bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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

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

Although 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

With 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

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

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 < .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

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

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 < z < 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 > 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

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.
The distribution of dust in edge-on galaxies: I. The global structure
Authors: Mosenkov Aleksandr V , Usachev Pavel A , Shakespear Zacory , Guerrette Jacob , Baes Maarten , Bianchi Simone , Xilouris Emmanuel M , Gontcharov George A , Il’in Vladimir B , Marchuk Alexander A , Savchenko Sergey S , Smirnov Anton A
Published: July 2022

In this first paper in a series we present a study of the global dust emission distribution in nearby edge-on spiral galaxies. Our sample consists of 16 angularly large and 13 less spatially resolved galaxies selected from the DustPedia sample. To explore the dust emission distribution, we exploit the Herschel photometry in the range 100–500 $\mu $m. We employ Sérsic and 3D disc models to fit the observed 2D profiles of the galaxies. Both approaches give similar results. Our analysis unequivocally states the case for the presence of extraplanar dust in between 6 and 10 large galaxies. The results reveal that both the disc scale length and height increase as a function of wavelength between 100 and 500 $\mu $m. The dust disc scale height positively correlates with the dust disc scale length, similar to what is observed for the stellar discs. We also find correlations between the scale lengths and scale heights in the near- and far-infrared which suggest that the stellar discs and their dust counterparts are tightly connected. Furthermore, the intrinsic flattening of the dust disc is inversely proportional to the maximum rotation velocity and the dust mass of the galaxy: more massive spiral galaxies host, on average, relatively thinner dust discs. Also, there is a tendency for the dust-to-stellar scale height ratio to decrease with the dust mass and rotation velocity. We conclude that low-mass spiral galaxies host a diffuse, puffed-up dust disc with a thickness similar to that of the stellar disc.
Revisiting bright δ Scuti stars and their period–luminosity relation with TESS and Gaia DR3
Authors: Barac Natascha , Bedding Timothy R , Murphy Simon J , Hey Daniel R
Published: July 2022

We have used NASA’s TESS mission to study catalogued δ Scuti stars. We examined TESS light curves for 434 stars, including many for which few previous observations exist. We found that 62 are not δ Scuti pulsators, with most instead showing variability from binarity. For the 372 δ Scuti stars, we provide a catalogue of the period and amplitude of the dominant pulsation mode. Using Gaia DR3 parallaxes, we place the stars in the period–luminosity (P–L) diagram and confirm previous findings that most stars lie on a ridge that corresponds to pulsation in the fundamental radial mode, and that many others fall on a second ridge that is a factor two shorter in period. This second ridge is seen more clearly than before, thanks to the revised periods and distances. We demonstrate the value of the P–L diagram in distinguishing δ Scuti stars from short-period RR Lyrae stars, and we find several new examples of high-frequency δ Scuti stars with regular sequences of overtone modes, including XX Pyx and 29 Cyg. Finally, we revisit the sample of δ Scuti stars observed by Kepler and show that they follow a tight period–density relation, with a pulsation constant for the fundamental mode of Q = 0.0315 d.
The response of a red supergiant to a common envelope jets supernova (CEJSN) impostor event
Authors: Ragoler Nitzan , Bear Ealeal , Schreier Ron , Hillel Shlomi , Soker Noam
Published: July 2022

