bluuebunny/crossref_metadata_2025 huggingface dataset:
Diffusion of Gender Norms: Evidence from Stalin’s Ethnic Deportations
Authors: Miho Antonela , Jarotschkin Alexandra , Zhuravskaya Ekaterina
Published: June 2023

We study horizontal between-group cultural transmission using Stalin’s ethnic deportations as a historical experiment. Over 2 million Soviet citizens, mostly Germans and Chechens, were forcibly relocated from the western to eastern parts of the USSR during WWII solely based on ethnicity. As a result, the native population of the deportation destinations was exogenously exposed to groups with drastically different gender norms and behavior. We combine historical and contemporary data to document that present-day gender equality in labor force participation, business leadership, and fertility as well as pro-gender-equality attitudes are higher among local native population of deportation destinations with a larger presence of Protestant compared to Muslim deportees. The effects are stronger for culturally closer groups and when adopting deportee norms is less costly. The results cannot be explained by selection, vertical cultural transmission, or deportee impact on the local economy. The evidence strongly suggests that gender norms diffused horizontally from deportees to the local population through imitation and learning.
The long-term effects of mass layoffs: do local economies (ever) recover?
Authors: Celli Viviana , Cerqua Augusto , Pellegrini Guido
Published: June 2023

This article investigates the long-term reaction of local labor markets (LLMs) to a mass layoff in a manufacturing plant. We adopt a non-parametric generalization of the difference-in-differences estimator expressly developed for time-series cross-sectional data and a new comprehensive dataset. Our results suggest that, on average, a mass layoff abruptly decreases industry employment by 22%; this negative impact is persistent even 9 years later. The shock has a negative and statistically significant effect only on the same industry of the affected LLM, while the rest of the local economy is, at most, mildly negatively affected. These findings depend on the initial level of development and call for the policymakers’ intervention to design efficient employment policies aimed at reducing the long-lasting social costs of a mass layoff at least for the less developed and less dynamic local economies.
Denoising for airborne transient electromagnetic data using noise-whitening-based weighted nuclear norm minimization
Authors: Peng Cong , Zhu Kaiguang , Fan Tianjiao , Yang Yang
Published: June 2023

Recovering anomalous information covered under noise in late gates can enhance airborne transient electromagnetic (ATEM) detection. Conventional denoising mainly comprises filtering and gate correlation-based decomposition algorithms; the former fails to extract anomalies contaminated by noise and the latter relies on the correlation between gates, which may yield false late gate anomalies caused by early large-amplitude anomalies in early gates. In ATEM profiles, the correlation between anomalies in adjacent gates makes the anomalies to be measured to have low-rank characteristics relative to the noise-contaminated profiles; the noise is uniformly distributed in the profiles, which have nonlocal self-similarity. Therefore, the low-rank matrix approximation algorithm is applicable to ATEM data denoising. In this study, an algorithm—noise-whitening-based weighted nuclear norm minimization (NW-WNNM)—is designed to remove ATEM profile noise. First, we analyze the influence of patch size in block matching on anomalous and noisy patches and estimate the profile patch size adaptively. Then, we combine the estimation of noise variance in weighted nuclear norm minimization (WNNM) with the noise whitening of similar patch matrices to reduce the noise interference on the nuclear norm and add a whitening factor in the weight vector to make the soft-thresholding function applicable to the low-rank reconstruction of the whitened matrix. By analyzing the reconstructed low-rank matrix and its feature distribution, compared with WNNM, NW-WNNM can detect the feature information more accurately and eliminate the influence of noise on the nuclear norm. Simulation and field profile results indicate that NW-WNNM is superior to comparison denoising methods.
Study on the targeted regulation of Scutellaria baicalensis leaf on glutamine–glutamate metabolism and glutathione synthesis in the liver of d-gal ageing rats
Authors: Chen Chunni , Yang Linlin , Li Mengru , Gao Li , Qin Xuemei , Du Guanhua , Zhou Yuzhi
Published: June 2023

Objectives

Scutellaria baicalensis leaf (SLE), the above-ground part of the traditional Chinese medicine Scutellaria baicalensis Georgi, is rich in resources and contains a large number of flavonoids with anti-inflammatory, antioxidant and neuroprotective functions. The present study evaluated the ameliorative effects and related mechanisms of SLE on d-gal-induced ageing rats, providing a theoretical basis for the exploitation of SLE.

Methods

This experiment investigated the mechanism of SLE for anti-ageing by non-targeted metabonomics technology combined with targeted quantitative analysis and molecular biology technology.

Key findings

Non-targeted metabonomics analysis showed that 39 different metabolites were screened out. Among them, 38 metabolites were regulated by SLE (0.4 g/kg), and 33 metabolites were regulated by SLE (0.8 g/kg). Through enrichment analysis, glutamine–glutamate metabolic pathway was identified as the key metabolic pathway. Subsequently, the results of targeted quantitative and biochemical analysis displayed that the contents of key metabolites and the activities of enzymes in glutamine-glutamate metabolic pathway and glutathione synthesis could be regulated by SLE. Furthermore, the results of Western blotting indicated that SLE significantly modulated the expression of Nrf2, GCLC, GCLM, HO-1, and NQO1 proteins.

