bluuebunny/crossref_metadata_2025 huggingface dataset:
The rapamycin analog Everolimus reversibly impairs male germ cell differentiation and fertility in the mouse†
Authors: Kirsanov Oleksandr , Renegar Randall H , Busada Jonathan T , Serra Nicholas D , Harrington Ellen V , Johnson Taylor A , Geyer Christopher B
Published: July 2020

Sirolimus, also known as rapamycin, and its closely related rapamycin analog (rapalog) Everolimus inhibit “mammalian target of rapamycin complex 1” (mTORC1), whose activity is required for spermatogenesis. Everolimus is Food and Drug Administration approved for treating human patients to slow growth of aggressive cancers and preventing organ transplant rejection. Here, we test the hypothesis that rapalog inhibition of mTORC1 activity has a negative, but reversible, impact upon spermatogenesis. Juvenile (P20) or adult (P>60) mice received daily injections of sirolimus or Everolimus for 30 days, and tissues were examined at completion of treatment or following a recovery period. Rapalog treatments reduced body and testis weights, testis weight/body weight ratios, cauda epididymal sperm counts, and seminal vesicle weights in animals of both ages. Following rapalog treatment, numbers of differentiating spermatogonia were reduced, with concomitant increases in the ratio of undifferentiated spermatogonia to total number of remaining germ cells. To determine if even low doses of Everolimus can inhibit spermatogenesis, an additional group of adult mice received a dose of Everolimus ∼6-fold lower than a human clinical dose used to treat cancer. In these animals, only testis weights, testis weight/body weight ratios, and tubule diameters were reduced. Return to control values following a recovery period was variable for each of the measured parameters and was duration and dose dependent. Together, these data indicate rapalogs exerted a dose-dependent restriction on overall growth of juvenile and adult mice and negative impact upon spermatogenesis that were largely reversed; following treatment cessation, males from all treatment groups were able to sire offspring.
Pig conceptuses secrete interferon gamma to recruit T cells to the endometrium during the peri-implantation period
Authors: McLendon Bryan A , Seo Heewon , Kramer Avery C , Burghardt Robert C , Bazer Fuller W , Johnson Greg A
Published: July 2020

The emerging paradigm in the immunology of pregnancy is that implantation of conceptuses does not progress in an immunologically suppressed environment. Rather, the endometrium undergoes a controlled inflammatory response during implantation as trophectoderm of elongating and implanting pig conceptuses secrete the pro-inflammatory cytokine interferon gamma (IFNG). Results of this study with pigs revealed: (1) accumulation of immune cells and apoptosis of stromal cells within the endometrium at sites of implantation during the period of IFNG secretion by conceptuses; (2) accumulation of proliferating cell nuclear antigen (PCNA)-positive T cells within the endometrium at sites of implantation; (3) significant increases in expression of T cell co-signaling receptors including programmed cell death 1 (PDCD1), CD28, cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and inducible T cell co-stimulator (ICOS), as well as chemokines CXCL9, 10, and 11 within the endometrium at sites of implantation; (4) significant increases in T cell co-signaling receptors, PDCD1 and ICOS, and chemokine CXCL9 in the endometrium of cyclic gilts infused with IFNG; and (5) identification of CD4+ (22.59%) as the major T cell subpopulation, with minor subpopulations of CD8+ (1.38%), CD4+CD25+ (1.08%), and CD4+CD8+ (0.61%) T cells within the endometrium at sites of implantation. Our results provide new insights into the immunology of implantation to suggest that trophectoderm cells of pigs secrete IFNG to recruit various subpopulations of T cells to the endometrium to contribute to a controlled inflammatory environment that supports the active breakdown and restructuring of the endometrium in response to implantation of the conceptus.
Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial
Authors: Pujol Miquel , Miró José-María , Shaw Evelyn , Aguado Jose-María , San-Juan Rafael , Puig-Asensio Mireia , Pigrau Carles , Calbo Esther , Montejo Miguel , Rodriguez-Álvarez Regino , Garcia-Pais María-Jose , Pintado Vicente , Escudero-Sánchez Rosa , Lopez-Contreras Joaquín , Morata Laura , Montero Milagros , Andrés Marta , Pasquau Juan , Arenas María-del-Mar , Padilla Belén , Murillas Javier , Jover-Sáenz Alfredo , López-Cortes Luis-Eduardo , García-Pardo Graciano , Gasch Oriol , Videla Sebastian , Hereu Pilar , Tebé Cristian , Pallarès Natalia , Sanllorente Mireia , Domínguez María-Ángeles , Càmara Jordi , Ferrer Anna , Padullés Ariadna , Cuervo Guillermo , Carratalà Jordi ,   MRSA Bacteremia (BACSARM) Trial Investigators, Soriano Alex , Almela Manel , Gómez Frederic , Chávez Fernando , Mirelis Beatriz , Padilla Emma , Dolores Pérez-Ramírez Maria , Espasa Mateu , Maria Sánchez-Díaz Ana , Cercenado Emilia , Ruiz de Gopegui Enrique , Siverio Ana , de Cueto Marina , García-Garrote Fernando , Garcia Mercè , Xercavins Mariona , Nieves Larrosa Maria
Published: July 2020

Background

We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis.

Methods

A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy.

Results

Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93–1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018).

Conclusions

Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events.

