bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expanding RNAi to Kidneys, Lungs, and Spleen via Selective ORgan Targeting (SORT) siRNA Lipid Nanoparticles
Authors: Vaidya Amogh , Moore Stephen , Chatterjee Sumanta , Guerrero Erick , Kim Minjeong , Farbiak Lukas , Dilliard Sean A. , Siegwart Daniel J. 
Published: June 2024

AbstractInhibition of disease‐causing mutations using RNA interference (RNAi) has resulted in clinically approved medicines with additional candidates in late stage trials. However, targetable tissues currently in preclinical development are limited to liver following systemic intravenous (IV) administration because predictable delivery of siRNA to non‐liver tissues remains an unsolved challenge. Here, evidence of durable extrahepatic gene silencing enabled by siRNA Selective ORgan Targeting lipid nanoparticles (siRNA SORT LNPs) to the kidneys, lungs, and spleen is provided. LNPs excel at dose‐dependent silencing of tissue‐enriched endogenous targets resulting in 60%–80% maximal knockdown after a single IV injection and up to 88% downregulation of protein expression in mouse lungs after two doses. To examine knockdown potency and unbiased organ targeting, B6.129TdTom/EGFP mice that constitutively express the TdTomato transgene across all cell types are utilized to demonstrate 58%, 45%, and 15% reduction in TdTomato fluorescence in lungs, spleen, and kidneys, respectively. Finally, physiological relevance of siRNA SORT LNP‐mediated gene silencing is established via acute suppression of endogenous Tie2 which induces lung‐specific phenotypic alteration of vascular endothelial barrier. Due to plethora of extrahepatic diseases that may benefit from RNAi interventions, it is anticipated that the findings will expand preclinical landscape of therapeutic targets beyond the liver.
Catalytic Activation of Bis(2,2,2‐trifluoroethyl) Phosphite with Hf(IV) for the Synthesis of Mixed Dialkyl Phosphites
Authors: Mrdović Dario , Saito Yuki , Kobayashi Shū 
Published: June 2024

AbstractWe developed a second generation of Lewis acid catalyst enabling selective and user‐friendly phosphonylation of diverse alcohols. This one‐pot method utilizes P(III) reagent bis(2,2,2–trifluoroethyl) phosphite under mild conditions. Exploring the influence of metal selection in Lewis acid catalysts revealed four highly active complexes for alcohol phosphonylation: Zn(II), Al(III), Zr(IV), and Hf(IV). Notably, Hf(IV) displayed superior selectivity compared to the previously developed Zn(II) catalyst.
The Toxoplasma Effector GRA4 Hijacks Host TBK1 to Oppositely Regulate Anti‐T. Gondii Immunity and Tumor Immunotherapy
Authors: Hu Zhiqiang , Zhang Yufen , Xie Yingchao , Yang Jianwu , Tang Haotian , Fan Bolin , Zeng Ke , Han Zhongxin , Lu Jiansen , Jiang Huaji , Peng Wenqiang , Li Hongyu , Chen Huadan , Wu Sha , Shen Bang , Lun Zhao‐Rong , Yu Xiao 
Published: June 2024

AbstractToxoplasma gondii (T. gondii)‐associated polymorphic effector proteins are crucial in parasite development and regulating host anti‐T. gondii immune responses. However, the mechanism remains obscure. Here, it is shown that Toxoplasma effector dense granules 4 (GRA4) restricts host IFN‐I activation. Infection with Δgra4 mutant T. gondii strain induces stronger IFN‐I responses and poses a severe threat to host health. Mechanistically, GRA4 binds to phosphorylated TBK1 to promote TRIM27‐catalyzed K48‐ubiquitination at Lys251/Lys372 residues, which enhances its recognition by autophagy receptor p62, ultimately leading to TBK1 autophagic degradation. Furthermore, an avirulent Δgra4 strain (ME49Δompdc/gra4) is constructed for tumor immunotherapy due to its ability to enhance IFN‐I production. Earlier vaccination with ME49Δompdc/gra4 confers complete host resistance to the tumor compared with the classical ME49Δompdc treatment. Notably, ME49Δompdc/gra4 vaccination induces a specific CD64+MAR‐1+CD11b+ dendritic cell subset, thereby enhancing T cell anti‐tumor responses. Overall, these findings identify the negative role of T. gondii GRA4 in modulating host IFN‐I signaling and suggest that GRA4 can be a potential target for the development of T. gondii vaccines and tumor immunotherapy.
3D Printed Organisms Enabled by Aspiration‐Assisted Adaptive Strategies
Authors: Han Guebum , Khosla Kanav , Smith Kieran T. , Ng Daniel Wai Hou , Lee JiYong , Ouyang Xia , Bischof John C. , McAlpine Michael C. 
Published: June 2024