Conclusion

To sum up, the anti-ageing mechanism of SLE was related to glutamine-glutamate metabolism pathway and Nrf2 signalling pathway.
Twin hearts—minimally invasive mitral valve repair in twin sisters with mitral annular disjunction and Loeys-Dietz syndrome: a case series
Authors: Ioannou Stelios , Shiakos George , Ntoskas Theodoros , Papasavvas Elias , Anastasiadi Violetta , Loizides Nikoleta Betsimea , Mavrommatis Petros , Tzanavaros Ioannis
Published: June 2023

In this case report, we present 31-year-old twin sisters diagnosed with severe Barlow mitral valve prolapse, mitral annular disjunction and presence of lateral mid-wall fibrosis diagnosed on MRI as well as ventricular arrhythmias, and a very rare variant of Loeys-Dietz syndrome, being referred to our center for surgical repair. Genetic testing detected pathogenic variants of clinical significance in SMAD3 and KCNH2 genes that are associated with autosomal dominant disease of Loeys-Dietz syndrome. Due to the presence of severe mitral valve regurgitation, the first patient was referred for minimally invasive mitral valve repair that was performed successfully. Before discharge, a subcutaneous ICD implantation was performed as primary prevention against malignant ventricular arrhythmias and sudden cardiac death. Her twin sister presented with the identical diagnosis and underwent the same surgical procedure with S-ICD implantation a few months later.
Pancreatic heterotopia of the gallbladder – possible cause of right upper quadrant pain, a case report
Authors: Laslett Kirby , Tan Kimberley , Gilhotra Amardeep , Haque Izhar-ul
Published: June 2023

Pancreatic heterotopia is characterized by ectopic pancreatic tissue found outside the pancreas without any anatomical or vascular connection to the pancreas. Pancreatic heterotopia of the gallbladder is a rare histological finding; there have been only a handful of cases described in the literature. Pancreatic heterotopia of the gallbladder is usually diagnosed incidentally at histological examination following cholecystectomy or autopsy. Clinical presentation of pancreatic heterotopia of the gallbladder can vary from biliary colic, biliary obstruction or it can be completely asymptomatic. It has been suggested that gallbladder pancreatic heterotopia may lead to pancreatitis of this ectopic tissue, which may present differently to typical biliary colic. Here, we present the case of a 43-year-old male that presented with 2 years of significant postprandial nausea and right upper quadrant pain. Histopathology following cholecystectomy revealed chronic cholecystitis with cholelithiasis, in addition to a focus of pancreatic heterotopia in the gallbladder wall.
Complete disruption of vastus intermedius tendon and partial rupture of vastus medialis tendon
Authors: Pallis Dimitrios , Tsivelekas Konstantinos , Nikolakakos Petros , Ampadiotaki Margarita-Michaela , Kokkinis Constantinos , Papadakis Stamatios A
Published: June 2023

Quadriceps tendon ruptures are common injuries, however isolated ruptures are rare. Particularly, reports for isolated vastus intermedius ruptures are very scarce. We present a case of a 62-years-old male patient who sustained a complete rupture of vastus intermedius tendon with a partial rupture of vastus medialis while rectus femoris tendon was intact, after a fall from standing height. Due to lag in extension, surgical treatment was performed, consisted of an end-to-end Krakow suture technique accompanied with two anchors placed on osseous attachment to the superior pole of the patella. A hinged knee brace locked in full extension was applied for 4 weeks. Gradual range of flexion was suggested after the 3rd postoperative week. Full range of motion was achieved in the 7th postoperative week.
Molecular typing and antifungal susceptibility of clinical isolates of Cryptococcus neoformans and Cryptococcus gattii species complexes from the National Invasive Fungal Surveillance Network of Uruguay
Authors: Puime Carlos Andrés , Bórmida Victoria , Pan Dinorah
Published: June 2023

Cryptococcus neoformans and C. gattii species complexes (phylum: Basidiomycota) are environmental yeasts and are the main cause of human cryptococcosis worldwide. The most recent molecular typing studies in Latin America have focused on the intertropical region. Thus, this study aimed to update the knowledge of human cryptococcosis in the South American temperate region. We obtained and analyzed 116 C. neoformans/C. gattii species complexes isolates from the Public Health Surveillance Laboratory between 2008–2013 and 2017–2021 (C. gattii species complex = 1 and C. neoformans species complex = 115). The average patient age was 45 years, with an overall male:female ratio of 3.1:1. The proportion of HIV-negative patients was significantly higher in the second study period. Restriction fragment length polymorphism typing of URA5 gene revealed that the C. neoformans species complex comprised 75.7% VNI, 2.6% VNII, 0.9% VNIII, 1.7% VNIV, 17.4% VNII/VNIV hybrids, and one C. neoformans isolate (0.9%) misidentified as VGI; the C. gattii species complex isolates comprised one VGII. The overall case fatality rate was 49.5%, with no differences in lethality between VNI and hybrid isolates. Of the four isolates responsible for episodes of reoccurrence, only one had a genotype different from the first episode. Antifungal susceptibility testing revealed that most isolates fell below the local epidemiological cut-off value. This study provides additional information for the analysis of C. neoformans/C. gattii species complexes dynamics in the South American temperate region.
The VVV near-IR galaxy catalogue in a Northern part of the Galactic disc
Authors: Daza-Perilla I V , Sgró M A , Baravalle L D , Alonso M V , Villalon C , Lares M , Soto M , Castellón J L Nilo , Valotto C , Cortés P Marchant , Minniti D , Hempel M
Published: June 2023

