bluuebunny/crossref_metadata_2025_split huggingface dataset:
De novo design of knotted tandem repeat proteins
Authors: Doyle Lindsey A. , Takushi Brittany , Kibler Ryan D. , Milles Lukas F. , Orozco Carolina T. , Jones Jonathan D. , Jackson Sophie E. , Stoddard Barry L. , Bradley Philip 
Published: October 2023

AbstractDe novo protein design methods can create proteins with folds not yet seen in nature. These methods largely focus on optimizing the compatibility between the designed sequence and the intended conformation, without explicit consideration of protein folding pathways. Deeply knotted proteins, whose topologies may introduce substantial barriers to folding, thus represent an interesting test case for protein design. Here we report our attempts to design proteins with trefoil (31) and pentafoil (51) knotted topologies. We extended previously described algorithms for tandem repeat protein design in order to construct deeply knotted backbones and matching designed repeat sequences (N = 3 repeats for the trefoil and N = 5 for the pentafoil). We confirmed the intended conformation for the trefoil design by X ray crystallography, and we report here on this protein’s structure, stability, and folding behaviour. The pentafoil design misfolded into an asymmetric structure (despite a 5-fold symmetric sequence); two of the four repeat-repeat units matched the designed backbone while the other two diverged to form local contacts, leading to a trefoil rather than pentafoil knotted topology. Our results also provide insights into the folding of knotted proteins.
Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial
Authors: Pouyiourou Maria , Kraft Bianca N. , Wohlfromm Timothy , Stahl Michael , Kubuschok Boris , Löffler Harald , Hacker Ulrich T. , Hübner Gerdt , Weiss Lena , Bitzer Michael , Ernst Thomas , Schütt Philipp , Hielscher Thomas , Delorme Stefan , Kirchner Martina , Kazdal Daniel , Ball Markus , Kluck Klaus , Stenzinger Albrecht , Bochtler Tilmann , Krämer Alwin 
Published: October 2023

AbstractCancer of unknown primary has a dismal prognosis, especially following failure of platinum-based chemotherapy. 10-20% of patients have a high tumor mutational burden (TMB), which predicts response to immunotherapy in many cancer types. In this prospective, non-randomized, open-label, multicenter Phase II trial (EudraCT 2018-004562-33; NCT04131621), patients relapsed or refractory after platinum-based chemotherapy received nivolumab and ipilimumab following TMBhigh vs. TMBlow stratification. Progression-free survival (PFS) represented the primary endpoint; overall survival (OS), response rates, duration of clinical benefit and safety were the secondary endpoints. The trial was prematurely terminated in March 2021 before reaching the preplanned sample size (n = 194). Among 31 evaluable patients, 16% had a high TMB ( > 12 mutations/Mb). Overall response rate was 16% (95% CI 6-34%), with 7.7% (95% CI 1-25%) vs. 60% (95% CI 15-95%) in TMBlow and TMBhigh, respectively. Although the primary endpoint was not met, high TMB was associated with better median PFS (18.3 vs. 2.4 months) and OS (18.3 vs. 3.6 months). Severe immune-related adverse events were reported in 29% of cases. Assessing on-treatment dynamics of circulating tumor DNA using combined targeted hotspot mutation and shallow whole genome sequencing as part of a predefined exploratory analysis identified patients benefiting from immunotherapy irrespective of initial radiologic response.
Maternal thyroid hormone receptor β activation in mice sparks brown fat thermogenesis in the offspring
Authors: Oelkrug Rebecca , Harder Lisbeth , Pedaran Mehdi , Hoffmann Anne , Kolms Beke , Inderhees Julica , Gachkar Sogol , Resch Julia , Johann Kornelia , Jöhren Olaf , Krause Kerstin , Mittag Jens 
Published: October 2023

