bluuebunny/crossref_metadata_2025 huggingface dataset:
Effort avoidance as a core mechanism of apathy in frontotemporal dementia
Authors: Le Bouc Raphaël , Borderies Nicolas , Carle Guilhem , Robriquet Chloé , Vinckier Fabien , Daunizeau Jean , Azuar Carole , Levy Richard , Pessiglione Mathias
Published: November 2022

Apathy is a core symptom in patients with behavioural variant frontotemporal dementia (bvFTD). It is defined by the observable reduction in goal-directed behaviour, but the underlying mechanisms are poorly understood. According to decision theory, engagement in goal-directed behaviour depends on a cost–benefit optimization trading off the estimated effort (related to the behaviour) against the expected reward (related to the goal). In this framework, apathy would thus result from either a decreased appetence for reward, or from an increased aversion to effort. Here, we phenotyped the motivational state of 21 patients with bvFTD and 40 matched healthy controls using computational analyses of behavioural responses in a comprehensive series of behavioural tasks, involving both expression of preference (comparing reward value and effort cost) and optimization of performance (adjusting effort production to the reward at stake). The primary finding was an elevated aversion to effort, consistent across preference and performance tasks in patients with bvFTD compared to controls. Within the bvFTD group, effort avoidance was correlated to cortical atrophy in the dorsal anterior cingulate cortex and to apathy score measured on a clinical scale. Thus, our results highlight elevated effort aversion (not reduced reward appetence) as a core dysfunction that might generate apathy in patients with bvFTD. More broadly, they provide novel behavioural tests and computational tools to identify the dysfunctional mechanisms producing motivation deficits in patients with brain damage.
Adolescent nicotine administration increases nicotinic acetylcholine receptor binding and functional connectivity in specific cortico-striatal-thalamic circuits
Authors: Keeley Robin J , Prillaman McKenzie E , Scarlata Miranda , Vrana Antonia , Tsai Pei-Jung , Gomez Juan L , Bonaventura Jordi , Lu Hanbing , Michaelides Michael , Stein Elliot A
Published: November 2022

Nicotine exposure is associated with regional changes in brain nicotinic acetylcholine receptors subtype expression patterns as a function of dose and age at the time of exposure. Moreover, nicotine dependence is associated with changes in brain circuit functional connectivity, but the relationship between such connectivity and concomitant regional distribution changes in nicotinic acetylcholine receptor subtypes following nicotine exposure is not understood. Although smoking typically begins in adolescence, developmental changes in brain circuits and nicotinic acetylcholine receptors following chronic nicotine exposure remain minimally investigated. Here, we combined in vitro nicotinic acetylcholine receptor autoradiography with resting state functional magnetic resonance imaging to measure changes in [3H]nicotine binding and α4ß2 subtype nicotinic acetylcholine receptor binding and circuit connectivity across the brain in adolescent (postnatal Day 33) and adult (postnatal Day 68) rats exposed to 6 weeks of nicotine administration (0, 1.2 and 4.8 mg/kg/day). Chronic nicotine exposure increased nicotinic acetylcholine receptor levels and induced discrete, developmental stage changes in regional nicotinic acetylcholine receptor subtype distribution. These effects were most pronounced in striatal, thalamic and cortical regions when nicotine was administered during adolescence but not in adults. Using these regional receptor changes as seeds, resting state functional magnetic resonance imaging identified dysregulations in cortico-striatal-thalamic-cortical circuits that were also dysregulated following adolescent nicotine exposure. Thus, nicotine-induced increases in cortical, striatal and thalamic nicotinic acetylcholine receptors during adolescence modifies processing and brain circuits within cortico-striatal-thalamic-cortical loops, which are known to be crucial for multisensory integration, action selection and motor output, and may alter the developmental trajectory of the adolescent brain. This unique multimodal study significantly advances our understanding of nicotine dependence and its effects on the adolescent brain.
Complement inhibition prevents glial nodal membrane injury in a GM1 antibody-mediated mouse model
Authors: Campbell Clare I , McGonigal Rhona , Barrie Jennifer A , Delaere Jolien , Bracke Laura , Cunningham Madeleine E , Yao Denggao , Delahaye Tim , Van de Walle Inge , Willison Hugh J
Published: November 2022