Using a 1D stellar evolution code, we simulate the response of a red supergiant (RSG) star to injection of energy and to mass removal. We take the values of the energy that we inject and the mass that we remove according to our previous 3D hydrodynamical simulations of a neutron star (NS) on a highly eccentric orbit that enters the envelope of an RSG star for half a year and launches jets as it accretes mass via an accretion disc. We find that for injected energies of $\simeq 10^{47} {--} 10^{48} {~\rm erg}$ and removed mass of $\simeq 0.03{--}0.6\, {\rm M}_\odot$ the RSG envelope expands to a large radius. Therefore, we expect the NS to continue to orbit inside this massive inflated envelope for several more months, up to about twice the initial RSG radius, to continue to accrete mass and launch jets for a prolonged period. Although these late jets are weaker than the jets that the NS launches while inside the original RSG envelope, the late jets might actually be more influential on the light curve, leading to a long, several months to few years, and bright, about $\gtrsim10^8\, {\rm L}_\odot$, transient event. The RSG returns to more or less a relaxed structure after about 10 yr, and so another transient event might occur in the next periastron passage of the NS. Our results add to the already rich variety of jet-driven explosions/outbursts that might account for many puzzling transient events.
Magnetic field measurement in TMC-1C using 22.3 GHz CCS Zeeman splitting
Authors: Koley Atanu , Roy Nirupam , Momjian Emmanuel , Sarma Anuj P , Datta Abhirup
Published: July 2022

Measurement of magnetic fields in dense molecular clouds is essential for understanding the fragmentation process prior to star formation. Radio interferometric observations of CCS 22.3 GHz emission, from the starless core TMC-1C, have been carried out with the Karl G. Jansky Very Large Array to search for Zeeman splitting of the line in order to constrain the magnetic field strength. Toward a region offset from the dust peak, we report a detection of the Zeeman splitting of the CCS 21–10 transition, with an inferred magnetic field of ∼2 mG. If we interpret the dust peak to be the core of TMC-1C, and the region where we have made a detection of the magnetic field to be the envelope, then our observed value for the magnetic field is consistent with a subcritical mass-to-flux ratio envelope around a core with supercritical mass-to-flux ratio. The ambipolar diffusion time-scale for the formation of the core is consistent with the relevant time-scale based on chemical modelling of the TMC-1C core. This work demonstrates the potential of deep CCS observation to carry out future measurements of magnetic field strengths in dense molecular clouds and, in turn, understand the role of the magnetic field in star formation.
A Phylogeny-aware GWAS Framework to Correct for Heritable Pathogen Effects on Infectious Disease Traits
Authors: Nadeau Sarah , Thorball Christian W , Kouyos Roger , Günthard Huldrych F , Böni Jürg , Yerly Sabine , Perreau Matthieu , Klimkait Thomas , Rauch Andri , Hirsch Hans H , Cavassini Matthias , Vernazza Pietro , Bernasconi Enos , Fellay Jacques , Mitov Venelin , Stadler Tanja ,   Swiss HIV Cohort Study (SHCS), Abela I , Aebi-Popp K , Anagnostopoulos A , Battegay M , Bernasconi E , Braun DL , Bucher HC , Calmy A , Cavassini M , Ciuffi A , Dollenmaier G , Egger M , Elzi L , Fehr J , Fellay J , Furrer H , Fux CA , Günthard HF , Hachfeld A , Haerry D , Hasse B , Hirsch HH , Hoffmann M , Hösli I , Huber M , Kahlert CR , Kaiser L , Keiser O , Klimkait T , Kouyos RD , Kovari H , Kusejko K , Martinetti G , Martinez de Tejada B , Marzolini C , Metzner KJ , Müller N , Nemeth J , Nicca D , Paioni P , Pantaleo G , Perreau M , Rauch A , Schmid P , Speck R , Stöckle M , Tarr P , Trkola A , Wandeler G , Yerly S
Published: August 2022

Infectious diseases are particularly challenging for genome-wide association studies (GWAS) because genetic effects from two organisms (pathogen and host) can influence a trait. Traditional GWAS assume individual samples are independent observations. However, pathogen effects on a trait can be heritable from donor to recipient in transmission chains. Thus, residuals in GWAS association tests for host genetic effects may not be independent due to shared pathogen ancestry. We propose a new method to estimate and remove heritable pathogen effects on a trait based on the pathogen phylogeny prior to host GWAS, thus restoring independence of samples. In simulations, we show this additional step can increase GWAS power to detect truly associated host variants when pathogen effects are highly heritable, with strong phylogenetic correlations. We applied our framework to data from two different host–pathogen systems, HIV in humans and X. arboricola in A. thaliana. In both systems, the heritability and thus phylogenetic correlations turn out to be low enough such that qualitative results of GWAS do not change when accounting for the pathogen shared ancestry through a correction step. This means that previous GWAS results applied to these two systems should not be biased due to shared pathogen ancestry. In summary, our framework provides additional information on the evolutionary dynamics of traits in pathogen populations and may improve GWAS if pathogen effects are highly phylogenetically correlated amongst individuals in a cohort.
Assessing Human Genome-wide Variation in the Massim Region of Papua New Guinea and Implications for the Kula Trading Tradition
Authors: Liu Dang , Peter Benjamin M , Schiefenhövel Wulf , Kayser Manfred , Stoneking Mark
Published: August 2022

