bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Flow‐Direction‐Dependent Dispersivity on Seawater Intrusion in Coastal Aquifers
Authors: Fahs Marwan , Koohbor Behshad , Shao Qian , Doummar Joanna , Baalousha Husam M. , Voss Clifford I.
Published: July 2022

Flow‐direction‐dependent (FDD) dispersivity in coastal aquifers (CAs) may strongly affect the inland extend of seawater intrusion (SWI) and the accompanying vertical salinity distribution. FDD dispersivity may predict greater inland intrusion of the saltwater wedge, but less vertical spreading of salinity than does the classical flow‐direction‐independent (FDI) dispersivity, the standard currently employed in most numerical CA models. Dispersion processes play a key role in the SWI process and directly affect CA pumped water quality. Constant FDI dispersivities may be inappropriate in representing mixing processes due to large differences between depth and horizontal salinity transport scales, and due to typical structured heterogeneities in aquifer fabrics. Comparison of FDI and FDD model forecasts for the classical Henry problem (HP) steady‐state SWI, based on a new HP semianalytical solution with FDD and on a numerical FDI model modified to additionally represent FDD, highlights the theoretical types of differences implied by these alternative dispersivity assumptions and exactly how each parameter affects the solution. Large differences between FDI and FDD dispersivity forecasts of time‐dependent SWI in large scale heterogeneous aquifers occur in a typical CA (Akkar CA, Lebanon). The FDD model forecasts that future salinities in pumping wells will exceed the potable water limit, whereas the FDI model greatly underestimates the historic inland intrusion of the saltwater wedge and forecasts no impact on future Akkar CA potable water supply. These results indicate the importance of employing the appropriate dispersion process representation when creating model‐based SWI forecasts, especially for developing effective CA management strategies.
Merging bound states in the continuum by harnessing higher-order topological charges
Authors: Kang Meng , Mao Li , Zhang Shunping , Xiao Meng , Xu Hongxing , Chan Che Ting
Published: July 2022

Bound states in the continuum (BICs) can confine light with a theoretically infinite Q factor. However, in practical on-chip resonators, scattering loss caused by inevitable fabrication imperfection leads to finite Q factors due to the coupling of BICs with nearby radiative states. Merging multiple BICs can improve the robustness of BICs against fabrication imperfection by improving the Q factors of nearby states over a broad wavevector range. To date, the studies of merging BICs have been limited to fundamental BICs with topological charges ±1. Here we show the unique advantages of higher-order BICs (those with higher-order topological charges) in constructing merging BICs. Merging multiple BICs with a higher-order BIC can further improve the Q factors compared with those involving only fundamental BICs. In addition, higher-order BICs offer great flexibility in realizing steerable off-Γ merging BICs. A higher-order BIC at Γ can split into a few off-Γ fundamental BICs by reducing the system symmetry. The split BICs can then be tuned to merge with another BIC, e.g., an accidental BIC, at an off-Γ point. When the in-plane mirror symmetry is further broken, merging BICs become steerable in the reciprocal space. Merging BICs provide a paradigm to achieve robust ultrahigh-Q resonances, which are important in enhancing nonlinear and quantum effects and improving the performance of optoelectronic devices.
Long-term follow-up of cladribine treatment in hairy cell leukemia: 30-year experience in a multicentric Italian study
Authors: Pagano Livio , Criscuolo Marianna , Broccoli Alessandro , Piciocchi Alfonso , Varettoni Marzia , Galli Eugenio , Anastasia Antonella , Cantonetti Maria , Trentin Livio , Kovalchuk Sofia , Orsucci Lorella , Frustaci Annamaria , Spolzino Angelica , Volpetti Stefano , Annibali Ombretta , Storti Sergio , Stelitano Caterina , Marchesi Francesco , Offidani Massimo , Casadei Beatrice , Nizzoli Maria Elena , De Luca Maria Lucia , Fianchi Luana , Motta Marina , Guarnera Luca , Simonetti Edoardo , Visentin Andrea , Vassallo Francesco , Deodato Marina , Sarlo Chiara , Olivieri Attilio , Falini Brunangelo , Pulsoni Alessandro , Tiacci Enrico , Zinzani Pier Luigi
Published: July 2022

Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with an excellent prognosis after treatment with cladribine (2CDA), although relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long-term remission rate, and overall survival (OS) in those patients who received 2CDA as first-line treatment. We retrospectively reviewed data of HCL patients treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers: 513 patients were evaluable for study purpose. The median age was 54 years (range 24–88) and ECOG was 0 in 84.9% of cases. A total of 330 (64.3%) patients received 2CDA intravenously and 183 (35.7%) subcutaneously. ORR was 91.8%: CR was obtained in 335 patients (65.3%), PR in 96 (18.7%), and hematological response in 40 (7.8%) patients; in 42 (8.2%) no response was observed. Hemoglobin value (p = 0.044), frequency of circulating hairy cells (p = 0.039), recovery of absolute neutrophil count (p = 0.006), and normalization of spleen (p ≤ 0.001) were associated with CR compared to PR in univariable analysis. At a median follow-up of 6.83 years (range 0.04–28.52), the median time to relapse was 12.2 years. A significant difference in duration of response was identified between patients that obtained a CR and PR (19.4 years versus 4.8 years, p < 0.0001). Non-hematological grade 3 or higher early toxicity was reported in 103 (20.1%) patients. Median OS was not reached: 95.3%, 92.4%, and 81.8% of patients were estimated to be alive at 5, 10, and 15 years, respectively. Forty-nine patients died (9.5%), following an infection in 14 cases (2.7%), natural causes in 14 (2.7%), cardiovascular events in 13 (2.5%), a second neoplasm in 6 (1.2%), and progression of HCL in 2 cases (0.4%). Following treatment of HCL with 2CDA, 80% of patients are estimated to be alive 15 years after diagnosis.
BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma
Authors: Weisberg Ellen , Chowdhury Basudev , Meng Chengcheng , Case Abigail E. , Ni Wei , Garg Swati , Sattler Martin , Azab Abdel Kareem , Sun Jennifer , Muz Barbara , Sanchez Dana , Toure Anthia , Stone Richard M. , Galinsky Ilene , Winer Eric , Gleim Scott , Gkountela Sofia , Kedves Alexia , Harrington Edmund , Abrams Tinya , Zoller Thomas , Vaupel Andrea , Manley Paul , Faller Michael , Chung BoYee , Chen Xin , Busenhart Philipp , Stephan Christine , Calkins Keith , Bonenfant Debora , Thoma Claudio R. , Forrester William , Griffin James D.
Published: July 2022

Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with other agents, as a novel strategy for acute leukemias and MM.
GsαR201C and estrogen reveal different subsets of bone marrow adiponectin expressing osteogenic cells
Authors: Palmisano Biagio , Labella Rossella , Donsante Samantha , Remoli Cristina , Spica Emanuela , Coletta Ilenia , Farinacci Giorgia , Dello Spedale Venti Michele , Saggio Isabella , Serafini Marta , Robey Pamela Gehron , Corsi Alessandro , Riminucci Mara
Published: July 2022

The Gsα/cAMP signaling pathway mediates the effect of a variety of hormones and factors that regulate the homeostasis of the post-natal skeleton. Hence, the dysregulated activity of Gsα due to gain-of-function mutations (R201C/R201H) results in severe architectural and functional derangements of the entire bone/bone marrow organ. While the consequences of gain-of-function mutations of Gsα have been extensively investigated in osteoblasts and in bone marrow osteoprogenitor cells at various differentiation stages, their effect in adipogenically-committed bone marrow stromal cells has remained unaddressed. We generated a mouse model with expression ofGsαR201Cdriven by theAdiponectin(Adq) promoter.Adq-GsαR201Cmice developed a complex combination of metaphyseal, diaphyseal and cortical bone changes. In the metaphysis,GsαR201Ccaused an early phase of bone resorption followed by bone deposition. Metaphyseal bone formation was sustained by cells that were traced byAdq-Creand eventually resulted in a high trabecular bone mass phenotype. In the diaphysis,GsαR201C, in combination with estrogen, triggered the osteogenic activity ofAdq-Cre-targeted perivascular bone marrow stromal cells leading to intramedullary bone formation. Finally, consistent with the previously unnoticed presence ofAdq-Cre-marked pericytes in intraosseous blood vessels,GsαR201Ccaused the development of a lytic phenotype that affected both cortical (increased porosity) and trabecular (tunneling resorption) bone. These results provide the first evidence that theAdq-cell network in the skeleton not only regulates bone resorption but also contributes to bone formation, and that the Gsα/cAMP pathway is a major modulator of both functions.
[11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer’s disease
Authors: Pascoal Tharick A. , Chamoun Mira , Lax Elad , Wey Hsiao-Ying , Shin Monica , Ng Kok Pin , Kang Min Su , Mathotaarachchi Sulantha , Benedet Andrea L. , Therriault Joseph , Lussier Firoza Z. , Schroeder Frederick A. , DuBois Jonathan M. , Hightower Baileigh G. , Gilbert Tonya M. , Zürcher Nicole R. , Wang Changning , Hopewell Robert , Chakravarty Mallar , Savard Melissa , Thomas Emilie , Mohaddes Sara , Farzin Sarah , Salaciak Alyssa , Tullo Stephanie , Cuello A. Claudio , Soucy Jean-Paul , Massarweh Gassan , Hwang Heungsun , Kobayashi Eliane , Hyman Bradley T. , Dickerson Bradford C. , Guiot Marie-Christine , Szyf Moshe , Gauthier Serge , Hooker Jacob M. , Rosa-Neto Pedro
Published: July 2022

Alzheimer’s disease (AD) is characterized by the brain accumulation of amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-β and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-β, tau, and class I histone deacetylase (HDAC I isoforms 1–3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-β PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-β and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-β plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology.
A brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours
Authors: Hamed Akram A. , Kunz Daniel J. , El-Hamamy Ibrahim , Trinh Quang M. , Subedar Omar D. , Richards Laura M. , Foltz Warren , Bullivant Garrett , Ware Matthaeus , Vladoiu Maria C. , Zhang Jiao , Raj Antony M. , Pugh Trevor J. , Taylor Michael D. , Teichmann Sarah A. , Stein Lincoln D. , Simons Benjamin D. , Dirks Peter B.
Published: July 2022

