bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of exosomal microRNAs and related hub genes associated with imatinib resistance in chronic myeloid leukemia
Authors: Karabay Arzu Zeynep , Ozkan Tulin , Karadag Gurel Aynur , Koc Asli , Hekmatshoar Yalda , Sunguroglu Asuman , Aktan Fugen , Buyukbingöl Zeliha 
Published: June 2024

AbstractChemotherapy resistance is a major obstacle in cancer therapy, and identifying novel druggable targets to reverse this phenomenon is essential. The exosome-mediated transmittance of drug resistance has been shown in various cancer models including ovarian and prostate cancer models. In this study, we aimed to investigate the role of exosomal miRNA transfer in chronic myeloid leukemia drug resistance. For this purpose, firstly exosomes were isolated from imatinib sensitive (K562S) and resistant (K562R) chronic myeloid leukemia (CML) cells and named as Sexo and Rexo, respectively. Then, miRNA microarray was used to compare miRNA profiles of K562S, K562R, Sexo, Rexo, and Rexo-treated K562S cells. According to our results, miR-125b-5p and miR-99a-5p exhibited increased expression in resistant cells, their exosomes, and Rexo-treated sensitive cells compared to their sensitive counterparts. On the other hand, miR-210-3p and miR-193b-3p were determined to be the two miRNAs which exhibited decreased expression profile in resistant cells and their exosomes compared to their sensitive counterparts. Gene targets, signaling pathways, and enrichment analysis were performed for these miRNAs by TargetScan, KEGG, and DAVID. Potential interactions between gene candidates at the protein level were analyzed via STRING and Cytoscape software. Our findings revealed CCR5, GRK2, EDN1, ARRB1, P2RY2, LAMC2, PAK3, PAK4, and GIT2 as novel gene targets that may play roles in exosomal imatinib resistance transfer as well as mTOR, STAT3, MCL1, LAMC1, and KRAS which are already linked to imatinib resistance. MDR1 mRNA exhibited higher expression in Rexo compared to Sexo as well as in K562S cells treated with Rexo compared to K562S cells which may suggest exosomal transfer of MDR1 mRNA.
Graphical Abstract
Analysis of clinical studies on clozapine from 2012-2022
Authors: Freibüchler Anton , Seifert Roland 
Published: June 2024

AbstractClozapine has been considered the “gold standard” in the treatment of schizophrenia for many years. Clozapine has a superior effect, particularly in the treatment of negative symptoms and suicidal behaviour. However, due to its numerous adverse reactions, clozapine is mainly used for treatment-resistant schizophrenia. The aim of this paper is to analyze the results of clinical studies on clozapine from 2012-2022. PubMed was used as the database. Sixty-four studies were included and categorised by topic. The pharmacokinetic properties of clozapine tablets and a clozapine suspension solution did not differ markedly. Clozapine was superior to olanzapine and risperidone in reducing aggression and depression. A long-term study showed that metabolic parameters changed comparably with olanzapine and clozapine after 8 years. Risperidone and ziprasidone can be used as an alternative to clozapine. Scopolamine, atropine drops, and metoclopramide are effective in the treatment of clozapine-induced hypersalivation. Eight drugs, including liraglutide, exenatide, metformin, and orlistat, are potentially effective in the treatment of clozapine-induced weight gain. Ziprasidone, haloperidol, and aripiprazole showed a positive effect on symptoms when added to clozapine. No investigated drug was superior to clozapine for the treatment of schizophrenia. Ziprasidone and risperidone can also be used well for the treatment of schizophrenia. In the treatment of clozapine-induced hypersalivation and weight gain, some drugs proved to be effective.
A randomized, open-label two-period crossover pilot study to evaluate the relative bioavailability in the fed state of atovaquone-proguanil (Atoguanil™) versus atovaquone-proguanil hydrochloride (Malarone®) in healthy adult participants
Authors: Kuemmerle Andrea , Gossen Denis , Marx Michael W. , Lorch Ulrike , Szramowska Maja , Kumar Ashok , Singh Dharmendra , Singh Satinder , Ramachandruni Hanu , Thankachen Byju , Kore Swapnil , Gaaloul Myriam El , Borghini-Fuhrer Isabelle , Chalon Stephan 
Published: June 2024