Clinical Trials Registration

NCT01898338.
A Comparison Between 12 Versus 20 Weeks of Trimethoprim-sulfamethoxazole as Oral Eradication Treatment for Melioidosis: An Open-label, Pragmatic, Multicenter, Non-inferiority, Randomized Controlled Trial
Authors: Anunnatsiri Siriluck , Chaowagul Wipada , Teparrukkul Prapit , Chetchotisakd Ploenchan , Tanwisaid Kittisak , Khemla Supphachoke , Narenpitak Surapong , Pattarapongsin Moragot , Kongsawasd Wirod , Pisuttimarn Pornrith , Thipmontree Wilawan , Mootsikapun Piroon , Chaisuksant Seksan , Chierakul Wirongrong , Day Nicholas P J , Limmathurotsakul Direk
Published: July 2020

Background

Treatment of melioidosis comprises intravenous drugs for at least 10 days, followed by oral trimethoprim-sulfamethoxazole (TMP-SMX) for 12 to 20 weeks. Oral TMP-SMX is recommended for 12 weeks in Australia and 20 weeks in Thailand.

Methods

For this open-label, pragmatic, multicenter, noninferiority, randomized controlled trial, we enrolled patients with culture-confirmed melioidosis who had received oral eradication treatment for 12 weeks and had no clinical evidence of active melioidosis. We randomly assigned patients to stop treatment (12-week regimen) or continue treatment for another 8 weeks (20-week regimen). The primary end point was culture-confirmed recurrent melioidosis within 1 year after enrollment. The noninferiority margin was a hazard ratio (HR) of 2.0. The secondary composite end point, combining overall recurrent melioidosis and mortality, was assessed post hoc.

Results

We enrolled 658 patients: 322 to the 12-week regimen and 336 to the 20-week regimen. There were 5 patients (2%) in the 12-week regimen and 2 patients (1%) in the 20-week regimen who developed culture-confirmed recurrent melioidosis (HR, 2.66; 95% confidence interval [CI], .52–13.69). The criterion for noninferiority of the primary event was not met (1-sided P = .37). However, all-cause mortality was significantly lower in the 12-week regimen group than in the 20-week regimen group (1 [.3%] vs 11 [3%], respectively; HR, 0.10; 95% CI, .01–.74). The criterion for noninferiority of the secondary composite end point, combining overall recurrent melioidosis and mortality, was met (1-sided P = .022).

Conclusions

Based on the lower total mortality and noninferiority of the secondary composite end point observed, we recommend the 12-week regimen of TMP-SMX for oral eradication treatment of melioidosis.

Clinical Trials Registration

NCT01420341.
Feasibility of evaluation of the natural history of kidney disease in the general population using electronic healthcare records
Authors: Cleary Faye , Prieto-Merino David , Hull Sally , Caplin Ben , Nitsch Dorothea
Published: July 2020

Background

Knowledge about the nature of long-term changes in kidney function in the general population is sparse. We aim to identify whether primary care electronic healthcare records capture sufficient information to study the natural history of kidney disease.

Methods

The National Chronic Kidney Disease Audit database covers ∼14% of the population of England and Wales. Availability of repeat serum creatinine tests was evaluated by risk factors for chronic kidney disease (CKD) and individual changes over time in estimated glomerular filtration rate (eGFR) were estimated using linear regression. Sensitivity of estimation to method of evaluation of eGFR compared laboratory-reported eGFR and recalculated eGFR (using laboratory-reported creatinine), to uncover any impact of historical creatinine calibration issues on slope estimation.

Results

Twenty-five per cent of all adults, 92% of diabetics and 96% of those with confirmed CKD had at least three creatinine tests, spanning a median of 5.7 years, 6.2 years and 6.1 years, respectively. Median changes in laboratory-reported eGFR (mL/min/1.73 m2/year) were −1.32 (CKD) and −0.60 (diabetes). Median changes in recalculated eGFR were −0.98 (CKD) and −0.11 (diabetes), underestimating decline. Magnitude of underestimation (and between-patient variation in magnitude) decreased with deteriorating eGFR. For CKD Stages 3, 4 and 5 (at latest eGFR), median slopes were −1.27, −2.49 and -3.87 for laboratory-reported eGFR and −0.89, −2.26 and −3.75 for recalculated eGFR.

Conclusions

Evaluation of long-term changes in renal function will be possible in those at greatest risk if methods are identified to overcome creatinine calibration problems. Bias will be reduced by focussing on patients with confirmed CKD.
In vivoanalysis of the origin and characteristics of gaseous microemboli during catheter-mediated irreversible electroporation
Authors: Groen Marijn H A , van Es René , van Klarenbosch Bas R , Stehouwer Marco , Loh Peter , Doevendans Pieter A , Wittkampf Fred H , Neven Kars
Published: July 2020

Aims 

Irreversible electroporation (IRE) ablation is a non-thermal ablation method based on the application of direct current between a multi-electrode catheter and skin electrode. The delivery of current through blood leads to electrolysis. Some studies suggest that gaseous (micro)emboli might be associated with myocardial damage and/or (a)symptomatic cerebral ischaemic events. The aim of this study was to compare the amount of gas generated during IRE ablation and during radiofrequency (RF) ablation.