The automated identification of extragalactic objects in large surveys provides reliable and reproducible samples of galaxies in less time than procedures involving human interaction. However, regions near the Galactic disc are more challenging due to the dust extinction. We present the methodology for the automatic classification of galaxies and non-galaxies at low Galactic latitude regions using both images and photometric and morphological near-IR data from the VISTA Variables in the Vía Láctea eXtended (VVVX) survey. Using the VVV NIR Galaxy Catalogue (VVV NIRGC), we analyse by statistical methods the most relevant features for galaxy identification. This catalogue was used to train a convolutional neural network with image data and an XGBoost model with both photometric and morphological data and then to generate a data set of extragalactic candidates. This allows us to derive probability catalogues used to analyse the completeness and purity as a function of the configuration parameters and to explore the best combinations of the models. As a test case, we apply this methodology to the Northern disc region of the VVVX survey, obtaining 172 396 extragalactic candidates with probabilities of being galaxies. We analyse the performance of our methodology in the VVV disc, reaching an F1-score of 0.67, a 65 per cent purity, and a 69 per cent completeness. We present the VVV NIRGC: Northern part of the Galactic disc comprising 1003 new galaxies, with probabilities greater than 0.6 for either model, with visual inspection and with only two previously identified galaxies. In the future, we intend to apply this methodology to other areas of the VVVX survey.
Single-pulse analysis and average emission characteristics of PSR J1820−0427 from observations made with the MWA and uGMRT
Authors: Janagal Parul , Chakraborty Manoneeta , Bhat N D Ramesh , McSweeney Samuel J , Sett Susmita
Published: June 2023

We have studied the pulse-to-pulse variability in PSR J1820−0427 and its frequency dependence using high-quality, wide-band observations made with the upgraded Giant Metrewave Radio Telescope (uGMRT; 300–750 MHz) and the Murchison Widefield Array (∼170–200 MHz). The low-frequency data reveal a previously unreported feature in the average profile (at 185 MHz) after accounting for the effects of temporal broadening arising from multipath scattering due to the interstellar medium. We advance a new method for flux density calibration of beamformed data from the uGMRT and use it to measure the single-pulse flux densities across the uGMRT band. Combined with previously published measurements, these flux densities are best fitted with a power-law spectrum with a low-frequency turnover. We also use calibrated flux densities to explore the relationship between pulse-to-pulse variability and the spectral index of individual pulses. Our analysis reveals a large scatter in the single-pulse spectral indices and a general tendency for brighter pulses to show a steepening of the spectral index. We also examine the frequency dependence of the pulse fluence distribution and its relation to the Stochastic Growth Theory.
Did Kepler-444 have a long-lived convective core?
Authors: Winther Mark Lykke , Aguirre Børsen-Koch Víctor , Rørsted Jakob Lysgaard , Stokholm Amalie , Verma Kuldeep
Published: June 2023

With the greater power to infer the state of stellar interiors provided by asteroseismology, it has become possible to study the survival of initially convective cores within stars during their main-sequence evolution. Standard theories of stellar evolution predict that convective cores in subsolar mass stars have lifetimes below $1\, {\rm Gyr}$. However, a recent asteroseismic study of the star Kepler-444 concluded that the initial convective core had survived for nearly $8\, {\rm Gyr}$. The goal of this paper is to study the convective-core evolution of Kepler-444 and to investigate its proposed longevity. We modify the input physics of stellar models to induce longer convective-core lifetimes and vary the associated parameter across a dense grid of evolutionary tracks. The observations of metallicity, effective temperature, mean density, and asteroseismic frequency ratios are fitted to the models using the basta pipeline. We explore different choices of constraints, from which a long convective-core lifetime is only recovered for a few specific combinations: mainly from the inclusion of potentially unreliable frequencies and/or excluding the covariances between the frequency ratios, whereas for the classical parameters, the derived luminosity has the largest influence. For all choices of observables, our analysis reliably constrains the convective-core lifetime of Kepler-444 to be short, with a median around $0.6\, {\rm Gyr}$ and a 1σ upper bound around $3.5\, {\rm Gyr}$.
Colour jumps across the spiral arms of Hubble Ultra Deep Field galaxies
Authors: Martínez-García Eric E , González-Lópezlira Rosa A , Puerari Ivânio
Published: June 2023

We have measured, at various wavelengths, the spiral arm pitch angles of a sample of distant spiral galaxies from the Hubble Space Telescope eXtreme Deep Field (XDF). According to density wave (DW) theory, we should detect colour jumps from red-to-blue across the spiral arms. Colour jumps are a consequence of large-scale shocks, which also generate the classic blue-to-red age/colour gradients, and have only been detected until now in nearby spiral galaxies. Our results indicate that colour jumps and gradients have been occurring in distant galaxies for at least the last 8 Gyr, in agreement with DW theory.
Subhalo abundance matching using progenitor mass at varying redshift: two modes of stellar mass growth imprinted into the Subaru HSC galaxy clustering
Authors: Masaki Shogo , Kashino Daichi , Ishikawa Shogo , Lin Yen-Ting
Published: June 2023