The involvement of the complement pathway in Guillain–Barré syndrome pathogenesis has been demonstrated in both patient biosamples and animal models. One proposed mechanism is that anti-ganglioside antibodies mediate neural membrane injury through the activation of complement and the formation of membrane attack complex pores, thereby allowing the uncontrolled influx of ions, including calcium, intracellularly. Calcium influx activates the calcium-dependent protease calpain, leading to the cleavage of neural cytoskeletal and transmembrane proteins and contributing to subsequent functional failure. Complement inhibition has been demonstrated to provide effective protection from injury in anti-ganglioside antibody-mediated mouse models of axonal variants of Guillain–Barré syndrome; however, the role of complement in the pathogenesis of demyelinating variants has yet to be established. Thus, it is currently unknown whether complement inhibition would be an effective therapeutic for Guillain–Barré syndrome patients with injuries to the Schwann cell membrane. To address this, we recently developed a mouse model whereby the Schwann cell membrane was selectively targeted with an anti-GM1 antibody resulting in significant disruption to the axo-glial junction and cytoplasmic paranodal loops, presenting as conduction block. Herein, we utilize this Schwann cell nodal membrane injury model to determine the relevance of inhibiting complement activation. We addressed the early complement component C2 as the therapeutic target within the complement cascade by using the anti-C2 humanized monoclonal antibody, ARGX-117. This anti-C2 antibody blocks the formation of C3 convertase, specifically inhibiting the classical and lectin complement pathways and preventing the production of downstream harmful anaphylatoxins (C3a and C5a) and membrane attack complexes. Here, we demonstrate that C2 inhibition significantly attenuates injury to paranodal proteins at the node of Ranvier and improves respiratory function in ex vivo and in vivo Schwann cell nodal membrane injury models. In parallel studies, C2 inhibition also protects axonal integrity in our well-established model of acute motor axonal neuropathy mediated by both mouse and human anti-GM1 antibodies. These data demonstrate that complement inhibition prevents injury in a Schwann cell nodal membrane injury model, which is representative of neuropathies associated with anti-GM1 antibodies, including Guillain–Barré syndrome and multifocal motor neuropathy. This outcome suggests that both the motor axonal and demyelinating variants of Guillain–Barré syndrome should be included in future complement inhibition clinical trials.
Functional connectome stability and optimality are markers of cognitive performance
Authors: Corriveau Anna , Yoo Kwangsun , Kwon Young Hye , Chun Marvin M , Rosenberg Monica D
Published: November 2022

Patterns of whole-brain fMRI functional connectivity, or connectomes, are unique to individuals. Previous work has identified subsets of functional connections within these patterns whose strength predicts aspects of attention and cognition. However, overall features of these connectomes, such as how stable they are over time and how similar they are to a group-average (typical) or high-performance (optimal) connectivity pattern, may also reflect cognitive and attentional abilities. Here, we test whether individuals who express more stable, typical, optimal, and distinctive patterns of functional connectivity perform better on cognitive tasks using data from three independent samples. We find that individuals with more stable task-based functional connectivity patterns perform better on attention and working memory tasks, even when controlling for behavioral performance stability. Additionally, we find initial evidence that individuals with more typical and optimal patterns of functional connectivity also perform better on these tasks. These results demonstrate that functional connectome stability within individuals and similarity across individuals predicts individual differences in cognition.
E-cigarette exposure augments murine abdominal aortic aneurysm development: role of Chil1
Authors: Mulorz Joscha , Spin Joshua M , Mulorz Pireyatharsheny , Wagenhäuser Markus Udo , Deng Alicia , Mattern Karin , Rhee Yae H , Toyama Kensuke , Adam Matti , Schelzig Hubert , Maegdefessel Lars , Tsao Philip S
Published: November 2022

Aims

Abdominal aortic aneurysm (AAA) is a common cardiovascular disease with a strong correlation to smoking, although underlying mechanisms have been minimally explored. Electronic cigarettes (e-cigs) have gained recent broad popularity and can deliver nicotine at comparable levels to tobacco cigarettes, but effects on AAA development are unknown.

Methods and results

We evaluated the impact of daily e-cig vaping with nicotine on AAA using two complementary murine models and found that exposure enhanced aneurysm development in both models and genders. E-cigs induced changes in key mediators of AAA development including cytokine chitinase-3-like protein 1 (CHI3L1/Chil1) and its targeting microRNA-24 (miR-24). We show that nicotine triggers inflammatory signalling and reactive oxygen species while modulating miR-24 and CHI3L1/Chil1 in vitro and that Chil1 is crucial to e-cig-augmented aneurysm formation using a knockout model.

Conclusions

In conclusion our work shows increased aneurysm formation along with augmented vascular inflammation in response to e-cig exposure with nicotine. Further, we identify Chil1 as a key mediator in this context. Our data raise concerns regarding the potentially harmful long-term effects of e-cig nicotine vaping.
Auctions with Privately Known Capacities: Understanding Competition Among Renewables
Authors: Fabra Natalia , Llobet Gerard
Published: November 2022

We study a multi-unit auction model in which bidders are privately informed about the maximum number of units they are willing to trade (which we refer to as ‘capacity’). No matter how big or small, private information on capacities changes the nature of the equilibrium as compared to when private information is on costs (or valuations). Also, the uniform-price and discriminatory auctions are not revenue equivalent, in contrast to when costs are independently drawn. In particular, with independently drawn capacities (and possibly costs), the discriminatory format reduces payments to firms relative to the uniform-price format. Our analysis is motivated by the performance of future electricity markets in which renewable energies will be predominant, but the set-up also applies to a variety of contexts (from central bank liquidity auctions to emissions trading).
InSAR-derived present-day crustal movement of Daliangshan on the southeastern margin of the Qinghai–Tibetan Plateau
Authors: Gong Wenyu , Song Xiaogang , Zhang Yingfeng , Hua Jun , Sun Haoyue , Zhao Dezheng , Zhu Chuanhua , Shan Xianjian
Published: November 2022

