bluuebunny/crossref_metadata_2025_split huggingface dataset:
How to do (or not to do)…using causal loop diagrams for health system research in low and middle-income settings
Authors: Cassidy Rachel , Borghi Josephine , Semwanga Agnes Rwashana , Binyaruka Peter , Singh Neha S , Blanchet Karl 
Published: August 2022

Abstract
Causal loop diagrams (CLDs) are a systems thinking method that can be used to visualize and unpack complex health system behaviour. They can be employed prospectively or retrospectively to identify the mechanisms and consequences of policies or interventions designed to strengthen health systems and inform discussion with policymakers and stakeholders on actions that may alleviate sub-optimal outcomes. Whilst the use of CLDs in health systems research has generally increased, there is still limited use in low- and middle-income settings. In addition to their suitability for evaluating complex systems, CLDs can be developed where opportunities for primary data collection may be limited (such as in humanitarian or conflict settings) and instead be formulated using secondary data, published or grey literature, health surveys/reports and policy documents. The purpose of this paper is to provide a step-by-step guide for designing a health system research study that uses CLDs as their chosen research method, with particular attention to issues of relevance to research in low- and middle-income countries (LMICs). The guidance draws on examples from the LMIC literature and authors’ own experience of using CLDs in this research area. This paper guides researchers in addressing the following four questions in the study design process; (1) What is the scope of this research? (2) What data do I need to collect or source? (3) What is my chosen method for CLD development? (4) How will I validate the CLD? In providing supporting information to readers on avenues for addressing these key design questions, authors hope to promote CLDs for wider use by health system researchers working in LMICs.
Huntingtin turnover: modulation of huntingtin degradation by cAMP-dependent protein kinase A (PKA) phosphorylation of C-HEAT domain Ser2550
Authors: Lee Yejin , Kim Hyeongju , Barker Douglas , Vijayvargia Ravi , Atwal Ranjit Singh , Specht Harrison , Keshishian Hasmik , Carr Steven A , Lee Ramee , Kwak Seung , Hyun Kyung-gi , Loupe Jacob , MacDonald Marcy E , Song Ji-Joon , Seong Ihn Sik 
Published: July 2022

Abstract
Huntington’s disease (HD) is a neurodegenerative disorder caused by an inherited unstable HTT CAG repeat that expands further, thereby eliciting a disease process that may be initiated by polyglutamine-expanded huntingtin or a short polyglutamine-product. Phosphorylation of selected candidate residues is reported to mediate polyglutamine-fragment degradation and toxicity. Here to support the discovery of phosphosites involved in the life-cycle of (full-length) huntingtin, we employed mass spectrometry-based phosphoproteomics to systematically identify sites in purified huntingtin and in the endogenous protein by proteomic and phosphoproteomic analyses of members of an HD neuronal progenitor cell panel. Our results bring total huntingtin phosphosites to 95, with more located in the N-HEAT domain relative to numbers in the Bridge and C-HEAT domains. Moreover, phosphorylation of C-HEAT Ser2550 by cAMP-dependent protein kinase (PKA), the top hit in kinase activity screens, was found to hasten huntingtin degradation, such that levels of the catalytic subunit (PRKACA) were inversely related to huntingtin levels. Taken together, these findings highlight categories of phosphosites that merit further study and provide a phosphosite kinase pair (pSer2550-PKA) with which to investigate the biological processes that regulate huntingtin degradation and thereby influence the steady state levels of huntingtin in HD cells.
A novel mouse model of CMT1B identifies hyperglycosylation as a new pathogenetic mechanism
Authors: Veneri Francesca A , Prada Valeria , Mastrangelo Rosa , Ferri Cinzia , Nobbio Lucilla , Passalacqua Mario , Milanesi Maria , Bianchi Francesca , Del Carro Ubaldo , Vallat Jean-Michel , Duong Phu , Svaren John , Schenone Angelo , Grandis Marina , D’Antonio Maurizio 
Published: July 2022

