bluuebunny/crossref_metadata_2025 huggingface dataset:
Becoming Beethoven: Theorizing Bonner Zeit Transitions
Authors: Everett Walter
Published: July 2020

Beethoven wrote about thirty sonata movements before leaving Bonn. Often disparaged as awkward (when not neglected entirely), these pieces deserve rehabilitation for the insights they can bring to the composer's masterworks. Influenced by local Rhenish models—Christian Gottlob
Neefe, Andrea Luchesi, and Johann Franz Xaver Sterkel, the Bonner Zeit music imbues a galant style with Empfindsam colorings, producing an idiosyncratic approach to transitions and genre blending—particularly involving cue play surrounding multiple medial caesuras, elisions,
phrase expansions, and undermined secondary themes—that responds immediately to Janet Schmalfeldt's perspective on the process of becoming as well as a mix of ideas from Heinrich Schenker, William Caplin, and the work of James Hepokoski and Warren Darcy, all applied here. Three of Beethoven's
Bonn sonatas, as well as several works by Rhineland contemporaries, are given close study for their transition-related harmony, voice leading, phrase rhythm, topics, and formal implications.
Paolucci Reading Caldara and Handel: Music Analysis in Eighteenth-Century Italy
Authors: Diergarten Felix
Published: July 2020

Giuseppe Paolucci's Arte pratica di contrappunto (1765–72) is a collection of analyses of forty-two compositions from the sixteenth to the eighteenth century. It offers insights into eighteenth-century practices of music analysis as well as into historical concepts of counterpoint
and fugue. Two analytical readings by Paolucci are translated and commented upon in this essay. Paolucci's analysis of Antonio Caldara's motet Peccavi super numerum is valuable for its references to rhetoric and the visual arts. The analysis of Handel's fugue "Then shall I teach thy
ways" (from the Chandos Anthem HWV 248) exemplifies the high esteem in which contemporary writers and composers held Handel's compositional techniques, which Paolucci describes meticulously, bar by bar. Paolucci's reading of Handel's fugue, which is similar to Italian partimento fugues of
that time, also provides material for the still-unwritten history of eighteenth-century Italian fugal theory.
Social Andragogue as a Helping Profession in the System of Residential Care for Seniors
Authors: Határ Ctibor
Published: July 2020

This study is of theoretical and conceptual nature and represents the author’s direct output of the project VEGA SAS-ME SR no. 1/0024/12 titled Evaluation of the Impact of Education on Quality of Life of Seniors in Residential Conditions. The aim of the study is to scientifically justify the need for engagement of social andragogues, or andragogues with extended socio-andragogical qualifications in social facilities for seniors and the need to establish a professiogram and a professional competency profile of a social andragogue for the specific target groups of the facilitie.
“Hands-On, Minds-On, and Science-Up”: A Concept-Based Learning Laboratory With a Taste of Research Experience for an Undergraduate Biomedical Engineering Course
Authors: Sigaeva Taisiya , Fiori Cyrus J. B. M. , Pino Alban Maria J. , Beauferris Youssef , Stagg Donovan , Di Martino Elena S.
Published: July 2020

In this paper, we bridged faculty research expertise with concept-based learning pedagogy to design and implement a unique laboratory experience for biomedical engineering undergraduate students enrolled in the biomechanics of tissues course at the University of Calgary. This laboratory aimed to increase student engagement, facilitate deeper understanding of course content, and provide an opportunity for accelerated undergraduate research through “hands-on,” “minds-on,” and “science-up” learning components, respectively. The laboratory exercise involves testing aortic tissues using a novel miniaturized planar biaxial machine. This type of machine is normally reserved for use in the context of research. The relevance of the proposed laboratory as a teaching tool was assessed using student feedback. Results indicate an overall valuable and positive learning experience for students.
Youth Sport Organizational Structure and Athlete Development
Authors: Armentrout Suzannah Mork , Dutove Julia
Published: July 2020

Chris Johansen is on the board for the Rockton Yuba Hockey Association, a robust and growing youth hockey association near St. Paul, MN. Parents in the association have brought to his attention a couple issues with the structural organization. Specifically, (1) some think athletes are limited in their opportunity to develop to their fullest potential because of the current structure of the association, and (2) others feel that if the youth hockey association was organized differently this would facilitate retention of players through high school. Chris has been charged by the president of the association to learn more about potential organizational changes and how these changes could impact the players and organization. Based on this information, the advisory committee has been asked to submit a recommendation to the board regarding potential organizational changes. The Integrative Model for Organizational Theory will be used to gain a better understanding of the organizational change process.
Acute Effect of Exercise on Cognitive Performance in Middle-Aged Adults: Aerobic Versus Balance
Authors: Formenti Damiano , Cavaggioni Luca , Duca Marco , Trecroci Athos , Rapelli Mattia , Alberti Giampietro , Komar John , Iodice Pierpaolo
Published: July 2020

