bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Pharmacology Considerations for the “Off‐the‐Shelf” Allogeneic Cell Therapies
Authors: Mody Hardik , Sutaria Dhruvitkumar S. , Miles Dale 
Published: March 2024

Autologous chimeric antigen receptor T‐cell (CAR‐T) therapies have garnered unprecedented clinical success with multiple regulatory approvals for the treatment of various hematological malignancies. However, there are still several clinical challenges that limit their broad utilization for aggressive disease conditions. To address some of these challenges, allogeneic cell therapies are evaluated as an alternative approach. As compared with autologous products, they offer several advantages, such as a more standardized “off the shelf” product, reduced manufacturing complexity, and no requirement of bridging therapy. As with autologous CAR‐T therapies, allogeneic cell therapies also present clinical pharmacology challenges due to their in vivo living nature, unique pharmacokinetics or cellular kinetics (CKs), and complex dose‐exposure‐response relationships that are impacted by various patient‐ and product‐related factors. On top of that, allogeneic cell therapies present additional unique challenges, including attenuated in vivo persistence and graft‐vs.‐host disease risk as compared with autologous counterparts. This review draws comparison between autologous and allogeneic cell therapies, summarizing key engineering aspects unique to allogeneic cell therapy. Clinical pharmacology learnings from emerging clinical data of allogeneic cell therapy programs are also highlighted, with particular emphasis on CK, dose‐exposure‐response relationship, lymphodepletion regimen, repeat dosing, and patient‐ and product‐related factors that can impact CK and patient outcomes. There are specific unique challenges and opportunities arising from the development of allogeneic cell therapies, especially in optimizing lymphodepletion and establishing a regimen for repeat dosing. This review highlights how clinical pharmacologists are well positioned to help address these challenges by leveraging novel clinical pharmacology and modeling and simulation approaches.
Human disturbance in riparian areas disrupts predator–prey interactions between grizzly bears and salmon
Authors: Adams Megan S. , Levi Taal , Bourbonnais Mathieu , Service Christina N. , Artelle Kyle , Bryan Heather , Paquet Paul , Nelson Trisalyn , Darimont Chris T. 
Published: March 2024

AbstractWildlife must increasingly balance trade‐offs between the need to access important foods and the mortality risks associated with human‐dominated landscapes. Human disturbance can profoundly influence wildlife behavior, but managers know little about the relationship between disturbance–behavior dynamics and associated consequences for foraging. We address this gap by empirically investigating the consequences of human activity on a keystone predator–prey interaction in a region with limited but varied industrial disturbance. Using stable isotope data from 226 hair samples of grizzly bears (Ursus arctos horribilis) collected from 1995 to 2014 across 22 salmon‐bearing watersheds (88,000 km2) in British Columbia, Canada, we examined how human activity influenced their consumption of spawning salmon (Oncorhynchus spp.), a fitness‐related food. Accounting for the abundance of salmon and other foods, salmon consumption strongly decreased (up to 59% for females) with increasing human disturbance (as measured by the human footprint index) in riparian zones of salmon‐bearing rivers. Declines in salmon consumption occurred with disturbance even in watersheds with low footprints. In a region currently among the least influenced by industrial activity, intensification of disturbance in river valleys is predicted to increasingly decouple bears from salmon, possibly driving associated reductions in population productivity and provisioning of salmon nutrients to terrestrial ecosystems. Accordingly, we draw on our results to make landscape‐scale and access‐related management recommendations beyond current streamside protection buffers. This work illustrates the interaction between habitat modification and food security for wildlife, highlighting the potential for unacknowledged interactions and cumulative effects in increasingly modified landscapes.
Phenotypic differentiation despite gene flow: Beak morphology, bite performance, and population genetics of Loggerhead Shrikes (Lanius ludovicianus)
Authors: Sustaita Diego , Wulf Gwendalyn K. , Sethuraman Arun 
Published: March 2024

