bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral blood mononuclear cell phenotype and function are maintained after overnight shipping of whole blood
Authors: Johnson Renee K. , Overlee Brittany L. , Sagen Jessica A. , Howe Charles L. 
Published: November 2022

AbstractSame day processing of biospecimens such as blood is not always feasible, which presents a challenge for research programs seeking to study a broad population or to characterize patients with rare diseases. Recruiting sites may not be equipped to process blood samples and variability in timing and technique employed to isolate peripheral blood mononuclear cells (PBMCs) at local sites may compromise reproducibility across patients. One solution is to send whole blood collected by routine phlebotomy via overnight courier to the testing site under ambient conditions. Determining the impact of shipping on subsequent leukocyte responses is a necessary prerequisite to any experimental analysis derived from transported samples. To this end, whole blood was collected from healthy control subjects and processed fresh or at 6, 24 and 48 h after collection and handling under modeled shipping conditions. At endpoint, whole blood was assessed via a complete blood count with differential and immunophenotyped using a standardized panel of antibodies [HLADR, CD66b, CD3, CD14, CD16]. PBMCs and neutrophils were isolated from whole blood and subjected to ex vivo stimulation with lipopolysaccharide and heat-killed Staphylococcus aureus. Stimulated release of cytokines and chemokines was assessed by cytometric bead array. RNA was also isolated from PBMCs to analyze transcriptional changes induced by shipping. The complete blood count with differential revealed that most parameters were maintained in shipped blood held for 24 h at ambient temperature. Immunophenotyping indicated preservation of cellular profiles at 24 h, although with broadening of some populations and a decrease in CD16 intensity on classical monocytes. At the transcriptional level, RNAseq analysis identified upregulation of a transcription factor module associated with inflammation in unstimulated PBMCs derived from whole blood shipped overnight. However, these changes were limited in both scale and number of impacted genes. Ex vivo stimulation of PBMCs further revealed preservation of functional responses in cells isolated from shipped blood held for 24 h at ambient temperature. However, neutrophil responses were largely abrogated by this time. By 48 h neither cell population responded within normal parameters. These findings indicate that robust immunophenotyping and PBMC stimulated response profiles are maintained in whole blood shipped overnight and processed within 24 h of collection, yielding results that are representative of those obtained from the sample immediately following venipuncture. This methodology is feasible for many patient recruitment sites to implement and allows for sophisticated immunological analysis of patient populations derived from large geographic areas. With regard to rare disease research, this meets a universal need to enroll patients in sufficient numbers for immunoprofiling and discovery of underlying pathogenic mechanisms.
TBX1 targets the miR-200–ZEB2 axis to induce epithelial differentiation and inhibit stem cell properties
Authors: Funato Noriko , Yanagisawa Hiromi 
Published: November 2022

AbstractTBX1, which encodes a T-box transcription factor, is considered a candidate gene for DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome. Transduction of TBX1 decreases cell proliferation in epithelial cancer cells and Tbx1 ablation induces epithelial proliferation during palatal development. Here, we report that TBX1 regulates stem cell properties and epithelial differentiation through the transcriptional activation of microRNAs. Stable expression of TBX1 induces microRNA-200 (miR-200), whose members repress the epithelial-to-mesenchymal transition and induce epithelial differentiation. TBX1 rescues ZEB2-dependent transcriptional inhibition of the miR-200b/200a/429 cluster, whose promoter region contains conserved overlapping cis-regulatory motifs of the ZEB-binding E-box and TBX-binding element. Consequently, TBX1 activates the expression of both miR-200 and stemness-inhibitor miR-203 to inhibit their common targets, BMI1 and ZEB2. Moreover, Tbx1 ablation affects the differentiation of the palatal epithelium and perturbs the expression of miR-200, miR-203, and their target genes. We propose that TBX1 links stem cell properties and epithelial differentiation by inducing miR-200 and miR-203. Thus, targeting of the ZEB2–miR-200 axis by TBX1 may have potential therapeutic implications in miR-200-associated tumors and cleft palate.
Effective degradation of organophosphate ester flame retardants and plasticizers in coastal sediments under high urban pressure
Authors: Castro-Jiménez J. , Cuny P. , Militon C. , Sylvi L. , Royer F. , Papillon L. , Sempéré R. 
Published: November 2022