Methods and results

In six 60–75 kg pigs, an extracorporeal femoral shunt was outfitted with a bubble-counter to detect the size and total volume of gas bubbles. Anodal and cathodal 200 J IRE applications were delivered in the left atrium (LA) using a 14-electrode circular catheter. The 30 and 60 s 40 W RF point-by-point ablations were performed. Using transoesophageal echocardiography (TOE), gas formation was visualized. Average gas volumes were 0.6 ± 0.6 and 56.9 ± 19.1 μL (P < 0.01) for each anodal and cathodal IRE application, respectively. Also, qualitative TOE imaging showed significantly less LA bubble contrast with anodal than with cathodal applications. Radiofrequency ablations produced 1.7 ± 2.9 and 6.7 ± 7.4 μL of gas, for 30 and 60 s ablation time, respectively.

Conclusion 

Anodal IRE applications result in significantly less gas formation than both cathodal IRE applications and RF applications. This finding is supported by TOE observations.
The Effects of Chloroquine and Hydroxychloroquine on ACE2-Related Coronavirus Pathology and the Cardiovascular System: An Evidence-Based Review
Authors: Chen Li , Chen Haiyan , Dong Shan , Huang Wei , Chen Li , Wei Yuan , Shi Liping , Li Jinying , Zhu Fengfeng , Zhu Zhu , Wang Yiyang , Lv Xiuxiu , Yu Xiaohui , Li Hongmei , Wei Wei , Zhang Keke , Zhu Lihong , Qu Chen , Hong Jian , Hu Chaofeng , Dong Jun , Qi Renbin , Lu Daxiang , Wang Huadong , Peng Shuang , Hao Guang
Published: July 2020

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global public health and there is currently no effective antiviral therapy. It has been suggested that chloroquine (CQ) and hydroxychloroquine (HCQ), which were primarily employed as prophylaxis and treatment for malaria, could be used to treat COVID-19. CQ and HCQ may be potential inhibitors of SARS-CoV-2 entry into host cells, which are mediated via the angiotensin-converting enzyme 2 (ACE2), and may also inhibit subsequent intracellular processes which lead to COVID-19, including damage to the cardiovascular (CV) system. However, paradoxically, CQ and HCQ have also been reported to cause damage to the CV system. In this review, we provide a critical examination of the published evidence. CQ and HCQ could potentially be useful drugs in the treatment of COVID-19 and other ACE2 involved virus infections, but the antiviral effects of CQ and HCQ need to be tested in more well-designed clinical randomized studies and their actions on the CV system need to be further elucidated. However, even if it were to turn out that CQ and HCQ are not useful drugs in practice, further studies of their mechanism of action could be helpful in improving our understanding of COVID-19 pathology.
Mid-term durability of polytetrafluoroethylene patches in unicuspid aortic valve repair
Authors: Karliova Irem , Ehrlich Tristan , Matsushima Shunsuke , Ewen Sebastian , Schäfers Hans-Joachim
Published: July 2020

OBJECTIVES

Unicuspid aortic valve (UAV) morphology is a cause for aortic valve dysfunction in childhood or adolescence. Repair requires the use of patch material, and polytetrafluoroethylene (PTFE) has been proposed for this purpose because of lack of calcification. We reviewed our mid-term experience with PTFE for the repair of UAV to analyse the durability of this technique.

METHODS

Out of 21 patients with an UAV undergoing aortic valve repair for severe aortic regurgitation between 2014 and 2016, 11 patients (52%) were treated using PTFE patch material. Aortic regurgitation was present in all patients, the primary indication for surgery was regurgitation in 8, stenosis in 2 and aneurysm in 1. Symmetric bicuspidization of the UAV was performed in all. One patient required additional root remodelling for root dilatation, and another 3 tubular ascending aortic replacement.

RESULTS

No patient died in hospital or during follow-up. Seven patients (63.6%) required reoperation for progressive AR. Freedom from reoperation was 58% at 1 and 35% at 5 years postoperatively. At reoperation the PTFE patches were found dehisced from aortic wall and/or native cusp tissue. In 3 patients re-repair was performed; a stable result was achieved in 1. Two patients underwent valve replacement 3 months and 1 year postoperatively. The other 4 patients underwent valve replacement.

CONCLUSIONS

The repair of UAVs using PTFE patch is associated with poor durability, a more durable patch with better healing characteristics material is needed.
Mid-term survival of patients with chronic kidney disease after extracorporeal membrane oxygenation
Authors: Lu Yueh-An , Chen Shao-Wei , Lee Cheng-Chia , Wu Victor Chien-Chia , Fan Pei-Chun , Kuo George , Chen Jia-Jin , Chu Po-Hsien , Chang Shang-Hung , Chang Chih-Hsiang
Published: July 2020

OBJECTIVES

Chronic kidney disease (CKD) impairs the elimination of fluids, electrolytes and metabolic wastes, which can affect the outcomes of extracorporeal membrane oxygenation (ECMO) treatment. This study aimed to elucidate the impact of CKD on in-hospital mortality and mid-term survival of adult patients who received ECMO treatment.

METHODS

Patients who received first-time ECMO treatment between 1 January 2003 and 31 December 2013 were included. Those with CKD were identified and matched to patients without CKD using a 1:2 ratio and were followed for 3 years. The study outcomes included in-hospital outcomes and the 3-year mortality rate. A subgroup analysis was conducted by comparing the dialytic patients with the non-dialytic CKD patients.