The Daliangshan area of Sichuan, China, is located on the southeastern margin of the Qinghai–Tibetan Plateau. It marks the central section of the left-lateral Xianshuihe–Xiaojiang Fault System (XXFS), which plays a crucial role in accommodating clockwise vertical-axis rotation of the expanding Qinghai–Tibetan Plateau relative to the South China Block. The area is seismically and tectonically active, and three major active faults—the Anninghe fault (ANHF), Zemuhe fault (ZMHF) and Daliangshan fault (DLSF)—together accommodate a significant amount of left-lateral strike-slip motion. Here, we present a geodetic study of the Daliangshan area mainly based on satellite interferometric synthetic aperture radar (InSAR). We processed Advanced Land Observing Satellite-2 (ALOS2) Phased-Array L-band Synthetic Aperture Radar-2 (PALSAR2) imagery to reconstruct the present-day interseismic deformation field. We developed an optimal atmospherics phase correction strategy to overcome the significant artefacts caused by ionospheric and tropospheric. By applying a multitemporal analysis on corrected interferograms, for the first time we generated a spatially continuous deformation rate field for the Daliangshan area. The satellite line-of-sight (LOS) rate field agrees with Global Positioning System (GPS) and levelling data to ∼2 mm yr–1, confirming that our processing approach is suitable for use in heavily vegetated areas. The InSAR rate map reveals displacements along the central and southern segments of the DLSF and ZMHF. By applying an inversion based on the Okada model, we quantitatively estimated the kinematic parameters of fault segments. Assuming a simple rectangular fault plane for each fault segment and constrained with the prior knowledge of the left-lateral slip, we determined that the ZMHF has a slip rate of 5.06$\pm 0.99{\rm{\ mm}}\,{\rm{yr}}^{-1}$ with a rake angle of ∼$38^\circ $ gently dipping to the SW. The southern section of the DLSF has a rake of $- 48^\circ \,\,{\rm to}\,\, - 41^\circ $ with the total slip rate of $4.93 \pm 0.4{\rm{\ mm}}\,{\rm{yr}}^{-1}$, dipping towards to the NE at $63.50^\circ \pm 2.31^\circ $. The modelled 3-D rate field has been validated with GPS and levelling measurements. Additionally, the inversion model and strain field suggest that the middle section of the DLSF undergoes strong deformation. We considered the implications of three factors—oblique convergence, gravity-driven movement, and the ELIP beneath the Sichuan–Yunnan area—for complex 3-D velocities in the transitional Daliangshan area.
Compilation of English Entries in the Contemporary Slovene Dictionary of Abbreviations
Authors: Lukančič Mojca Kompara
Published: November 2022

This article presents the compilation of entries for English abbreviations starting with A, which is part of a larger work, the Contemporary Slovene Dictionary of Abbreviations (CSDA), which is available on the Termania webpage. The structure of the entries was determined following an analysis of the layout and characteristics of entries in English dictionaries of abbreviations. Eleven Slovene terminological dictionaries and seven English dictionaries of abbreviations were examined to determine the structure of the entries. Based on the examples presented, a compilation structure was determined, and examples of entries for English abbreviations starting with A are presented. The structure used for the English abbreviations is an example of good practice that will be used in further compilation of CSDA.
Practical fundamental rights impact assessments
Authors: Janssen Heleen , Seng Ah Lee Michelle , Singh Jatinder
Published: November 2022

The European Union’s General Data Protection Regulation tasks organizations to perform a Data Protection Impact Assessment (DPIA) to consider fundamental rights risks of their artificial intelligence (AI) system. However, assessing risks can be challenging, as fundamental rights are often considered abstract in nature. So far, guidance regarding DPIAs has largely focussed on data protection, leaving broader fundamental rights aspects less elaborated. This is problematic because potential negative societal consequences of AI systems may remain unaddressed and damage public trust in organizations using AI. Towards this, we introduce a practical, four-Phased framework, assisting organizations with performing fundamental rights impact assessments. This involves organizations (i) defining the system’s purposes and tasks, and the responsibilities of parties involved in the AI system; (ii) assessing the risks regarding the system’s development; (iii) justifying why the risks of potential infringements on rights are proportionate; and (iv) adopt organizational and/or technical measures mitigating risks identified. We further indicate how regulators might support these processes with practical guidance.
Improving antimicrobial stewardship with penicillin allergy testing: a review of current practices and unmet needs
Authors: Mabilat Claude , Gros Marie-Françoise , Van Belkum Alex , Trubiano Jason A , Blumenthal Kimberly G , Romano Antonino , Timbrook Tristan T
Published: November 2022

Penicillin allergy, the most frequently reported drug allergy, has been associated with suboptimal antibiotic therapy, increased antimicrobial resistance, increased rates of Clostridioides difficile colonization and infection, as well as extended hospital length of stay and increased cost. Although up to 10% of all patients may report penicillin allergy, most penicillin allergies are not confirmed. As such, most patients with a penicillin allergy can still safely use penicillin and related drugs following a more precise assessment. Herein, we review the current practices and unmet needs in penicillin allergy testing.

The diagnostic algorithm is mostly based on a clinical history assessment followed by in vivo testing, i.e. skin test and/or drug challenge. As these tests are labour and resource intensive, there is increased interest in point-of-care penicillin allergy de-labelling solutions incorporated into Antimicrobial Stewardship Programmes including digital assessment tools. These can be locally parameterized on the basis of characteristics of target populations, incidence of specific allergies and local antibiotic usage to perform clinical risk stratification. Safely ruling out any residual risk remains essential and in vivo drug challenge and/or skin testing should be systematically encouraged. Gradual understanding and convergence of the risk stratification of the clinical presentation of penicillin allergy is enabling a wider implementation of this essential aspect of antimicrobial stewardship through digitalized decision tools and in vivo testing. More research is needed to deliver point of care in vitro diagnostic tools to democratize this de-labelling practice, which would be highly beneficial to patient care. This progress, together with better education of patients and clinicians about the availability, efficacy and safety of penicillin allergy testing, will increase the dissemination of penicillin allergy assessment as an important component of Antimicrobial Stewardship Programmes.
A systematic scoping review of faropenem and other oral penems: treatment of Enterobacterales infections, development of resistance and cross-resistance to carbapenems
Authors: Gandra Sumanth , Takahashi Satoshi , Mitrani-Gold Fanny S , Mulgirigama Aruni , Ferrinho Diogo A
Published: November 2022