Human cerebral cancers are known to contain cell types resembling the varying stages of neural development. However, the basis of this association remains unclear. Here, we map the development of mouse cerebrum across the developmental time-course, from embryonic day 12.5 to postnatal day 365, performing single-cell transcriptomics on >100,000 cells. By comparing this reference atlas to single-cell data from >100 glial tumours of the adult and paediatric human cerebrum, we find that tumour cells have an expression signature that overlaps with temporally restricted, embryonic radial glial precursors (RGPs) and their immediate sublineages. Further, we demonstrate that prenatal transformation of RGPs in a genetic mouse model gives rise to adult cerebral tumours that show an embryonic/juvenile RGP identity. Together, these findings implicate the acquisition of embryonic-like states in the genesis of adult glioma, providing insight into the origins of human glioma, and identifying specific developmental cell types for therapeutic targeting.
Rational design of a topological polymeric solid electrolyte for high-performance all-solid-state alkali metal batteries
Authors: Su Yun , Rong Xiaohui , Gao Ang , Liu Yuan , Li Jianwei , Mao Minglei , Qi Xingguo , Chai Guoliang , Zhang Qinghua , Suo Liumin , Gu Lin , Li Hong , Huang Xuejie , Chen Liquan , Liu Binyuan , Hu Yong-Sheng
Published: July 2022

Poly(ethylene oxide)-based solid-state electrolytes are widely considered promising candidates for the next generation of lithium and sodium metal batteries. However, several challenges, including low oxidation resistance and low cation transference number, hinder poly(ethylene oxide)-based electrolytes for broad applications. To circumvent these issues, here, we propose the design, synthesis and application of a fluoropolymer, i.e., poly(2,2,2-trifluoroethyl methacrylate). This polymer, when introduced into a poly(ethylene oxide)-based solid electrolyte, improves the electrochemical window stability and transference number. Via multiple physicochemical and theoretical characterizations, we identify the presence of tailored supramolecular bonds and peculiar morphological structures as the main factors responsible for the improved electrochemical performances. The polymeric solid electrolyte is also investigated in full lithium and sodium metal lab-scale cells. Interestingly, when tested in a single-layer pouch cell configuration in combination with a Li metal negative electrode and a LiMn0.6Fe0.4PO4-based positive electrode, the polymeric solid-state electrolyte enables 200 cycles at 42 mA·g−1 and 70 °C with a stable discharge capacity of approximately 2.5 mAh when an external pressure of 0.28 MPa is applied.
TGFBR1*6A as a modifier of breast cancer risk and progression: advances and future prospects
Authors: Agyemang Kojo , Johansen Allan M. , Barker Grayson W. , Pennison Michael J. , Sheffield Kimberly , Jimenez Hugo , Blackman Carl , Sharma Sambad , Fordjour Patrick A. , Singh Ravi , Cook Katherine L. , Lin Hui-Kuan , Zhang Wei , Lo Hui-Wen , Watabe Kounosuke , Sun Peiqing , Langefeld Carl D. , Pasche Boris
Published: July 2022

There is growing evidence that germline mutations in certain genes influence cancer susceptibility, tumor evolution, as well as clinical outcomes. Identification of a disease-causing genetic variant enables testing and diagnosis of at-risk individuals. For breast cancer, several genes such as BRCA1, BRCA2, PALB2, ATM, and CHEK2 act as high- to moderate-penetrance cancer susceptibility genes. Genotyping of these genes informs genetic risk assessment and counseling, as well as treatment and management decisions in the case of high-penetrance genes. TGFBR1*6A (rs11466445) is a common variant of the TGF-β receptor type I (TGFBR1) that has a global minor allelic frequency (MAF) of 0.051 according to the 1000 Genomes Project Consortium. It is emerging as a high frequency, low penetrance tumor susceptibility allele associated with increased cancer risk among several cancer types. The TGFBR1*6A allele has been associated with increased breast cancer risk in women, OR 1.15 (95% CI 1.01–1.31). Functionally, TGFBR1*6A promotes breast cancer cell proliferation, migration, and invasion through the regulation of the ERK pathway and Rho-GTP activation. This review discusses current findings on the genetic, functional, and mechanistic associations between TGFBR1*6A and breast cancer risk and proposes future directions as it relates to genetic association studies and mechanisms of action for tumor growth, metastasis, and immune suppression.
Validating ground-based aerodynamic levitation surface tension measurements through a study on Al2O3
Authors: Sun Yifan , Duan Guangtao , Yamaji Akifumi , Takatani Tomoya , Muta Hiroaki , Ohishi Yuji
Published: July 2022

The surface tension of a molten sample can be evaluated based on its resonant frequency with various levitation techniques. Under a 1-G condition, the use of levitation forces to counteract gravity will cause the levitated sample’s resonant frequency to differ from that under microgravity. A mathematical relationship to correct for this deviation is not available for a sample levitated with aerodynamic levitation (ADL), which raises issues on the validity of surface tension measurements done with ADL. In this study, we compared the surface tension of molten Al2O3 obtained using the front tracking (FT) simulation method, the drop-bounce method with ADL, and the oscillating drop method with ADL. The drop-bounce method simulates microgravity by allowing the sample to free-fall over a period of tens of milliseconds. Based on the results of this comparison, we determined that the surface tension of molten materials measured with ground-based ADL with the oscillating drop method, calculated using the resonant frequency of the l=2 m=0 mode, only shows a small deviation from that obtained under microgravity.
Phylogeographic inference of Sumatran ranids bearing gastromyzophorous tadpoles with regard to the Pleistocene drainage systems of Sundaland
Authors: Arifin Umilaela , Smart Utpal , Husemann Martin , Hertwig Stefan T. , Smith Eric N. , Iskandar Djoko T. , Haas Alexander
Published: July 2022