Abstract
Mutations in the Myelin Protein Zero gene (MPZ), encoding P0, the major structural glycoprotein of peripheral nerve myelin, are the cause of Charcot–Marie-Tooth (CMT) type 1B neuropathy, and most P0 mutations appear to act through gain-of-function mechanisms. Here, we investigated how misglycosylation, a pathomechanism encompassing several genetic disorders, may affect P0 function. Using in vitro assays, we showed that gain of glycosylation is more damaging for P0 trafficking and functionality as compared with a loss of glycosylation. Hence, we generated, via CRISPR/Cas9, a mouse model carrying the MPZD61N mutation, predicted to generate a new N-glycosylation site in P0. In humans, MPZD61N causes a severe early-onset form of CMT1B, suggesting that hyperglycosylation may interfere with myelin formation, leading to pathology. We show here that MPZD61N/+ mice develop a tremor as early as P15 which worsens with age and correlates with a significant motor impairment, reduced muscular strength and substantial alterations in neurophysiology. The pathological analysis confirmed a dysmyelinating phenotype characterized by diffuse hypomyelination and focal hypermyelination. We find that the mutant P0D61N does not cause significant endoplasmic reticulum stress, a common pathomechanism in CMT1B, but is properly trafficked to myelin where it causes myelin uncompaction. Finally, we show that myelinating dorsal root ganglia cultures from MPZD61N mice replicate some of the abnormalities seen in vivo, suggesting that they may represent a valuable tool to investigate therapeutic approaches. Collectively, our data indicate that the MPZD61N/+ mouse represents an authentic model of severe CMT1B affirming gain-of-glycosylation in P0 as a novel pathomechanism of disease.
SOX9 and SRY binding sites on mouse mXYSRa/Enh13 enhancer redundantly regulate Sox9 expression to varying degrees
Authors: Ogawa Yuya , Terao Miho , Tsuji-Hosokawa Atsumi , Tsuchiya Iku , Hasegawa Midori , Takada Shuji 
Published: August 2022

Abstract
Sox9 plays an essential role in mammalian testis formation. It has been reported that gene expression in the testes is regulated by enhancers. Among them, mXYSRa/Enh13—which is located at far upstream of the transcription start site—plays a critical role, wherein its deletion causes complete male-to-female sex reversal in mice. It has been proposed that the binding sites (BSs) of SOX9 and SRY, the latter of which is the sex determining gene on the Y chromosome, are associated with mXYSRa/Enh13. They function as an enhancer, whereby the sequences are evolutionarily conserved and in vivo binding of SOX9 and SRY to mXYSRa/Enh13 has been demonstrated previously. However, their precise in vivo functions have not been examined to date. To this end, this study generated mice with substitutions on the SOX9 and SRY BSs to reveal their in vivo functions. Homozygous mutants of SOX9 and SRY BS were indistinguishable from XY males, whereas double mutants had small testes, suggesting that these functions are redundant and that there is another functional sequence on mXYSRa/Enh13, since mXYSRa/Enh13 deletion mice are XY females. In addition, the majority of hemizygous mice with substitutions in SOX9 BS and SRY BS were female and male, respectively, suggesting that SOX9 BS contributes more to SRY BS for mXYSRa/Enh13 to function. The additive effect of SOX9 and SRY via these BSs was verified using an in vitro assay. In conclusion, SOX9 BS and SRY BS function redundantly in vivo, and at least one more functional sequence should exist in mXYSRa/Enh13.
Tumor suppressor genes are reactivated by miR-26A1 via enhancer reprogramming in NSCLC
Authors: Li Hongling , Da Dezhuan , Yu Wenqiang , Chen Lu , Yang Shuai , Zhang Baolong , Wang Yongying , Li Linyu , Dang Chunyan 
Published: August 2022

Abstract
Non-small cell lung cancer (NSCLC) is one of the most malignant epithelial tumors. Studies have suggested that DNA hypermethylation of promoters and abnormal histone modifications could induce tumor suppressor genes (TSGs) downregulation in NSCLC. However, the exact mechanism of TSGs downregulation remains unclear. In this study, we found that there is no difference in the regions of most TSGs promoters in NSCLC. Moreover, we found that there is no DNA methylation difference in the region of VILL promoter in NSCLC compared with adjacent tissue samples by pyrosequencing. We further demonstrated that VILL was markedly reactivated in A549 and H1703 cells infected with miR-26A1 lentivirus while this activation was inhibited by JQ1, an enhancer inhibitor. In addition, we identified that miR-26A1 could function as a tumor suppressor to inhibit proliferation and metastasis of NSCLC cells. Chromatin immunoprecipitation assays revealed that overexpression of miR-26A1 could significantly induce the enrichment of H3K27ac at the enhancer regions in A549 cells. To sum up, our findings revealed that enhancer-mediated TSGs regulation occured in NSCLC, suggesting that miR-26A1 could serve as a key regulator and may be a potential therapeutic target for NSCLC.
Making Sense of China's Belt and Road Initiative: A Review Essay
Authors: Hall Todd H , Krolikowski Alanna 
Published: August 2022