Background

Antimicrobial resistance is an urgent global healthcare concern. Beyond carbapenems as broad-spectrum, often ‘last resort’ antibiotics, oral penem antibiotics currently are approved only in Japan and India, used for the treatment of indications including urinary tract infections (UTIs). Exploring oral penem use to better understand the impact of antibiotic resistance on public health would help inform the management of infectious diseases, including UTIs.

Scoping Review Methodology

This scoping review investigated the impact of faropenem and other oral penems on Enterobacterales infection treatment and evaluated evidence for faropenem resistance and cross-resistance to carbapenems. PubMed, Embase, J-STAGE and CiNii were searched for relevant English- or Japanese-language articles published between 1 January 1996 and 6 August 2021.

Key Findings

From 705 unique publications, 29 eligible articles were included (16 in vitro studies; 10 clinical trials; 2 in vitro and in vivo studies; and 1 retrospective medical chart review). Limited evidence described faropenem to treat infectious disease; only four randomized clinical trials were identified. Faropenem dosing regimens varied broadly within and between indications. One study indicated potential dependence of penem efficacy on underlying antibiotic resistance mechanisms, while several studies reported UTI persistence or recurrence after faropenem treatment. In vitro MIC data suggested some potential bacterial resistance to faropenem, while limited clinical data showed resistance emergence after faropenem treatment. Preliminary in vitro evidence suggested faropenem resistance might foster cross-resistance to carbapenems. Overall, very limited clinical evidence describes faropenem for treating infectious diseases. Preclinical and clinical research investment and dedicated community surveillance monitoring is crucial for understanding faropenem treatment patterns, resistance and potential cross-resistance to carbapenems.
Performance drift in a mortality prediction algorithm among patients with cancer during the SARS-CoV-2 pandemic
Authors: Parikh Ravi B , Zhang Yichen , Kolla Likhitha , Chivers Corey , Courtright Katherine R , Zhu Jingsan , Navathe Amol S , Chen Jinbo
Published: November 2022

Sudden changes in health care utilization during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic may have impacted the performance of clinical predictive models that were trained prior to the pandemic. In this study, we evaluated the performance over time of a machine learning, electronic health record-based mortality prediction algorithm currently used in clinical practice to identify patients with cancer who may benefit from early advance care planning conversations. We show that during the pandemic period, algorithm identification of high-risk patients had a substantial and sustained decline. Decreases in laboratory utilization during the peak of the pandemic may have contributed to drift. Calibration and overall discrimination did not markedly decline during the pandemic. This argues for careful attention to the performance and retraining of predictive algorithms that use inputs from the pandemic period.
Redox-Based Colorimetric Sensor for the Selective Determination of Ascorbic Acid in Fixed-Dose Combination Tablets
Authors: El-Malla Samah F , Mansour Fotouh R , Elattar Rehab H , Kamal Amira H
Published: November 2022

Background

Ascorbic acid (ASC; vitamin C) is a weak chromophore, so its presence cannot be determined directly by spectrophotometry.

Objective

This work aims to develop and validate a simple and ecofriendly analytical method for the determination of ASC concentration based on the reaction of ASC with the metal complex, ferric salicylate.

Methods

The visible absorbance of ferric salicylate was found to be inversely proportional to the concentration of ASC. The possible mechanism of the reaction between ASC and ferric salicylate was investigated: ferric salicylate was found to be reduced by ASC under the applied experimental conditions. Different parameters that may affect the reaction were also investigated: ferric salicylate concentration, pH, ionic strength, and the time of reaction. The optimum concentration of ferric salicylate was found to be 1000 µM and the optimum pH was 5.5. The developed method was validated according to International Conference on Harmonization (ICH) guidelines.

Results

The linearity range of the developed method was 5–70 µg/mL and the correlation coefficient was 0.9994. The limits of detection and quantitation were 0.38 µg/mL and 1.16 µg/mL, respectively. The method was successfully applied to the determination of ASC concentration in commercial Ruta-C60® tablets. The mean recovery ± standard deviation was found to be 101.10 ± 0.70%. The results were statistically compared to those obtained by a reported HPLC method. Good agreement was observed.

Conclusion

The developed method is simple, fast, cost-effective, and suitable for routine pharmaceutical analysis of ASC.