AbstractAtoguanil™ is a novel complex of atovaquone (ATV) and proguanil (PG) with enhanced ATV bioavailability compared to Malarone®. This pilot study assessed whether the relative bioavailability (Frel) of ATV, PG, and the primary PG metabolite cycloguanil (CG) following a single oral dose in the fed state of Atoguanil was similar to Malarone despite a 50% lower ATV dose. This open-label, single-dose, randomized 2-period, 2-treatment, balanced crossover study was conducted between 17th November 2021 and 18th March 2022. Eligible participants (aged 18–55 years) were randomized (1:1) in period 1 to Atoguanil (ATV/PG 500/348 mg) or Malarone (ATV/PG hydrochloride 1000/400 mg) administered following a high-fat, high caloric meal. After a 24-day washout period, participants crossed treatment arms. For the doses tested, Frel was assumed similar if 90%CIs were between 80 and 125% for the geometric mean ratio of the least square mean differences for each exposure parameter. In 15 evaluable participants, Frel was similar for ATV Cmax (93.6% [90%CI 83.6, 104.9]) but not AUC0-inf (77.8% [67.4, 89.8]), for PG AUC0-inf (95.6% [92.1, 99.2]) but not Cmax (82.4% [75.8, 89.5]), and for both CG Cmax (100.8% [95.0, 107.0]) and AUC0-inf (102.9% [98.4, 107.7]). Nine adverse events occurred; all were of mild severity and not considered treatment related. At the doses tested, ATV Frel was lower following Atoguanil versus Malarone based on AUC0-inf, though when adjusted for dose Frel increased by 156%. Both drugs were well tolerated with no safety concerns. ClinicalTrials.gov: NCT04866602 (April 26th, 2021)
Short-term adaptation as a tool to improve bioethanol production using grass press-juice as fermentation medium
Authors: Varriale Ludovica , Geib Doris , Ulber Roland 
Published: June 2024

Abstract
Grass raw materials collected from grasslands cover more than 30% of Europe’s agricultural area. They are considered very attractive for the production of different biochemicals and biofuels due to their high availability and renewability. In this study, a perennial ryegrass (Lolium perenne) was exploited for second-generation bioethanol production. Grass press–cake and grass press-juice were separated using mechanical pretreatment, and the obtained juice was used as a fermentation medium. In this work, Saccharomyces cerevisiae was utilized for bioethanol production using the grass press-juice as the sole fermentation medium. The yeast was able to release about 11 g/L of ethanol in 72 h, with a total production yield of 0.38 ± 0.2 gEthanol/gsugars. It was assessed to improve the fermentation ability of Saccharomyces cerevisiae by using the short-term adaptation. For this purpose, the yeast was initially propagated in increasing the concentration of press-juice. Then, the yeast cells were re-cultivated in 100%(v/v) fresh juice to verify if it had improved the fermentation efficiency. The fructose conversion increased from 79 to 90%, and the ethanol titers reached 18 g/L resulting in a final yield of 0.50 ± 0.06 gEthanol/gsugars with a volumetric productivity of 0.44 ± 0.00 g/Lh. The overall results proved that short-term adaptation was successfully used to improve bioethanol production with S. cerevisiae using grass press-juice as fermentation medium.

Key points
• Mechanical pretreatment of grass raw materials
• Production of bioethanol using grass press-juice as fermentation medium
• Short-term adaptation as a tool to improve the bioethanol production
Biocalorimetry-aided monitoring of fungal pretreatment of lignocellulosic agricultural residues
Authors: Duong Hieu Linh , Paufler Sven , Harms Hauke , Maskow Thomas , Schlosser Dietmar 
Published: June 2024

Abstract
The present study aimed to investigate whether and how non-invasive biocalorimetric measurements could serve for process monitoring of fungal pretreatment during solid-state fermentation (SSF) of lignocellulosic agricultural residues such as wheat straw. Seven filamentous fungi representing different lignocellulose decay types were employed. Water-soluble sugars being immediately available after fungal pretreatment and those becoming water-extractable after enzymatic digestion of pretreated wheat straw with hydrolysing (hemi)cellulases were considered to constitute the total bioaccessible sugar fraction. The latter was used to indicate the success of pretreatments and linked to corresponding species-specific metabolic heat yield coefficients (YQ/X) derived from metabolic heat flux measurements during fungal wheat straw colonisation. An YQ/X range of about 120 to 140 kJ/g was seemingly optimal for pretreatment upon consideration of all investigated fungi and application of a non-linear Gaussian fitting model. Upon exclusion from analysis of the brown-rot basidiomycete Gloeophyllum trabeum, which differs from all other here investigated fungi in employing extracellular Fenton chemistry for lignocellulose decomposition, a linear relationship where amounts of total bioaccessible sugars were suggested to increase with increasing YQ/X values was obtained. It remains to be elucidated whether an YQ/X range being optimal for fungal pretreatment could firmly be established, or if the sugar accessibility for post-treatment generally increases with increasing YQ/X values as long as “conventional” enzymatic, i.e. (hemi)cellulase-based, lignocellulose decomposition mechanisms are operative. In any case, metabolic heat measurement–derived parameters such as YQ/X values may become very valuable tools supporting the assessment of the suitability of different fungal species for pretreatment of lignocellulosic substrates.