Rivers are known to act as biogeographic barriers in several strictly terrestrial taxa, while possibly serving as conduits of dispersal for freshwater-tolerant or -dependent species. However, the influence of river systems on genetic diversity depends on taxa-specific life history traits as well as other geographic factors. In amphibians, several studies have demonstrated that river systems have only minor influence on their divergence. Here, we assess the role of the paleodrainage systems of the Sunda region (with a focus on the island of Sumatra) in shaping the evolutionary history of two genera of frogs (SumateranaandWijayarana) whose tadpoles are highly dependent on cascading stream habitats. Our phylogenetic results show no clear association between the genetic diversification patterns of both anurans genera and the existence of paleodrainage systems. Time-calibrated phylogenies and biogeographical models suggest that these frogs colonized Sumatra and diversified on the island before the occurrence of the Pleistocene drainage systems. Both genera demonstrate phylogenetic structuring along a north–south geographic axis, the temporal dynamics of which coincide with the geological chronology of proto Sumatran and -Javan volcanic islands. Our results also highlight the chronic underestimation of Sumatran biodiversity and call for more intense sampling efforts on the island.
Ultra-wide-band millimeter-wave generator using spin torque oscillator with strong interlayer exchange couplings
Authors: Kurokawa Yuichiro , Yamada Keisuke , Taniguchi Tomohiro , Horiike Shu , Tanaka Terumitsu , Yuasa Hiromi
Published: July 2022

Recent increased development interest in millimeter-wave oscillator devices has necessitated realization of small oscillators with high frequency, wide frequency tunability, and room-temperature operation. Spin-torque oscillators (STOs) are fascinating candidates for such applications because of their nanometer size and suitability for room-temperature operation. However, their oscillation frequency and tunable range are limited to the order of 100 MHz–10 GHz. Here, we propose use of bilinear (J1) and biquadratic (J2) interlayer exchange couplings between ferromagnets in STOs to overcome these problems. The bilinear coupling contributes to oscillation frequency enhancement, whereas the biquadratic coupling facilitates frequency tunability via a current. Using micromagnetic simulation with parameters estimated from a material with small saturation magnetization, for J1 = 0 and J2 =  − 1.0 mJ/m2, respectively, we find that the STO exhibits high frequency from 23 to 576 GHz and that its tunability reaches 61 GHz/(1011 A/m2) for current densities of − 0.5 to − 9.5 × 1011 A/m2. An analytical theory based on the macrospin model is also developed, which exhibits good quantitative agreement with the micromagnetic simulations. These results introduce new possibilities for spintronics applications in high-frequency devices such as next-generation mobile communications.
Kynurenine metabolites predict survival in pulmonary arterial hypertension: A role for IL-6/IL-6Rα
Authors: Cai Zongye , Tian Siyu , Klein Theo , Tu Ly , Geenen Laurie W. , Koudstaal Thomas , van den Bosch Annemien E. , de Rijke Yolanda B. , Reiss Irwin K. M. , Boersma Eric , van der Ley Claude , Van Faassen Martijn , Kema Ido , Duncker Dirk J. , Boomars Karin A. , Tran-Lundmark Karin , Guignabert Christophe , Merkus Daphne
Published: July 2022

Activation of the kynurenine pathway (KP) has been reported in patients with pulmonary arterial hypertension (PAH) undergoing PAH therapy. We aimed to determine KP-metabolism in treatment-naïve PAH patients, investigate its prognostic values, evaluate the effect of PAH therapy on KP-metabolites and identify cytokines responsible for altered KP-metabolism. KP-metabolite levels were determined in plasma from PAH patients (median follow-up 42 months) and in rats with monocrotaline- and Sugen/hypoxia-induced PH. Blood sampling of PAH patients was performed at the time of diagnosis, six months and one year after PAH therapy. KP activation with lower tryptophan, higher kynurenine (Kyn), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA), and anthranilic acid was observed in treatment-naïve PAH patients compared with controls. A similar KP-metabolite profile was observed in monocrotaline, but not Sugen/hypoxia-induced PAH. Human lung primary cells (microvascular endothelial cells, pulmonary artery smooth muscle cells, and fibroblasts) were exposed to different cytokines in vitro. Following exposure to interleukin-6 (IL-6)/IL-6 receptor α (IL-6Rα) complex, all cell types exhibit a similar KP-metabolite profile as observed in PAH patients. PAH therapy partially normalized this profile in survivors after one year. Increased KP-metabolites correlated with higher pulmonary vascular resistance, shorter six-minute walking distance, and worse functional class. High levels of Kyn, 3-HK, QA, and KA measured at the latest time-point were associated with worse long-term survival. KP-metabolism was activated in treatment-naïve PAH patients, likely mediated through IL-6/IL-6Rα signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.
Interrupted time series analysis for the impact of integrated medical insurance on direct hospitalization expense of catastrophic illness
Authors: Niu Li , Song Qiuhe , Liu Yan , Wang Xin
Published: July 2022