Highlights

The developed method is more sensitive than the other spectrophotometric methods reported for determination of ASC.
Characteristics and exchange interactions observed in L-emission spectra of Fe, Mn and their oxides by using a high-energy-resolution soft X-ray emission spectroscopy instrument
Authors: Terauchi Masami , Ebisu Ryogo , Sato Yohei K , Koike Masato
Published: November 2022

For examining the characteristics of L-emission spectra of Fe, Mn and their oxides, a larger energy-dispersion spectrometer for an electron probe microanalyser was constructed. The energy resolution was evaluated to be 0.3 eV at the Fermi edge observed for the B K-emission of LaB6. The Lα,β-emission profiles and peak positions of those oxides were different from those of pure metals, reflecting the different density of states of valence bands and different charge states of metal elements. The Lℓ-emission profiles of the oxides showed shoulder structures, even though the emission is caused by transitions between two inner shell levels. The presence of the shoulder structures was assigned to the result of the 3s3d exchange interaction in the final state of the Lℓ emission, in which the 3s state has a spin. The Lℓ profiles were decomposed into two peaks by Lorentz fit, and the energy separation was evaluated to be ∼3 eV.
Analysis of general functional bearing model in a single-span bridge to identify structure response and suitable friction coefficient under near- and far-fault earthquakes
Authors: Ummati Alfinna Mahya , Chen Chih-Shian , Wang Ren-Zuo , Wang Chung-Yue
Published: November 2022

Analysis of a single-span bridge with rubber bearing as the isolation system is performed under earthquakes. The conventional bridge seismic design requires the whole structure to be perfectly connected to avoid interrupting the transfer of earthquake energy from the ground through the bridge. A bridge with this typical design requires a high-cost construction due to the need for a huge section of the bridge to resist the earthquake force demand. Thus, many bridges in Taiwan are designed with a rubber bearing only put in between the column and girder without an anchor system. Thus, the bridge movement by rubber displacement is permissible, but the sliding displacement must be accommodated to limit the movement. The sliding displacement is the method to exploit the friction force provided by the sliding on the top and bottom interface of the rubber with the girder and column to dissipate the earthquake input energy transmitted to the structure. By involving the role of surface friction, the shear force transmitted to the structure can be reduced and the bridge performance optimized. General Functional Bearing Model (GFBM) analysis is a rubber bearing analysis which unmerges the function of friction and restoring force. In contrast with the conventional method, the rubber bearing designed with GFBM analysis may reduce the bridge stiffness and deck acceleration, and it is more convenient because only sliding displacement needs to be controlled. This research proposed GFBM analysis to simulate the rubber bearing that is reflected in the real conditions of bridges in Taiwan.
Three-dimensional numerical simulations of structured gamma-ray burst jets
Authors: Urrutia Gerardo , De Colle Fabio , López-Cámara Diego
Published: November 2022

After the detection of GRB 170817A, the first unambiguous off-axis gamma-ray burst (GRB), several studies tried to understand the structure of GRB jets. The initial jet structure (directly produced by the central engine) can be partially preserved, or can be completely modified by the interaction with the environment. In this study, we perform three-dimensional, special relativistic hydrodynamics simulations of long GRB jets evolving through a massive progenitor star. Different jet scenarios were considered: Top-hat, Gaussian jets dominated by pressure or by kinetic energy, as well as a model of a supernova (SN) plus a jet both propagating through the progenitor. We found that, while propagating inside the progenitor star, jets with different initial structures are nearly indistinguishable. Kinetic-dominated jets are faster and more collimated than pressure-dominated jets. The dynamics of jets inside the progenitor star strongly depends on the presence of an associated SN, which can substantially decelerate the jet propagation. We show that the initial structure of GRB jets is preserved, or not, mainly depending on the jet collimation. The initial structure is preserved in uncollimated jets, i.e. jets which move through low-density environments. Meanwhile, jets which move through dense environments are shaped by the interaction with the medium and remain collimated.
Formation of super-Earths in icy dead zones around low-mass stars
Authors: Vallet David , Childs Anna C , Martin Rebecca G , Livio Mario , Lepp Stephen
Published: November 2022

While giant planet occurrence rates increase with stellar mass, occurrence rates of close-in super-Earths decrease. This is in contradiction to the expectation that the total mass of the planets in a system scale with the protoplanetary disc mass and hence the stellar mass. Since the snow line plays an important role in the planet formation process, we examine differences in the temperature structure of protoplanetary gas discs around stars of different mass. Protoplanetary discs likely contain a dead zone at the mid-plane that is sufficiently cold and dense for the magneto-rotational instability to be suppressed. As material builds up, the outer parts of the dead zone may be heated by self-gravity. The temperature in the disc can be below the snow line temperature far from the star and in the inner parts of a dead zone. The inner icy region has a larger radial extent around smaller mass stars. The increased mass of solid icy material may allow for the in situ formation of larger and more numerous planets close to a low-mass star. Super-Earths that form in the inner icy region may have a composition that includes a significant fraction of volatiles.
Substrate Affinity Versus Catalytic Efficiency: Ancestral Sequence Reconstruction of tRNA Nucleotidyltransferases Solves an Enzyme Puzzle
Authors: Hager Martina , Pöhler Marie-Theres , Reinhardt Franziska , Wellner Karolin , Hübner Jessica , Betat Heike , Prohaska Sonja , Mörl Mario
Published: November 2022