AbstractAlthough less than a decade old, the People's Republic of China's (PRC) Belt and Road Initiative (BRI) has been the subject of considerable attention and conjecture. After initial waves of speculation and punditry, now more rigorous work on the plans, structure, and implementation of this initiative is beginning to contribute to the debate. In this essay, we showcase how three recent monographs make sense of the BRI: One Belt One Road: Chinese Power Meets the World, by Eyck Freymann; The Belt Road and Beyond: State-Mobilized Globalization in China: 1998–2018, by Min Ye; and Orchestration: China's Economic Statecraft across Asia and Europe, by James Reilly. Surveying the arguments and findings of these works together, we seek to draw out insights and implications for how we should understand the BRI. In particular, we highlight the political significance of the BRI's close association with PRC leader Xi Jinping, the ways in which the BRI follows long-standing patterns of campaign-style mobilization within the PRC, the crucial role of local partners, and the BRI's potential consequences for the larger international system in light of the broader literature in international relations. We conclude by discussing the need to now also consider unintended outcomes.
The Magnitude Heuristic: Larger Differences Increase Perceived Causality
Authors: Daniels David P , Kupor Daniella 
Published: August 2022

AbstractWith the rise of machine learning and “big data,” many large yet spurious relationships between variables are discovered, leveraged by marketing communications, and publicized in the media. Thus, consumers are increasingly exposed to many large-magnitude relationships between variables that do not signal causal effects. This exposure may carry a substantial cost. Seven studies demonstrate that the magnitudes of relationships between variables can distort consumers’ judgments about whether those relationships reflect causal effects. Specifically, consumers often use a magnitude heuristic: consumers infer that relationships with larger perceived magnitudes are more likely to reflect causal effects, even when this is not true (and even when relationships’ correlations are held constant). In many situations, relying on the magnitude heuristic will distort causality judgments, such as when large-magnitude relationships between variables are spurious, or when normatively extraneous factors (e.g., reference points) distort perceptions of magnitudes. Moreover, magnitude-distorted (mis)perceptions of causality, in turn, distort consumers’ purchase and consumption decisions. Since consumers often encounter spurious relationships with large magnitudes in the health domain and in other consequential domains, the magnitude heuristic is likely to lead to biases in some of consumers’ most important decisions.
Real-world effectiveness of nivolumab plus ipilimumab and second-line therapy in Japanese untreated patients with metastatic renal cell carcinoma: 2-year analysis from a multicenter retrospective clinical study (J-cardinal study)
Authors: Kojima Takahiro , Kato Renpei , Sazuka Tomokazu , Yamamoto Hayato , Fukuda Shohei , Yamana Kazutoshi , Nakaigawa Noboru , Sugino Yusuke , Hamamoto Shuzo , Ito Hiroaki , Murakami Hiroshi , Obara Wataru 
Published: August 2022

Abstract

Background
Nivolumab plus ipilimumab combination therapy is one of the standard therapies for untreated renal cell carcinoma patients with an International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor risk. We have previously reported the 1-year analysis results of the effectiveness and safety of nivolumab plus ipilimumab combination therapy in the real-world setting in Japan. Here, we report the effectiveness of nivolumab plus ipilimumab combination therapy and of second-line therapy, using 2-year analysis.

Methods
This retrospective observational study enrolled Japanese patients with previously untreated metastatic renal cell carcinoma who initiated nivolumab plus ipilimumab combination therapy between August 2018 and January 2019. Data were collected from patients’ medical records at baseline and at 3 months, 1 year and 2 years after the last enrollment.

Results
Of the 45 patients enrolled, 10 patients (22.2%) each had non-clear cell renal cell carcinoma and Eastern Cooperative Oncology Group performance status ≥2 at baseline. Median follow-up period was 24.0 months; objective response rate was 41.5%, with 6 patients achieving complete response; median progression-free survival was 17.8 months and 24-month progression-free survival and overall survival rates were 41.6 and 59.1%, respectively. Second-line therapy achieved an objective response rate of 20%; median progression-free survival was 9.8 months. Median progression-free survival 2 was 26.4 months.

