. The diverse ways that prosociality is defined and the heterogeneity of prosocial decisions have created challenges for interpreting findings across studies and identifying their neural correlates. To overcome these challenges, we aimed to organize the prosocial decision-making task-space of neuroimaging studies. We conducted a systematic search for studies in which participants made decisions to increase the welfare of others during fMRI. We identified shared and distinct features of these tasks and employed an unsupervised graph-based approach to assess how various forms of prosocial decision-making are related in terms of their low-level components (e.g., task features like potential cost to the agent or potential for reciprocity). Analyses uncovered three clusters of prosocial decisions, which we labeled cooperation, equity, and altruism. This feature-based representation of the task structure was supported by results of a neuroimaging meta-analysis that each type of prosocial decisions recruited diverging neural systems. Results clarify some of the existing heterogeneity in how prosociality is conceptualized and generate insight for future research and task paradigm development.
Regional structural-functional connectome coupling is heritable and associated with age, sex and cognitive scores in adults
Authors: Gu Zijin , Jamison Keith Wakefield , Sabuncu Mert Rory , Kuceyeski Amy
Published: December 2020

Large scale white matter brain connections quantified via the structural connectome (SC) act as the backbone for the flow of functional activation, which can be represented via the functional connectome (FC). Many studies have used statistical analysis or computational modeling techniques to relate SC and FC at a global, whole-brain level. However, relatively few studies have investigated the relationship between individual cortical and subcortical regions’ structural and functional connectivity profiles, here called SC-FC coupling, or how this SC-FC coupling may be heritable or related to age, sex and cognitive abilities. Here, we quantify regional SC-FC coupling in a large group of healthy young adults (22 to 37 years) using diffusion-weighted MRI and resting-state functional MRI data from the Human Connectome Project. We find that while regional SC-FC coupling strengths vary widely across cortical, subcortical and cerebellar regions, they were strongest in highly structurally connected visual and subcortical areas. Additionally, depending on the region, SC-FC coupling varied across sexes and with age and composite cognitive scores. Specifically, SC-FC coupling in the cerebellum tended to decrease with age while coupling in medial fronto-orbital areas tended to increase with age. Males had stronger coupling in many regions, particularly in the right orbito-frontal region and areas in the ventral attention and default mode networks, while females had higher coupling strength in right hippocampus. Furthermore, increased SC-FC coupling in the right insula and decreased coupling in bilateral middle cingulate and supplementary motor areas was associated with higher composite cognitive scores. Finally, we found SC-FC coupling to be highly heritable, particularly in higher order default mode, dorsal/ventral attention and fronto-parietal networks. Taken together, these results suggest regional structure-function coupling in young adults varies with age, is generally stronger in males, is associated with composite cognitive scores and is highly heritable.
Osteoclasts contribute to early development of chronic inflammation by promoting dysregulated hematopoiesis and myeloid skewing
Authors: Madel Maria-Bernadette , Ibáñez Lidia , Ciucci Thomas , Halper Julia , Topi Majlinda , Garchon Henri-Jean , Rouleau Matthieu , Mueller Christopher G , Peyrin-Biroulet Laurent , Moulin David , Blin-Wakkach Claudine , Wakkach Abdelilah
Published: December 2020

Increased myelopoiesis is a hallmark of many chronic inflammatory diseases. However, the mechanisms involved in the myeloid skewing of hematopoiesis upon inflammation are still incompletely understood. Here, we identify an unexpected role of bone-resorbing osteoclasts in promoting hematopoietic stem cell (HSC) proliferation and differentiation towards myeloipoiesis in the early phases of chronic colitis. RNAseq analysis revealed that osteoclasts in colitis differ from control ones and overexpress genes involved in the remodeling of HSC niches. We showed that colitic osteoclasts modulate the interaction of HSCs with their niche and promote myeloid differentiation. Increased osteoclast activity was correlated with an augmentation of myelopoiesis in patients with chronic colitis. Therapeutic blockade of osteoclasts reduced HSC proliferation and myeloid skewing and resulted in a decreased inflammation and severity of colitis. Together, these data identify osteoclasts as potent regulators of HSCs and promising target in chronic colitis.
Extracellular Vesicles Analysis in the COVID-19 Era: Insights on Serum Inactivation Protocols Towards Downstream Isolation and Analysis
Authors: Frigerio Roberto , Musicò Angelo , Brucale Marco , Ridolfi Andrea , Galbiati Silvia , Vago Riccardo , Bergamaschi Greta , Ferretti Anna , Chiari Marcella , Valle Francesco , Gori Alessandro , Cretich Marina
Published: December 2020