Background: Recent evidence has suggested that chronic physical activities including balance exercises have positive effects on cognition, but their acute effects are still unknown. In the present study, the authors tested the hypothesis that an acute bout of balance exercise would enhance cognitive performance compared with aerobic activity.Methods: A total of 20 healthy middle-aged adults completed 2 acute 30-minute balance and moderate-intensity aerobic exercise sessions on 2 counterbalanced separate occasions. To assess cognitive functions, performance tasks in executive control, perceptual speed, and simple reaction time were tested before and immediately after each exercise session.Results: Although there were no significant interactions (time × exercise condition,P > .05), the main effects of time were significant in executive control (P < .05), perceptual speed (P < .05), and simple reaction time (P < .001), showing improvements after both exercises.Conclusions: These findings highlight that both types of exercise (aerobic, more metabolic and less cognitively demanding; balance, more cognitively and less metabolically demanding) were able to positively affect simple reaction time performance, perceptual speed, and executive control independently of physiological adjustments occurring during aerobic or balance exercise.
Move to Read Pilot Program for Academically Struggling Students to Improve Sight Word Performance
Authors: Chen Weiyun , Bowers Cynthia , Hodges Kulinna Pamela
Published: July 2020

Purpose: To present a pilot study that uses experiential learning theory to understand the effect of a Move to Read (MTR) program on student performance on a sight word test. Methods: Two groups in a school were compared. The academic struggling students (n = 37) received MTR activities in the classroom and physical education, whereas the regular academic achieving group (n = 28) only had the MTR activities in physical education during the eight and a half months’ pilot study. Students were tested using the Dolch Sight Word test. Results: Analysis of covariance showed no group differences. Repeated-measures analysis of variance showed significant increases in the sight word test for the academically struggling group over time (F2 = 152.276, p < .001, ). Conclusions: The MTR program shows promise for improving sight word performance using movement.
OnfD, an AraC-Type Transcriptional Regulator Encoded by
Rhizobium tropici
CIAT 899 and Involved in Nod Factor Synthesis and Symbiosis
Authors: del Cerro Pablo , Ayala-García Paula , Buzón Pablo , Castells-Graells Roger , López-Baena Francisco Javier , Ollero Francisco Javier , Pérez-Montaño Francisco
Published: July 2020

The synthesis and export of rhizobial NF are mediated by a conserved group of LysR-type regulators, the NodD proteins. Here, we have demonstrated that a non-LysR-type regulator, an AraC-type protein, is required for the transcriptional activation of symbiotic genes and for the synthesis of symbiotically active NF under salt stress conditions.
Type I and Type III Interferons Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures
Authors: Vanderheiden Abigail , Ralfs Philipp , Chirkova Tatiana , Upadhyay Amit A. , Zimmerman Matthew G. , Bedoya Shamika , Aoued Hadj , Tharp Gregory M. , Pellegrini Kathryn L. , Manfredi Candela , Sorscher Eric , Mainou Bernardo , Lobby Jenna L. , Kohlmeier Jacob E. , Lowen Anice C. , Shi Pei-Yong , Menachery Vineet D. , Anderson Larry J. , Grakoui Arash , Bosinger Steven E. , Suthar Mehul S.
Published: July 2020

The current pandemic of respiratory illness, COVID-19, is caused by a recently emerged coronavirus named SARS-CoV-2. This virus infects airway and lung cells causing fever, dry cough, and shortness of breath. Severe cases of COVID-19 can result in lung damage, low blood oxygen levels, and even death. As there are currently no vaccines approved for use in humans, studies of the mechanisms of SARS-CoV-2 infection are urgently needed. Our research identifies an excellent system to model SARS-CoV-2 infection of the human airways that can be used to test various treatments. Analysis of infection in this model system found that human airway epithelial cell cultures induce a strong proinflammatory cytokine response yet block the production of type I and III IFNs to SARS-CoV-2. However, treatment of airway cultures with the immune molecules type I or type III interferon (IFN) was able to inhibit SARS-CoV-2 infection. Thus, our model system identified type I or type III IFN as potential antiviral treatments for COVID-19 patients.
Ectopic lacrimal gland in the lacrimal sac mimicking tumour: literature review
Authors: Saratziotis Athanasios , Zanotti Claudia , Baldovin Maria , Emanuelli Enzo
Published: July 2020

An 80-year-old man referred with repeated episode of dacryocystitis from the left lacrimal drainage system and palpable swelling. For many years, he has being presented with epiphora unilaterally with chronic dacryocystitis. Investigations with dye-test revealed subocclusion of the natural passage of the tears, and CT and MRI scans revealed solid mass in the lacrimal sac. The lacrimal sac was opened by endonasal endoscopic approach, the sacral mass was identified and completely removed. The histopathological examination showed lacrimal gland in ectopic position. Patient followed for 18 months with complete recovery of symptoms. In our differential diagnosis, the ectopic lacrimal gland is also identified, when a mass in the lacrimal sac and duct is present. Successful surgical excision required considerable multidisciplinary teamwork between ophtalmologist–ENT (Otolaryngologist) and radiologist. Endonasal endoscopic approach is perfectly safe with direct control and ensures a smooth postoperative recovery.
Using structural equation modelling to characterise multilevel socioecological predictors and mediators of condom use among transgender women and cisgender men who have sex with men in the Philippines
Authors: Restar Arjee , Ogunbajo Adedotun , Adia Alexander , Nazareno Jennifer , Hernandez Laufred , Sandfort Theo , Lurie Mark , Cu-Uvin Susan , Operario Don
Published: July 2020

Background

Risks for condomless sex among transgender women and cisgender men who have sex with men (trans-WSM and cis-MSM, respectively) in the Philippines, where HIV recently became a national public health crisis, are shaped and exacerbated by various risk factors across multiple levels.