AbstractIt is well established that maternal thyroid hormones play an important role for the developing fetus; however, the consequences of maternal hyperthyroidism for the offspring remain poorly understood. Here we show in mice that maternal 3,3’,5-triiodothyronine (T3) treatment during pregnancy leads to improved glucose tolerance in the adult male offspring and hyperactivity of brown adipose tissue (BAT) thermogenesis in both sexes starting early after birth. The activated BAT provides advantages upon cold exposure, reducing the strain on other thermogenic organs like muscle. This maternal BAT programming requires intact maternal thyroid hormone receptor β (TRβ) signaling, as offspring of mothers lacking this receptor display the opposite phenotype. On the molecular level, we identify distinct T3 induced alterations in maternal serum metabolites, including choline, a key metabolite for healthy pregnancy. Taken together, our results connect maternal TRβ activation to the fetal programming of a thermoregulatory phenotype in the offspring.
Uncertainty-inspired open set learning for retinal anomaly identification
Authors: Wang Meng , Lin Tian , Wang Lianyu , Lin Aidi , Zou Ke , Xu Xinxing , Zhou Yi , Peng Yuanyuan , Meng Qingquan , Qian Yiming , Deng Guoyao , Wu Zhiqun , Chen Junhong , Lin Jianhong , Zhang Mingzhi , Zhu Weifang , Zhang Changqing , Zhang Daoqiang , Goh Rick Siow Mong , Liu Yong , Pang Chi Pui , Chen Xinjian , Chen Haoyu , Fu Huazhu 
Published: October 2023

AbstractFailure to recognize samples from the classes unseen during training is a major limitation of artificial intelligence in the real-world implementation for recognition and classification of retinal anomalies. We establish an uncertainty-inspired open set (UIOS) model, which is trained with fundus images of 9 retinal conditions. Besides assessing the probability of each category, UIOS also calculates an uncertainty score to express its confidence. Our UIOS model with thresholding strategy achieves an F1 score of 99.55%, 97.01% and 91.91% for the internal testing set, external target categories (TC)-JSIEC dataset and TC-unseen testing set, respectively, compared to the F1 score of 92.20%, 80.69% and 64.74% by the standard AI model. Furthermore, UIOS correctly predicts high uncertainty scores, which would prompt the need for a manual check in the datasets of non-target categories retinal diseases, low-quality fundus images, and non-fundus images. UIOS provides a robust method for real-world screening of retinal anomalies.
Twistedly hydrophobic basis with suitable aromatic metrics in covalent organic networks govern micropollutant decontamination
Authors: Qin Chencheng , Yang Yi , Wu Xiaodong , Chen Long , Liu Zhaoli , Tang Lin , Lyu Lai , Huang Danlian , Wang Dongbo , Zhang Chang , Yuan Xingzhong , Liu Wen , Wang Hou 
Published: October 2023

AbstractThe pre-designable structure and unique architectures of covalent organic frameworks (COFs) render them attractive as active and porous medium for water crisis. However, the effect of functional basis with different metrics on the regulation of interfacial behavior in advanced oxidation decontamination remains a significant challenge. In this study, we pre-design and fabricate different molecular interfaces by creating ordered π skeletons, incorporating different pore sizes, and engineering hydrophilic or hydrophobic channels. These synergically break through the adsorption energy barrier and promote inner-surface renewal, achieving a high removal rate for typical antibiotic contaminants (like levofloxacin) by BTT-DATP-COF, compared with BTT-DADP-COF and BTT-DAB-COF. The experimental and theoretical calculations reveal that such functional basis engineering enable the hole-driven levofloxacin oxidation at the interface of BTT fragments to occur, accompanying with electron-mediated oxygen reduction on terphenyl motif to active radicals, endowing it facilitate the balanced extraction of holes and electrons.
Synergistic performance of a new bimetallic complex supported on magnetic nanoparticles for Sonogashira and C–N coupling reactions
Authors: Nasseri Fatemeh , Nasseri Mohammad Ali , Kassaee Mohamad Zaman , Yavari Issa 
Published: October 2023