Key points
• Biocalorimetry was used to monitor wheat straw pretreatment with seven filamentous fungi.
• Metabolic heat yield coefficients (YQ/X) seem to indicate pretreatment success.
• YQ/X values may support the selection of suitable fungal strains for pretreatment.
Ruxolitinib for the treatment of acute graft-versus-host disease: a retrospective analysis
Authors: Denk Alexander , Edinger Matthias , Weber Daniela , Holler Ernst , Fante Matthias , Meedt Elisabeth , Gunes Sibel , Poeck Hendrik , Mittermaier Cornelia , Herr Wolfgang , Wolff Daniel 
Published: June 2024

AbstractSteroid-refractory acute graft-versus-host disease (aGvHD) is a serious complication after allogeneic hematopoietic stem cell transplantation, associated with significant mortality. Ruxolitinib was the first drug approved for aGvHD, based on results of the REACH2 trial; however, real-world data are limited. We retrospectively analyzed the safety and efficacy of ruxolitinib for treatment of aGvHD at our center from March 2016 to August 2022 and assessed biomarkers of risk. We identified 49 patients receiving ruxolitinib as second- (33/49), third- (11/49), fourth- (3/49), or fifth-line (2/49) treatment. Ruxolitinib was started on median day 11 (range, 7–21) after aGvHD onset; median duration of administration was 37 days (range, 20–86), with 10 patients continuing treatment at last follow-up. Median follow-up period was 501 days (range, 95–905). In the primary analysis at the 1-month assessment, overall response rate was 65%, and failure-free survival was 78%. Infectious complications ≥ CTCAE Grade III were observed in 10/49 patients within 1-month followup. Patients responding to ruxolitinib therapy required fewer steroids and exhibited lower levels of the serum biomarkers regenerating islet-derived protein 3-alpha, suppression of tumorigenicity 2, and the Mount Sinai Acute GVHD International Consortium algorithm probability. A univariate regression model revealed steroid-dependent aGvHD as a significant predictor of better response to ruxolitinib. Within 6-months follow-up, four patients experienced recurrence of underlying malignancy, and eight died due to treatment-related mortality. Overall, ruxolitinib was welltolerated and showed response in heavily pretreated patients, with results comparable to those of the REACH2 trial. Biomarkers may be useful predictors of response to ruxolitinib.
Efficacy and safety of ruxolitinib in the treatment of chronic graft-versus-host disease: a retrospective analysis
Authors: Denk Alexander , Mittermaier Cornelia , Weber Daniela , Fante Matthias , Güneş Sibel , Edinger Matthias , Herr Wolfgang , Wolff Daniel 
Published: June 2024

AbstractSteroid-refractory chronic graft-versus-host disease (cGvHD) is associated with significant morbidity and mortality, with ruxolitinib being the first drug approved for its treatment. We retrospectively analyzed the safety and efficacy of ruxolitinib for treatment of cGvHD at our center between 07/2015 and 12/2022 and identified 48 patients receiving ruxolitinib as second (18/48) or advanced (30/48) treatment line. Ruxolitinib was started on median day 340 (range 119–595) after cGvHD onset; median duration of administration was 176 (range, 79–294) days with 16/48 patients continuing treatment at last follow-up. National Institutes of Health organ grading and the intensity of immunosuppression were assessed at the start of ruxolitinib treatment and repeated after 1, 3, 6, and 12 months. Response assessment was terminated at the start of any additional new immunosuppressant treatment. The median time of follow-up was 582 (range, 104–1161) days. At the primary analysis after six months on ruxolitinib treatment, the overall response rate was 33%, and failure-free survival was 58%. Infectious adverse events ≥ CTCAE grade III were observed in 10/48 patients. The response rate was not associated with the severity of cGvHD, number of previous treatment lines, or number of additional agents combined with ruxolitinib applying a univariate regression model. At the time of the 12-month follow-up, four patients experienced recurrence of the underlying malignancy and two patients had experienced non-relapse-related mortality. Overall, ruxolitinib was relatively well-tolerated and showed outcomes comparable to the REACH3 trial in a heavily pretreated patient population.
In distributive phosphorylation catalytic constants enable non-trivial dynamics
Authors: Conradi Carsten , Mincheva Maya 
Published: June 2024