RESULTS

The study comprised 1008 CKD patients and 2016 non-CKD patients after propensity score matching. The CKD patients had higher in-hospital mortality rates [69.5% vs 62.2%; adjusted odds ratio 1.41; 95% confidence interval (CI) 1.15–1.72] than the non-CKD patients. The 3-year mortality rate was 80.4% in the CKD group and 68% in the non-CKD group (adjusted hazard ratio 1.17; 95% CI 1.06–1.28). The subgroup analysis showed that the 3-year mortality rates were 84.5% and 78.4% in the dialytic and non-dialytic patients, respectively. No difference in the 3-year mortality rate was noted between the 2 CKD subgroups (P = 0.111).

CONCLUSIONS

CKD was associated with increased risks of in-hospital and mid-term mortalities in patients who received ECMO treatment. Furthermore, no difference in survival was observed between the patients with end-stage renal disease and non-dialytic CKD patients.
The Short and Long(er) of It: The Effect of Hard Times on Regional Institutionalization
Authors: Haftel Yoram Z , Wajner Daniel F , Eran Dan
Published: July 2020

What are the implications of hard economic times for regional economic cooperation? Existing research is sharply divided on the answer to this question. Some studies suggest that economic crises encourage governments to strengthen their regional institutions, but others indicate that they lead to decreasing investment in such initiatives. Both sides overlook the possibility that the passage of time conditions these relationships, however. We aim to bridge these opposing perspectives by distinguishing between short-term and long-term effects of economic hard times on institutionalized regional cooperation. We argue that in the short term economic crises impede regional institutionalization due to protectionist pressures, nationalistic public sentiments, and political instability. This effect is reversed in the longer term, as interest groups and the public adopt more favorable attitudes toward regional economic organizations (REOs) and governments employ these institutions to demonstrate their competence and to improve economic conditions. We evaluate this argument in relations to regional institutionalization, which refers to the functional scope and structure of REOs. Using a data set that contains information on this dimension for thirty REOs over four decades, we find strong support for the theoretical framework: regional institutionalization remains stagnant in the immediate aftermath of economic crises, but increases in subsequent years.
Using a Head Pointer or Eye Gaze: The Effect of Gaze on Spatial AR Remote Collaboration for Physical Tasks
Authors: Wang Peng , Bai Xiaoliang , Billinghurst Mark , Zhang Shusheng , He Weiping , Han Dechuan , Wang Yue , Min Haitao , Lan Weiqi , Han Shu
Published: July 2020

This paper investigates the effect of using augmented reality (AR) annotations and two different gaze visualizations, head pointer (HP) and eye gaze (EG), in an AR system for remote collaboration on physical tasks. First, we developed a spatial AR remote collaboration platform that supports sharing the remote expert’s HP or EG cues. Then the prototype system was evaluated with a user study comparing three conditions for sharing non-verbal cues: (1) a cursor pointer (CP), (2) HP and (3) EG with respect to task performance, workload assessment and user experience. We found that there was a clear difference between these three conditions in the performance time but no significant difference between the HP and EG conditions. When considering the perceived collaboration quality, the HP/EG interface was statistically significantly higher than the CP interface, but there was no significant difference for workload assessment between these three conditions. We used low-cost head tracking for the HP cue and found that this served as an effective referential pointer. This implies that in some circumstances, HP could be a good proxy for EG in remote collaboration. Head pointing is more accessible and cheaper to use than more expensive eye-tracking hardware and paves the way for multi-modal interaction based on HP and gesture in AR remote collaboration.
Pandemic Powers: Why Human Rights Organizations Should Not Lose Focus on Civil and Political Rights
Authors: Seyhan Eda
Published: July 2020

In response to the rise of ‘populism’ and the perceived threat to human rights that it represents, human rights advocates have argued that NGOs must speak to the economic anxieties of majority populations by increasing work on economic and social rights. In this essay, I present a counter-argument to this proposal, drawing on insights from the COVID-19 pandemic and my experiences working at Amnesty International and monitoring emergency powers during the pandemic for Covid State Watch. I argue that international human rights NGOs should retain a focus on civil and political rights for three reasons. The COVID-19 pandemic has (1) revealed and reinforced the vast repressive power of the state and consequent serious risks to civil and political rights in the global North and (2) demonstrated that human rights NGOs are often alone in challenging restrictions to civil and political rights, especially during crises. I further suggest that, in contrast to the civil and political rights sphere, (3) human rights NGOs offer little ‘value added’ in the field of economic and social rights in the global North. I conclude by proposing that human rights serve their most useful function when they protect those who few others are willing to defend, such as the vector of disease, the terrorist and the criminal.
Ultrashort-segment Hirschsprung disease in a 4-year-old female
Authors: Rodas Alejandra , Barillas Sabrina , Ardebol Javier
Published: July 2020

Hirschsprung disease (HSCR) is characterized by the absence of neuronal ganglion cells in a distal portion of the intestinal tract [1]. In 1691, Frederick Ruysch described the disease as congenital megacolon. HSCR-associated congenital anomalies have been reported in 5–32% of affected patients [2]. The clinical symptoms of HSCR are usually evident in the neonatal period. However, in some cases where the extent of the aganglionic segment is short, symptoms may become clinically relevant later in childhood [3]. HSCR is one of the most difficult diseases to identify in pediatric surgery due to its multiple clinical, histological and radiological variations [2, 3]. The goal of surgical management is to remove the aganglionic segment and reconstruct the intestinal tract through techniques such as Swenson, Duhamel and Soave [4]. The following case consists of a 4-year-old patient with a chronic presentation of constipation secondary to ultrashort-segment Hirschsprung disease.
How unusual is the Milky Way’s assembly history?
Authors: Evans Tilly A , Fattahi Azadeh , Deason Alis J , Frenk Carlos S
Published: July 2020