AbstractDevising an approach to deterministically position organisms can impact various fields such as bioimaging, cybernetics, cryopreservation, and organism‐integrated devices. This requires continuously assessing the locations of randomly distributed organisms to collect and transfer them to target spaces without harm. Here, an aspiration‐assisted adaptive printing system is developed that tracks, harvests, and relocates living and moving organisms on target spaces via a pick‐and‐place mechanism that continuously adapts to updated visual and spatial information about the organisms and target spaces. These adaptive printing strategies successfully positioned a single static organism, multiple organisms in droplets, and a single moving organism on target spaces. Their capabilities are exemplified by printing vitrification‐ready organisms in cryoprotectant droplets, sorting live organisms from dead ones, positioning organisms on curved surfaces, organizing organism‐powered displays, and integrating organisms with materials and devices in customizable shapes. These printing strategies can ultimately lead to autonomous biomanufacturing methods to evaluate and assemble organisms for a variety of single and multi‐organism‐based applications.
Cross‐Modal Graph Contrastive Learning with Cellular Images
Authors: Zheng Shuangjia , Rao Jiahua , Zhang Jixian , Zhou Lianyu , Xie Jiancong , Cohen Ethan , Lu Wei , Li Chengtao , Yang Yuedong 
Published: June 2024

AbstractConstructing discriminative representations of molecules lies at the core of a number of domains such as drug discovery, chemistry, and medicine. State‐of‐the‐art methods employ graph neural networks and self‐supervised learning (SSL) to learn unlabeled data for structural representations, which can then be fine‐tuned for downstream tasks. Albeit powerful, these methods are pre‐trained solely on molecular structures and thus often struggle with tasks involved in intricate biological processes. Here, it is proposed to assist the learning of molecular representation by using the perturbed high‐content cell microscopy images at the phenotypic level. To incorporate the cross‐modal pre‐training, a unified framework is constructed to align them through multiple types of contrastive loss functions, which is proven effective in the formulated novel tasks to retrieve the molecules and corresponding images mutually. More importantly, the model can infer functional molecules according to cellular images generated by genetic perturbations. In parallel, the proposed model can transfer non‐trivially to molecular property predictions, and has shown great improvement over clinical outcome predictions. These results suggest that such cross‐modality learning can bridge molecules and phenotype to play important roles in drug discovery.
Statistical considerations when estimating time‐saving treatment effects in Alzheimer's disease clinical trials
Authors: Wang Guoqiao , Cutter Gary , Oxtoby Neil P. , Shan Guogen , Wang Whedy , Mangal Brian , Liao Yijie , Llibre‐Guerra Jorge J. , Li Yan , Xiong Chengjie , McDade Eric , Delmar Paul , Bateman Randall J. , Schneider Lon 
Published: June 2024

AbstractINTRODUCTIONEstimating treatment effects as time savings in disease progression may be more easily interpretable than assessing the absolute difference or a percentage reduction. In this study, we investigate the statistical considerations of the existing method for estimating time savings and propose alternative complementary methods.METHODSWe propose five alternative methods to estimate the time savings from different perspectives. These methods are applied to simulated clinical trial data that mimic or modify the Clinical Dementia Rating Sum of Boxes progression trajectories observed in the Clarity AD lecanemab trial.RESULTSOur study demonstrates that the proposed methods can generate more precise estimates by considering two crucial factors: (1) the absolute difference between treatment arms, and (2) the observed progression rate in the treatment arm.DISCUSSIONQuantifying treatment effects as time savings in disease progression offers distinct advantages. To provide comprehensive estimations, it is important to use various methods.Highlights
We explore the statistical considerations of the current method for estimating time savings.
We proposed alternative methods that provide time savings estimations based on the observed absolute differences.
By using various methods, a more comprehensive estimation of time savings can be achieved.
Enhancement of mechanical and flame‐retardant properties of PLA composites through the combined action of flexible chain segments and hydrogen bonding interactions
Authors: Xiao Xingzhen , Lin Xiaoling , Zhong Wei , Lan Jiashui , Lv Jiaojiao , Lan Yongqiang , Zhang Huagui , Chen Mingfeng 
Published: June 2024