AbstractThis paper describes the synthesis of a novel Cu–Ni bimetallic system comprising of magnetic nanoparticles, as the core, and 4-amino-3,5-bis(pyridin-2-yl)-1,2,4-triazole (4-ABPT), as a conjugated bridge, between nickel and copper species. With low Cu and Ni loading (0.06 mol% Ni, 0.08 mol% Cu), the resulting Fe3O4@SiO2@4-ABPT/Cu–Ni showed to be a highly efficient catalyst for the Sonogashira and C–N cross-coupling reactions. The developed catalyst was well characterized by FT-IR, XRD, EDX-mapping, FE-SEM, TEM, ICP, VSM, TGA/DTG/DTA, LSV, and XPS techniques. Fe3O4@SiO2@4-ABPT/Cu–Ni nanocatalyst was compatible with a wide range of amines and aryl halides in the Sonogashira and C–N cross-coupling reactions and offered desired coupling products in high to excellent yields under palladium- and solvent-free conditions. Based on the XPS results, the 4-ABPT ligand can adjust electron transfer between Ni and Cu in Fe3O4@SiO2@4-ABPT/Cu–Ni, promoting the formation and stabilization of Cu+ and Ni3+ species. Electronic interactions and the synergistic effect between these metals increased the selectivity and activity of Fe3O4@SiO2@4-ABPT/Cu–Ni catalyst in the Sonogashira and C–N cross-coupling reactions compared with its monometallic counterparts. Additionally, the magnetic properties of Fe3O4@SiO2@4-ABPT/Cu–Ni facilitated its separation from the reaction mixture, promoting its reuse for several times with no significant loss in its catalytic activity or performance.
Knee synovial fluid flow and heat transfer, a power law model
Authors: Hasnain Shahid , Abbas Imran , Al-Atawi Nawal Odah , Saqib Muhammad , Afzaal Muhammad F. , Mashat Daoud S. 
Published: October 2023

AbstractFor the purpose of understanding, the governing system of partial differential equations for synovial fluid flow velocity and temperature distribution in the knee joint has been successfully solved for the first time. Therefore, such an article is shedding light on the convective diffusion of the viscous flow along the articular surfaces of the joints through the introduction of power-law fluids with different features of permeability, and stagnation point flow along a magnetic field. Henceforth, the frictional energy causes the knee joint’s temperature to increase. By way of filtration, heated synovial fluid reaches the articular cartilage and provides heat to the bone and cartilage. The lubricant in the joint cavity is properly mixed with this cooled fluid. A rectangular region flow and diffusion model is used to define the issue, thermal diffusion and flow inside the intra-articular gap, as well as flow and thermal diffusion within the porous matrix covering the approaching bones at the joint. Using the similarity solution approach, the linked mixed boundary value problem is addressed. The fluid has been shown to resist moving into or out of the cartilage in certain sick and/or aging synovial joints, causing the temperature to increase. By changing the values of the parameters from their usual levels, it is observed that the temperature did increase in aged and sick joints which impact cartilage and/or synovial fluid degradation.
Evaluation of antimicrobial usage in companion animals at a Veterinary Teaching Hospital in Nigeria
Authors: Adebowale O. O. , Jimoh A. B. , Adebayo O. O. , Alamu A. A. , Adeleye A. I. , Fasanmi O. G. , Olasoju M. , Olagunju P. O. , Fasina F. O. 
Published: October 2023

AbstractThis study investigated various qualitative and quantitative indices of antimicrobial use (AMU) in companion animals (CAs) at a Veterinary Teaching Hospital (VTH-A) and its annex (VTH- B) from 2019 to 2021. For 694 documented animals, antimicrobial administrations (AADs) were 5, 278 times, of which 98.8% (5217) and 1.2% (61) were in dogs and cats respectively. At the VTH- A, oxytetracycline (1185 times, 22.5%) was mostly administered in dogs and metronidazole (26 times, 0.5%) in cats. Similarly, at VTH- B, oxytetracycline was administered 895 times (17.0%) in dogs while amoxicillin was given 7 times (0.1%) in cats. The prescription diversity (PD) was estimated at 0.73 and 0.82 in VTH-A and VTH-B respectively. The quantity of antimicrobials (AMs) used was 10.1 kg (A, 6.2 kg and B, 3.9 kg). Oxytetracycline administrations and quantity of metronidazole (P < 0.0001) were higher than other Active Ingredients (AIs). Furthermore, 16.5% of AIs were classified as Critically Important Antibiotics (CIA) with the highest priority, while enrofloxacin, ciprofloxacin, and azithromycin fell under the World Health Organisation (WHO) Watch group. The In-Depth Interview (IDI) indicated that the high frequency of oxytetracycline administrations was linked with being the first choice for blood parasite treatment by the clinicians at the hospital. The quantity of metronidazole used was perceived to be higher due to the clinicians' preference for the treatment of acute gastroenteritis, its wider dose range, and the frequency of administration (bi-daily). The study provides baseline data on AMU indices in CAs, for the development of antimicrobial stewardship (AMS) and communication training, and policy modifications to enhance antimicrobial therapy optimization in tertiary veterinary hospital care in Nigeria.
Evolutionary and ecological correlates of thiaminase in fishes
Authors: Rowland Freya E. , Richter Catherine A. , Tillitt Donald E. , Walters David M. 
Published: October 2023