We propose a novel subhalo abundance matching (SHAM) model that uses the virial mass of the main progenitor of each (sub)halo Mprog as a proxy of the galaxy stellar mass M* at the time of observation. This Mprog model predicts the two-point correlation functions depending on the choice of the epoch zprog at which Mprog is quoted. With zprog as a fitting parameter, we apply the Mprog model to the angular correlation functions measured with varying stellar mass thresholds from M*, lim/(h−2 M⊙) = 1011–108.6 using a sample of galaxies at z ≃ 0.4 from the Subaru Hyper Suprime-Cam survey. The Mprog model can reproduce the observations very well over 10 h−1kpc–10 h−1Mpc. We find that, for the samples of 109.2 ≤ M*, lim/(h−2 M⊙) ≤ 1010.2, the correlation functions predicted by the widely used Vpeak model lack amplitudes at ≲1 h−1 Mpc, suggesting that Mprog is a better proxy of the galaxy stellar mass than conventional Vpeak. The zprog parameter is highest (zprog ≃ 3) for intermediate mass galaxies at M* ≃ 109.9 h−2 M⊙, and becomes smaller down to zprog ≃ 1 for both lower and higher mass galaxies. We interpret these trends as reflecting the downsizing in the in situ star formation in lower mass galaxies and the larger contribution of the ex situ stellar mass growth in higher mass galaxies.
Unveiling the gravitationally unstable disc of a massive star-forming galaxy using NOEMA and MUSE
Authors: Puschnig Johannes , Hayes Matthew , Agertz Oscar , Emsellem Eric , Cannon John M , Le Reste Alexandra , Melinder Jens , Östlin Göran , Herenz Christian , Menacho Veronica
Published: June 2023

Using new high-resolution data of CO (2–1), H$\alpha$ and H$\beta$ obtained with the Northern Extended Millimeter Array (NOEMA) and the Multi-Unit Spectroscopic Explorer (MUSE) at the Very Large Telescope, we have performed a Toomre Q disc stability analysis and studied star formation, gas depletion times and other environmental parameters on sub-kpc scales within the z ∼ 0 galaxy SDSS J125013.84+073444.5 (LARS 8). The galaxy hosts a massive, clumpy disc and is a proto-typical analogue of main-sequence galaxies at z ∼ 1 − 2. We show that the massive (molecular) clumps in LARS 8 are the result of an extremely gravitationally unstable gas disc, with large scale instabilities found across the whole extent of the rotating disc, with only the innermost 500 pc being stabilized by its bulge-like structure. The radial profiles further reveal that – contrary to typical disc galaxies – the molecular gas depletion time decreases from more than 1 Gyr in the centre to less than ∼100 Myr in the outskirts of the disc, supporting the findings of a Toomre-unstable disc. We further identified and analysed 12 individual massive molecular clumps. They are virialized and follow the mass–size relation, indicating that on local (cloud/clump) scales the stars form with efficiencies comparable to those in Milky Way clouds. The observed high star formation rate must thus be the result of triggering of cloud/clump formation over large scales due to disc instability. Our study provides evidence that ‘in-situ’ massive clump formation (as also observed at high redshifts) is very efficiently induced by large-scale instabilities.
The VISCACHA survey – VII. Assembly history of the Magellanic Bridge and SMC Wing from star clusters
Authors: Oliveira R A P , Maia F F S , Barbuy B , Dias B , Santos J F C , Souza S O , Kerber L O , Bica E , Sanmartim D , Quint B , Fraga L , Armond T , Minniti D , Parisi M C , Katime Santrich O J , Angelo M S , Pérez-Villegas A , De Bórtoli B J
Published: June 2023

The formation scenario of the Magellanic Bridge during an encounter between the Large and Small Magellanic Clouds ∼200 Myr ago, as proposed by N-body models, would be imprinted in the chemical enrichment and kinematics of its stars and sites of ongoing star formation along its extension. We present an analysis of 33 Bridge star clusters using photometry obtained with the SOAR 4-m telescope equipped with adaptive optics for the VISCACHA survey. We performed a membership selection and derived self-consistent ages, metallicities, distances, and reddening values via statistical isochrone fitting, as well as tidal radii and integrated masses from structure analysis. Two groups are clearly detected: 13 well-studied clusters older than the Bridge, with 0.5–6.8 Gyr and $\hbox{[Fe/H]} < -0.6$ dex; and 15 clusters with <200 Myr and $\rm {[Fe/H]} > -0.5$ dex, probably formed in situ. The old clusters follow the overall age and metallicity gradients of the SMC, whereas the younger ones are uniformly distributed along the Bridge. The main results are as follows: (i) we derive ages and metallicities for the first time for 9 and 18 clusters, respectively; (ii) we detect two metallicity dips in the age-metallicity relation of the Bridge at ∼200 Myr and 1.5 Gyr ago for the first time, possibly chemical signatures of the formation of the Bridge and Magellanic Stream; (iii) we estimate a minimum stellar mass for the Bridge of 3–5 × 105 M⊙; (iv) we confirm that all the young Bridge clusters at ${\rm RA} < 3^h$ are metal-rich with $\rm {[Fe/H]} \sim -0.4$ dex.
Linear analysis of the Kelvin–Helmholtz instability in relativistic magnetized symmetric flows
Authors: Chow Anthony , Rowan Michael E , Sironi Lorenzo , Davelaar Jordy , Bodo Gianluigi , Narayan Ramesh
Published: June 2023