Methods

Between June 2018 and August 2019, we conducted a cross-sectional online study with 318 trans-WSM and cis-MSM respondents from Manila and Cebu cities. Structural equational modelling procedures were performed to determine direct, indirect and overall effects between condom use and latent variables across multiple socioecological levels: personal (ie, condom self-efficacy), social (ie, social capital), environmental (ie, barriers to condom and HIV services) and structural (ie, structural violence, antidiscrimination policies).

Results

Adjusted for gender, age, location and income, our model showed that: (1) all latent variables at the structural and environmental levels were significantly positively associated with each other (all ps<0.05); (2) barriers to condom and HIV services were significantly negatively associated with social capital (p<0.001) as well as condom self-efficacy (p<0.001); and (3) there were significantly positive associations between social capital and condom self-efficacy (p<0.001), and between condom self-efficacy and condom use (p<0.001). Moreover, social capital and condom self-efficacy fully mediated and buffered the negative effects between environmental and structural barriers and condom use.

Conclusion

This is the first known study pointing to multiple relationships and pathways across multiple socioecological levels that can potentially be leveraged for future interventions aimed at improving condom use among Filipinx trans-WSM and cis-MSM. Such interventions should be multicomponent and build and/or strengthen social capital and condom self-efficacy, as well as intentionally target prominent structural and environmental barriers to condom use.
Practical lessons for phone-based assessments of learning
Authors: Angrist Noam , Bergman Peter , Evans David K , Hares Susannah , Jukes Matthew C H , Letsomo Thato
Published: July 2020

School closures affecting more than 1.5 billion children are designed to prevent the spread of current public health risks from the COVID-19 pandemic, but they simultaneously introduce new short-term and long-term health risks through lost education. Measuring these effects in real time is critical to inform effective public health responses, and remote phone-based approaches are one of the only viable options with extreme social distancing in place. However, both the health and education literature are sparse on guidance for phone-based assessments. In this article, we draw on our pilot testing of phone-based assessments in Botswana, along with the existing literature on oral testing of reading and mathematics, to propose a series of preliminary practical lessons to guide researchers and service providers as they try phone-based learning assessments. We provide preliminary evidence that phone-based assessments can accurately capture basic numeracy skills. We provide guidance to help teams (1) ensure that children are not put at risk, (2) test the reliability and validity of phone-based measures, (3) use simple instructions and practice items to ensure the assessment is focused on the target skill, not general language and test-taking skills, (4) adapt the items from oral assessments that will be most effective in phone-based assessments, (5) keep assessments brief while still gathering meaningful learning data, (6) use effective strategies to encourage respondents to pick up the phone, (7) build rapport with adult caregivers and youth respondents, (8) choose the most cost-effective medium and (9) account for potential bias in samples.
Ultrasound-guided tendon debridement improves pain, function and structure in persistent patellar tendinopathy: short term follow-up of a case series
Authors: Masci Lorenzo , Alfredson Hakan , Neal Brad , Wynter Bee William
Published: July 2020

There is a need for effective therapeutic options for resistant patellar tendinopathy. Ultrasound (US)-guided arthroscopic debridement has demonstrated promising clinical results.

Objectives

To prospectively evaluate pain, function, tendon structure and adverse events after US and colour Doppler (CD)-guided arthroscopic debridement for persistent painful patellar tendinopathy.

Materials and methods

Twenty-three consecutive patients (19 males and 4 females, mean age 28 years (±8), symptom duration 25 months (±21)), who had failed conservative management including progressive loading, were included. US+CD and ultrasound tissue characterisation (UTC) examination verified the clinical diagnosis and quantified baseline tendon structure. Patients were treated with US+CD-guided arthroscopic debridement followed by a specific rehabilitation protocol. Outcomes were VISA-P score for pain and function and UTC for tendon structure. Adverse events were specifically elicited.

Results

At 6-month follow-up, mean VISA-P score increased from 40 (±21.0) to 82 (±15) (mean deviation (MD)=42.0, 95% CI 32 to 53,d=2.4), while organised echo pixels (combined UTC type I+II) increased from 55.0% (±17.0) to 69.0% (±15.0) (MD=14.0,d=0.7, 95% CI 2 to 21). Both outcomes exceeded minimum detectable change values. Twenty-one participants returned to their prediagnosis activity levels, and there were no significant adverse events.

Conclusions

US-guided patellar tendon debridement for persistent patellar tendinopathy improved symptoms and tendon structure without complications at 6-month follow-up. A majority (21/23) of the patients returned to their preinjury activity level. Further studies with longer follow-ups, preferably randomised and controlled, are needed.
Improved efficacy of taxanes and ramucirumab combination chemotherapy after exposure to anti-PD-1 therapy in advanced gastric cancer
Authors: Sasaki Akinori , Kawazoe Akihito , Eto Testuya , Okunaka Mashiro , Mishima Saori , Sawada Kentaro , Nakamura Yoshiaki , Kotani Daisuke , Kuboki Yasutoshi , Taniguchi Hiroya , Kojima Takashi , Doi Toshihiko , Yoshino Takayuki , Akimoto Tetsuo , Shitara Kohei
Published: July 2020

Background

The efficacy and safety of chemotherapy (CTx) after anti-PD-1 therapy in patients with advanced gastric cancer (AGC) remains unclear.