Since the outbreak of COVID-19 crisis, the handling of biological samples from confirmed or suspected SARS-CoV-2 positive individuals demanded the use of inactivation protocols to ensure laboratory operators safety. While not standardized, these practices can be roughly divided in two categories, namely heat inactivation and solvent-detergent treatments. As such, these routine procedures should also apply to samples intended for Extracellular Vesicles (EVs) analysis. Assessing the impact of virus inactivating pre-treatments is therefore of pivotal importance, given the well-known variability introduced by different pre-analytical steps on downstream EVs isolation and analysis. Arguably, shared guidelines on inactivation protocols tailored to best address EVs-specific requirements will be needed among the EVs community, yet deep investigations in this direction haven’t been reported so far.

In the attempt of sparking interest on this highly relevant topic, we here provide preliminary insights on SARS-CoV-2 inactivation practices to be adopted prior serum EVs analysis by comparing solvent/detergent treatment vs. heat inactivation. Our analysis entailed the evaluation of EVs recovery and purity along with biochemical, biophysical and biomolecular profiling by means of Nanoparticle Tracking Analysis, Western Blotting, Atomic Force Microscopy, miRNA content (digital droplet PCR) and tetraspanin assessment by microarrays. Our data suggest an increase in ultracentrifugation (UC) recovery following heat-treatment, however accompanied by a marked enrichment in EVs-associated contaminants. On the contrary, solvent/detergent treatment is promising for small EVs (< 150 nm range), yet a depletion of larger vesicular entities was detected. This work represents a first step towards the identification of optimal serum inactivation protocols targeted to EVs analysis.
Effectors with different gears: divergence ofUstilago maydiseffector genes is associated with their temporal expression pattern during plant infection
Authors: Depotter Jasper R.L. , Zuo Weiliang , Hansen Maike , Zhang Boqi , Xu Mingliang , Doehlemann Gunther
Published: December 2020

Plant pathogens secrete a variety of effector proteins that enable host colonization but are also typical pathogen detection targets for the host immune system. Consequently, effector genes encounter high selection pressures, which typically makes them fast evolving. The corn smut pathogenUstilago maydishas an effector gene repertoire with a dynamic expression across the different disease stages. We determined the amino acid divergence ofU. maydiseffector candidates withSporisorium reilianumorthologs, a close relative ofU. maydis. Intriguingly, there are two distinct groups of effector candidates, ones with a respective conserved and diverged protein evolution. Conservatively evolving effector genes especially have their peak expression during the (pre-)penetration stages of the disease cycle. In contrast, expression of divergently evolving effector genes generally peaks during fungal proliferation within the host. To test if this interspecific effector diversity corresponds to intraspecific diversity, we sampled and sequenced a diverse collection ofU. maydisstrains from the most important maize breeding and production regions in China. Effector candidates with a diverged interspecific evolution had more intraspecific amino acid variation than candidates with a conserved evolution. In conclusion, we highlight diversity in evolution within theU. maydiseffector repertoire with dynamically and conservatively evolving members.
Efficacy and accuracy responses of DNA mini-barcodes in species identification under a supervised machine learning approach
Authors: Karim Mohimenul , Abid Rashid
Published: December 2020

Specific gene regions in DNA, such as cytochrome c oxidase I (COI) in animals, are defined as DNA barcodes and can be used as identifiers to distinguish species. The standard length of a DNA barcode is approximately 650 base pairs (bp). However, because of the challenges associated with sequencing technologies and the unavailability of high-quality genomic DNA, it is not always possible to obtain the full-length barcode sequence of an organism. Recent studies suggest that mini-barcodes, which are shorter (100-300 bp) barcode sequences, can contribute significantly to species identification. Among various methods proposed for the identification task, supervised machine learning methods are effective. However, any prior work indicating the efficacy of mini-barcodes in species identification under a machine learning approach is elusive to find. In this study, we analyzed the effect of different barcode lengths on species identification using supervised machine learning and proposed a general approximation of the required length of the minibarcode. Since Naïve Bayes is seen to generally outperform other supervised methods in species identification in other studies, we implemented this classifier and showed the effectiveness of the mini-barcode by demonstrating the accuracy responses obtained after varying the length of the DNA barcode sequences.