AbstractEmpirical evidence of the effective degradation at environmentally relevant conditions of organophosphate esters (OPEs) flame retardants and plasticizers in coastal sediments from an impacted area in the NW Mediterranean Sea is provided. Half-lives varied from 23.3 to 77.0 (abiotic conditions) and from 16.8 to 46.8 days (biotic conditions), depending on the compound, highlighting the relevant role of microbial assemblages enhancing OPE degradation. After an immediate significant reduction of the bacterial abundance due to OPE addition to the sediment at the very beginning of the experiment, the observed biodegradation was associated to a general stimulation of the growth of the bacterial community during a first period, but without a marked change of the structure of the community. However, OPE contamination induced a decrease on the diversity of the bacterial community in the coastal sediment, noticeable after 14 days of incubation. It is likely that on one side the contamination had favoured the growth of some bacterial groups maybe involved in the biodegradation of these compounds but, on the other side, had also impacted some sensitive bacteria. The estimated half-lives fill a data gap concerning OPE degradation rates in marine sediments and will be valuable data for the refinement of OPE chemical risk assessment in marine environments, particularly on impacted sites.
MEK inhibitor resistance in lung adenocarcinoma is associated with addiction to sustained ERK suppression
Authors: Farnsworth Dylan A. , Inoue Yusuke , Johnson Fraser D. , de Rappard-Yuswack Georgia , Lu Daniel , Shi Rocky , Ma Lok In Josephine , Mattar Marissa S. , Somwar Romel , Ladanyi Marc , Unni Arun M. , Lockwood William W. 
Published: November 2022

AbstractMEK inhibitors (MEKi) have limited efficacy in KRAS mutant lung adenocarcinoma (LUAD) patients, and this is attributed to both intrinsic and adaptive mechanisms of drug resistance. While many studies have focused on the former, there remains a dearth of data regarding acquired resistance to MEKi in LUAD. We established trametinib-resistant KRAS mutant LUAD cells through dose escalation and performed targeted MSK-IMPACT sequencing to identify drivers of MEKi resistance. Comparing resistant cells to their sensitive counterparts revealed alteration of genes associated with trametinib response. We describe a state of “drug addiction” in resistant cases where cells are dependent on continuous culture in trametinib for survival. We show that dependence on ERK2 suppression underlies this phenomenon and that trametinib removal hyperactivates ERK, resulting in ER stress and apoptosis. Amplification of KRASG12C occurs in drug-addicted cells and blocking mutant-specific activity with AMG 510 rescues the lethality associated with trametinib withdrawal. Furthermore, we show that increased KRASG12C expression is lethal to other KRAS mutant LUAD cells, consequential to ERK hyperactivation. Our study determines the drug-addicted phenotype in lung cancer is associated with KRAS amplification and demonstrates that toxic acquired genetic changes can develop de novo in the background of MAPK suppression with MEK inhibitors. We suggest that the presence of mutant KRAS amplification in patients may identify those that may benefit from a “drug holiday” to circumvent drug resistance. These findings demonstrate the toxic potential of hyperactive ERK signaling and highlight potential therapeutic opportunities in patients bearing KRAS mutations.
Co-targeting KRAS G12C and EGFR reduces both mutant and wild-type RAS-GTP
Authors: McFall Thomas , Trogdon Michael , Guizar Anita C. , Langenheim John F. , Sisk-Hackworth Laura , Stites Edward C. 
Published: November 2022

AbstractThe combination of KRAS G12C inhibitors with EGFR inhibitors has reproducibly been shown to be beneficial. Here, we identify another benefit of this combination: it effectively inhibits both wild-type and mutant RAS. We believe that targeting both mutant and wild-type RAS helps explain why this combination of inhibitors is effective.
High-refractive index and mechanically cleavable non-van der Waals InGaS3
Authors: Toksumakov Adilet N. , Ermolaev Georgy A. , Slavich Aleksandr S. , Doroshina Natalia V. , Sukhanova Ekaterina V. , Yakubovsky Dmitry I. , Syuy Alexander V. , Novikov Sergey M. , Romanov Roman I. , Markeev Andrey M. , Oreshonkov Aleksandr S. , Tsymbarenko Dmitry M. , Popov Zakhar I. , Kvashnin Dmitry G. , Vyshnevyy Andrey A. , Arsenin Aleksey V. , Ghazaryan Davit A. , Volkov Valentyn S. 
Published: November 2022