Methods

Medical records of consecutive patients with AGC treated with both CTx (taxanes plus ramucirumab, taxanes monotherapy or irinotecan) and anti-PD-1 therapy from June 2015 to April 2019 were retrospectively analysed. Patients were divided into two groups based on prior exposure to anti-PD-1 therapy: anti-PD-1-exposed and anti-PD-1-naïve groups. CTx-related outcomes were compared between two groups in the overall population and each CTx population.

Results

In total, 233 patients (67 anti-PD-1-exposed, 166 anti-PD-1-naïve) were included. In the overall population, the objective response rate (ORR) to CTX was 44.6% in the anti-PD-1-exposed group and 19.6% in the anti-PD-1-naïve group (p=0.001); the median progression-free survivals (PFS) were 3.7 months and 3.3 months (HR=0.82, p=0.20), respectively. Among patients receiving taxanes plus ramucirumab (n=149), ORR (60.6% vs 20.0%, p<0.001) and median PFS (4.8 vs 3.4 months, p=0.004, HR=0.56) were significantly better in the anti-PD-1-exposed group (n=39) compared with the anti-PD-1-naïve group (n=110). These differences were not observed in patients receiving taxane monotherapy (n=34) or irinotecan (n=50). CTx after anti-PD-1 therapy showed no severe or unexpected adverse events.

Conclusions

Prior anti-PD-1 therapy might increase tumour response to taxanes plus ramucirumab without unexpected adverse events, which warrants further investigations in a large cohort.
Checkpoint inhibitor-related renal vasculitis and use of rituximab
Authors: Mamlouk Omar , Lin Jamie S , Abdelrahim Maen , Tchakarov Amanda S , Glass William F , Selamet Umut , Buni Maryam , Abdel-Wahab Noha , Abudayyeh Ala
Published: July 2020

The percentage of patients with cancer eligible for checkpoint inhibitor (CPI) therapy has increased rapidly over the past few years and approaches 45%. As a result, more cases of CPI-related nephrotoxicity, including a rare subset with vasculitis, are being reported. To elucidate the clinical presentation of CPI-associated renal vasculitis and its possible mechanisms, treatment options and prognosis, we describe cases from a comprehensive cancer center and reviewed the literature for similar cases. We retrospectively reviewed the charts of all patients with cancer from 2014 to 2020 who were diagnosed with CPI-related nephrotoxicity and underwent a kidney biopsy. We identified five cases of renal vasculitis: three patients were diagnosed with seronegative antineutrophil cytoplasm antibody (ANCA)-associated vasculitis, one case with seropositive ANCA-associated vasculitis and one case was diagnosed with IgA vasculitis. Of these cases, four patients were receiving nivolumab, and one patient was receiving tremelimumab. All patients had microscopic hematuria, four out of five patients had negative ANCA serology, one patient had concurrent lung involvement and positive ANCA serology, and all had severe acute kidney injury with creatinine >4.50 mg/dL on diagnosis. All patients were treated by discontinuing CPI and initiating corticosteroids and rituximab. Three patients received plasmapheresis; two of these required renal replacement therapy including the patient with lung involvement. All patients after rituximab had a partial or complete renal response. Two patients died within 8 months of diagnosis due to malignancy progression. None of the patients had a relapse of vasculitis. We demonstrated that CPI can be associated with different types of renal vasculitis that are predominantly ANCA negative and manifest as severe acute kidney injury. Despite the lack of strong evidence, treatment similar to treatment of primary seropositive ANCA-associated vasculitis with corticosteroids and rituximab is well tolerated with favorable renal outcomes.
Optimal local anesthetic regimen for saddle block in ambulatory anorectal surgery: an evidence-based systematic review
Authors: Yung Eric M , Abdallah Faraj W , Todaro Carla , Spence Emily , Grant Andrew , Brull Richard
Published: July 2020

Background

Ambulatory anorectal surgery requires an anesthetic of short duration but profound depth. Saddle block anesthesia (SBA) can provide dense sacral anesthesia with minimal motor blockade, but the ideal local anesthetic agent remains undefined. This systematic review aims to identify the optimal SBA regimen for ambulatory anorectal surgery.

Methods

We sought randomized trials examining SBA for ambulatory anorectal surgery and stratified patients into four subgroups according to local anesthetic type and dose: (1) longer acting, higher dose; (2) longer acting, lower dose; (3) shorter acting, higher dose; and (4) shorter acting, lower dose. Longer acting agents included bupivacaine and levobupivacaine; shorter acting agents included chloroprocaine, mepivacaine, and prilocaine. Lower dose was defined as ≤5 mg and ≤20 mg for longer and shorter acting local anesthetics, respectively. The primary outcome was time to discharge; secondary outcomes included times to sensory and motor block regression, urine voiding, and ambulation, as well as block success.

Results

A total of 11 trials (1063 patients) were included. Overall study quality and reporting consistency was poor. Doses ranged from 1.5–7.5 mg to 3–30 mg of longer and shorter acting local anesthetics, respectively. Hyperbaric local anesthetics were used in eight trials (953 patients, 86%). The median time to discharge appeared similar across all subgroups with an overall time of 182 (IQR 102) min. The use of long-acting, lower dose regimens was associated with a faster median time to motor block regression. Block success approached 99% among all trials.