The Massim, a cultural region that includes the southeastern tip of mainland Papua New Guinea (PNG) and nearby PNG offshore islands, is renowned for a trading network called Kula, in which different valuable items circulate in different directions among some of the islands. Although the Massim has been a focus of anthropological investigation since the pioneering work of Malinowski in 1922, the genetic background of its inhabitants remains relatively unexplored. To characterize the Massim genomically, we generated genome-wide SNP data from 192 individuals from 15 groups spanning the entire region. Analyzing these together with comparative data, we found that all Massim individuals have variable Papuan-related (indigenous) and Austronesian-related (arriving ∼3,000 years ago) ancestries. Individuals from Rossel Island in southern Massim, speaking an isolate Papuan language, have the highest amount of a distinct Papuan ancestry. We also investigated the recent contact via sharing of identical by descent (IBD) genomic segments and found that Austronesian-related IBD tracts are widely distributed geographically, but Papuan-related tracts are shared exclusively between the PNG mainland and Massim, and between the Bismarck and Solomon Archipelagoes. Moreover, the Kula-practicing groups of the Massim show higher IBD sharing among themselves than do groups that do not participate in Kula. This higher sharing predates the formation of Kula, suggesting that extensive contact between these groups since the Austronesian settlement may have facilitated the formation of Kula. Our study provides the first comprehensive genome-wide assessment of Massim inhabitants and new insights into the fascinating Kula system.
Long-term safety and efficacy of filgotinib treatment for rheumatoid arthritis in Japanese patients naïve to MTX treatment (FINCH 3)
Authors: Atsumi Tatsuya , Tanaka Yoshiya , Matsubara Tsukasa , Amano Koichi , Ishiguro Naoki , Sugiyama Eiji , Yamaoka Kunihiro , Westhovens René , Ching Daniel W T , Messina Osvaldo Daniel , Burmester Gerd R , Genovese Mark , Bartok Beatrix , Pechonkina Alena , Kondo Akira , Yin Zhaoyu , Gong Qi , Tasset Chantal , Takeuchi Tsutomu
Published: August 2022

Objectives

To evaluate the long-term safety and efficacy of filgotinib (FIL) for Japanese patients with rheumatoid arthritis (RA) and limited/no prior methotrexate (MTX) exposure. We present a Japanese population subanalysis of a global randomised-controlled trial at Week 52 and interim long-term extension (LTE) to Week 48 through June 2020.

Methods

Patients were randomised to FIL 200 mg plus MTX, FIL 100 mg plus MTX, FIL 200 mg, or MTX for 52 weeks. At completion, eligible patients could enrol in the LTE. Those receiving FIL continued; those receiving MTX were rerandomised (blinded) to FIL 200 or 100 mg upon discontinuation of MTX. After a 4-week washout period, MTX could be re-added.

Results

Adverse event rates at Week 52 and in the LTE to Week 48 were comparable across treatment groups. Week 52 American College of Rheumatology 20% improvement (ACR20) rates were 83% (19/23), 82% (9/11), 75% (9/12), and 76% (19/25) for FIL 200 mg plus MTX, FIL 100 mg plus MTX, FIL 200 mg, and MTX, respectively. Through LTE Week 48, ACR20 rates were maintained.