AbstractThiamine (vitamin B1) is required by all living organisms in multiple metabolic pathways. It is scarce in natural systems, and deficiency can lead to reproductive failure, neurological issues, and death. One major cause of thiamine deficiency is an overreliance on diet items containing the enzyme thiaminase. Thiaminase activity has been noted in many prey fishes and linked to cohort failure in salmonid predators that eat prey fish with thiaminase activity, yet it is generally unknown whether evolutionary history, fish traits, and/or environmental conditions lead to production of thiaminase. We conducted literature and GenBank BLAST sequence searches to collect thiaminase activity data and sequence homology data in expressed protein sequences for 300 freshwater and marine fishes. We then tested whether presence or absence of thiaminase could be predicted by evolutionary relationships, trophic level, omega-3 fatty acid concentrations, habitat, climate, invasive potential, and body size. There was no evolutionary relationship with thiaminase activity. It first appears in Class Actinoptergyii (bony ray-finned fishes) and is present across the entire Actinoptergyii phylogeny in both primitive and derived fish orders. Instead, ecological factors explained the most variation in thiaminase: fishes were more likely to express thiaminase if they fed closer to the base of the food web, were high in polyunsaturated fatty acids, lived in freshwater, and were from tropical climates. These data provide a foundation for understanding sources of thiaminase leading to thiamine deficiency in fisheries and other organisms, including humans that eat uncooked fish.
A machine learning approach to predict the glaucoma filtration surgery outcome
Authors: Agnifili Luca , Figus Michele , Porreca Annamaria , Brescia Lorenza , Sacchi Matteo , Covello Giuseppe , Posarelli Chiara , Di Nicola Marta , Mastropasqua Rodolfo , Nucci Paolo , Mastropasqua Leonardo 
Published: October 2023

AbstractThis study aimed at predicting the filtration surgery (FS) outcome using a machine learning (ML) approach. 102 glaucomatous patients undergoing FS were enrolled and underwent ocular surface clinical tests (OSCTs), determination of surgical site-related biometric parameters (SSPs) and conjunctival vascularization. Break-up-time, Schirmer test I, corneal fluorescein staining, Meibomian gland expressibility; conjunctival hyperemia, upper bulbar conjunctiva area of exposure, limbus to superior eyelid distance; and conjunctival epithelial and stromal (CET, CST) thickness and reflectivity (ECR, SCR) at AS-OCT were considered. Successful FS required a 30% baseline intraocular pressure reduction, with values ≤ 18 mmHg with or without medications. The classification tree (CT) was the ML algorithm used to analyze data. At the twelfth month, FS was successful in 60.8% of cases, whereas failed in 39.2%. At the variable importance ranking, CST and SCR were the predictors with the greater relative importance to the CART tree construction, followed by age. CET and ECR showed less relative importance, whereas OSCTs and SSPs were not important features. Within the CT, CST turned out the most important variable for discriminating success from failure, followed by SCR and age, with cut-off values of 75 µm, 169 on gray scale, and 62 years, respectively. The ROC curve for the classifier showed an AUC of 0.784 (0.692–0.860). In this ML approach, CT analysis found that conjunctival stroma thickness and reflectivity, along with age, can predict the FS outcome with good accuracy. A pre-operative thick and hyper-reflective stroma, and a younger age increase the risk of FS failure.
Radiomics–clinical nomogram based on pretreatment 18F-FDG PET-CT radiomics features for individualized prediction of local failure in nasopharyngeal carcinoma
Authors: Ding Jianming , Li Zirong , Lin Yuhao , Huang Chaoxiong , Chen Jiawei , Hong Jiabiao , Fei Zhaodong , Zhou Qichao , Chen Chuanben 
Published: October 2023