Conclusions

There is presently insufficient qualitative and quantitative evidence to identify an optimal SBA regimen for ambulatory anorectal surgery. Nonetheless, we found that doses as low as 1.5 and 3 mg of longer and shorter acting hyperbaric local anesthetics, respectively, can achieve effective and reliable SBA with timely hospital discharge. Despite similar discharge times, longer acting, lower dose local anesthetics may produce faster motor block regression following SBA for ambulatory anorectal surgery.
Multiframings of 3-manifolds
Authors: Shimizu Tatsuro
Published: July 2020

We investigate multiframings of a closed oriented 3-manifold. We show that multiframings give a geometric realization of the tensor product of the homotopy set of framings and [Formula: see text]. We prove that the Hirzebruch defect defines a bijection from the homotopy set of multiframings to [Formula: see text] for any connected closed oriented 3-manifold, and we prove that any multiframing defined near the boundary of a compact oriented 3-manifold extends to the bounded manifold.
Dynamic Modeling and Improved Control of a Grid-Connected DFIG Used in Wind Energy Conversion Systems
Authors: Jabal Laafou Abdeslam , Ait Madi Abdessalam , Addaim Adnane , Intidam Abdessamad
Published: July 2020

The proposed work presented in this paper is mainly focused on the control of the active and reactive stator powers generated by a wind energy conversion system (WECS) based on the dual feed induction generator (DFIG). This control is achieved by acting on the rotor side converter (RSC) to extract the maximum power from the wind turbine (WT) while regulating the rotor currents. Furthermore, another control objective is achieved by acting on the grid side converter (GSC), in which the DC bus voltage is maintained constant and a unity power factor is ensured. To do that, a new robust control known as active disturbance rejection control (ADRC) has been proposed and applied to the WECS. This control is based on the extended state observer (ESO), which is the main core of this algorithm; it makes the estimation and cancellation of the total effect of various uncertainties (internal and external disturbances) possible in real time. To validate the effectiveness of the proposed approach, the system was modeled and simulated by using the Matlab/Simulink software. Two tests, namely, tracking and robustness tests, were performed to compare the proposed ADRC technique and classical PI controllers. The obtained results are promising and have shown that the proposed control strategy based on ADRC, especially when varying the mode parameters, is performant and very useful.
Investigation of Rotating Stall Phenomenon and Optimization in Mixed‐Flow Waterjet Propulsion Device
Authors: Luo Can , Zhang Di , Zhang Congcong , Lei Shuaihao , Xia Chenzhi , Wang Chuan , Cheng Li
Published: July 2020

The rotating stall is a kind of flow phenomenon in the impeller harming the navigation speed of vessels propelled by a waterjet propulsion device when the waterjet propulsion device operates at the small flow rate conditions. The numerical simulated hydraulic performance was compared with experimental results so that the reliability of the CFD method was verified. The grooves are proposed before the inlet of an impeller to suppress the rotating stall. The orthogonal experiment is designed to seek the appropriate values of the parameters such as the length, width, depth, and number of the groove. The results show that the width of groove has the greatest influence on the performance of the device, followed by the number, the depth, and the length. The width, number, depth, and length of the selected groove scheme are 3.10 × 10−2D, 72, 3.10 × 10−2D, and 7.75 × 10−2D, respectively. At the rotating stall conditions, the selected groove scheme is numerically calculated. In contradistinction to the original scheme, it is found that the groove can improve the flow in the impeller and enhance the head of valley point condition, but the efficiency drops due to the increasing local hydraulic loss near the groove. When the groove is installed, the positive slop region on the flow rate‐head curve disappears related to the static pressure difference on the blade, especially depending on the static pressure on the suction side. The flow pattern on the span surface of the vortex core is smooth, and then, the head increases. On the contrary, the head decreases. The outcome is beneficial to improve the performance of the waterjet propulsion device and enrich the rotating stall theory.
Retrograde Labeling of Different Distribution Features of DRG P2X2 and P2X3 Receptors in a Neuropathic Pain Rat Model
Authors: Chen Lin , Leng Changlong , Ru Qin , Xiong Qi , Zhou Mei , Wu Yuxiang
Published: July 2020

The distributions of P2X subtypes during peripheral neuropathic pain conditions and their differential roles are not fully understood. To explore these characteristics, the lumbosacral dorsal root ganglion (DRG) in the chronic constriction injury (CCI) sciatic nerve rat model was studied. Retrograde trace labeling combined with immunofluorescence technology was applied to analyze the distribution of neuropathic nociceptive P2X1‐6 receptors. Our results suggest that Fluoro‐Gold (FG) retrograde trace labeling is an efficient method for studying lumbosacral DRG neurons in the CCI rat model, especially when the DRG neurons are divided into small, medium, and large subgroups. We found that neuropathic nociceptive lumbosacral DRG neurons (i.e., FG‐positive cells) were significantly increased in medium DRG neurons, while they declined in the large DRG neurons in the CCI group. P2X3 receptors were markedly upregulated in medium while P2X2 receptors were significantly decreased in small FG‐positive DRG neurons. There were no significant changes in other P2X receptors (including P2X1, P2X4, P2X5, and P2X6). We anticipate that P2X receptors modulate nociceptive sensitivity primarily through P2X3 subtypes that are upregulated in medium neuropathic nociceptive DRG neurons and/or via the downregulation of P2X2 cells in neuropathic nociceptive small DRG neurons.
Pyrvinium Pamoate Induces Death of Triple-Negative Breast Cancer Stem–Like Cells and Reduces Metastases through Effects on Lipid Anabolism
Authors: Dattilo Rosanna , Mottini Carla , Camera Emanuela , Lamolinara Alessia , Auslander Noam , Doglioni Ginevra , Muscolini Michela , Tang Wei , Planque Melanie , Ercolani Cristiana , Buglioni Simonetta , Manni Isabella , Trisciuoglio Daniela , Boe Alessandra , Grande Sveva , Luciani Anna Maria , Iezzi Manuela , Ciliberto Gennaro , Ambs Stefan , De Maria Ruggero , Fendt Sarah-Maria , Ruppin Eytan , Cardone Luca
Published: July 2020