Conclusions

In the 56 Japanese patients treated with FIL, efficacy was maintained through Week 52 and beyond, with no increases in the incidence of adverse events.
Protracted febrile myalgia as a first and challenging manifestation of familial Mediterranean fever
Authors: Arslanoglu Aydin Elif , Baglan Esra , Bagrul Ilknur , Tuncez Serife , Ozdel Semanur , Bulbul Mehmet
Published: August 2022

Objectives

Familial Mediterranean fever (FMF) is an auto-inflammatory disease that causes recurrent episodes of fever, abdominal pain, chest pain, and arthritis. Although FMF is well known, protracted febrile myalgia syndrome (PFMS) is a clinical condition that is rare and difficult to diagnose than other symptoms of FMF. PFMS causes fever, myalgia, and acute phase reactant elevation that lasts 2–4 weeks if corticosteroid treatment is not given. In some cases, fever may not be seen. The purpose of this report is to share our experience with PFMS patients in our clinic.

Methods

This is an observational, retrospective, single-centre study. We evaluated patients who had been diagnosed with PFMS at our paediatric rheumatology clinic.

Results

Protracted febrile myalgia syndrome was observed in 14 patients. Nine of the patients were female. The median age at the time of diagnosis of PFMS was 10 years. Only three patients had previously been diagnosed with FMF. Most of our patients were patients who had no previous complaint of FMF. PFMS attack was seen as the first clinical manifestation of FMF in 11 patients. Two patients who did not respond to steroid treatment improved with anakinra treatment.

Conclusions

PFMS is a rare condition of FMF disease. It may be the first clinical manifestation of FMF disease. Fever may not be seen in all patients. Clinicians should be aware of this situation.
Outcomes and risk factors for mortality in Pneumocystis pneumonia patients with rheumatoid arthritis: A multicentre retrospective cohort study
Authors: Mori Shunsuke , Ueki Yukitaka , Miyamura Tomoya , Ishii Koji , Hidaka Toshihiko , Yoshitama Tamami , Nakamura Kazuyoshi , Suenaga Yasuo
Published: August 2022

Objectives

The aim is to evaluate outcomes and risk factors for death in patients with rheumatoid arthritis (RA) who developed Pneumocystis pneumonia (PCP).

Methods

We included RA patients who were diagnosed with PCP at seven participating community hospitals between July 2005 and October 2020. Clinical features were compared between survivors and non-survivors. Disease-modifying antirheumatic drugs (DMARDs) before PCP onset and after PCP recovery were also examined.

Results

Seventy RA patients developed PCP, and among them, 60 (85.7%) received methotrexate (MTX) monotherapy (40%) or MTX combination therapy with other DMARDs (45.7%). PCP was more likely to occur after 12 months of MTX monotherapy and within 3 months of MTX combination therapy. Thirteen patients (18.6%) died despite PCP treatment. Multivariable logistic regression analysis revealed that coexisting RA-associated interstitial lung disease (odds ratio, 6.18; 95% confidence interval, 1.17–32.63) and delayed PCP treatment with anti-Pneumocystis drugs (odds ratio, 15.29; 95% confidence interval, 1.50–156.15) are significant risk factors for PCP mortality in RA patients. Most survivors successfully resumed DMARD therapy without PCP prophylaxis; one recurrent PCP case was observed during follow-up (median, 4.1 years).

Conclusions

To avoid a treatment delay, RA patients should be followed up for signs and symptoms of PCP development, especially those with RA-associated interstitial lung disease.
Intratracheally administered LNA gapmer antisense oligonucleotides induce robust gene silencing in mouse lung fibroblasts
Authors: Shin Minwook , Chan Io Long , Cao Yuming , Gruntman Alisha M , Lee Jonathan , Sousa Jacquelyn , Rodríguez Tomás C , Echeverria Dimas , Devi Gitali , Debacker Alexandre J , Moazami Michael P , Krishnamurthy Pranathi Meda , Rembetsy-Brown Julia M , Kelly Karen , Yukselen Onur , Donnard Elisa , Parsons Teagan J , Khvorova Anastasia , Sontheimer Erik J , Maehr René , Garber Manuel , Watts Jonathan K
Published: August 2022