Conclusions
The effectiveness of nivolumab plus ipilimumab combination therapy at 2-year analysis in the real-world setting in Japan was comparable to that reported in CheckMate 214. The current analysis also demonstrated the effectiveness of second-line therapy after nivolumab plus ipilimumab combination therapy.
Discoidin Domain Receptor-Driven Gene Signatures as Markers of Patient Response to Anti–PD-L1 Immune Checkpoint Therapy
Authors: You Sungyong , Kim Minhyung , Hoi Xen Ping , Lee Yu Cheng , Wang Li , Spetzler David , Abraham Jim , Magee Dan , Jain Prerna , Galsky Matthew D , Chan Keith Syson , Theodorescu Dan 
Published: August 2022

Abstract

Background
Anti–programmed cell death 1 (anti–PD-1) and PD ligand 1 (PD-L1) immune checkpoint therapies (ICTs) provided durable responses only in a subset of cancer patients. Thus, biomarkers are needed to predict nonresponders and offer them alternative treatments. We recently implicated discoidin domain receptor tyrosine kinase 2 (DDR2) as a contributor to anti–PD-1 resistance in animal models; therefore, we sought to investigate whether this gene family may provide ICT response prediction.

Methods
We assessed mRNA expression of DDR2 and its family member DDR1. Transcriptome analysis of bladder cancer (BCa) models in which DDR1 and 2 were perturbed was used to derive DDR1- and DDR2-driven signature scores. DDR mRNA expression and gene signature scores were evaluated using BCa–The Cancer Genome Atlas (n = 259) and IMvigor210 (n = 298) datasets, and their relationship to BCa subtypes, pathway enrichment, and immune deconvolution analyses was performed. The potential of DDR-driven signatures to predict ICT response was evaluated and independently validated through a statistical framework in bladder and lung cancer cohorts. All statistical tests were 2-sided.

Results
DDR1 and DDR2 showed mutually exclusive gene expression patterns in human tumors. DDR2high BCa exhibited activation of immune pathways and a high immune score, indicative of a T-cell–inflamed phenotype, whereas DDR1high BCa exhibited a non–T-cell–inflamed phenotype. In IMvigor210 cohort, tumors with high DDR1 (hazard ratio [HR] = 1.53, 95% confidence interval [CI] = 1.16 to 2.06; P = .003) or DDR2 (HR = 1.42, 95% CI = 1.01 to 1.92; P = .04) scores had poor overall survival. Of note, DDR2high tumors from IMvigor210 and CheckMate 275 (n = 73) cohorts exhibited poorer overall survival (HR = 1.56, 95% CI = 1.20 to 2.06; P &lt; .001) and progression-free survival (HR = 1.77 95%, CI = 1.05 to 3.00; P = .047), respectively. This result was validated in independent cancer datasets.

Conclusions
These findings implicate DDR1 and DDR2 driven signature scores in predicting ICT response.
Compact groups in GDM cosmological simulations
Authors: López-Sánchez Jessica N , Munive-Villa Erick , Avilez-López Ana , Martínez-Bravo Oscar M 
Published: July 2022

ABSTRACT
In this work, we study some properties of the Hickson Compact Groups (HCGs) using N-body simulations for the Generalized Dark Matter (GDM) model, described by three free functions, the sound speed, the viscosity, and the equation of state. We consider three GDM models associated with different values of the free functions to neglect collisional effects. We constructed the initial seeds of our simulations according to the matter power spectrum of GDM linear perturbations, which hold a cut-off at small scales, and explored their effects on the non-linear structure formation at small and intermediate scales. We generated mock catalogues of galaxies for different models and classified HCGs by implementing an algorithm that adapts the original selection method for mock catalogues. Once the HCGs samples were classified, we analysed their properties and compared them between models. We found that a larger amount of HCGs are counted in GDM simulations in comparison to CDM counts. This difference suggests that HCGs can proliferate within GDM despite the suppressed substructure, which indicates a possible modification in the HCG formation process within models where DM is not perfectly like CDM. Additionally, we identified different mechanisms of clustering, for models with a large amount of galaxy-haloes self-agglomerate because of their abundance while models with fewer galaxy-haloes need massive haloes acting as a dominant potential well. Finally, by comparing distributions of different observables of simulated HCGs against observations, we found a good agreement in the intrinsic properties. However, a discrepancy in the velocity dispersion remains unsolved.
Bayesian hierarchical modelling of the M*–SFR relation from 1 ≲ z ≲ 6 in ASTRODEEP
Authors: Sandles L , Curtis-Lake E , Charlot S , Chevallard J , Maiolino R 
Published: July 2022