AbstractThe development of high toughness as well as flame‐retardant polylactic acid (PLA) materials is important for expanding the practical applications. Herein, a type of high toughness PLA composites with improved flame retardancy was developed through combining modified carbon nanotubes (CNT) and polysiliconoxaborane (PBSi) with PLA matrix. The optimal PLA composite (PLA/PBSi/CNT‐3.0) exhibited excellent crystallization degree (18.7%), thermal stability (the Ea significantly increased), flame retardancy (the values of peak heat release rate (PHRR) polarized optical microscopy and total heat release (THR) decreased to 287.1 W/g and 15.5 kJ/m2, respectively), and mechanical properties (the elongation at break increased to 149.5%, with an increasement of 1745.7%) due to the combined action of flexible chain segments and hydrogen bonding interactions. Furthermore, the toughening mechanism of the PLA/PBSi/CNT composites was illustrated and attributed to the combination of flexible SiOBO segments and two dominant energy dissipation processes (the breakage of hydrogen bond and the destruction of microcrystals). Overall, this work provided a facile approach for improving the toughness and flame retardancy of PLA, which was conducive to expanding the application range of PLA.
The surprising complexity and diversity of sperm storage structures across Galliformes
Authors: Assersohn Katherine , Richards J. Paul , Hemmings Nicola 
Published: June 2024

AbstractIn internal fertilisers, the precise timing of ovulation with the arrival of sperm at the site of fertilisation is essential for fertilisation success. In birds, mating is often not synchronised with ovulation, but instead females utilise specialised sperm storage tubules (SSTs) in the reproductive tract, which can ensure sperm are always available for fertilisation at the time of ovulation, whilst simultaneously providing a mechanism of post‐copulatory sexual selection. Despite the clear importance of SSTs for fertilisation success, we know little about the mechanisms involved in sperm acceptance, storage, and release. Furthermore, most research has been conducted on only a small number of species, based on which SSTs are usually assumed to look and function in the same way across all species. Here, we conduct a comparative exploration of SST morphology across 26 species of Galliformes. We show that SSTs, and the surrounding tissue, can vary significantly in morphology across species. We provide observational evidence that Galliformes exhibit at least 5 distinct categories of tubule types, including distinctive coiled and multi‐branched tubules, and describe 2 additional features of the surrounding tissue. We suggest functional explanations for variation in tubule morphology and propose next steps for future research. Our findings indicate that SSTs are likely to be far more variable than has previously been assumed, with potentially important consequences for our understanding of sperm storage in birds and post‐copulatory sexual selection in general.
Extreme specificity in obligate mutualism—A role for competition?
Authors: Agarwal Renuka , Althoff David M. 
Published: June 2024

AbstractObligate mutualisms, reciprocally obligate beneficial interactions, are some of the most important mutualisms on the planet, providing the basis for the evolution of the eukaryotic cell, the formation and persistence of terrestrial ecosystems and the establishment and expansion of coral reefs. In addition, these mutualisms can also lead to the diversification of interacting partner species. Accompanying this diversification is a general pattern of a high degree of specificity among interacting partner species. A survey of obligate mutualisms demonstrates that greater than half of these systems have only one or two mutualist species on each side of the interaction. This is in stark contrast to facultative mutualisms that can have dozens of interacting mutualist species. We posit that the high degree of specificity in obligate mutualisms is driven by competition within obligate mutualist guilds that limits species richness. Competition may be particularly potent in these mutualisms because mutualistic partners are totally dependent on each other's fitness gains, which may fuel interspecific competition. Theory and the limited number of empirical studies testing for the role of competition in determining specificity suggest that competition may be an important force that fuels the high degree of specificity. Further empirical research is needed to dissect the relative roles of trait complementarity, mutualism regulation, and competition among mutualist guild members in determining mutualism specificity at local scales.
Hydrogen Bonding vs Dihydrogen Bonding in the Air Stable Primary Phosphine ortho‐Phosphinophenol
Authors: Protasiewicz John D. , Stone Alexander M. , Golden Andrew R. , Daniel Shan M. , Rheingold Arnold L. 
Published: June 2024