The lung is a complex organ with various cell types having distinct roles. Antisense oligonucleotides (ASOs) have been studied in the lung, but it has been challenging to determine their effectiveness in each cell type due to the lack of appropriate analytical methods. We employed three distinct approaches to study silencing efficacy within different cell types. First, we used lineage markers to identify cell types in flow cytometry, and simultaneously measured ASO-induced silencing of cell-surface proteins CD47 or CD98. Second, we applied single-cell RNA sequencing (scRNA-seq) to measure silencing efficacy in distinct cell types; to the best of our knowledge, this is the first time scRNA-seq has been applied to measure the efficacy of oligonucleotide therapeutics. In both approaches, fibroblasts were the most susceptible to locally delivered ASOs, with significant silencing also in endothelial cells. Third, we confirmed that the robust silencing in fibroblasts is broadly applicable by silencing two targets expressed mainly in fibroblasts, Mfap4 and Adam33. Across independent approaches, we demonstrate that intratracheally administered LNA gapmer ASOs robustly induce gene silencing in lung fibroblasts. ASO-induced gene silencing in fibroblasts was durable, lasting 4–8 weeks after a single dose. Thus, lung fibroblasts are well aligned with ASOs as therapeutics.
Alteration of DNA supercoiling serves as a trigger of short-term cold shock repressed genes ofE. coli
Authors: Dash Suchintak , Palma Cristina S D , Baptista Ines S C , Almeida Bilena L B , Bahrudeen Mohamed N M , Chauhan Vatsala , Jagadeesan Rahul , Ribeiro Andre S
Published: August 2022

Cold shock adaptability is a key survival skill of gut bacteria of warm-blooded animals. Escherichia coli cold shock responses are controlled by a complex multi-gene, timely-ordered transcriptional program. We investigated its underlying mechanisms. Having identified short-term, cold shock repressed genes, we show that their responsiveness is unrelated to their transcription factors or global regulators, while their single-cell protein numbers’ variability increases after cold shock. We hypothesized that some cold shock repressed genes could be triggered by high propensity for transcription locking due to changes in DNA supercoiling (likely due to DNA relaxation caused by an overall reduction in negative supercoiling). Concomitantly, we found that nearly half of cold shock repressed genes are also highly responsive to gyrase inhibition (albeit most genes responsive to gyrase inhibition are not cold shock responsive). Further, their response strengths to cold shock and gyrase inhibition correlate. Meanwhile, under cold shock, nucleoid density increases, and gyrases and nucleoid become more colocalized. Moreover, the cellular energy decreases, which may hinder positive supercoils resolution. Overall, we conclude that sensitivity to diminished negative supercoiling is a core feature of E. coli’s short-term, cold shock transcriptional program, and could be used to regulate the temperature sensitivity of synthetic circuits.
Racial disparities in inpatient clinical presentation, treatment, and outcomes in brain metastasis
Authors: McCray Edwin , Waguia Romaric , de la Garza Ramos Rafael , Price Meghan J , Williamson Theresa , Dalton Tara , Sciubba Daniel M , Yassari Reza , Goodwin Andrea N , Fecci Peter , Johnson Margaret O , Chaichana Kaisorn , Goodwin C Rory
Published: July 2022

Background

Few studies have assessed the impact of race on short-term patient outcomes in the brain metastasis population. The goal of this study is to evaluate the association of race with inpatient clinical presentation, treatment, in-hospital complications, and in-hospital mortality rates for patients with brain metastases (BM).

Method

Using data collected from the National Inpatient Sample between 2004 and 2014, we retrospectively identified adult patients with a primary diagnosis of BM. Outcomes included nonroutine discharge, prolonged length of stay (pLOS), in-hospital complications, and mortality.