AbstractPrevious studies of Loggerhead Shrikes (Laniidae: Lanius ludovicianus) in North America have indicated considerable intraspecific genetic and phenotypic differentiation, but the congruence between genetic and phenotypic differentiation remains obscure. We examined phenotypic differences in beak shape and bite force among geographic groupings across a 950 km range, from the lower Imperial Valley to the upper Central Valley of California, USA. We integrated these analyses with a population genetic analysis of six microsatellite markers to test for correspondence between phenotypic and genetic differences among geographic groups. We found significant phenotypic differentiation despite a lack of significant genetic differentiation among groups. Pairwise beak shape and bite force distances nevertheless were correlated with genetic (FST) distances among geographic groups. Furthermore, the phenotypic and genetic distance matrices were correlated with pairwise geographic distances. Takentogether, these results suggest that phenotypic differences might be influenced by neutral processes, inbreeding (as indicated by high heterozygosity deficiencies we observed), local adaptation, and/or phenotypic plasticity.
Mitogenomics reveals extremely low genetic diversity in the endangered Jilin clawed salamander: Implications for its conservation
Authors: Zhou Yu , Li Ningkun , Zhou Hongjun , Zhou Ruoyan , Cui Shuyan , Zheng Guo 
Published: March 2024

AbstractThe Jilin clawed salamander (Onychodactylus zhangyapingi) is an endemic, endangered, and level‐two protected amphibian species of China. In the context of serious threats to amphibians worldwide, conservation studies of this endangered species are urgently needed. In this study, mitogenomic conservation genetics and species distribution modeling analyses were performed for O. zhangyapingi. Sixty‐three samples were collected from nine different locations, and the complete mitochondrial genome was sequenced. Population genetic analyses revealed that O. zhangyapingi exhibits only one genetic structure with extremely low nucleotide diversity. Late Pleistocene climate cooling may have led to a reduction in effective population size and extremely low mitogenomic nucleotide diversity in this salamander, and the subsequent temperature increase (~20 kya to present) provided the opportunity for rapid population growth. The continuous highly suitable region for O. zhangyapingi is only approximately 3000 km2 on the southeastern boundary of Jilin Province, China. Fortunately, there are three large forested national nature reserves within the distribution of O. zhangyapingi that can effectively protect endangered species. Our findings suggest that O. zhangyapingi is a vulnerable species with a narrow distribution and extremely low genetic diversity, and we should pay more attention to the conservation management of this species.
Tree regeneration in models of forest dynamics: A key priority for further research
Authors: Díaz‐Yáñez Olalla , Käber Yannek , Anders Tim , Bohn Friedrich , Braziunas Kristin H. , Brůna Josef , Fischer Rico , Fischer Samuel M. , Hetzer Jessica , Hickler Thomas , Hochauer Christian , Lexer Manfred J. , Lischke Heike , Mairota Paola , Merganič Ján , Merganičová Katarina , Mette Tobias , Mina Marco , Morin Xavier , Nieberg Mats , Rammer Werner , Reyer Christopher P. O. , Scheiter Simon , Scherrer Daniel , Bugmann Harald 
Published: March 2024