In 2016, China initiated the merge of the urban resident basic medical insurance scheme and new rural cooperative medical scheme into one unified health insurance scheme: the urban and rural resident basic medical insurance. This study investigates the impact of integrated insurance on the direct hospitalization cost of inpatients with catastrophic illnesses. An interrupted time series analysis was conducted based on a sample of 6174 inpatients with catastrophic illness from January 2014 to December 2018. The factors surveyed included per capita total inpatient expense, out-of-pocket expense, and reimbursement ratio. Univariate analysis indicated that after the implementation of the unified urban and rural medical insurance, the reimbursed expense increased from 9398 to 13,842 Yuan (P < 0.001), average reimbursement ratio increased from 0.57 to 0.59 (P < 0.05). Expenses on both western and traditional medicines increased, although the proportion of medicine expense decreased after the integration. Interrupted time series analysis showed that per capita total inpatient expense and per capita out-of-pocket expense increased but showed a gradually decreasing trend after the integration. After the integration of urban and rural medical insurance, the average reimbursement ratio increased slightly, which had limited effect on the alleviation of patients’ financial burden. Furthermore, the integration effect on inpatient expense is offset by increased out-of-pocket medical expense due to suspected supplier-induced demand.
A study of high neuroticism in long-term survivors of childhood, adolescence, and young adult cancers
Authors: Dahl Alv A. , Kiserud Cecilie Essholt , Fosså Sophie D. , Loge Jon Håvard , Reinertsen Kristin Valborg , Ruud Ellen , Lie Hanne C.
Published: July 2022

Neuroticism is a basic personality trait concerning negative feelings under stressful conditions. Our purpose was to examine the rate of high neuroticism and factors associated with high neuroticism in long-term (≥ 5 years) survivors of childhood, adolescent, and young adult cancer (CAYACSs). Norwegian CAYACSs aged 0–39 years when diagnosed and treated between 1985 and 2009 for cancer in childhood/adolescence (0–18 years), or as young adults (19–39 years) and alive in 2015 were mailed a questionnaire. Data from 1629 CAYACSs (481 children/adolescents and 1148 young adults) were analyzed. High neuroticism was found in 44% of survivors of childhood/adolescent cancers versus 34% in survivors of young adult cancer (p < 0.001). The rate of high neuroticism in female CAYACSs was 40% and in males 30% (p < 0.001). The corresponding difference between male survivor group was non-significant. In multivariable analysis, young age at survey, more adverse effects, poor self-rated health, female sex, chronic fatigue, and increased depression remained significantly associated with high neuroticism. Cancer treatment, comorbidity, and lifestyle were significant in bivariate analyses. Cancer at earlier age could increase the risk of high neuroticism among adult survivors. Screening for neuroticism could identify CAYACSs at risk for experiencing multiple health concerns and needing special follow-up attention.
On the weekly cycle of atmospheric ammonia over European agricultural hotspots
Authors: Van Damme Martin , Clarisse Lieven , Stavrakou Trissevgeni , Wichink Kruit Roy , Sellekaerts Louise , Viatte Camille , Clerbaux Cathy , Coheur Pierre-François
Published: July 2022

The presence of a weekly cycle in the abundance of an atmospheric constituent is a typical fingerprint for the anthropogenic nature of its emission sources. However, while ammonia is mainly emitted as a consequence of human activities, a weekly cycle has never been detected in its abundances at large scale. We expose here for the first time the presence of a weekend effect in the NH3 total columns measured by the IASI satellite sounder over the main agricultural source regions in Europe: northwestern Europe (Belgium-the Netherlands-northwest Germany), the Po Valley, Brittany, and, to a lesser extent, the Ebro Valley. A decrease of 15% relative to the weekly mean is seen on Sunday–Monday observations in northwestern Europe, as a result of reduced NH3 emissions over the weekend. This is confirmed by in situ NH3 concentration data from the National Air Quality Monitoring Network in the Netherlands, where an average reduction of 10% is found around midnight on Sunday. The identified weekend effect presents a strong seasonal variability, with two peaks, one in spring and one in summer, coinciding with the two main (manure) fertilization periods. In spring, a reduction on Sunday–Monday up to 53 and 26% is found in the NH3 satellite columns and in situ concentrations, respectively, as fertilization largely drives atmospheric NH3 abundances at this time of the year.
Connecting nutritional facts with the traditional ranking of ethnobotanically used fodder grasses by local farmers in Central Punjab of Pakistan
Authors: Harun Nidaa , Chaudhry Abdul Shakoor , Shaheen Shabnum , Ahmad Mushtaq , Sahan Zeynep , Bashir Hira
Published: July 2022