In the lambda cold dark matter (ΛCDM) model of structure formation galactic haloes build-up by accretion of mass and mergers of smaller haloes. The most recent massive merger event experienced by the Milky Way (MW) halo was the accretion of the Large Magellanic Cloud (LMC; which has a stellar mass of ∼109M⊙). Recent analyses of galactic stellar data from the Gaia satellite have uncovered an earlier massive accretion event, the Gaia-Enceladus Sausage (GES), which merged with the MW around 10 Gyr ago. Here, we use the EAGLE cosmological hydrodynamics simulation to study properties of simulated MW-mass haloes constrained to have accretion histories similar to that of the MW, specifically the recent accretion of an ‘LMC’ galaxy and a ‘GES’ merger, with a quiescent period between the GES merger and the infall of the LMC (the ‘LMC and GES’ category). We find that ∼16 per cent of MW-mass haloes have an LMC; ∼5 per cent have a GES event and no further merger with an equally massive object since z = 1; and only 0.65 per cent belong to the LMC and GES category. The progenitors of the MWs in this last category are much less massive than average at early times but eventually catch up with the mean. The LMC and GES category of galaxies naturally end up in the ‘blue cloud’ in the colour–magnitude diagram at z = 0, tend to have a disc morphology and have a larger than average number of satellite galaxies.
Bar effect on gas-phase abundance gradients – II. Luminosity-dependent flattening
Authors: Zurita A , Florido E , Bresolin F , Pérez I , Pérez-Montero E
Published: July 2020

We present here the second part of a project that aims at solving the controversy regarding the issue of the bar effect on the radial distribution of metals in the gas-phase of spiral galaxies. In Paper I, we presented a compilation of more than 2800 H ii regions belonging to 51 nearby galaxies for which we derived chemical abundances and radial abundance profiles from a homogeneous methodology. In this paper, we analyse the derived gas-phase radial abundance profiles of 12+log (O/H) and log (N/O), for barred and unbarred galaxies separately, and find that the differences in slope between barred and unbarred galaxies depend on galaxy luminosity. This is due to a different dependence of the abundance gradients (in dex kpc−1) on luminosity for the two types of galaxies: in the galaxy sample under consideration the gradients appear to be considerably shallower for strongly barred galaxies in the whole luminosity range, while profile slopes for unbarred galaxies become steeper with decreasing luminosity. Therefore, we only detect differences in slope for the lower luminosity (lower mass) galaxies (MB ≳ −19.5 or M* ≲ 1010.4 M⊙). We discuss the results in terms of the disc evolution and radial mixing induced by bars and spiral arms. Our results reconcile previous discrepant findings that were biased by the luminosity (mass) distribution of the sample galaxies and possibly by the abundance diagnostics employed.
NRF2 preserves genomic integrity by facilitating ATR activation and G2 cell cycle arrest
Authors: Sun Xiaohui , Wang Yan , Ji Kaihua , Liu Yang , Kong Yangyang , Nie Shasha , Li Na , Hao Jianxiu , Xie Yi , Xu Chang , Du Liqing , Liu Qiang
Published: July 2020

Nuclear factor erythroid 2-related factor 2 (NRF2) is a well-characterized transcription factor that protects cells against oxidative and electrophilic stresses. Emerging evidence has suggested that NRF2 protects cells against DNA damage by mechanisms other than antioxidation, yet the mechanism remains poorly understood. Here, we demonstrate that knockout of NRF2 in cells results in hypersensitivity to ionizing radiation (IR) in the presence or absence of reactive oxygen species (ROS). Under ROS scavenging conditions, induction of DNA double-strand breaks (DSBs) increases the NRF2 protein level and recruits NRF2 to DNA damage sites where it interacts with ATR, resulting in activation of the ATR–CHK1–CDC2 signaling pathway. In turn, this leads to G2 cell cycle arrest and the promotion of homologous recombination repair of DSBs, thereby preserving genome stability. The inhibition of NRF2 by brusatol increased the radiosensitivity of tumor cells in xenografts by perturbing ATR and CHK1 activation. Collectively, our results reveal a novel function of NRF2 as an ATR activator in the regulation of the cellular response to DSBs. This shift in perspective should help furnish a more complete understanding of the function of NRF2 and the DNA damage response.
A Prognostic Gene-Expression Signature and Risk Score for Meningioma Recurrence After Resection
Authors: Chen William C , Vasudevan Harish N , Choudhury Abrar , Pekmezci Melike , Lucas Calixto-Hope G , Phillips Joanna , Magill Stephen T , Susko Matthew S , Braunstein Steve E , Oberheim Bush Nancy Ann , Boreta Lauren , Nakamura Jean L , Villanueva-Meyer Javier E , Sneed Penny K , Perry Arie , McDermott Michael W , Solomon David A , Theodosopoulos Philip V , Raleigh David R
Published: July 2020

BACKGROUND

Prognostic markers for meningioma are needed to risk-stratify patients and guide postoperative surveillance and adjuvant therapy.

OBJECTIVE

To identify a prognostic gene signature for meningioma recurrence and mortality after resection using targeted gene-expression analysis.