AbstractTree regeneration is a key process in forest dynamics, particularly in the context of forest resilience and climate change. Models are pivotal for assessing long‐term forest dynamics, and they have been in use for more than 50 years. However, there is a need to evaluate their capacity to accurately represent tree regeneration. We assess how well current models capture the overall abundance, species composition, and mortality of tree regeneration. Using 15 models built to capture long‐term forest dynamics at the stand, landscape, and global levels, we simulate tree regeneration at 200 sites representing large environmental gradients across Central Europe. The results are evaluated against extensive data from unmanaged forests. Most of the models overestimate recruitment levels, which is compensated only in some models by high simulated mortality rates in the early stages of individual‐tree dynamics. Simulated species diversity of recruitment generally matches observed ranges. Models simulating higher stand‐level species diversity do not feature higher species diversity in the recruitment layer. The effect of light availability on recruitment levels is captured better than the effects of temperature and soil moisture, but patterns are not consistent across models. Increasing complexity in the tree regeneration modules is not related to higher accuracy of simulated tree recruitment. Furthermore, individual model design is more important than scale (stand, landscape, and global) and approach (empirical and process‐based) for accurately capturing tree regeneration. Despite the mismatches between simulation results and data, it is remarkable that most models capture the essential features of the highly complex process of tree regeneration, while not having been parameterized with such data. We conclude that much can be gained by evaluating and refining the modeling of tree regeneration processes. This has the potential to render long‐term projections of forest dynamics under changing environmental conditions much more robust.
Photochemical Trifluoromethylative Difunctionalization of Styrenes and Phenylacetylenes via a Catalytic EDA Platform
Authors: Nasireddy Seshadri Reddy , Upreti Ganesh Chandra , Singh Anand 
Published: March 2024

AbstractHerein we report a visible‐light‐induced trifluoromethylative difunctionalization of styrenes and phenylacetylenes using trifluoromethyl thianthrenium triflate (TT‐CF3+OTf−). The transformation was enabled by the discovery of a photoactive catalytic EDA complex formed between carbazolyl dithiocarbamate and TT‐CF3+OTf−. This three‐component reactivity platform establishes a new paradigm for TT‐CF3+OTf−, significantly expanding its repertoire of photochemically enabled trifluoromethylation reactions.
Review on allosteric modulators of dopamine receptors so far
Authors: Girmaw Fentaw 
Published: March 2024

AbstractBackgroundContemporary research is predominantly directed towards allosteric modulators, a class of compounds designed to interact with specific sites distinct from the orthosteric site on G protein‐coupled receptors. These allosteric modulators play a pivotal role in influencing diverse pharmacological effects, such as agonism/inverse agonism, efficacy modulation, and affinity modulation. One particularly intriguing aspect is the demonstrated capacity of allosteric modulation to enhance drug selectivity for therapeutic purposes, potentially leading to a reduction in serious side effects associated with traditional approaches. Allosteric ligands, a majority of which fall into the categories of negative allosteric modulators or positive allosteric modulators, exhibit the unique ability to either diminish or enhance the effects of endogenous ligands. Negative allosteric modulators weaken the response, while positive allosteric modulators intensify it. Additionally, silent allosteric modulators represent a distinct class that neither activates nor blocks the effects of endogenous ligands, adding complexity to the spectrum of allosteric modulation. In the broader context of central nervous system disorders, allosteric modulation takes center stage, particularly in the realm of dopamine receptors specifically, D1, D2, and D3 receptors. These receptors hold immense therapeutic potential for a range of conditions spanning neurodegenerative disorders to neurobehavioral and psychiatric disorders. The intricate modulation of dopamine receptors through allosteric mechanisms offers a nuanced and versatile approach to drug development. As research endeavors continue to unfold, the exploration of allosteric modulation stands as a promising frontier, holding the potential to reshape the landscape of drug discovery and therapeutic interventions in the field of neurology and psychiatry.
Automatic detection of knee osteoarthritis grading using artificial intelligence‐based methods
Authors: Yildirim Muhammed , Mutlu Hurşit Burak 
Published: March 2024