Results

Minority (Black, Hispanic/other) patients were less likely to receive surgical intervention compared to White patients (odds ratio [OR] 0.70; 95% confidence interval [CI] 0.66–0.74, p < 0.001; OR 0.88; 95% CI 0.84–0.93, p < 0.001). Black patients were more likely to develop an in-hospital complication than White patients (OR 1.35, 95% CI 1.28–1.41, p < 0.001). Additionally, minority patients were more likely to experience pLOS than White patients (OR 1.48; 95% CI 1.41–1.57, p < 0.001; OR 1.34; 95% CI 1.27–1.42, p < 0.001). Black patients were more likely to experience a nonroutine discharge (OR 1.25; 95% CI 1.19–1.31, p < 0.001) and higher in-hospital mortality than White (OR 1.13; 95% CI 1.03–1.23, p = 0.008).

Conclusion

Our analysis demonstrated that race is associated with disparate short-term outcomes in patients with BM. More efforts are needed to address these disparities, provide equitable care, and allow for similar outcomes regardless of care.
Overexpression of Chloroplast Triosephosphate Isomerase Marginally Improves Photosynthesis at Elevated CO2 Levels in Rice
Authors: Suzuki Yuji , Shiina Mizuki , Takegahara-Tamakawa Yuki , Miyake Chikahiro , Makino Amane
Published: August 2022

We recently suggested that chloroplast triosephosphate isomerase (cpTPI) has moderate control over the rate of CO2 assimilation (A) at elevated CO2 levels via the capacity for triose phosphate utilization (TPU) in rice (Oryza sativa L.) from its antisense-suppression study. In the present study, the effects of cpTPI overexpression on photosynthesis were examined in transgenic rice plants overexpressing the gene encoding cpTPI. The amounts of cpTPI protein in the two lines of transgenic plants were 4.8- and 12.1-folds higher than in wild-type plants, respectively. The magnitude of the increase approximately corresponded to the increase in transcript levels of cpTPI. A at CO2 levels of 100 and 120 Pa increased by 6–9% in the transgenic plants, whereas those at ambient and low CO2 levels were scarcely affected. Similar increases were observed for TPU capacity estimated from the CO2 response curves of A. These results indicate that the overexpression of cpTPI marginally improved photosynthesis at elevated CO2 levels via improvement in TPU capacity in rice. However, biomass production at a CO2 level of 120 Pa did not increase in transgenic plants, suggesting that the improvement in photosynthesis by cpTPI overexpression was not sufficient to improve biomass production in rice.
Flow similarity, stochastic branching, and quarter-power scaling in plants
Authors: Price Charles A , Drake Paul , Veneklaas Erik J , Renton Michael
Published: August 2022

The origin of allometric scaling patterns that are multiples of one-fourth has long fascinated biologists. While not universal, quarter-power scaling relationships are common and have been described in all major clades. Several models have been advanced to explain the origin of such patterns, but questions regarding the discordance between model predictions and empirical data have limited their widespread acceptance. Notable among these is a fractal branching model that predicts power-law scaling of both metabolism and physical dimensions. While a power law is a useful first approximation to some data sets, nonlinear data compilations suggest the possibility of alternative mechanisms. Here, we show that quarter-power scaling can be derived using only the preservation of volume flow rate and velocity as model constraints. Applying our model to land plants, we show that incorporating biomechanical principles and allowing different parts of plant branching networks to be optimized to serve different functions predicts nonlinearity in allometric relationships and helps explain why interspecific scaling exponents covary along a fractal continuum. We also demonstrate that while branching may be a stochastic process, due to the conservation of volume, data may still be consistent with the expectations for a fractal network when one examines sub-trees within a tree. Data from numerous sources at the level of plant shoots, stems, and petioles show strong agreement with our model predictions. This theoretical framework provides an easily testable alternative to current general models of plant metabolic allometry.
Ultrasonography in the prediction of gout flares: a 12-month prospective observational study
Authors: Cipolletta Edoardo , Abhishek Abhishek , Di Battista Jacopo , Grassi Walter , Filippucci Emilio
Published: August 2022

Objectives

To evaluate whether US findings indicating MSU deposits and US-detected inflammation (i.e. power Doppler signal) predict gout flares over 12 months.