Cancer stem-like cells (CSC) induce aggressive tumor phenotypes such as metastasis formation, which is associated with poor prognosis in triple-negative breast cancer (TNBC). Repurposing of FDA-approved drugs that can eradicate the CSC subcompartment in primary tumors may prevent metastatic disease, thus representing an effective strategy to improve the prognosis of TNBC. Here, we investigated spheroid-forming cells in a metastatic TNBC model. This strategy enabled us to specifically study a population of long-lived tumor cells enriched in CSCs, which show stem-like characteristics and induce metastases. To repurpose FDA-approved drugs potentially toxic for CSCs, we focused on pyrvinium pamoate (PP), an anthelmintic drug with documented anticancer activity in preclinical models. PP induced cytotoxic effects in CSCs and prevented metastasis formation. Mechanistically, the cell killing effects of PP were a result of inhibition of lipid anabolism and, more specifically, the impairment of anabolic flux from glucose to cholesterol and fatty acids. CSCs were strongly dependent upon activation of lipid biosynthetic pathways; activation of these pathways exhibited an unfavorable prognostic value in a cohort of breast cancer patients, where it predicted high probability of metastatic dissemination and tumor relapse. Overall, this work describes a new approach to target aggressive CSCs that may substantially improve clinical outcomes for patients with TNBC, who currently lack effective targeted therapeutic options.

Significance:

These findings provide preclinical evidence that a drug repurposing approach to prevent metastatic disease in TNBC exploits lipid anabolism as a metabolic vulnerability against CSCs in primary tumors.
Clinical BRCA1/2 Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance
Authors: Pettitt Stephen J. , Frankum Jessica R. , Punta Marco , Lise Stefano , Alexander John , Chen Yi , Yap Timothy A. , Haider Syed , Tutt Andrew N.J. , Lord Christopher J.
Published: July 2020

Reversion mutations in BRCA1 or BRCA2 are associated with resistance to PARP inhibitors and platinum. To better understand the nature of these mutations, we collated, codified, and analyzed more than 300 reversions. This identified reversion “hotspots” and “deserts” in regions encoding the N and C terminus, respectively, of BRCA2, suggesting that pathogenic mutations in these regions may be at higher or lower risk of reversion. Missense and splice-site pathogenic mutations in BRCA1/2 also appeared less likely to revert than truncating mutations. Most reversions were <100 bp deletions. Although many deletions exhibited microhomology, this was not universal, suggesting that multiple DNA-repair processes cause reversion. Finally, we found that many reversions were predicted to encode immunogenic neopeptides, suggesting a route to the treatment of reverted disease. As well as providing a freely available database for the collation of future reversion cases, these observations have implications for how drug resistance might be managed in BRCA-mutant cancers.

Significance:

Reversion mutations in BRCA genes are a major cause of clinical platinum and PARP inhibitor resistance. This analysis of all reported clinical reversions suggests that the position of BRCA2 mutations affects the risk of reversion. Many reversions are also predicted to encode tumor neoantigens, providing a potential route to targeting resistance.

This article is highlighted in the In This Issue feature, p. 1426
Fitness, Strength and Body Composition during Weight Loss in Women with Clinically Severe Obesity: A Randomised Clinical Trial
Authors: Miller Clint T. , Fraser Steve F. , Selig Steve E. , Rice Toni , Grima Mariee , van den Hoek Daniel J. , Ika Sari Carolina , Lambert Gavin W. , Dixon John B.
Published: July 2020

Introduction: To determine whether combined exercise training with an energy-restricted diet leads to improved physical fitness and body composition when compared to energy restriction alone in free-living premenopausal women with clinically severe obesity. Methods: Sixty premenopausal women (BMI of 40.4 ± 6.7) were randomised to energy restriction only (ER) or to exercise plus energy restriction (EXER) for 12 months. Body composition and fitness were measured at baseline, 3, 6 and 12 months. Results: VO2 peak improved more for EXER compared to ER at 3 (mean difference ± SEM 2.5 ± 0.9 mL ∙ kg–1 ∙ min–1, p = 0.006) and 6 (3.1 ± 1.2 mL ∙ kg–1 ∙ min–1, p = 0.007) but not 12 months (2.3 ± 1.6 mL ∙ kg–1 ∙ min–1, p = 0.15). Muscle strength improved more for EXER compared to ER at all time points. No differences between groups for lean mass were observed at 12 months. Conclusion: Combining exercise training with an energy-restricted diet did not lead to greater aerobic power, total body mass, fat mass or limit lean body mass loss at 12 months when compared to energy restriction alone for premenopausal women with clinically severe obesity in free-living situations. Future research should aim to determine an effective lifestyle approach which can be applied in the community setting for this high-risk group.
Right Kidney Mini-Invasive Living Donor Nephrectomy: A Safe and Efficient Alternative
Authors: Broudeur Lucas , Karam Georges , Rana Magar Reshma , Glemain Pascal , Loubersac Thomas , Fosse Arthur , De Vergie Stéphane , Chelghaf Ismaël , Perrouin-Verbe Marie-Aimée , Rigaud Jérôme , Branchereau Julien
Published: July 2020