AbstractOrdered distributive double phosphorylation is a recurrent motif in intracellular signaling and control. It is either sequential (where the site phosphorylated last is dephosphorylated first) or cyclic (where the site phosphorylated first is dephosphorylated first). Sequential distributive double phosphorylation has been extensively studied and an inequality involving only the catalytic constants of kinase and phosphatase is known to be sufficient for multistationarity. As multistationarity is necessary for bistability it has been argued that these constants enable bistability. Here we show for cyclic distributive double phosphorylation that if its catalytic constants satisfy an analogous inequality, then Hopf bifurcations and hence sustained oscillations can occur. Hence we argue that in distributive double phosphorylation (sequential or distributive) the catalytic constants enable non-trivial dynamics. In fact, if the rate constant values in a network of cyclic distributive double phosphorylation satisfy this inequality, then a network of sequential distributive double phosphorylation with the same rate constant values will show multistationarity—albeit for different values of the total concentrations. For cyclic distributive double phosphorylation we further describe a procedure to generate rate constant values where Hopf bifurcations and hence sustained oscillations can occur. This may, for example, allow for an efficient sampling of oscillatory regions in parameter space. Our analysis is greatly simplified by the fact that it is possible to reduce the network of cyclic distributive double phosphorylation to what we call a network with a single extreme ray. We summarize key properties of these networks.
Is there a connection between spine alignment, chest mobility, shoulder joint and respiratory parameters of patients with ankylosing spondylitis?
Authors: Szewczyk Daniel , Sadura-Sieklucka Teresa , Tarnacka Beata , Sokołowska Beata 
Published: June 2024

Abstract
Introduction
Ankylosing spondylitis is chronic progressive disease, which decrease functions of musculoskeletal system including chest area. Those changes influences respiratory mechanics, worsen conditions of proper ventilation of lungs.

Objectives
Rating of functional and respiratory parameters and dependence between them at patients with ankylosing spondylitis.

Materials & methods
The study included 45 patients with diagnosed ankylosing spondylitis. Chest and upper limbs mobility, resting spinal curvature alignment were assessed, and respiratory parameters were measured in a plethysmographic chamber JAGGER MasterScreen Body.

Results
Ankylosing spondylitis patients had lower respiratory parameters especially sReff, and FRC. Restriction of chest and upper limbs mobility was also demonstrated. Forward head extension was observed based on the occipital wall test. Correlations between functional parameters and correlations between functional and respiratory parameters were shown, in particular MIP, MEP, sReff, Rtot, TLC, ERV.

Conclusions
The study confirmed a decrease in functional and respiratory parameters in the examined patients with ankylosing spondylitis compared to the applicable standards. A significant relationship was found between functional parameters in the upper body and respiratory parameters, which worsen with increasing thoracic dysfunction. The obtained results indicate the directions of therapy that should be taken into account to improve respiratory parameters and reduce respiratory dysfunction in these patients. Chest-focused physiotherapy appears to be an important element in improving function in patients with ankylosing spondylitis.
Evaluating Ecological Nano-Calcium from Eggshells: Effects on Calcium Nutrition and Oxidative Stress in Lettuce Under Saline and Boron Toxicity
Authors: Sahin Ozge , Yagcioglu Kiymet Deniz , Kadioglu Yusuf Kagan , Gunes Aydin 
Published: June 2024