AbstractThe growing family of two-dimensional crystals has been recognized as a promising platform for investigation of rich low-dimension physics and production of a variety of devices. Of particular interest are recently reported atomic sheets of non-van der Waals materials, which reshape our understanding of chemical bonds and enable heterostructures with novel functionality. Here, we study the structural and optical properties of ultrathin non-van der Waals InGaS3 sheets produced by standard mechanical cleavage. Our ab initio calculations reveal weak out-of-plane covalent bonds, responsible for the layered structure of the material. The energy required for isolation of a single layer is as low as ~50 meVÅ–2, which is comparable with the conventional van der Waals material’s monolayer isolation energies of 20–60 meVÅ–2. A comprehensive study of the structural, vibrational, and optical properties of the material reveals its wide bandgap (2.73 eV), high refractive index (>2.5) and negligible losses in the visible and infrared spectral ranges. These properties make it a perfect candidate for visible-range all-dielectric nanophotonics.
Inhibition of VMAT2 by β2-adrenergic agonists, antagonists, and the atypical antipsychotic ziprasidone
Authors: Støve Svein Isungset , Skjevik Åge Aleksander , Teigen Knut , Martinez Aurora 
Published: November 2022

AbstractVesicular monoamine transporter 2 (VMAT2) is responsible for packing monoamine neurotransmitters into synaptic vesicles for storage and subsequent neurotransmission. VMAT2 inhibitors are approved for symptomatic treatment of tardive dyskinesia and Huntington’s chorea, but despite being much-studied inhibitors their exact binding site and mechanism behind binding and inhibition of monoamine transport are not known. Here we report the identification of several approved drugs, notably β2-adrenergic agonists salmeterol, vilanterol and formoterol, β2-adrenergic antagonist carvedilol and the atypical antipsychotic ziprasidone as inhibitors of rat VMAT2. Further, plausible binding modes of the established VMAT2 inhibitors reserpine and tetrabenazine and hit compounds salmeterol and ziprasidone were identified using molecular dynamics simulations and functional assays using VMAT2 wild-type and mutants. Our findings show VMAT2 as a potential off-target of treatments with several approved drugs in use today and can also provide important first steps in both drug repurposing and therapy development targeting VMAT2 function.
Rapid blue- and redshifted excursions in Hα line profiles synthesized from realistic 3D magnetohydrodynamic simulations
Authors: Danilovic S. , Bjørgen J. P. , Leenaarts J. , Rempel M. 
Published: November 2022

Context. Rapid blue- and redshifted excursions (RBEs and RREs) may play an important role in mass-loading and heating the solar corona, but their nature and origin are still debatable.
Aims. We aim to model these features to learn more about their properties, formation, and origin.
Methods. We created a realistic three-dimensional (3D) magnetohydrodynamic model of a solar plage region. Synthetic Hα spectra were generated and the spectral signatures of these features identified. The magnetic field lines associated with these events were traced, and the underlying dynamic was studied.
Results. The model reproduces many properties of RBEs and RREs well, such as spatial distribution, lateral movement, length, and lifetimes. Synthetic Hα line profiles, similarly to observed ones, show a strong blue- or redshift as well as asymmetries. These line profiles are caused by the vertical component of velocities higher than 30 − 40 km s−1, which mostly appear in the height range 2 − 4 Mm. By tracing magnetic field lines, we show that the vertical velocity that causes the appearance of RBEs or RREs is always associated with the component of velocity perpendicular to the magnetic field lines.
Conclusions. The study confirms the hypothesis that RBEs and RREs are signs of Alfvénic waves with, in some cases, a significant contribution from slow magneto-acoustic modes.
Sub-stellar engulfment by a main-sequence star: Where is the lithium?
Authors: Cabezón R. M. , Abia C. , Domínguez I. , García-Senz D. 
Published: November 2022