ortho‐Phosphinophenol (oPP) is an unusual example of an air‐stable primary phosphine and a valuable precursor to a variety of useful organophosphorus compounds. The presence of PH2 and OH functionalities offers the possibility of intermolecular and intramolecular P•••HO hydrogen bonding (HB). The close proximity of these two groups also offers the opportunity for intramolecular PH2•••HO dihydrogen bonding (DHB). This work provides experimental and computational evidence for these various types of interactions. In the solid state, oPP is associated by significant intermolecular P•••HO hydrogen bonds as revealed by a single crystal X‐ray structural determination. Multinuclear NMR and IR spectroscopic studies, coupled with DFT computational studies, suggest that oPP adopts multiple conformations in solution whose nature varies with the identity of the solvent. In the gas phase or non‐polar solvents (such as cyclohexane) an equilibrium between four conformations of oPP is proposed. Interestingly, in silico, an isomer having bifurcated intramolecular PH2•••HO DHB (PP4) is found to be more stable than an isomer having intramolecular P•••HO HB (PP1). In polar solvents (S), NMR studies indicate intermolecular OH•••HB play a dominant role on the 31P NMR chemical shifts.
Metal‐Free Visible‐Light‐Induced Hydrodifluoroalkylation of Electron‐Deficient Alkenes Using Hantzsch Ester
Authors: Wang Juan , Ren Ke , Hao Jian , Wan Wen 
Published: June 2024

AbstractA mild, metal‐free Giese‐type hydrodifluoroalkylation of electron‐deficient alkenes under visible‐light irradiation has been developed. This highly reducing photoactivated Hantzsch ester facilitates C(sp3)−CF2 bond formation through photoinduced electron transfer (PET) and hydrogen atom transfer (HAT) processes, providing an easy access to diverse gem‐difluorinated alkanes.
Exploring new pipelines to fill the nursing shortage
Authors: Elfman Lois 
Published: June 2024

A veteran nursing educator, Dr. Patty Knecht now uses her position in the corporate world to address the imminent nursing shortage. In an article published in The Hill last fall, she wrote that by 2025 the United States will have a six‐figure shortfall in the number of nurses needed for direct patient care. With approximately 100,000 nurses having left the profession due to pandemic burnout, a significant influx of new nurses entering the healthcare workforce is needed.
Energy conversion efficiency and its improving methods for “Region” solar cell
Authors: Jonoshita Isamu 
Published: June 2024

AbstractIn this paper, a proper noun “Region” is used for nm‐scale n‐type dopant‐rich region in p‐type Si crystal. Using this Region, certain solar cells have been assumed. By resonance absorption between photon energy and potential barrier of the Region, the cell can absorb most photons for visible light frequency without passing loss or thermal loss. This light absorption mechanism is different from conventional band gap absorption. Despite this benefit, output voltage is anticipated to decline according to the principle of detail balance. To control the decline, two methods are proposed in this paper. Theoretical energy conversion efficiencies for several cases are calculated with an ideal condition. The calculation result is over 70% as a theoretical value.
Enhancement of the underground cable current capacity by using nano‐dielectrics
Authors: Gouda Ossama E. , Darwish Mohamed M. F. , Thabet Ahmed , Lehtonen Matti , Osman Gomaa F. A. 
Published: June 2024

AbstractIn most underground power cables, cross‐linked polyethylene (XLPE) is utilized as the main insulating material, while polyvinyl chloride (PVC) is usually used as a nonmetallic sheath or jacketing for the cable. Accordingly, improving the electrical and thermal characteristics of these materials leads to an increase in cable dielectric strength, besides a rise in the current capacity of the underground power cables. Thus, enhancing the thermal characteristics of cable insulation is the goal of many research studies. In this regard, increasing the current capacity of underground power cables is an essential topic for electrical distribution and transmission networks. This usually occurs by increasing the cross‐sectional area of the cable conductor, which means raising the cost of transmitting electrical energy. Another proposed alternative may be to improve the thermal properties of the dielectric material using nanotechnology to allow better dissipation of heat resulting from the cable losses. This article proposes the use of nano‐composite dielectrics to increase the current capacities of underground power cables. Nano‐fillers are used to enhance the thermal and electrical characteristics of XLPE and PVC, which represent cable dielectric materials. Accordingly, in this paper, many experiments are conducted on various nano‐dielectric materials to choose the most appropriate nano‐dielectrics for improving both the thermal and electrical properties. Hence, measurements are performed on the thermal and electrical properties of dielectric nano‐materials manufactured in the laboratory. Further, calculations of the cable's current capacities by the use of the measured properties of nano‐dielectrics are done considering several backfill soils. From the obtained measurements and calculations carried out on cable capacities, it is concluded that the use of XLPE/ZnO 5 wt.% as the insulation and PVC/ZnO 5 wt.% as the jacket material increased the cable current capacity by 6.2% for a cable of 33 kV rating, 9.2% for 66 kV cable, and 15.7% for 220 kV cable when wet clay is used as backfill soil. From the calculations carried out it is found that the use of nano‐composite dielectrics reduces the temperature of the cable components by significant values. For example, the core temperature of the 33 kV cable is reduced by 15.6°C, while for the 66 kV cable, the cable core temperature is decreased by 12.6°C, and for 220 kV the conductor temperature is reduced from 71.3°C to 58.3°C when each cable is loaded by its rating.
Developing and validating a new neural network model for early identification of high‐risk acute pancreatitis patients
Authors: İslam Mehmet Muzaffer , Osoydan Satıcı Merve , Ademoğlu Enis , Erdil Fahriye Naz , Odabaşı Turancan , Eroğlu Serkan Emre 
Published: June 2024