Introduction: Right kidney living donor transplantation is considered more difficult and associated with more complications. The objective was to evaluate donor safety and graft function of right hand-assisted laparoscopic donor nephrectomy (HALDN). Methods: A total of 270 consecutive HALDN procedures have been performed in our institution up to April 2017. We retrospectively compared the outcomes of right-sided nephrectomy (R-HALDN) to left-sided nephrectomy (L-HALDN) to evaluate donor safety and graft function of R-HALDN. Results: Sixty-seven right kidneys were removed for functional asymmetry in favour of left kidney (35/67) or left kidney multiple arteries (28/67). Among the donors, neither conversion to open surgery nor preoperative blood transfusion was necessary. There was no significant difference in operative time, compared to L-HALDN group (170 ± 37 min vs. 171 ± 32 min; p value = 0.182). Warm ischaemia time was significantly longer for R-HALDN (4.0 ± 1.6 min vs. 3.0 ± 1.7 min; p < 0.001). There was no significant difference in terms of post-operative complications and serum Cr levels. Among the recipients, there were no graft venous thrombosis. There was no significant difference in delayed graft function (3 for R-HALDN group and 8 for L-HALDN group; p value = 0.847), serum Cr levels, and graft survival. Conclusion: R-HALDN is a safe procedure for kidney donors, with excellent graft function for the recipients, compared to L-HALDN.
Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm
Authors: Pedroza Albert J. , Tashima Yasushi , Shad Rohan , Cheng Paul , Wirka Robert , Churovich Samantha , Nakamura Ken , Yokoyama Nobu , Cui Jason Z. , Iosef Cristiana , Hiesinger William , Quertermous Thomas , Fischbein Michael P.
Published: July 2020

Objective:

To delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS).

Approach and Results:

We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue from
Fbn1

C1041G/
+

(MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult
Fbn1

C1041G/
+

mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE
−/−
mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 (
Serpine1
) and Kruppel-like factor 4 (
Klf4
). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis of
Fbn1

C1041G/
+

SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in young
Fbn1

C1041G/
+

mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult
Fbn1

C1041G/
+

descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF-β (transforming growth factor beta)-responsive genes correlated with SMC modulation in mouse and human data sets.

Conclusions:

Dynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-β plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-β signaling and
Klf4
overexpression as potential upstream drivers of SMC modulation.
Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association
Authors: Musunuru Kiran , Hershberger Ray E. , Day Sharlene M. , Klinedinst N. Jennifer , Landstrom Andrew P. , Parikh Victoria N. , Prakash Siddharth , Semsarian Christopher , Sturm Amy C. ,   on behalf of the American Heart Association Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology
Published: July 2020

Advances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases, including cardiomyopathies, arrhythmic disorders, vascular disorders, and lipid disorders such as familial hypercholesterolemia. However, not all cardiovascular practitioners are fully aware of the utility and potential pitfalls of incorporating genetic test results into the care of patients and their families. This statement summarizes current best practices with respect to genetic testing and its implications for the management of inherited cardiovascular diseases.
Para- and Proto-Sports Diplomacy of Contested Territories: CONIFA as a Platform for Football Diplomacy
Authors: Ganohariti Ramesh , Dijxhoorn Ernst
Published: July 2020

International relations and sport have become increasingly intertwined, with sport and sports events being used for various diplomatic and political goals. Yet, membership of FIFA and the IOC is largely organised along lines of sovereign statehood. Like other fora of diplomacy, this excludes contested territories that wish to engage in diplomacy for various political, economic, and cultural reasons. Yet, these entities can engage in international sports (diplomacy) through membership of the Confederation of Independent Football Associations (CONIFA). This paper finds that while the participating entities often make a political statement, there is little evidence that participation in CONIFA has positively impacted their foreign policy goals. Furthermore, beyond CONIFA, contested territories have been unable to advance their sporting sovereignty or engage in diplomatic relations with recognised states. However, CONIFA aids in nation branding through hosting rights and media attention, and contributes to strengthening the ‘national’ identity of the participants.
Senses as Capacities
Authors: O’Callaghan Casey
Published: July 2020