The local farmers of Central Punjab, Pakistan have been using indigenous grasses as vital components of ruminant diets, but little is reported about their nutritional potential. Hence this study investigated nutritive potential of a selection of ethnobotanically important fodder grasses. Multiple nutritional parameters (proximate components, fibre fractions), secondary metabolites (phenolics, tannins) and in vitro digestibility values were determined. Furthermore, the legitimacy of ethnobotanical knowledge of local inhabitants about these grasses was also verified. The results suggested that majority (77%) of these grasses can be regarded as good quality fodders because of their high protein (169 g/kg) and good digestibility (457 g/kg) with moderate fibre (≤ 602 g/kg), lignin (≤ 50 g/kg) and secondary metabolites (total phenols ≤ 87 g/kg, total tannins ≤ 78 g/kg, condensed tannins ≤ 61 g/kg). Pearson correlation between nutritional parameters indicated that in vitro digestibility values were positively correlated with crude proteins (IVDMD, r = + 0.83 and IVOMD, r = + 0.83 respectively) and negatively correlated with fibre (NDF, r = − 0.91), ADF, r = − 0.84 and ADL, r = − 0.82) contents. Moreover, a positive relationship was identified between ethnobotanical knowledge and laboratory findings for studied grasses. Spearman correlation test showed that ranking of grasses based on ethnobotanical preferences were highly correlated (r values) with the laboratory results for CP (0.85), NDF (− 0.76), ADF (− 0.72) and ADL (− 0.62). The resilient complementarities between ethnobotanical preferences and nutritive analysis authenticate farmer’s traditional knowledge, which needed to be aligned with the corresponding scientific data. Farmers can use these findings for appropriate fodder selection and development of precise supplements for feeding ruminants within a sustainable and economically viable livestock industry for food security.
A Niclosamide-releasing hot-melt extruded catheter prevents Staphylococcus aureus experimental biomaterial-associated infection
Authors: Vazquez-Rodriguez Jesus Augusto , Shaqour Bahaa , Guarch-Pérez Clara , Choińska Emilia , Riool Martijn , Verleije Bart , Beyers Koen , Costantini Vivian J. A. , Święszkowski Wojciech , Zaat Sebastian A. J. , Cos Paul , Felici Antonio , Ferrari Livia
Published: July 2022

Biomaterial-associated infections are a major healthcare challenge as they are responsible for high disease burden in critically ill patients. In this study, we have developed drug-eluting antibacterial catheters to prevent catheter-related infections. Niclosamide (NIC), originally an antiparasitic drug, was incorporated into the polymeric matrix of thermoplastic polyurethane (TPU) via solvent casting, and catheters were fabricated using hot-melt extrusion technology. The mechanical and physicochemical properties of TPU polymers loaded with NIC were studied. NIC was released in a sustained manner from the catheters and exhibited in vitro antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis. Moreover, the antibacterial efficacy of NIC-loaded catheters was validated in an in vivo biomaterial-associated infection model using a methicillin-susceptible and methicillin-resistant strain of S. aureus. The released NIC from the produced catheters reduced bacterial colonization of the catheter as well as of the surrounding tissue. In summary, the NIC-releasing hot-melt extruded catheters prevented implant colonization and reduced the bacterial colonization of peri-catheter tissue by methicillin sensitive as well as resistant S. aureus in a biomaterial-associated infection mouse model and has good prospects for preclinical development.
Activation function 1 of progesterone receptor is required for mammary development and regulation of RANKL during pregnancy
Authors: Lee Shi Hao , Yap Yeannie H. Y. , Lim Chew Leng , Woo Amanda Rui En , Lin Valerie C. L.
Published: July 2022

Progesterone receptor (PGR) is a member of the nuclear receptor superfamily of transcription factors. It is critical for mammary stem cells expansion, mammary ductal branching and alveologenesis. The transcriptional activity of PGR is mainly mediated by activation functions AF1 and AF2. Although the discovery of AF1 and AF2 propelled the understanding of the mechanism of gene regulation by nuclear receptors, their physiological roles are still poorly understood. This is largely due to the lack of suitable genetic models. The present study reports gain or loss of AF1 function mutant mouse models in the study of mammary development. The gain of function mutant AF1_QQQ exhibits hyperactivity while the loss of function mutant AF1_FFF shows hypoactivity on mammary development. However, the involvement of AF1 is context dependent. Whereas the AF1_FFF mutation causes significant impairment in mammary development during pregnancy or in response to estrogen and progesterone, it has no effect on mammary development in nulliparous mice. Furthermore, Rankl, but not Wnt4 and Areg is a major target gene of AF1. In conclusion, PGR AF1 is a pivotal ligand-dependent activation domain critical for mammary development during pregnancy and it exerts gene specific effect on PGR regulated genes.
Combination of UV and green light synergistically enhances the attractiveness of light to green stink bugs Nezara spp
Authors: Endo Nobuyuki , Hironaka Mantaro , Honda Yoshiyuki , Iwamoto Tetsuhiro
Published: July 2022

The southern green stink bug Nezara viridula and its congener N. antennata are important agricultural pests worldwide. These species show positive phototaxis and their compound eyes have high sensitivity to UV and green lights. The attractiveness of monochromatic UV, green lights and combined UV and green light to stink bugs was investigated under field conditions. The number of stink bugs caught increased with the number of UV LEDs, but very few bugs were caught using green light, irrespective of the number of LEDs. However, the most stink bugs were caught when both colors were combined. These results indicate that monochromatic green light is less attractive to Nezara bugs, but when mixed with UV light, it synergistically enhances the attractiveness of UV light. This finding contributes to the construction of reliable and highly specific light traps to monitor Nezara bugs. The addition of green light hardly affected the attractiveness of the UV light to other insects, such as Anomala beetles, which are often caught in light traps. We conclude that the spectral composition of light that is attractive to nocturnal insects depends on the species, hence it is possible to make ecologically friendly light traps that are target specific.
Protective effects of rituximab on puromycin-induced apoptosis, loss of adhesion and cytoskeletal alterations in human podocytes
Authors: Jeruschke Stefanie , Alex Dana , Hoyer Peter Friedrich , Weber Stefanie
Published: July 2022