ABSTRACT
The Hubble Frontier Fields represent the opportunity to probe the high-redshift evolution of the main sequence of star-forming galaxies to lower masses than possible in blank fields thanks to foreground lensing of massive galaxy clusters. We use the beagle SED-fitting code to derive stellar masses, $\rm{{M_{\star }}}=\log ({\it M}/{\rm{M_{\odot }}})$, SFRs, $\rm{{\Psi }}=\log (\rm{{\psi }}/{\rm{M_{\odot }}}\, {\rm{yr}}^{-1})$, and redshifts from galaxies within the astrodeep catalogue. We fit a fully Bayesian hierarchical model of the main sequence over 1.25 &lt; z &lt; 6 of the form $\rm{{\Psi }}= \rm{\alpha _\mathrm{9.7}}(z) + \rm{\beta }({\rm{M_{\star }}}-9.7) + \mathcal {N}(0,\rm{\sigma }^2)$ while explicitly modelling the outlier distribution. The redshift-dependent intercept at $\rm{{M_{\star }}}=9.7$ is parametrized as $\rm{\alpha _\mathrm{9.7}}(z) = \log [{\it N}(1+{\it z})^{\rm{\gamma }}] + 0.7$. Our results agree with an increase in normalization of the main sequence to high redshifts that follows the redshift-dependent rate of accretion of gas on to dark matter haloes with $\rm{\gamma }=2.40^{+0.18}_{-0.18}$. We measure a slope and intrinsic scatter of $\rm{\beta }=0.79^{+0.03}_{-0.04}$ and $\rm{\sigma }=0.26^{+0.02}_{-0.02}$. We find that the sampling of the SED provided by the combination of filters (Hubble + ground-based Ks-band + Spitzer 3.6 and 4.5 μm) is insufficient to constrain M⋆ and Ψ over the full dynamic range of the observed main sequence, even at the lowest redshifts studied. While this filter set represents the best current sampling of high-redshift galaxy SEDs out to z &gt; 3, measurements of the main sequence to low masses and high redshifts still strongly depend on priors employed in SED fitting (as well as other fitting assumptions). Future data sets with JWST should improve this.
Photometric characterization and trajectory accuracy of Starlink satellites: implications for ground-based astronomical surveys
Authors: Halferty Grace , Reddy Vishnu , Campbell Tanner , Battle Adam , Furfaro Roberto 
Published: July 2022

ABSTRACT
Starlink is a low-Earth orbit (LEO) satellite constellation operated by Space Exploration Technologies Corp. (SpaceX) which aims to provide global satellite internet access. Thus far, most photometric observations of Starlink satellites have primarily been from citizen scientists’ visual observations without using quantitative detectors. This paper aims to characterize Starlink satellites and investigate the impact of mega constellations on ground-based astronomy, considering both the observed magnitude and two-line element (TLE) residuals. We collected 353 observations of 61 different Starlink satellites over a 16-month period and we found an average GAIA G magnitude of 5.5 ± 0.13 with a standard deviation of 1.12. The average magnitude of V1.0 (pre-VisorSat) Starlinks was 5.1 ± 0.13 with a standard deviation of 1.13. SpaceX briefly used a low-albedo coating on a Starlink satellite called DarkSat to test light pollution mitigation technologies. The brightness of DarkSat was found to be 7.3 ± 0.13 with a standard deviation of 0.78, or 7.6 times fainter than V1.0 Starlinks. This concept was later abandoned due to thermal control issues and sun visors were used in future models called VisorSats. The brightness of VisorSats was found to be 6.0 ± 0.13 with a standard deviation of 0.79, or 2.3 times fainter than V1.0 Starlinks. Over the span of the observations, we found that TLEs were accurate to within an average of 0.12 deg in right ascension and –0.08 deg in declination. The error is predominantly along-track, corresponding to a 0.3 s time error between the observed and TLE trajectories. Our observations show that a time difference of 0.3 ± 0.28 s is viable for a proposed 10 s shutter closure time to avoid Starlinks in images.