Context. Since the discovery of exoplanetary systems, questions have been raised as to the sub-stellar companions that can survive encounters with their host star, and how this interaction may affect the internal structure and evolution of the hosting star, and particularly its surface chemical composition.
Aims. We study whether the engulfment of a brown dwarf (BD) by a solar-like main-sequence (MS) star can significantly alter the structure of the star and the Li content on its surface.
Methods. We performed 3D smoothed particle hydrodynamics simulations of the engulfment of a BD with masses 0.01 and 0.019 M⊙, on an MS star of 1 M⊙ and solar composition, in three different scenarios: a head-on collision, a grazing collision with an impact parameter η = 0.5 R⊙, and a merger. We studied the dynamics of the interaction in detail, and the relevance of the type of interaction and the mass of the BD on the final fate of the sub-stellar object and the host star in terms of mass loss of the system, angular momentum transfer, and changes in the Li abundance on the surface of the host star.
Results. In all the studied scenarios, most of the BD mass is diluted in the denser region of the MS star. Only in the merger scenario a significant fraction (∼40%) of the BD material would remain in the outer layers. We find a clear increase in the surface rotational velocity of the host star after the interaction, ranging between 25 km s−1 (grazing collision) to 50 km s−1 (merger). We also find a significant mass loss from the system (in the range 10−4 − 10−3 M⊙) due to the engulfment, which in the case of the merger may form a circumstellar disk-like structure. Assuming that neither the depth of the convective envelope of the host star nor its mass content are modified during the interaction, a small change in the surface Li abundance in the head-on and grazing collisions is found. However, in the merger we find large Li enhancements, by factors of 20 − 30, depending on the BD mass. Some of these features could be detected observationally in the host star, provided they remained for a long enough time.
Conclusions. In our 3D simulations, a sizable fraction of the BD survives long enough to be mixed with the inner core of the MS star. This is at odds with previous suggestions based on 1D simulations. In some cases the final surface rotational velocity is very high, coupled with enough mass loss that may form a circumstellar disk. Merger scenarios tend to dilute considerably more BD material on the surface of the MS star, which could be detected as a Li-enhancement. The dynamic of the simulated scenarios suggests the development of asymmetries in the structure of the host star that can only be tackled with 3D codes, including the long-term evolution of the system.
ISPY: NACO Imaging Survey for Planets around Young stars
Authors: Cugno G. , Pearce T. D. , Launhardt R. , Bonse M. J. , Ma J. , Henning T. , Quirrenbach A. , Ségransan D. , Matthews E. C. , Quanz S. P. , Kennedy G. M. , Müller A. , Reffert S. , Rickman E. L. 
Published: November 2022

Context. Planet formation is a frequent process, but little observational constraints exist about the mechanisms involved, especially for giant planets at large separation. The NaCo-ISPY large program is a 120 night L′-band direct imaging survey aimed at investigating the giant planet population on wide orbits (a > 10 au) around stars hosting disks.
Aims. Here we present the statistical analysis of a subsample of 45 young stars surrounded by protoplanetary disks (PPDs). This is the largest imaging survey uniquely focused on PPDs to date. Our goal is to search for young forming companions embedded in the disk material and to constrain their occurrence rate in relation to the formation mechanism.
Methods. We used principal component analysis based point spread function subtraction techniques to reveal young companions forming in the disks. We calculated detection limits for our datasets and adopted a black-body model to derive temperature upper limits of potential forming planets. We then used Monte Carlo simulations to constrain the population of forming gas giant companions and compare our results to different types of formation scenarios.
Results. Our data revealed a new binary system (HD 38120) and a recently identified triple system with a brown dwarf companion orbiting a binary system (HD 101412), in addition to 12 known companions. Furthermore, we detected signals from 17 disks, two of which (HD 72106 and T CrA) were imaged for the first time. We reached median detection limits of L′ = 15.4 mag at 2″.0, which were used to investigate the temperature of potentially embedded forming companions. We can constrain the occurrence of forming planets with semi-major axis a in [20–500] au and Teff in [600–3000] K to be 21.2-13.6+24.3%, 14.8-9.6+17.5%, and 10.8-7.0+12.6% for Rp = 2, 3, 5 RJ, which is in line with the statistical results obtained for more evolved systems from other direct imaging surveys. These values are obtained under the assumption that extinction from circumstellar and circumplanetary material does not affect the companion signal, but we show the potential impact these factors might have on the detectability of forming objects.
Conclusions. The NaCo-ISPY data confirm that massive bright planets accreting at high rates are rare. More powerful instruments with better sensitivity in the near- to mid-infrared are likely required to unveil the wealth of forming planets sculpting the observed disk substructures.
Chemoenzymatic Enantioselective Synthesis of the Hancock Alkaloids (S)- and (R)-Galipeine, (S)-Cuspareine, (S)-Galipinine, and (S)-Angustureine
Authors: Diaz-Muñoz Gaspar , da Cruz Nilton Gonçalves , de Miranda Amanda Silva , Vieira Henriete da Silva , Kohlhoff Markus , Mendonça João Guilherme Pereira , Diaz Marisa Alves Nogueira 
Published: November 2022