METHODS

Targeted gene-expression analysis was used to interrogate a discovery cohort of 96 meningiomas and an independent validation cohort of 56 meningiomas with comprehensive clinical follow-up data from separate institutions. Bioinformatic analysis was used to identify prognostic genes and generate a gene-signature risk score between 0 and 1 for local recurrence.

RESULTS

We identified a 36-gene signature of meningioma recurrence after resection that achieved an area under the curve of 0.86 in identifying tumors at risk for adverse clinical outcomes. The gene-signature risk score compared favorably to World Health Organization (WHO) grade in stratifying cases by local freedom from recurrence (LFFR, P < .001 vs .09, log-rank test), shorter time to failure (TTF, F-test, P < .0001), and overall survival (OS, P < .0001 vs .07) and was independently associated with worse LFFR (relative risk [RR] 1.56, 95% CI 1.30-1.90) and OS (RR 1.32, 95% CI 1.07-1.64), after adjusting for clinical covariates. When tested on an independent validation cohort, the gene-signature risk score remained associated with shorter TTF (F-test, P = .002), compared favorably to WHO grade in stratifying cases by OS (P = .003 vs P = .10), and was significantly associated with worse OS (RR 1.86, 95% CI 1.19-2.88) on multivariate analysis.

CONCLUSION

The prognostic meningioma gene-expression signature and risk score presented may be useful for identifying patients at risk for recurrence.
The Effects of Competition and Entry in Multi-sided Markets
Authors: Tan Guofu , Zhou Junjie
Published: July 2020

We study price competition and entry of platforms in multi-sided markets. Utilizing the simplicity of the equilibrium pricing formula in our setting with heterogeneity of customers’ membership benefits, we demonstrate that in the presence of externalities, the standard effects of competition can be reversed: as platform competition increases, prices, and platform profits can go up and consumer surplus can go down. We identify economic forces that jointly determine the social inefficiency of the free-entry equilibrium and provide conditions under which free entry is socially excessive as well as an example in which free entry is socially insufficient.
Building the City: From Slums to a Modern Metropolis
Authors: Henderson J Vernon , Regan Tanner , Venables Anthony J
Published: July 2020

We model the building of a city, estimate parameters of the model, and calculate welfare losses from institutional frictions encountered in changing land-use. We distinguish formal and slum construction technologies; in contrast to slums, formal structures can be built tall, are durable, and non-malleable. As the city grows areas are initially developed informally, then formally, and then redeveloped periodically. Slums are modelled as a technology choice; however, institutional frictions in land markets may hinder their conversion to formal usage that requires secure property rights. Using unique data on Nairobi for 2003 and 2015, we develop a novel set of facts that support assumptions of the model, estimate all parameters of the model, and calculate welfare losses of conversion frictions. We track the dynamic evolution of the city and compare it with model predictions. In the core city formal sector, about a third of buildings were torn down over 12 years and replaced by buildings on average three times higher. For slums in older areas near the centre, even after buying out slumlords, overcoming institutional frictions would yield gains amounting to about ${\$}$18,000 per slum household, thirty times typical annual slum rent payments.
Individual and familial characteristics of patients with podoconiosis attending a clinic in Musanze District, Rwanda: A retrospective study
Authors: Bikorimana Jean Paul , Bayisenge Ursin , Huston Tonya , Ruberanziza Eugene , Mbonigaba Jean Bosco , Dukuzimana Marie Josee , Davey Gail
Published: July 2020

Background

Podoconiosis is a progressive swelling of the legs affecting genetically susceptible people who live in areas with irritant red clay soils and walk barefoot. The disease is a public health concern in many countries, including Rwanda.

Methods

This retrospective study described individual and familial characteristics of patients with podoconiosis attending the Heart and Sole Africa (HASA) clinics in Rwanda. Data on patient characteristics and family history were retrieved from electronic medical records (January 2013 – August 2019). A multiple regression analysis was used to explore factors influencing age of onset of podoconiosis.

Results

Among 467 patients with podoconiosis, the mean (standard deviation) age of onset was 34.4 (19.6) years, 139 (29.8%) patients developed podoconiosis at <20 years of age, 417 (89%) came from Musanze or neighboring Burera Districts, and 238 (51.0%) had a family history of podoconiosis. Increasing patient age was associated with older age at onset of disease (p<0.001), while an increased number of relatives with podoconiosis (p<0.002) was significantly associated with earlier disease onset.

Conclusion

Most patients with podoconiosis were women, and more than half had a family history of podoconiosis. An increased number of relatives with podoconiosis was associated with a significantly younger age at disease onset.
Complete Genome Sequencing Provides Novel Insight Into the Virulence Repertories and Phylogenetic Position of Dry Beans PathogenCurtobacterium flaccumfacienspv.flaccumfaciens
Authors: Chen Gongyou , Khojasteh Moein , Taheri-Dehkordi Ayat , Taghavi S. Mohsen , Rahimi Touraj , Osdaghi Ebrahim
Published: July 2020