In tRNA maturation, CCA-addition by tRNA nucleotidyltransferase is a unique and highly accurate reaction. While the mechanism of nucleotide selection and polymerization is well understood, it remains a mystery why bacterial and eukaryotic enzymes exhibit an unexpected and surprisingly low tRNA substrate affinity while they efficiently catalyze the CCA-addition. To get insights into the evolution of this high-fidelity RNA synthesis, the reconstruction and characterization of ancestral enzymes is a versatile tool. Here, we investigate a reconstructed candidate of a 2 billion years old CCA-adding enzyme from Gammaproteobacteria and compare it to the corresponding modern enzyme of Escherichia coli. We show that the ancestral candidate catalyzes an error-free CCA-addition, but has a much higher tRNA affinity compared with the extant enzyme. The consequence of this increased substrate binding is an enhanced reverse reaction, where the enzyme removes the CCA end from the mature tRNA. As a result, the ancestral candidate exhibits a lower catalytic efficiency in vitro as well as in vivo. Furthermore, the efficient tRNA interaction leads to a processive polymerization, while the extant enzyme catalyzes nucleotide addition in a distributive way. Thus, the modern enzymes increased their polymerization efficiency by lowering the binding affinity to tRNA, so that CCA synthesis is efficiently promoted due to a reduced reverse reaction. Hence, the puzzling and at a first glance contradicting and detrimental weak substrate interaction represents a distinct activity enhancement in the evolution of CCA-adding enzymes.
Safety and effectiveness of tofacitinib in Korean adult patients with rheumatoid arthritis: A post-marketing surveillance study
Authors: Ju Ji Hyeon , Sung Yoon-Kyoung , Jo Joo-young , Jeon Ja-Young , Yoo Hyun-Jeong , Lee Eun Bong
Published: November 2022

Objectives

The aim of this article is to assess the safety and effectiveness of tofacitinib in patients with rheumatoid arthritis in routine clinical settings in Korea.

Methods

This is a prospective, multi-centre post-marketing surveillance study. Data were prospectively collected within 6 months after the start of tofacitinib therapy. Safety was evaluated based on the presence of adverse events (AEs) observed in patients who received at least one dose of tofacitinib. Effectiveness was assessed according to the proportion of patients who achieved low disease activity and remission, American College of Rheumatology 20 criteria (ACR20), European League Against Rheumatism (EULAR) response, and change of Disease Activity Score in 28 Joints (DAS28).

Results

The incidence rates [patients with events per 100 patient-years (PY)] of AEs and serious AEs were 56.92 and 10.69, respectively. Regarding AEs of special interest, the incidence rates were 4.33 per 100 PY for serious infections and infestations, 5.78 per 100 PY for herpes zoster, no event of tuberculosis, 0.29 per 100 PY for malignancy, 0.29 per 100 PY for venous thromboembolism (one event of deep vein thrombosis and no event of pulmonary embolism), 0.87 per 100 PY for major adverse cardiovascular event, and 0.58 per 100 PY for mortality. Moreover, ∼40.48% and 21.60% of patients achieved low disease activity and remission of DAS28-erythrocyte sedimentation rate. The EULAR response was classified as good responders with 39.12% in the DAS28-erythrocyte sedimentation rate.

Conclusions

The benefit/risk profile of tofacitinib in adult patients with rheumatoid arthritis in routine clinical settings in Korea was similar to long-term clinical trial data.
LTBK-08. Inferring cell type and cell state composition in glioblastoma from bulk DNA methylation profiles using multi-omic single-cell analyses
Authors: Silverbush Dana , Suva Mario , Hovestadt Volker
Published: November 2022

OBJECTIVE

Cellular heterogeneity determines tumor phenotype and response to therapy. This is particularly pronounced in glioblastoma (GBM), which is characterized by multiple malignant cell states with distinct proliferation potentials, and different cell types of the microenvironment. Ideally, cellular heterogeneity is characterized using single cell genomic profiling techniques. However, these techniques remain challenging to apply in a diagnostic setting and to large retrospective patient cohorts (TCGA, GLASS, DKFZ and clinical trials). Instead, clinicians routinely support their diagnosis with bulk DNA methylation profiling, which generates robust results from low quality material but does not inform on cellular heterogeneity. We have developed a powerful new computational method to deconvolute bulk DNA methylation data and infer cellular heterogeneity within individual tumors, to support prognostic accuracy and personalized treatment decisions.

METHODS

Using both bulk and single-cell multi-omic datasets, we created a DNA methylation-based reference of cell types (malignant, glial, neuronal, and immune) within GBM tumors, and the state of malignant cells therein (stem-like vs. differentiated-like). Using this reference, our computational approach accurately deconvolutes bulk DNA methylation profiles of individual query samples.

RESULTS

High deconvolution accuracy of GBM heterogeneity was achieved from frozen and FFPE tissue samples, including those of low quality or purity (Jensen Shannon divergence for composition similarity < 0.05). Our approach eliminates bias derived from the microenvironment, and results in patient stratification that harmonizes the DNA methylation- and RNA-based classifications of GBM. It also reveals the inter- and intra-tumoral links between the genetic, DNA methylation, and transcriptomic components of GBM pathology, and suggests their specific impacts on treatment efficacy. To facilitate clinical translation, we created a public website that allows clinicians to infer the relative abundance of different cell states within a tumor at the click of a button.
Stable HIV Reservoir Despite Prolonged Low-Dose Mycophenolate to Limit CD4+ T-cell Proliferation
Authors: Schiffer Joshua T , Levy Claire , Hughes Sean M , Pandey Urvashi , Padullo Mel , Jerome Keith R , Zhu Haiying , Puckett Katrina , Helgeson Eric , Harrington Robert D , Hladik Florian
Published: November 2022

Background

The HIV reservoir of latently infected CD4+ T cells represents the barrier to cure. CD4+ T-cell proliferation is a mechanism that sustains the reservoir even during prolonged antiretroviral therapy (ART). Blocking proliferation may therefore deplete the reservoir.