We study the linear stability of a planar interface separating two fluids in relative motion, focusing on the symmetric configuration where the two fluids have the same properties (density, temperature, magnetic field strength, and direction). We consider the most general case with arbitrary sound speed cs, Alfvén speed vA, and magnetic field orientation. For the instability associated with the fast mode, we find that the lower bound of unstable shear velocities is set by the requirement that the projection of the velocity on to the fluid-frame wavevector is larger than the projection of the Alfvén speed on to the same direction, i.e. shear should overcome the effect of magnetic tension. In the frame where the two fluids move in opposite directions with equal speed v, the upper bound of unstable velocities corresponds to an effective relativistic Mach number $M_{\rm re}\equiv v/v_{\rm {f}\perp }\sqrt{(1-v_{\rm {f}\perp }^2)/(1-v^2)} \cos \theta =\sqrt{2}$, where $v_{\rm {f}\perp }=[v_{\rm {A}}^2+c_{\rm s}^2(1-v_{\rm {A}}^2)]^{1/2}$ is the fast speed assuming a magnetic field perpendicular to the wavevector (here, all velocities are in units of the speed of light), and θ is the laboratory-frame angle between the flow velocity and the wavevector projection on to the shear interface. Our results have implications for shear flows in the magnetospheres of neutron stars and black holes – both for single objects and for merging binaries – where the Alfvén speed may approach the speed of light.
Constraints on dark matter–neutrino interaction from 21-cm cosmology and forecasts on SKA1-Low
Authors: Dey Antara , Paul Arnab , Pal Supratik
Published: June 2023

In this article, we have done a thorough investigation of the possible effects of interaction between dark matter (DM) and neutrinos on reionization history. We have constrained the interaction strength using 21-cm cosmology and found out possible deviations from standard, non-interacting Lambda cold dark matter scenario. Comparing the results with the existing constraints from present cosmological observations reveals that 21-cm observations are more competent to constrain the interaction strength by a few orders of magnitude. We have also searched for prospects of detecting any such interaction in the upcoming 21-cm mission SKA1-Low by doing a forecast analysis and error estimation.
Birthright Entitlements and Obligations in an Intergenerational Political Society
Authors: Thompson Janna
Published: June 2023

Political societies are essentially intergenerational—not only because they often last for many generations and because they maintain their existence largely through members having or adopting children, but because the children of members acquire entitlements simply as a result of being born or adopted by members. Even in a liberal political society, members by birth or adoption are supposed to enjoy from birth the irrevocable status of membership and the privileges it entails. They have opportunities and civil rights that outsiders cannot claim. In liberal welfare states they are entitled to assistance in need. But from a liberal point of view birthright entitlements, and the obligations they entail, are problematic. I will discuss three attempts to justify them.
Screening the complex biological behavior of late lanthanides through genome-wide interactions
Authors: Pallares Roger M , An Dahlia D , Hebert Solene , Loguinov Alex , Proctor Michael , Villalobos Jonathan A , Bjornstad Kathleen A , Rosen Chris J , Vulpe Christopher , Abergel Rebecca J
Published: June 2023

Despite their similar physicochemical properties, recent studies have demonstrated that lanthanides can display different biological behaviors. Hence, the lanthanide series can be divided into three parts, namely early, mid, and late lanthanides, based on their interactions with biological systems. In particular, the late lanthanides demonstrate distinct, but poorly understood biological activity. In the current study, we employed genome-wide functional screening to help understand biological effects of exposure to Yb(III) and Lu(III), which were selected as representatives of the late lanthanides. As a model organism, we used Saccharomyces cerevisiae, since it shares many biological functions with humans. Analysis of the functional screening results indicated toxicity of late lanthanides is consistent with disruption of vesicle-mediated transport, and further supported a role for calcium transport processes and mitophagy in mitigating toxicity. Unexpectedly, our analysis suggested that late lanthanides target proteins with SH3 domains, which may underlie the observed toxicity. This study provides fundamental insights into the unique biological chemistry of late lanthanides, which may help devise new avenues toward the development of decorporation strategies and bio-inspired separation processes.
Chimeric antigen receptor T cell-based targeting of CD317 as a novel immunotherapeutic strategy against glioblastoma
Authors: Hänsch Lena , Peipp Matthias , Mastall Maximilian , Villars Danielle , Myburgh Renier , Silginer Manuela , Weiss Tobias , Gramatzki Dorothee , Vasella Flavio , Manz Markus G , Weller Michael , Roth Patrick
Published: June 2023

Background

Chimeric antigen receptor (CAR) T cell therapy has proven to be successful against hematological malignancies. However, exploiting CAR T cells to treat solid tumors is more challenging for various reasons including the lack of suitable target antigens. Here, we identify the transmembrane protein CD317 as a novel target antigen for CAR T cell therapy against glioblastoma, one of the most aggressive solid tumors.

Methods

CD317-targeting CAR T cells were generated by lentivirally transducing human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells toward various glioma cells was assessed in vitro in cell lysis assays. Subsequently, we determined the efficacy of CD317-CAR T cells to control tumor growth in vivo in clinically relevant mouse glioma models.

Results

We generated CD317-specific CAR T cells and demonstrate strong anti-tumor activity against several glioma cell lines as well as primary patient-derived cells with varying CD317 expression levels in vitro. A CRISPR/Cas9-mediated knockout of CD317 protected glioma cells from CAR T cell lysis, demonstrating the target specificity of the approach. Silencing of CD317 expression in T cells by RNA interference reduced fratricide of engineered T cells and further improved their effector function. Using orthotopic glioma mouse models, we demonstrate the antigen-specific anti-tumor activity of CD317-CAR T cells, which resulted in prolonged survival and cure of a fraction of CAR T cell-treated animals.