Bacterial wilt of dry beans (family Fabaceae) caused by the actinobacterial agent Curtobacterium flaccumfaciens pv. flaccumfaciens is one of the most important diseases threatening edible legume production around the globe. Despite the economic losses due to the bacterial wilt disease, the pathogen has not so far been investigated for its genomic features, pathogenicity determinants, and virulence strategies. Here we present the first complete genome sequence of a highly virulent bacteriocin-producing C. flaccumfaciens pv. flaccumfaciens strain P990. The bacterium has a circular chromosome consisting of 3,736 kbp with the G+C% content of 71.0%. Furthermore, a 147-kbp circular plasmid (pCff1) with 66.1% G+C% content as well as two circular plasmid-like DNAs with sizes of 25 and 22 kbp were detected within the genomic contents of C. flaccumfaciens pv. flaccumfaciens. Phylogenetic analyses revealed that only a few number of Curtobacterium sp. strains deposited in the public databases could be classified within the species C. flaccumfaciens. Comparative genomics of C. flaccumfaciens pv. flaccumfaciens using the genome sequences of actinobacterial plant pathogens revealed the presence of a set of unique low G+C% content genomic islands in the C. flaccumfaciens pv. flaccumfaciens genome. Homologs of pathogenicity-determinant loci capable of producing 1,4-beta-xylanase (xysA), pectate lyase (pelA1 and pelA2), serine protease (chpC, chpG, and pat-1), and sortase (srtA) were detected in C. flaccumfaciens pv. flaccumfaciens genome. The genomic data presented here extend our understanding of the C. flaccumfaciens pv. flaccumfaciens genomic features and pave the ways of research on functional and interaction genetics to combat the risk of bacterial wilt disease in the 21st century’s dry bean industry.
Religion and Spirituality, Meaning, and Faith in American Psychiatry From the 19th to the 21st Century
Authors: Hirshbein Laura
Published: July 2020

Since the beginning of American psychiatry, we have discovered and rediscovered connections among religion, spirituality, meaning, and mental health. In the 19th century, religion was an embedded attribute of moral therapy, the framework for treatment in mental institutions. During the decades in the 20th century when psychoanalysis was ascendant in the profession, some psychiatrists collaborated with the emerging field of pastoral care. As biological psychiatry has come to dominate the profession, though, pastoral care providers and some psychiatric researchers have identified gaps in the human interactions that characterize ideal and meaningful encounters with patients. This article examines how religion has been mobilized in American psychiatry over the centuries within institutional settings, but also looks at a broad consideration of faith in psychiatrists' clinical interventions, how that has affected their interactions with religious ideas and people, and where they have found meaning and purpose in mental health care.
Numerical modelling of hydrodynamics and tidal energy extraction in the Alderney Race: a review
Authors: Thiébot Jérôme , Coles D. S. , Bennis Anne-Claire , Guillou Nicolas , Neill Simon , Guillou Sylvain , Piggott Matthew
Published: July 2020

The tides are a predictable, renewable, source of energy that, if harnessed, can provide significant levels of electricity generation. The Alderney Race (AR), with current speeds that exceed 5 m s
−1
during spring tides, is one of the most concentrated regions of tidal energy in the world, with the upper-bound resource estimated at 5.1 GW. Owing to its significance, the AR is frequently used for model case studies of tidal energy conversion, and here we review these model applications and outcomes. We examine a range of temporal and spatial modelling scales, from regional models applied to resource assessment and characterization, to more detailed models that include energy extraction and array optimization. We also examine a range of physical processes that influence the tidal energy resource, including the role of waves and turbulence in tidal energy resource assessment and loadings on turbines. The review discusses model validation, and covers a range of numerical modelling approaches, from two-dimensional to three-dimensional tidal models, two-way coupled wave-tide models, Large Eddy Simulation (LES) models, and the application of optimization techniques. The review contains guidance on model approaches and sources of data that can be used for future studies of the AR, or translated to other tidal energy regions.

This article is part of the theme issue ‘New insights on tidal dynamics and tidal energy harvesting in the Alderney Race’.
Identifying economically viable tidal sites within the Alderney Race through optimization of levelized cost of energy
Authors: Goss Z. L. , Coles D. S. , Piggott M. D.
Published: July 2020

Costs of tidal stream energy generation are anticipated to fall considerably with array expansion and time. This is due to both economies of volume, where arrays comprising of large numbers of turbines can split fixed costs over a greater number of devices, and learning rates, where the industry matures and so arrays of the same size become cheaper due to lessons learned from previous installations. This paper investigates how tidal energy arrays can be designed to minimize the levelized cost of energy (LCOE), by optimizing not only the location but also the number of devices, to find a suitable balance between decreased costs due to economies of volume and diminishing returns due to global blockage effects. It focuses on the Alderney Race as a case study site due to the high velocities found there, making it a highly suitable site for large-scale arrays. It is demonstrated that between 1 and 2 GW could be feasibly extracted as costs in the tidal industry fall, with the LCOE depending greatly on the assumed costs. A Monte–Carlo analysis is undertaken to account for variability in capital and operational cost data used as inputs to the array optimization. Once optimized, the estimated P50 LCOE of an 80 MW array is £110/MWh. This estimate aligns closely with the level of subsidy considered for tidal stream projects in the Alderney Race in the past.