Methods

We conducted an unblinded, uncontrolled clinical trial of mycophenolate, a T-cell antiproliferative compound, in people with HIV on chronic suppressive ART. Study drug dose selection was based on calibration to an observed ex vivo antiproliferative effect. The primary outcome was clinically significant reduction (>0.25 log10) in the HIV reservoir, measured by total and intact HIV DNA per million T cells in blood over 48 weeks.

Results

Five participants enrolled in the trial. Four participants took mycophenolate mofetil (MMF). One had a per-protocol switch to enteric-coated mycophenolate sodium (Myfortic) due to nausea but left the study for personal reasons. One participant developed finger cellulitis, but there were no opportunistic infections. In the 4 participants who completed the protocol, there was no clinically significant reduction in total or intact HIV DNA. There was no change in blood CD4+ T-cell subset composition within the HIV reservoir or the entire CD4+ T-cell population, although total CD4+ T cells decreased slightly in all 4 participants. An ex vivo antiproliferative effect was observed using participant serum obtained 1 hour after dosing, but this effect was severely diminished at drug trough.

Conclusions

Mycophenolate given over 48 weeks did not reduce the volume or composition of the HIV reservoir.

Clinical Trials registration

NCT03262441.
Male-linked geneTsRPL10a′in androdioecious treeTapiscia sinensis: implications for sex differentiation by influencing gynoecium development
Authors: Wang Feng , Ren Xiaolong , Jiang Minggao , Hou Kunpeng , Xin Guiliang , Yan Feng , Zhao Peng , Liu Wenzhe
Published: November 2022

The mechanism of sex differentiation in androdioecy is of great significance for illuminating the origin and evolution of dioecy. Tapiscia sinensis Oliv. is a functionally androdioecious species with both male and hermaphroditic individuals. Male flowers of T. sinensis lack the ovules of gynoecia compared with hermaphrodites. To identify sex simply and accurately, and further find the potential determinants of sex differentiation in T. sinensis, we found that TsRPL10a′, a duplicate of TsRPL10a, was a male-linked gene. The promoter (5′ untranslated region and the first intron) of TsRPL10a′ can be used to accurately identify sex in T. sinensis. TsRPL10a is a ribosomal protein that is involved in gynoecium development, and sufficient ribosomal levels are necessary for female gametogenesis. The expression level of TsRPL10a was significantly downregulated in male flower primordia compared with hermaphrodites. The RNA fluorescence in situ hybridization (FISH) assay demonstrated that TsRPL10a was almost undetectable in male gynoecia at the gynoecial ridge stage, which was a key period of ovule formation by scanning electron microscope observation. In male flowers, although the promoter activity of TsRPL10a was significantly higher than TsRPL10a′ verified by transgenic Arabidopsis thaliana, the transcriptional expression ratio of TsRPL10a was obviously lower than TsRPL10a′ and reached its lowest at the gynoecial ridge stage, indicating the existence of a female suppressor. The promoter similarity of TsRPL10a and TsRPL10a′ was only 45.29%; the genomic sequence similarity was 89.8%; four amino acids were altered in TsRPL10a′. The secondary structure of TsRPL10a′ was different from TsRPL10a, and TsRPL10a′ did not exhibit FISH and GUS expression in the gynoecium the way TsRPL10a did. From the perspective of RT-qPCR, its high expression level, followed by the low expression level of TsRPL10a in male flowers, indicates its antagonism function with TsRPL10a. The evolutionary analysis, subcellular localization and flower expression pattern suggested that TsRPL10a might be functionally conserved with AtRPL10aA, AtRPL10aB and AtRPL10aC in A. thaliana. Overall, we speculated that TsRPL10a and its duplicate TsRPL10a′ might be involved in sex differentiation by influencing gynoecium development in T. sinensis.
Modification of Papaya Ringspot Virus HC-Pro to Generate Effective Attenuated Mutants for Overcoming the Problem of Strain-Specific Cross Protection
Authors: Cheng Hao-Wen , Lin Tzu-Tung , Huang Chung-Hao , Raja Joseph A. J. , Yeh Shyi-Dong
Published: November 2022

Cross protection application of HA5-1, an attenuated mutant of papaya ringspot virus (PRSV) HA strain from Hawaii, was withdrawn from Taiwan due to the narrow geographic strain specificity of HA5-1. Here, to overcome this problem, we created attenuated mutants of PRSV YK, a dominant severe strain from Taiwan, by mutating helper component protease (HC-Pro) at F7, R181, F206, and D397 residues critical for potyviral pathogenicity. PRSV YK HC-Pro R181I, F206L, and D397N single-mutant viruses induced mild symptoms, but their adverse effects on growth of papaya plants disqualified them as useful protective viruses. However, F7I single-mutant and F7I + F206L double-mutant viruses displayed mild symptoms followed by recovery, and they showed a zigzag pattern of accumulation in papaya plants, indicating their potential to trigger RNA silencing and retain partial antagonistic suppression of host defense. Although F7I + R181I and F7I + D397N double-mutant viruses caused symptomless infection, they accumulated barely above mock level and, thus, were not qualified as proper protective viruses. RNA silencing suppression (RSS) analysis by agroinfiltration in Nicotiana benthamiana plants revealed that the HC-Pro F7I and F7I + F206L mutant proteins were weaker in RSS ability than the wild-type protein. Under greenhouse conditions, F7I and F7I + F206L mutant viruses were genetically stable but not aphid transmissible. Compared with the HA5-1 mutant’s low degree (10%) of protection to papaya plants, the F7I and F7I + F206L mutants provided complete (100%) protection to papaya and horn melon plants against strain YK. Thus, F7I and F7I + F206L mutants solve the problem of strain-specific protection and have great potential for control of PRSV in Taiwan.
Distribution, Diversity, and Soil Associations of Wine Grape Plant-Parasitic Nematodes in Georgia, U.S.A., Vineyards
Authors: Martin Katherine F. , Brannen Phillip M. , Jagdale Ganpati B. , Holladay Ted , Severns Paul M.
Published: November 2022