Podocytes are highly specialized cells playing a key role in the filtration function of the kidney. A damaged podocyte ultrastructure is associated with a reorganization of the actin cytoskeleton and accompanied with a loss of adhesion to the glomerular basement membrane leading to proteinuria in many forms of glomerular diseases, e.g. nephrotic syndrome. If the first-line therapy with glucocorticoids fails, alternative immunosuppressive agents are used, which are known to have the potential to stabilize the actin cytoskeleton. A new option for preventing relapses in steroid dependent nephrotic syndrome is the monoclonal antibody rituximab, which, in addition to its B-cell depleting effect, is assumed to have direct effects on podocytes. We here provide data on the non-immunological off-target effects of the immunosuppressant rituximab on podocyte structure and dynamics in an in vitro puromycin aminonucleoside model of podocyte injury. A conditionally immortalized human podocyte cell line was used. Differentiated podocytes were treated with puromycin aminonucleoside and rituximab. Our studies focussed on analyzing the structure of the actin cytoskeleton, cellular adhesion and apoptosis using immunofluorescence staining and protein biochemistry methods. Treatment with rituximab resulted in a stabilization of podocyte actin stress fibers in the puromycin aminonucleoside model, leading to an improvement in cell adhesion. A lower apoptosis rate was observed after parallel treatment with puromycin aminonucleoside and rituximab visualized by reduced nuclear fragmentation. Consistent with this data, Western-blot analyses demonstrated that rituximab directly affects the caspase pathways by inhibiting the activation of Caspases-8, -9 and -3, suggesting that rituximab may inhibit apoptosis. In conclusion, our results indicate an important role of the immunosuppressant rituximab in terms of stability and morphogenesis of podocytes, involving apoptosis pathways. This could help to improve therapeutical concepts for patients with proteinuria mediated by diseased podocytes.
Conformational landscape of the yeast SAGA complex as revealed by cryo-EM
Authors: Vasyliuk Diana , Felt Joeseph , Zhong Ellen D. , Berger Bonnie , Davis Joseph H. , Yip Calvin K.
Published: July 2022

Spt-Ada-Gcn5-Acetyltransferase (SAGA) is a conserved multi-subunit complex that activates RNA polymerase II-mediated transcription by acetylating and deubiquitinating nucleosomal histones and by recruiting TATA box binding protein (TBP) to DNA. The prototypical yeast Saccharomyces cerevisiae SAGA contains 19 subunits that are organized into Tra1, core, histone acetyltransferase, and deubiquitination modules. Recent cryo-electron microscopy studies have generated high-resolution structural information on the Tra1 and core modules of yeast SAGA. However, the two catalytical modules were poorly resolved due to conformational flexibility of the full assembly. Furthermore, the high sample requirement created a formidable barrier to further structural investigations of SAGA. Here, we report a workflow for isolating/stabilizing yeast SAGA and preparing cryo-EM specimens at low protein concentration using a graphene oxide support layer. With this procedure, we were able to determine a cryo-EM reconstruction of yeast SAGA at 3.1 Å resolution and examine its conformational landscape with the neural network-based algorithm cryoDRGN. Our analysis revealed that SAGA adopts a range of conformations with its HAT module and central core in different orientations relative to Tra1.
PDA modification and properties of α-AlH3
Authors: Qin Mingna , Yao Bingjie , Shi Qiang , Tang Wang , Chen Shaoli , Guo Tao , Wang Wei , Zhang Yan , Ge Zhongxue
Published: July 2022

We present a novel surface coating to resolve the stability of α-AlH3. Inspired by the strong chemical adhesion of mussels, the polymerization of dopamine was first introduced to coat α-AlH3 through simple situ polymerization. The α-AlH3 was used as a substrate. In-depth characterizations confirmed the formation of polydopamine (PDA) on the α-AlH3 surface. The coated α-AlH3 sample was characterized by X-ray diffraction X-ray photoelectron spectrometry and Scanning Electron Microscope. The results show that a strong PDA film is formed on the surface of α-AlH3, and PDA@α-AlH3 retains its primary morphology. The crystal form of α-AlH3 does not change after coating with PDA. The XPS analysis results show that N1 s appears on the material after coating with PDA, indicating that polydopamine is formed on the surface of α-AlH3. The moisture absorption tests show that the moisture absorption rate of α-AlH3 is greatly reduced after being coated with PDA. The excellent intact ability of PDA prevents α-AlH3 from reacting with water in air. The thermal stability of α-AlH3 before and after coating was analyzed by DSC. This work demonstrates the successful applications of dopamine chemistry to α-AlH3, thereby providing a potential method for metastable materials.
Structured assessment of modifiable lifestyle habits among patients with mental illnesses in primary care
Authors: Pikkemaat Miriam , Nymberg Veronica Milos , Nymberg Peter
Published: July 2022