AbstractIntroductionExisting research studies on the use of machine‐learning algorithms for predicting mortality in acute pancreatitis patients is limited and characterized by low methodological quality. Furthermore, those risk‐scoring systems have demonstrated suboptimal performance. Our objective was to develop a high‐performing, robust neural network (NN) model that can identify acute pancreatitis patients who are at risk of 30‐day mortality early.MethodsAdult patients with confirmed diagnosis of acute pancreatitis were included in our study. Patients with preexisting diagnoses of pancreatic cancer, iatrogenic endoscopic pancreatitis, abdominal trauma, exacerbations of chronic pancreatitis, or pregnancy were excluded. The measurements of the variables were obtained within the first hour after their admission to the emergency department. The patients were divided into development and validation cohorts with a ratio of 75 to 25 and a NN model was derived in the derivation cohort after oversampling. For the NN model, multilayer perceptron was used. 5‐fold cross‐validation was performed for internal validation and the final model was externally validated. DeLong's test was used to compare the area under the curves (AUC).ResultsThere were 279 and 93 patients in the development and validation cohorts, respectively. In the out of sample validation, the model had an AUC of 0.936 (95% confidence interval (CI) = 0.864–0.999), sensitivity of 100% (95% CI = 47.8–100), specificity of 80.7% (95% CI = 70.9–88.3), and negative likelihood ratio of ≈0.ConclusionOur NN model demonstrated excellent performance in both the derivation and validation phases for the early identification of acute pancreatitis patients at high mortality risk. Notably, it was able to identify all patients who had 30‐day mortality. Our study offers several key advantages, including a transparent methodology, credible validation, and the provision of a calculator to assess the model's performance across different populations and settings.
SPECT myocardial perfusion imaging for the evaluation of left ventricular mechanical dyssynchrony in obese patients
Authors: Caliskan Billur , Inanir Mehmet 
Published: June 2024

AbstractObjectiveLeft ventricular dyssynchrony (LVD), the loss of coordinated contraction in the left ventricle, is an early sign of heart failure. LVD can be assessed using phase analysis techniques with gated single‐photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). This study aimed to investigate the impact of obesity on LVD through phase analysis.MethodsWe retrospectively enrolled 152 obese patients and 80 age‐ and sex‐matched nonobese patients who showed normal myocardial perfusion and normal left ventricular ejection fraction (LVEF) on MPI. Phase standard deviation (PSD) and phase histogram bandwidth (PBW), as phase analysis parameters, were compared between patients with and without obesity.ResultsAlthough PSD values were within the normal range (cut‐off value >23) for both groups, the PSD values of obese patients were higher than those of the nonobese (20.49 ± 8.66 vs. 14.81 ± 4.93; p < 0.05). PBW values of obese patients were statistically significantly higher than those of the nonobese (57.03 ± 23.17 vs. 41.40 ± 9.96; p < 0.05). The PBW values of obese patients exceeded the normal limits (cut‐off value >49). A weak positive correlation was observed between body mass index (BMI) and PBW values in obese patients (r = 0.181, p < 0.05). In patients of normal weight, no correlations were found between BMI and phase analysis parameters.ConclusionLVD may develop in obese patients, even when myocardial perfusion and ejection fraction are preserved. The use of phase analysis with gated SPECT could be an additional finding improving the early detection of left ventricular dyssynchrony in obese patients.