This paper presents an account of the senses and what differentiates them that is compatible with richly multisensory perception and consciousness. According to this proposal, senses are ways of perceiving. Each sense is a subfaculty that comprises a collection of perceptual capacities. What each sense shares and what differentiates one sense from another is the manner in which those capacities are exercised. Each way of perceiving involves a distinct type of information gathering, individuated by the information it functions to extract and the medium from which it does so. This approach distinguishes the project of characterizing and differentiating senses from that of attributing experiences to sensory modalities. Perceptual experiences are episodes in which perceptual capacities are exercised. Conscious perceptual episodes may be ascribed to distinct sensory modalities, according to the manners in which perceptual capacities are deployed on an occasion. According to this account, senses are not exclusive. First, their capacities may overlap. Second, perceptual episodes, including conscious experiences, may belong to multiple senses. Indeed, some episodes require the joint use of several senses. In this account, subjects have only limited first-person knowledge of the senses they employ.
Redescription of Cerebratulus marginatus auct. (Nemertea: Pilidiophora) from Hokkaido, Japan, as a new species
Authors: KAJIHARA HIROSHI
Published: July 2020

The heteronemertean Cerebratulus orochi sp. nov. is described based on material collected intertidally at a muddy beach in Akkeshi, northern Japan. For the last 80 years, the species has been confused with Cerebratulus marginatus Renier, 1804; the latter was originally described from the Adriatic and once believed to occur in many places in the northern hemisphere including Japan. Cerebratulus orochi sp. nov. is morphologically different from all the congeners including C. marginatus by the following combination of characters: several layers of diagonal-muscle meshwork coated with connective tissue, proximo-distally distributed in cross section from the distal portion of the body-wall outer longitudinal muscle layer to the cutis-gland zone throughout the anterior portion of the body from the precerebral to the foregut regions; the cephalic vascular system consisting of lateral and mid-dorsal vessels; and the sub-rhynchocoelic vessel possessing a pair of antero-lateral diverticula before the former forks posteriorly into a pair of lower lateral vessels in the post-cerebral, pre-oral region. Previous records of C. marginatus from Japanese waters are no longer considered to be substantiated. Multi-locus phylogenetic analyses based on the mitochondrial 16S rRNA and cytochrome c oxidase subunit I (COI), as well as the nuclear 18S rRNA, 28S rRNA, and histone H3 genes among heteronemerteans comprising the “Cerebratulus clade” indicated that C. orochi sp. nov. was closely related to C. cf. marginatus from the US Pacific coast. A MegaBLAST search at the NCBI website with the 16S rRNA gene sequence from C. orochi sp. nov. followed by a couple of species delimitation analyses suggests that larvae of the species are also distributed in Vostok Bay, Far East Russia.
Caves as a key habitat for rare and endemic species of the west coast of North America: a taxonomic revision of the spider genus Oaphantes (Araneae: Linyphiidae)
Authors: PAQUIN P. , DUPÉRRÉ N. , BUCKLE D.J. , UBICK D.
Published: July 2020

The genus Oaphantes is known from the West Coast of North America. Here we revise the genus which now includes three species, two of which are new: O. cryophilus n. sp. and O. prometheus n. sp. All Members of the genus Oaphantes show affinities for cave habitats. Oaphantes pallidulus is known from caves of the Coast Ranges of California and also from epigean records. Oaphantes cryophilus n. sp. is restricted to caves in the southern limit of its distribution in the Sierra Nevada Mountains of California, but in the north it is known from epigean records in Oregon, Washington and British Columbia. Oaphantes prometheus n. sp. is an eyeless troglobite endemic to a single cave in the Sierra Nevada of California. The distribution and relationships of the three species suggest an evolutive scenario likely due to climatic variations and affinities for colder conditions.
Analysis of Variance Based Significance Analysis of Cartilage Tumor
Authors: Li Yuan , Xu Zili , Liu Xiangyang , Peng Xiandong , Cao Shu , Yang Zhulin
Published: July 2020

Chondrosarcoma is a malignant bone tumor with poor prognosis. Surgical treatment is the first choice for chondrosarcomas. Chondrosarcoma is not sensitive to chemotherapy and radiotherapy. Identification of biological markers is important for the early diagnosis and targeted treatment
of chondrosarcoma. This study aimed to investigate the protein expression and clinicopathological significance of APEX1 and Haptoglobin in 85 chondrosarcomas and 38 osteochondromas based on deep learning. The APEX1 and Haptoglobin protein expression in tissues was measured by immunohistochemistry.
The percentage of positive APEX1 and Haptoglobin expression was significantly higher in patients with chondrosarcoma than in patients with osteochondroma (P < 0001). The percentage of positive APEX1 and Haptoglobin expression was significantly lower in patients with histological
grade I, AJCC stage I, Enneking stage I and non-metastatic chondrosarcoma than patients with histological grade III, AJCC stage III+IV, Enneking stage III, and metastatic chondrosarcoma (P < 0005 or P < 0001). APEX1 expression was positively correlated with Haptoglobin
expression in chondrosarcoma (P < 0001). Kaplan—Meier survival analysis demonstrated that histological grade, AJCC stage, Enneking stage, metastasis, invasion, and APEX1 and Haptoglobin expression significantly correlated with a short mean survival time of patients with chondrosarcoma
(P < 0005 or P < 0001). Cox multivariate analysis showed that positive APEX1 and Haptoglobin expressions were independent prognostic factors that negatively correlated with postoperative survival and positively correlated with mortality. The AUC for APEX1 (AUC = 0.673, 95% CI:
0.573—0.772), or Haptoglobin (AUC = 0.649, 95% CI: 0.548—0.750), respectively. Positive APEX1 and Haptoglobin expression is associated with the carcinogenesis, progression and poor prognosis of chondrosarcoma.