Conclusions

These data reveal a promising role of CD317-CAR T cell therapy against glioblastoma, which warrants further evaluation to translate this immunotherapeutic strategy into clinical neuro-oncology.
The dilemma of sodium intake in preeclampsia: beneficial or detrimental?
Authors: Afsar Baris , Elsurer Afsar Rengin
Published: June 2023

Preeclampsia (PE) is a disorder involving de novo development of hypertension plus end organ damage after 20 weeks of gestation. PE is considered to be a heterogeneous disease. There are 2 main types of PE: early-onset (<34 weeks of gestation), which is considered to be a placental disorder and is associated with vasoconstriction, low cardiac output, and placental hypoperfusion and organ damage due to decreased microcirculation to maternal organs; and late-onset PE, which is primarily a disorder of pregnant women with obesity, diabetes, and/or cardiovascular abnormalities. In late-onset PE, there is avid sodium reabsorption by the maternal kidneys, causing hypervolemia and increased cardiac output, along with vasodilatation causing venous congestion of organs. Although PE has been a well-known disease for a long time, it is interesting to note that there is no specific sodium (salt) intake recommendation for these patients. This may be due to the fact that studies since as far back as the 1900s have shown conflicting results, and the reasons for the inconsistent findings have not been fully explained; furthermore, the type of PE in these studies was not specifically defined. Some studies suggest that sodium restriction may be detrimental in early-onset PE, but may be feasible in late-onset PE. To explore this paradox, the current review explains the hemodynamic factors involved in these 2 types of PE, summarizes the findings of the current studies, and highlights the knowledge gaps and the research needed to determine whether increase or restriction of salt or sodium intake is beneficial in different types of PE.
Establishing the Validity of Using the COPD Assessment Test to Screen for Fatigue in People With Chronic Obstructive Pulmonary Disease Referred to Pulmonary Rehabilitation
Authors: Reizes Zoe , McNamara Renae J , Dale Marita , McKeough Zoe
Published: June 2023

Objective

Fatigue is the second most prevalent symptom in chronic obstructive pulmonary disease (COPD), yet it is often undetected in pulmonary rehabilitation. The aim of this study was to assess the validity of using a health status questionnaire (COPD Assessment Test [CAT] and CAT-energy score) to detect fatigue in people with COPD referred to a pulmonary rehabilitation program.

Methods

This study was a retrospective audit of people with COPD referred to pulmonary rehabilitation. The validity of the CAT-total score and CAT-energy score for detecting fatigue was analyzed compared to a validated fatigue questionnaire, the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Cut-off values defining fatigue included a CAT-total score ≥ 10, a CAT-energy score ≥ 2, and a FACIT-F score ≤ 43. Data were analyzed using 2 × 2 tables from which accuracy, sensitivity, specificity, and likelihood ratios were calculated.

Results

Data from 97 participants with COPD (age in years mean [SD] = 72 [9]; FEV1% predicted mean [SD] = 46% [18]) were used. The FACIT-F score ≤ 43 classified 84 participants (87%) as fatigued. A CAT-total score ≥ 10 yielded an accuracy of 0.87, sensitivity of 0.95, specificity of 0.31, and positive and negative likelihood ratios of 1.38 and 0.15, respectively. A CAT-energy score ≥ 2 yielded an accuracy of 0.85, sensitivity of 0.93, a specificity of 0.31, and positive and negative likelihood ratios of 1.34 and 0.23, respectively.

Conclusion

The CAT-total score is an accurate and sensitive measure for fatigue, and the CAT could be an appropriate tool to screen for fatigue in people with COPD referred to pulmonary rehabilitation.

Impact

Use of the CAT as a screening tool for fatigue has the potential to improve clinician awareness of fatigue, simplify the pulmonary rehabilitation assessment process by reducing survey burden, and inform fatigue management, which may subsequently reduce the symptomatic burden of fatigue in people with COPD.
Unconventional Monetary Policies and the Yield Curve: Estimating Non-Affine Term Structure Models with Unspanned Macro Risk by Factor Extraction
Authors: Goliński Adam , Spencer Peter
Published: June 2023

We show how the Joslin, Singleton, and Zhu (2011) factor extraction approach to estimating the Gaussian term structure model can be modified to handle the interest rate lower bound without the approximations used in other approaches. This drastically reduces the computation time and produces more robust estimates of the lower bound parameter and the shadow rate. It makes feasible the extensive specification search necessary to allow for unspanned factors as in Joslin, Priebsch, and Singleton (2014), allowing the term structure model to be used to better assess the effects of policy on the term premium and market expectations. (JEL G12, C13, E43)
Photorhabdus-Derived Secondary Metabolites Reduce Root Infection by Meloidogyne incognita in Cowpea
Authors: Kusakabe Ayako , Molnár István , Stock S. Patricia
Published: June 2023