AbstractNano-fertilizers with higher efficacy compared to conventional fertilizers can provide advantage for plant cultivation in both productive and problematic soils. Therefore, this study aimed to determine the effect of nano-calcium (nano-Ca) on lettuce plants grown in saline-boron toxic soil. Nano-calcium fertilizer was prepared from eggshells. Functional and structural properties of nano-Ca was determined by scanning electron microscopy (SEM), x-ray diffraction (XRD) and fourier transform infrared spectroscopy (FTIR) before plant experiment. The treatments was; control, 40 mM NaCl and 20 mg kg−1 B (NaCl + B), and 40 mM NaCl and 20 mg kg−1 B with 4 mM Nano-Ca (NaCl + B + nano-Ca). The nano-Ca significantly increased the dry weight and calcium (Ca) concentration of lettuce plants under saline-B toxic conditions. Although there was a decrease in the concentrations of sodium (Na), chloride (Cl), and boron (B) with nano-Ca treatment, it was not statistically significant. Salinity and boron toxicity lead to increased lipid peroxidation. In the present study, the production of malondialdehyde (MDA) as a marker for lipid peroxidation, along with a significant decrease in hydrogen peroxide (H2O2) concentration, was observed with the application of nano-Ca. There was no significant alteration in superoxide dismutase activity (SOD) observed in lettuce grown under saline and boron toxic conditions. However, catalase activity (CAT) increased with nano-Ca application, while the activity of ascorbate peroxidase (APX) decreased. The study results suggest that nano-Ca serves a protective function for lettuce plants cultivated under saline and boron toxic conditions.
Mechanisms of early and late summer precipitation in Southwest China: dynamic and thermodynamic processes
Authors: Sun Xiaoting , Li Qingquan , Wu Qingyuan 
Published: June 2024

AbstractThis study investigates dynamic and thermodynamic components of moisture flux convergence in Southwest China (SW-MFC) and their underlying physical mechanisms during early and late summer. Using precipitation observation and CRA-40 reanalysis datasets from 1979 to 2023, the results show that both dynamic and thermodynamic processes modulate the SW-MFC in early summer (May-June), with dynamics playing a pivotal role. In contrast, the precipitation anomaly in late summer (July-August) is predominantly driven by the dynamic factors. Meanwhile, the large-scale circulation over the northern Indian Peninsula significantly modulates the SW-MFC. In early summer, anomalous convection around the Maritime Continent with the tripole sea surface temperature (SST) mode in the tropical Indo-Pacific can trigger the formation of “double ring” vertical zonal circulation cells. A large-scale westerly anomaly at the lower troposphere over the northern Arabian Sea foster cyclone strengthening over the northern Indian Peninsula, enhancing southerly moisture transport and increasing precipitation over Southwest China. During the late summer, large-scale dipole SST pattern between the subtropical central-eastern Pacific and the Indo-Pacific warm pool generates significant easterly anomalies towards the Maritime Continent. The SST gradient stimulates an extensive anticyclonic shear zone over the western equatorial Pacific, with an intensified low-pressure zone to its north. This atmospheric pattern over Southwest China and Indian Peninsula can form a vertical circulation circle that largely intensifies widespread precipitation. Numerical model experiments can reproduce the mechanisms of tropical Indo-Pacific joint effects on the Southwest precipitation in both early and late summer, providing a theoretical basis for understanding and forecasting summer precipitation over Southwest China.
Handedness in schizophrenia and affective disorders: a large-scale cross-disorder study
Authors: Mundorf Annakarina , Lischke Alexander , Peterburs Jutta , Alexander Nina , Bonnekoh Linda M. , Brosch Katharina , Flinkenflügel Kira , Goltermann Janik , Hahn Tim , Jansen Andreas , Meinert Susanne , Nenadić Igor , Schürmeyer Navid Nico , Stein Frederike , Straube Benjamin , Thiel Katharina , Teutenberg Lea , Thomas-Odenthal Florian , Usemann Paula , Winter Alexandra , Dannlowski Udo , Kircher Tilo , Ocklenburg Sebastian 
Published: June 2024

AbstractWhile most people are right-handed, a minority are left-handed or mixed-handed. It has been suggested that mental and developmental disorders are associated with increased prevalence of left-handedness and mixed-handedness. However, substantial heterogeneity exists across disorders, indicating that not all disorders are associated with a considerable shift away from right-handedness. Increased frequencies in left- and mixed-handedness have also been associated with more severe clinical symptoms, indicating that symptom severity rather than diagnosis explains the high prevalence of non-right-handedness in mental disorders. To address this issue, the present study investigated the association between handedness and measures of stress reactivity, depression, mania, anxiety, and positive and negative symptoms in a large sample of 994 healthy controls and 1213 patients with DSM IV affective disorders, schizoaffective disorders, or schizophrenia. A series of complementary analyses revealed lower lateralization and a higher percentage of mixed-handedness in patients with major depression (14.9%) and schizophrenia (24.0%) compared to healthy controls (12%). For patients with schizophrenia, higher symptom severity was associated with an increasing tendency towards left-handedness. No associations were found for patients diagnosed with major depression, bipolar disorder, or schizoaffective disorder. In healthy controls, no association between hand preference and symptoms was evident. Taken together, these findings suggest that both diagnosis and symptom severity are relevant for the shift away from right-handedness in mental disorders like schizophrenia and major depression.