AbstractThe enantioselective synthesis of the Hancock 1,2,3,4-tetrahydroquinoline alkaloids (S)-galipeine, (S)-cuspareine, (S)-galipinine, and (S)-angustureine and the nonnatural enantiomer (R)-galipeine is described herein. The target compounds were obtained in five steps from a racemic quinaldinic acid derived α-amino ester in overall yields of 21.2% to 37.5%. The synthetic route comprised two key steps: an enzymatic kinetic resolution to control the C-2 stereocenter, affording (R)- and (S)-α-amino esters as key chiral intermediates with 94% and 72% ee, respectively, and Wittig olefination of (R)- and (S)-α-amino aldehyde synthons with the corresponding phosphonium salts using a phase-transfer system (t-BuOH/CH2Cl2), thereby allowing the introduction of alkyl substituents at C-2. Finally, the enantioselective synthesis was concluded with the catalytic hydrogenation of olefinic bonds on the Wittig adducts to furnish the target Hancock alkaloids, including (R)-galipeine, whose synthesis is described here for the first time.
Challenging Cases in Neurology: Neurologic Complications of COVID-19
Authors: Horta Lucas , Bakhtyari Ava , Greige Tatiana , Anand Pria 
Published: November 2022

AbstractSince the first reported cases of pneumonia in December 2019, coronavirus disease 2019 (COVID-19) has rapidly become recognized as a multisystem illness, with known effects on virtually every organ system. In particular, neurologic complications of COVID-19 have been reported since the beginning of the pandemic in both ambulatory patients with mild disease and critically ill patients. Although it remains unclear whether severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has the potential to directly invade the central nervous system, strokes and other neurovascular complications, sequelae of critical illness and metabolic derangements, parainfectious inflammatory disorders, and a poorly understood post-COVID syndrome have all been reported in patients with COVID-19. Here, we describe cases representing a diverse range of neurologic complications in patients infected with COVID-19.
Increased Number of Functional Tics Seen in Danish Adolescents during the COVID-19 Pandemic
Authors: Okkels Kirstine Birkebæk , Skov Liselotte , Klansø Susanne , Aaslet Lone , Grejsen Judy , Reenberg Annika , Sørensen Camilla Birgitte , Debes Nanette Marinette Monique Mol 
Published: November 2022

Abstract
Background Global increase in functional tics in adolescents has been observed. Differentiating functional from classic tics is important since pathophysiology and treatment differ. We investigated possible triggers for development of functional tics and discuss the possible role of the coronavirus disease 2019 (COVID-19) pandemic and social media exposure in cases of functional tics seen during this period. Moreover, the treatment, and its efficacy is discussed.
Methods Medical records of 28 Danish adolescents diagnosed with functional tics at the National Tourette Clinic, Department of Pediatrics, Herlev University Hospital, Denmark, from May 2020 to June 2021 have been retrospectively reviewed. Descriptive statistical analyses were used to analyze the data.
Main Findings A total of 28 patients diagnosed with functional tics were included, 96.4% girls and 3.6% boys, mean age 14.4 years. Tic phenomenology differed from classic tics with more complex tics and no rostrocaudal progression. Note that 69.2% reported harmful tics. Also, 78.6% had trauma/precipitating event and 40% denounced lockdown related to the COVID-19 pandemic as trigger, both prior to onset of functional tics. Note that 60.7% reported psychiatric symptoms/diagnoses, 42.9% had a first-degree family member with psychiatric symptoms/diagnoses, and 96.4% were exposed to tics on social media prior to onset. Treatment consisted of psychoeducation, elements from cognitive behavioral therapy, and focus on psychiatric symptoms. All patients responded to the treatment.
Conclusion The vulnerability of the adolescents is characteristic. Treatment strategy has shown immediate positive effect. Consequences of the COVID-19 pandemic in combination with exposure to tics on social media could be part of the cause for the increase in number of functional tics.