Root-knot nematodes (RKNs) cause significant economic damage to crop plants, spurring demand for safe, affordable, and sustainable nematicides. A previous study by our research team showed that the combination of two nematicidal secondary metabolites (SMs) derived from Photorhabdus bacteria, trans-cinnamic acid (t-CA), and (4E)-5-phenylpent-4-enoic acid (PPA) have a synergistic effect against RKNs in vitro. In this study, we considered in planta assays to assess the effects of this SM mixture on the virulence and reproductive fitness of the RKN Meloidogyne incognita in a cowpea. Factorial combinations of five t-CA + PPA concentrations (0, 9.0, 22.9, 57.8, and 91.0 μg/ml) and two nematode inoculation conditions (presence or absence) were evaluated in 6-week growth chamber experiments. Results from this study showed that a single root application of the t-CA + PPA mixture significantly reduced the penetration of M. incognita infective juveniles (J2s) into the cowpea roots. The potential toxicity of t-CA + PPA on RKN-susceptible cowpea seedlings was also investigated. The effect of t-CA + PPA × nematode inoculation interactions and the t-CA + PPA mixture did not show significant phytotoxic effects, nor did it adversely affect plant growth parameters or alter leaf chlorophyll content. Total leaf chlorophyll and chlorophyll b content were significantly reduced (by 15 and 22%, respectively) only by the nematode inoculum and not by any of the SM treatments. Our results suggest that a single root application of a mixture of t-CA and PPA reduces M. incognita J2’s ability to infect the roots without impairing plant growth or chlorophyll content.
One size does not fit all: Differential benefits of simultaneous liver-kidney transplantation by eligibility criteria
Authors: Cheng Xingxing S. , McElroy Lisa M. , Sanoff Scott L. , Kwong Allison J.
Published: June 2023

Standard eligibility criteria for simultaneous liver-kidney transplantation (SLK) are in place in the United States. We hypothesize that the benefit associated with SLK over liver transplant alone differs by patient, depending on the specific SLK criteria met. We analyzed a retrospective US cohort of 5446 adult liver transplant or SLK recipients between January 1, 2015, and December 31, 2018, who are potentially qualified for SLK. Exposure was a receipt of SLK. We tested effect modification by the specific SLK eligibility criteria met (end-stage kidney disease, acute kidney injury, chronic kidney disease, or unknown). The primary outcome was death within 1 year of a liver transplant. We used a modified Cox regression analysis containing an interaction term of SLK * time from transplant. Two hundred ten (9%) SLK recipients and 351 (11%) liver-alone recipients died in 1 year. In the overall population, SLK was associated with a mortality benefit over liver transplant on the day of the transplant, without adjustment [HR: 0.59 (95% CI, 0.46–0.76)] and with adjustment [aHR: 0.50 (95% CI, 0.35–0.71)]. However, when SLK eligibility criteria were included, only in patients with end-stage kidney disease was SLK associated with a sustained survival benefit at day 0 [HR: 0.17 (0.08–0.35)] up to 288 (95% CI, 120–649) days post-transplant. Benefit within the first year post-transplant associated with SLK over liver-alone transplantation was only pronounced in patients with end-stage kidney disease but not present in patients meeting other criteria for SLK. A “strict SLK liberal Safety Net” strategy may warrant consideration at the national policy level.
INVESTIGATION OF THE PATHOLOGICAL EFFECTS OF HISTONES, DNA, AND NUCLEOSOMES IN A MURINE MODEL OF SEPSIS
Authors: Medeiros Sarah K. , Sharma Neha , Dwivedi Dhruva , Liaw Patricia C.
Published: June 2023

Background: In sepsis, neutrophil extracellular traps (NETs) are an important interface between innate immunity and coagulation. The major structural component of neutrophil extracellular traps is nucleosomes (DNA-histone complexes). In vitro, DNA and histones exert procoagulant/cytotoxic effects whereas nucleosomes are not harmful. However, whether DNA, histones, and/or nucleosomes exert harmful effects in vivo remain unclear. Objectives: (1) The aims of the study are to investigate the cytotoxic effects of nucleosomes ± DNase I and heparin in vitro and (2) to investigate whether DNA, histones, and/or nucleosomes are harmful when injected into healthy and septic mice. Methods: The cytotoxic effects of DNA, histones, and nucleosomes (± DNaseI or ±heparin) were assessed in HEK293 cells. Mice underwent cecal ligation and puncture or sham surgery and then received injections of DNA (8 mg/kg), histones (8.5 mg/kg), or nucleosomes at 4 and 6 h. Organs and blood were harvested at 8 h. Cell-free DNA, IL-6, thrombin-anti-thrombin, and protein C were quantified from plasma. Results:
In vitro, incubation of HEK293 cells with DNaseI-treated nucleosomes reduced cell survival compared with nucleosome-treated cells, suggesting that DNaseI releases cytotoxic histones from nucleosomes. Addition of heparin to DNaseI-treated nucleosomes rescued cell death. In vivo, administration of histones to septic mice increased markers of inflammation (IL-6) and coagulation (thrombin-anti-thrombin), which was not observed in sham or septic mice administered DNA or nucleosomes. Conclusions: Our studies suggest that DNA masks the harmful effects of histones in vitro and in vivo. Although administration of histones contributed to the pathogenesis of sepsis, administration of nucleosomes or DNA was not harmful in healthy or septic mice.
Gene-environment interactions for Parkinson’s disease
Authors: Reynoso Alexandra , Torricelli Roberta , Jacobs Benjamin Meir , Shi Jingchunzi , Aslibekyan Stella , Kaufmann Lucy , Noyce Alastair J , Heilbron Karl
Published: June 2023

Importance

Parkinson’s disease (PD) is a neurodegenerative disorder with complex aetiology. Multiple genetic and environmental factors have been associated with PD, but most PD risk remains unexplained.

Objective

The aim of this study was to test for statistical interactions between PD-related genetic and environmental exposures/phenotypic traits in the 23andMe, Inc. research dataset.