Patients with mental illness have an increased risk of cardiovascular morbidity. The Swedish-developed Health Dialogue is a pedagogical tool to individualize lifestyle counselling, used in specific age-groups to improve lifestyle habits and decrease mortality, but not tested specifically for patients with mental illness. Patients > 18 years old seeking primary care due to symptoms related to mental illness and diagnosed with depression, sleeping disorders, stress and anxiety, were included. A nurse-led health dialogue was conducted, focusing on lifestyle habits, anthropometric measurements, and blood samples, resulting in tailored advice regarding the individual’s risk profile. All 64 participants had lifestyle areas with increased risk level. Approximately 20% had elevated fasting glucose, blood pressure or cholesterol levels, and over 40% had highest risk level in Waist–Hip-Ratio. 30% were overweight, or physical inactive. The results suggest the need of a larger cohort study with long-term follow up, to establish potentially positive effects on wellbeing, and decreased cardiovascular risk in patients with mental illness.

Clinical trial registration: The study was registered at ClinicalTrials.gov January 6th, 2022, registration number NCT05181254.
Predicting mortality among ischemic stroke patients using pathways-derived polygenic risk scores
Authors: Li Jiang , Chaudhary Durgesh , Griessenauer Christoph J. , Carey David J. , Zand Ramin , Abedi Vida
Published: July 2022

We aim to determine whether ischemic stroke(IS)-related PRSs are also associated with and further predict 3-year all-cause mortality. 1756 IS patients with European ancestry were randomly split into training (n = 1226) and testing (n = 530) groups with 3-year post-event observations. Univariate Cox proportional hazards regression model (CoxPH) was used for primary screening of individual prognostic PRSs. Only the significantly associated PRSs and clinical risk factors with the same direction for a causal relationship with IS were used to construct a multivariate CoxPH. Feature selection was conducted by the LASSO method. After feature selection, a prediction model with 11 disease-associated pathway-specific PRSs outperformed the base model, as demonstrated by a higher concordance index (0.751, 95%CI [0.693–0.809] versus 0.729, 95%CI [0.676–0.782]) in the testing sample. A PRS derived from endothelial cell apoptosis showed independent predictability in the multivariate CoxPH (Hazard Ratio = 1.193 [1.027–1.385], p = 0.021). These PRSs fine-tuned the model by better stratifying high, intermediate, and low-risk groups. Several pathway-specific PRSs were associated with clinical risk factors in an age-dependent manner and further confirmed some known etiologies of IS and all-cause mortality. In conclusion, Pathway-specific PRSs for IS are associated with all-cause mortality, and the integrated multivariate risk model provides prognostic value in this context.
Methods for stroke severity assessment by chart review in the Atherosclerosis Risk in Communities study
Authors: Koton Silvia , Patole Shalom , Carlson Julia M. , Haight Taylor , Johansen Michelle , Schneider Andrea L. C. , Pike James Russell , Gottesman Rebecca F. , Coresh Josef
Published: July 2022

Stroke severity is the most important predictor of post-stroke outcome. Most longitudinal cohort studies do not include direct and validated measures of stroke severity, yet these indicators may provide valuable information about post-stroke outcomes, as well as risk factor associations. In the Atherosclerosis Risk in Communities (ARIC) study, stroke severity data were retrospectively collected, and this paper outlines the procedures used and shares them as a model for assessment of stroke severity in other large epidemiologic studies. Trained physician abstractors, who were blinded to other clinical events, reviewed hospital charts of all definite/probable stroke events occurring in ARIC. In this analysis we included 1,198 ischemic stroke events occurring from ARIC baseline (1987–1989) through December 31, 2009. Stroke severity was categorized according to the National Institutes of Health Stroke Scale (NIHSS) score and classified into 5 levels: NIHSS ≤ 5 (minor), NIHSS 6–10 (mild), NIHSS 11–15 (moderate), NIHSS 16–20 (severe), and NIHSS > 20 (very severe). We assessed interrater reliability in a subgroup of 180 stroke events, reviewed independently by the lead abstraction physician and one of the four secondary physician abstractors. Interrater correlation coefficients for continuous NIHSS score as well as percentage of absolute agreement and Cohen Kappa Statistic for NIHSS categories were presented. Determination of stroke severity by the NIHSS, based on data abstracted from hospital charts, was possible for 97% of all ischemic stroke events. Median (25%-75%) NIHSS score was 5 (2–8). The distribution of NIHSS category was NIHSS ≤ 5 = 58.3%, NIHSS 6–10 = 24.5%, NIHSS 11–15 = 8.9%, NIHSS 16–20 = 4.7%, NIHSS > 20 = 3.6%. Overall agreement in the classification of severity by NIHSS category was present in 145/180 events (80.56%). Cohen’s simple Kappa statistic (95% CI) was 0.64 (0.55–0.74) and weighted Kappa was 0.79 (0.72–0.86). Mean (SD) NIHSS score was 5.84 (5.88), with a median score of 4 and range 0–31 for the lead reviewer (rater 1) and mean (SD) 6.16 (6.10), median 4.5 and range 0–36 in the second independent assessment (rater 2). There was a very high correlation between the scores reported in both assessments (Pearson r = 0.90). Based on our findings, we conclude that hospital chart-based retrospective assessment of stroke severity using the NIHSS is feasible and reliable.