Wine grape (Vitis vinifera and V. vinifera hybrids) production in Georgia occurs in three distinct regions (North, West, and South) which can be characterized by sandy, sandy-loam, or sandy clay-loam soils. We studied plant-parasitic nematode (PPN) communities in 15 wine grape vineyards from the three primary growing regions to understand which nematodes are a concern and what soil characteristics are associated with their occurrence and relative abundance. Twelve genera of PPNs were detected throughout the state: Belonolaimus, Helicotylenchus, Hemicycliophora, Heterodera, Hoplolaimus, Meloidogyne, Mesocriconema, Paratrichodorus, Paratylenchus, Pratylenchus, Tylenchorhynchus, and Xiphinema. Nonmetric multidimensional scaling ordination and multirank permutation procedure identified PPN community differences and soil characteristics that were associated by region. Indicator species analysis identified Helicotylenchus, Mesocriconema, Tylenchorhynchus, and Xiphinema as statistically associated with the West while Meloidogyne and Paratrichodorus were associated with the South. Our analyses further suggested that soil texture (percent sand, percent clay, and percent silt) and the lime buffer capacity at equilibrium (LBCEQ) were associated with PPN community structure while pH was not. When focused on a single vineyard in the North, multiple logistic regression analysis suggested a statistically significant association between Meloidogyne spp. and soil characteristics, including percentages of sand, pH, and LBCEQ. Our study supports the association between soil characteristics and specific nematode genera, as well as the emergence of LBCEQ, the soil measurement with the strongest statistical association with nematode community structure and Meloidogyne presence.
Fatigue of hybrid fibre-reinforced plastics
Authors: Carvelli Valter , Lomov Stepan V. , Sapozhnikov Sergei B. , Breite Christian , Swolfs Yentl
Published: November 2022

Understanding the fatigue behaviour of hybrid fibre-reinforced plastics is desirable for exploiting their features in safe, durable and reliable industrial components. The fatigue performance of hybrid composites has not been extensively investigated yet. The paper presents an overview of the available knowledge on the fatigue of hybrid fibre-reinforced plastics, and, more specifically, reports the fatigue behaviour of a quasi-isotropic pseudo-ductile all-carbon fibre interlayer hybrid composite by experimental measurements and observations, with emphasis on the damage development. The fatigue conditions are tension-tension stress- and strain-controlled cyclic loading. The results include fatigue life for different maximum stress and strain levels, stiffness evolution and damage observations by X-ray micro-computed tomography. The studied hybrid all-carbon fibre quasi-isotropic composite exhibits pseudo-ductility in quasi-static testing. For stress-controlled fatigue, the fatigue load over the limit of elastic response is not sustained. Contrary to that, the composite retains its load-carrying ability in the pseudo-ductile regime for a strain-controlled regime, albeit with lowered stiffness.

This article is part of the theme issue 'Ageing and durability of composite materials'.
Two murine cytomegalovirus microRNAs target the major viral immediate early 3 gene
Authors: Herb Stefanie , Zeleznjak Jelena , Hennig Thomas , L'Hernault Anne , Lodha Manivel , Jürges Christopher , Trsan Tihana , Juranic Lisnic Vanda , Jonjic Stipan , Erhard Florian , Krmpotic Astrid , Dölken Lars
Published: November 2022

Human cytomegalovirus is responsible for morbidity and mortality in immune compromised patients and is the leading viral cause of congenital infection. Virus-encoded microRNAs (miRNAs) represent interesting targets for novel antiviral agents. While many cellular targets that augment productive infection have been identified in recent years, regulation of viral genes such as the major viral immediate early protein 72 (IE72) by hcmv-miR-UL112-1 may contribute to both the establishment and the maintenance of latent infection. We employed photoactivated ribonucleotide-enhanced individual nucleotide resolution crosslinking (PAR-iCLIP) to identify murine cytomegalovirus (MCMV) miRNA targets during lytic infection. While the PAR-iCLIP data were of insufficient quality to obtain a comprehensive list of cellular and viral miRNA targets, the most prominent PAR-iCLIP peak in the MCMV genome mapped to the 3′ untranslated region of the major viral immediate early 3 (ie3) transcript. We show that this results from two closely positioned binding sites for the abundant MCMV miRNAs miR-M23-2-3p and miR-m01-2-3p. Their pre-expression significantly impaired viral plaque formation. However, mutation of the respective binding sites did not alter viral fitness during acute or subacute infection in vivo. Furthermore, no differences in the induction of virus-specific CD8+ T cells were observed. Future studies will probably need to go beyond studying immunocompetent laboratory mice housed in pathogen-free conditions to reveal the functional relevance of viral miRNA-mediated regulation of key viral immediate early genes.