Design

Nested cross-sectional case-control study.

Setting

Population-based cohort.

Participants

PD subjects were recruited to join the 23andMe, Inc study population in collaboration with the Michael J. Fox Foundation and other PD patient advocacy groups, and/or via online surveys. Participants that reported a change or uncertainty in diagnosis during follow-up were excluded. Controls were recruited from 23andMe participants that did not report a diagnosis of PD at entry or on subsequent follow-up surveys.

Exposures

Using a validated PD polygenic risk score (PRS) and common PD-associated variants in theGBAgene, we explored interactions between genetic susceptibility factors and phenotypic traits: body mass index (BMI), type 2 diabetes (T2D), tobacco use, caffeine consumption, pesticide exposure, head injury, and physical activity (PA).

Main Outcomes and Measures

Self-reported PD case/control status.

Results

The dataset contained 18,819 PD cases (40.2% female) and 545,751 controls (55.7% female). The average age of PD cases and controls was 73.1 and 73.0 years, respectively (SDPD= 10.8 years, SDcontrol= 10.8 years). In models without gene-by-environment interactions, we observed that higher BMI, T2D, caffeine consumption, and tobacco use were associated with lower odds of PD, while head injury, pesticide exposure, andGBAcarrier status were associated with increased odds. We observed no significant association between PA and PD. PRS was associated with increased odds of PD and there was statistical evidence for an interaction between PRS and BMI, PRS and T2D, PRS and PA, and PRS and tobacco use (p=4.314E-4; p=6.502E-8; p=8.745E-5, p=2.236E-3, respectively). Whilst BMI and tobacco use were associated with lower odds of PD regardless of the extent of individual genetic liability, the direction of the relationship between odds of PD and T2D as well as PA, varied depending on PRS.

Conclusions and Relevance

We provide preliminary evidence that associations between phenotypic traits and PD may be modified by genotype.
Repurposing Remdesivir for COVID-19: Computational Drug Design Targeting SARS-CoV-2 RNA Polymerase and Main Protease using Molecular Dynamics Approach
Authors: Shikder Mita , Ahmed Kazi Ahsan , Moin Abu Tayab , Patil Rajesh B. , Hasib Tasnin Al , Hossan Mohammad Imran , Mahasin Deera , Sakib Mohammad Najmul , Ahmed Iqrar , Patel Harun , Chowdhury Afrin Sultana
Published: June 2023

The coronavirus disease of 2019 (COVID-19) is a highly contagious respiratory illness that has become a global health crisis with new variants, an unprecedented number of infections, and deaths and demands urgent manufacturing of potent therapeutics. Despite the success of vaccination campaigns around the globe, there is no particular therapeutics approved to date for efficiently treating infected individuals. Repositioning or repurposing previously effective antivirals against RNA viruses to treat COVID-19 patients is a feasible option. Remdesivir is a broad-spectrum antiviral drug that the Food and Drug Administration (FDA) licenses for treating COVID-19 patients who are critically ill patients. Remdesivir’s low efficacy, which has been shown in some clinical trials, possible adverse effects, and dose-related toxicities are issues with its use in clinical use. Our study aimed to design potent derivatives of remdesivir through the functional group modification of the parent drug targeting RNA-dependent RNA polymerase (RdRp) and main protease (MPro) of SARS-CoV-2. The efficacy and stability of the proposed derivatives were assessed by molecular docking and extended molecular dynamics simulation analyses. Furthermore, the pharmacokinetic activity was measured to ensure the safety and drug potential of the designed derivatives. The derivatives were non-carcinogenic, chemically reactive, highly interactive, and stable with the target proteins. D-CF3 is one of the designed derivatives that finally showed stronger interaction than the parent drug, according to the docking and dynamics simulation analyses, with both target proteins. However,in vitroandin vivoinvestigations are guaranteed to validate the findings in the future.
Fungal small RNAs ride in extracellular vesicles to enter plant cells through clathrin-mediated endocytosis
Authors: He Baoye , Wang Huan , Liu Guosheng , Chen Angela , Calvo Alejandra , Cai Qiang , Jin Hailing
Published: June 2023

Small RNAs (sRNAs) of the fungal pathogenBotrytis cinereacan enter plant cells and hijack host Argonaute protein 1 (AGO1) to silence host immunity genes. However, the mechanism by which these fungal sRNAs are secreted and enter host cells remains unclear. Here, we demonstrate thatB. cinereautilizes extracellular vesicles (EVs) to secrete Bc-sRNAs, which are then internalized by plant cells through clathrin-mediated endocytosis (CME). TheB. cinereatetraspanin protein, Punchless 1 (BcPLS1), serves as an EV biomarker and plays an essential role in fungal pathogenicity. We observe numerousArabidopsisclathrin-coated vesicles (CCVs) aroundB. cinereainfection sites and the colocalization ofB. cinereaEV marker BcPLS1 andArabidopsis CLATHRIN LIGHT CHAIN 1, one of the core components of CCV. Meanwhile, BcPLS1 and theB. cinerea-secreted sRNAs are detected in purified CCVs after infection.Arabidopsisknockout mutants and inducible dominant-negative mutants of key components of CME pathway exhibit increased resistance toB. cinereainfection. Furthermore, Bc-sRNA loading intoArabidopsisAGO1 and host target gene suppression are attenuated in those CME mutants. Together, our results demonstrate that fungi secrete sRNAs via EVs, which then enter host plant cells mainly through CME.