This article is part of the theme issue ‘New insights on tidal dynamics and tidal energy harvesting in the Alderney Race’.
Population Data-Driven Formulation of a COVID-19 Therapeutic
Authors: Campbell Heather R. , Cecil Regan , Lodder Robert A.
Published: July 2020

This study is designed to utilize computer modeling of the US population through NHANES to reduce the need for preclinical formulation and toxicology studies of an Ebola anti-viral (BSN389) being repurposed for COVID-19, and to thereby speed the candidate therapeutic to the clinic.
COVID-19 Patients Form Memory CD8+ T Cells that Recognize a Small Set of Shared Immunodominant Epitopes in SARS-CoV-2
Authors: Ferretti Andrew P. , Kula Tomasz , Wang Yifan , Nguyen Dalena M.V. , Weinheimer Adam , Dunlap Garrett S. , Xu Qikai , Nabilsi Nancy , Perullo Candace R. , Cristofaro Alexander W. , Whitton Holly J. , Virbasius Amy , Olivier Kenneth J. , Baiamonte Lyndsey B. , Alistar Angela T. , Whitman Eric D. , Bertino Sarah A. , Chattopadhyay Shrikanta , MacBeath Gavin
Published: July 2020

Development of effective strategies to detect, treat, or prevent COVID-19 requires a robust understanding of the natural immune response to SARS-CoV-2, including the cellular response mediated by T cells. We used an unbiased, genome-wide screening technology, termed T-Scan, to identify specific epitopes in SARS-CoV-2 that are recognized by the memory CD8+ T cells of 25 COVID-19 convalescent patients, focusing on epitopes presented by the six most prevalent HLA types: A*02:01, A*01:01, A*03:01, A*11:01, A*24:02, and B*07:02. For each HLA type, the patients’ T cells recognized 3–8 immunodominant epitopes that are broadly shared among patients. Remarkably, 94% of screened patients had T cells that recognized at least one of the three most dominant epitopes for a given HLA, and 53% of patients had T cells that recognized all three. Subsequent validation studies in 18 additional A*02:01 patients confirmed the presence of memory CD8+ T cells specific for the top six A*02:01 epitopes, and single-cell sequencing revealed that patients often have many different T cell clones targeting each epitope, but that the same T cell receptor Vα regions are predominantly used to recognize these epitopes, even across patients. In total, we identified 29 shared epitopes across the six HLA types studied. T cells that target most of these epitopes (27 of 29) do not cross-react with the endemic coronaviruses that cause the common cold, and the epitopes do not occur in regions with high mutational variation. Notably, only 3 of the 29 epitopes reside in the spike protein, highlighting the need to design new classes of vaccines that recapitulate natural CD8+ T cell responses to SARS-CoV-2.
SEIHCRD Model for COVID-19 spread scenarios, disease predictions and estimates the basic reproduction number, case fatality rate, hospital, and ICU beds requirement
Authors: Singh Avaneesh , Bajpai Manish Kumar
Published: July 2020

We have proposed a new mathematical method, SEIHCRD-Model that is an extension of the SEIR-Model adding hospitalized and critical two-compartments. SEIHCRD model has seven compartments: susceptible (S), exposed (E), infected (I), hospitalized (H), critical (C), recovered (R), and deceased or death (D), collectively termed SEIHCRD. We have studied COVID-19 cases of six countries, where the impact of this disease in the highest are Brazil, India, Italy, Spain, the United Kingdom, and the United States. SEIHCRD model is estimating COVID-19 spread and forecasting under uncertainties, constrained by various observed data in the present manuscript. We have first collected the data for a specific period, then fit the model for death cases, got the values of some parameters from it, and then estimate the basic reproduction number over time, which is nearly equal to real data, infection rate, and recovery rate of COVID-19. We also compute the case fatality rate over time of COVID-19 most affected countries. SEIHCRD model computes two types of Case fatality rate one is CFR daily and the second one is total CFR. We analyze the spread and endpoint of COVID-19 based on these estimates. SEIHCRD model is time-dependent hence we estimate the date and magnitude of peaks of corresponding to the number of exposed cases, infected cases, hospitalized cases, critical cases, and the number of deceased cases of COVID-19 over time. SEIHCRD model has incorporated the social distancing parameter, different age groups analysis, number of ICU beds, number of hospital beds, and estimation of how much hospital beds and ICU beds are required in near future.
Effects of individual base-pairs onin vivotarget search and destruction kinetics of small RNA
Authors: Poddar Anustup , Azam Muhammad S. , Kayikcioglu Tunc , Bobrovskyy Maksym , Zhang Jichuan , Ma Xiangqian , Labhsetwar Piyush , Fei Jingyi , Singh Digvijay , Luthey-Schulten Zaida , Vanderpool Carin K. , Ha Taekjip
Published: July 2020

Base-pairing interactions mediate intermolecular target recognition in many biological systems and applications, including DNA repair, CRISPR, microRNA, small RNA (sRNA) and antisense oligo therapies. Even a single base-pair mismatch can cause a substantial difference in biological activity but presently we do not yet know how the target search kineticsin vivoare influenced by single nucleotide level changes. Here, we used high-throughput sequencing to identify functionally relevant single point mutants of the bacterial sRNA, SgrS, and quantitative super-resolution microscopy to probe the mutational impact on the regulation of its primary target,ptsGmRNA. Our super-resolution imaging and analysis platform allowed us to further dissect mutational effects on SgrS lifetimes, and even subtle changes in thein vivorates of target association,kon, and dissociation,koff. Mutations that disrupt binding of a chaperone protein, Hfq, and are distal to the mRNA annealing region still decreasedkonand increasedkoff, providing anin vivodemonstration that Hfq directly facilitates sRNA-mRNA annealing. Single base-pair mismatches in the annealing region reducedkonby 24-31% and increasedkoffby 14-25%, extending the time it takes to find and destroy the target mRNA by about a third, depending on whether an AU or GC base-pair is disrupted. The effects of disrupting contiguous base-pairing are much more modest than that expected from thermodynamics, suggesting that Hfq also buffers base-pair disruptions.