Methods

Gout patients on urate-lowering therapy for at least the preceding 6 months were enrolled consecutively in this 12-month prospective, observational, single-centre study. A nested case–control analysis was performed. Cases were participants with at least one flare in the follow-up period, while controls did not self-report any gout flare. The US assessment included elbows, wrists, second MCP joints, knees, ankles, and first MTP joints. The US findings indicating MSU deposits [i.e. aggregates, double contour (DC) sign and tophi] were identified as present/absent according to the Outcome Measure in Rheumatology definitions. Power Doppler signal was scored semiquantitatively. Summated scores were calculated for each US finding.

Results

Eighty-one gout participants were enrolled, and 71 completed the study. Thirty (42.3%) of 71 participants experienced at least one flare over 12 months, with a median of 2.0 flares. Cases had a greater US burden of MSU deposits (6.7 ± 4.7 vs 2.9 ± 2.6, P = 0.01) and power Doppler signal (3.73 ± 3.53 vs 0.82 ± 1.44, P < 0.01) than controls, at baseline. The baseline US scores indicating MSU deposits and US-detected inflammation were significantly associated with the occurrence (total MSU score, adjusted odds ratio:1.75, 95% CI: 1.26, 2.43; power Doppler score, adjusted odds ratio: 1.63, 95% CI: 1.12, 2.40) and the number (total MSU score, adjusted incidence risk ratio: 1.17, 95% CI: 1.08, 1.26; power Doppler score, adjusted incidence risk ratio: 1.29, 95% CI: 1.19, 1.40) of flares over 12 months in multivariate analyses.

Conclusions

Baseline US findings indicating MSU deposits and US-detected inflammation are independent predictors of gout flares over 12 months.
Different COVID-19 outcomes among systemic rheumatic diseases: a nation-wide cohort study
Authors: Bournia Vasiliki-Kalliopi , Fragoulis George E , Mitrou Panagiota , Mathioudakis Konstantinos , Tsolakidis Anastasios , Konstantonis George , Tseti Ioulia , Vourli Georgia , Tektonidou Maria G , Paraskevis Dimitrios , Sfikakis Petros P
Published: August 2022

Objectives

To investigate coronavirus disease 2019 (COVID-19)-associated risk of hospitalization and death in RA, AS, PsA, SLE and SSc in comparison with the general population during the first year of the pandemic, and compare their overall mortality with 2019.

Methods

Interlinking nationwide electronic registries, we recorded confirmed COVID-19-associated infections, hospitalizations and deaths, and all-cause deaths between 1 March 2020 and 28 February 2021 in all adults with RA, AS, PsA, SLE and SSc under treatment (n = 74 970, median age 67.5, 51.2, 58.1, 56.2 and 62.2 years, respectively) and in random comparators from the general population matched (1:5) on age, sex and region of domicile. Deaths from all causes during 2019 were also recorded.

Results

Compared with the general population, incidence rates (IR) for COVID-19-associated hospitalization were higher in RA [IR ratio (IRR) 1.71(1.50–1.95)], SLE [2.0 (1.4–2.7)] and SSc [2.28 (1.29–3.90)], while COVID-19-associated death rates were higher in RA [1.91 (1.46–2.49)]. When focusing only on severe acute respiratory syndrome coronavirus 2–infected subjects, after adjusting for age and gender, the odds ratio for COVID-19 associated death was higher in RA [1.47 (1.11–1.94)] and SSc [2.92 (1.07–7.99)] compared with the general population. The all-cause mortality rate compared with the general population increased in RA during the first year of the pandemic (IRR 0.71) with reference to 2019 (0.59), and decreased in SSc (IRR 1.94 vs 4.36).

Conclusion

COVID-19 may have a more severe impact in patients with systemic rheumatic disease than in the general population. COVID-19-related mortality is increased in subgroups of patients with specific rheumatic diseases, underscoring the need for priority vaccination and access to targeted treatments.