AbstractTo explore the prognostic significance of PET/CT-based radiomics signatures and clinical features for local recurrence-free survival (LRFS) in nasopharyngeal carcinoma (NPC). We retrospectively reviewed 726 patients who underwent pretreatment PET/CT at our center. Least absolute shrinkage and selection operator (LASSO) regression and the Cox proportional hazards model were applied to construct Rad-score, which represented the radiomics features of PET-CT images. Univariate and multivariate analyses were used to establish a nomogram model. The concordance index (C-index) and calibration curve were used to evaluate the predictive accuracy and discriminative ability. Receiver operating characteristic analysis was performed to stratify the local recurrence risk of patients. The nomogram was validated by evaluating its discrimination ability and calibration in the validation cohort. A total of eight features were selected to construct Rad-score. A radiomics–clinical nomogram was built after the selection of univariate and multivariable Cox regression analyses, including the Rad-score and maximum standardized uptake value (SUVmax). The C-index was 0.71 (0.67–0.74) in the training cohort and 0.70 (0.64–0.76) in the validation cohort. The nomogram also performed far better than the 8th T-staging system with an area under the receiver operating characteristic curve (AUC) of 0.75 vs. 0.60 for 2 years and 0.71 vs. 0.60 for 3 years. The calibration curves show that the nomogram indicated accurate predictions. Decision curve analysis (DCA) revealed significantly better net benefits with this nomogram model. The log-rank test results revealed a distinct difference in prognosis between the two risk groups. The PET/CT-based radiomics nomogram showed good performance in predicting LRFS and showed potential to identify patients at high-risk of developing NPC.
Examining indicators of complex network vulnerability across diverse attack scenarios
Authors: Al Musawi Ahmad F. , Roy Satyaki , Ghosh Preetam 
Published: October 2023

AbstractComplex networks capture the structure, dynamics, and relationships among entities in real-world networked systems, encompassing domains like communications, society, chemistry, biology, ecology, politics, etc. Analysis of complex networks lends insight into the critical nodes, key pathways, and potential points of failure that may impact the connectivity and operational integrity of the underlying system. In this work, we investigate the topological properties or indicators, such as shortest path length, modularity, efficiency, graph density, diameter, assortativity, and clustering coefficient, that determine the vulnerability to (or robustness against) diverse attack scenarios. Specifically, we examine how node- and link-based network growth or depletion based on specific attack criteria affect their robustness gauged in terms of the largest connected component (LCC) size and diameter. We employ partial least squares discriminant analysis to quantify the individual contribution of the indicators on LCC preservation while accounting for the collinearity stemming from the possible correlation between indicators. Our analysis of 14 complex network datasets and 5 attack models invariably reveals high modularity and disassortativity to be prime indicators of vulnerability, corroborating prior works that report disassortative modular networks to be particularly susceptible to targeted attacks. We conclude with a discussion as well as an illustrative example of the application of this work in fending off strategic attacks on critical infrastructures through models that adaptively and distributively achieve network robustness.
Continuous therapy response references for BCR::ABL1 monitoring in pediatric chronic myeloid leukemia
Authors: Volz Christian , Zerjatke Thomas , Gottschalk Andrea , Semper Sabine , Suttorp Meinolf , Glauche Ingmar , Krumbholz Manuela , Metzler Markus 
Published: October 2023

AbstractResponse to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML) is monitored by quantification of BCR::ABL1 transcript levels. Milestones for assessing optimal treatment response have been defined in adult CML patients and are applied to children and adolescents although it is questionable whether transferability to pediatric patients is appropriate regarding genetic and clinical differences. Therefore, we analyzed the molecular response kinetics to TKI therapy in 129 pediatric CML patients and investigated whether response assessment based on continuous references can support an early individual therapy adjustment. We applied a moving quantiles approach to establish a high-resolution response target curve and contrasted the median responses in all patients with the median of the ideal target curve obtained from a subgroup of optimal responders. The high-resolution response target curve of the optimal responder group presents a valuable tool for continuous therapy monitoring of individual pediatric CML patients in addition to the fixed milestones. By further comparing BCR::ABL1 transcript levels with BCR::ABL1 fusion gene copy numbers, it is also possible to model the differential dynamics of BCR::ABL1 expression and cell number under therapy. The developed methodology can be transferred to other biomarkers for continuous therapy monitoring.