AbstractOsteoarthritis (OA) means that the slippery cartilage tissue that covers the bone surfaces in the joints and allows the joint to move easily loses its properties and wears out. Knee OA is the wear and tear of the cartilage in the knee joint. Knee OA is a disease whose incidence increases especially after a certain age. Knee OA is difficult and costly to be detected by specialists using traditional methods and may lead to misdiagnosis. In this study, computer‐aided systems were used to prevent errors in traditional methods of detecting knee OA, shorten the diagnosis time, and accelerate the treatment process. In this study, a hybrid model was developed by using Darknet53, Histogram of Directional Gradients (HOG), Local Binary Model (LBP) methods for feature extraction, and Neighborhood Component Analysis (NCA) for feature selection. Our dataset used in experiments contains 1650 knee joint images and consists of five classes: Normal, Doubtful, Mild, Moderate, and Severe. In the experimental studies performed, the performance of the proposed method was compared with eight different Convolutional Neural Networks (CNN) Models. The developed model achieved better performance metrics than the eight different models used in the study and similar studies in the literature. The accuracy value of the developed model is 83.6%.
One‐stage versus two‐stage endoscopic management for acute cholangitis caused by common bile duct stones: A retrospective multicenter cohort study
Authors: Maruta Akinori , Iwashita Takuji , Yoshida Kensaku , Iwasa Yuhei , Okuno Mitsuru , Iwata Keisuke , Tezuka Ryuichi , Uemura Shinya , Shimizu Shogo , Shimizu Masahito 
Published: March 2024

AbstractBackgroundOne‐stage endoscopic management, where papillary interventions and stone removal are simultaneously performed, has been reported to be an effective treatment for acute cholangitis caused by common bile duct stones (CBDS). However, there have been few reports comparing it with two‐stage management, and there is no established strategy for the indication of one‐stage management. The aim of the present study was to compare the short‐ and long‐term outcomes between one‐ and two‐stage management for acute cholangitis caused by CBDS.MethodsWe retrospectively studied 577 patients who underwent one‐ or two‐stage endoscopic management for acute cholangitis between May 2010 and December 2020. The patients were divided into one‐ and two‐stage groups by endoscopic management. The clinical outcomes were compared between groups.ResultsThe technical and clinical success were similar in both groups, although the length of hospital stay was significantly shorter in the one‐stage group. Although there was no difference in the early adverse event (AE) between two groups, post‐ERCP pancreatitis was recognized in 3.4% and 10.0%, which was significantly higher in the two‐stage group. The cumulative late AE rate was 22.6% and 14.1%, which was significantly higher in the one‐stage group. In the multivariate analyses, intervention (one‐stage), number of CBDS ≥2, biliary drainage, the use of ML, and gallbladder stone were identified as significant factors associated with the recurrence of CBDS.ConclusionAlthough one‐stage endoscopic management is useful and safe with reducing hospital stays, diligent postoperative follow‐up with consideration to recurrence of CBDS is essential.
Predictors of female American black bear body mass in an anthropogenic landscape
Authors: Nelson Shelley L. , Carr Patrick C. , McBride Anthony , Aubry Lise M. 
Published: March 2024

AbstractAnthropogenic pressure, such as urbanization and habitat loss, can wield many effects on wildlife that radiate through ecosystems. Large carnivores tend to experience these effects more severely than other species, diminishing their viability and altering ecosystem function by suppressing their role as an apex predator. Yet opportunistic carnivores that rely on an omnivorous diet can sometimes take advantage of anthropogenic food and improve their fitness prospects. We quantified the effect of phenotypic and ecological factors on female body mass of the American black bear (Ursus americanus) in New Jersey, USA. Habitat and reliable mast crops in New Jersey keep adult female black bear body mass and reproduction higher than many parts of the United States, and historically, female black bears in the mid‐Atlantic states tend to be larger than in other parts of their range. We used data collected from den surveys (n = 317) in northern New Jersey from 1984 to 2019 to examine the shared roles of climate, anthropogenic pressure (human food subsidies, harvest), habitat composition and configuration, natural food availability (hard mast production), and bear characteristics (age, history of human–black bear conflict) on female black bear body mass using generalized linear mixed models. Adult female body mass was heaviest with increased availability of cultivated crop and within low‐intensity developed land covers, suggesting anthropogenic food subsidies found in these 2 land cover types are contributing to female overall body mass. A history of conflict with humans explained heavier females, and a quadratic effect of age on body mass supported a senescent decline in adult female body mass later in life. Our results suggest that access to specific land cover types (i.e., crops, low‐intensity developments) that provide a diversity of food (e.g., corn, soft and hard mast) and support low human densities, explains female black bear body mass in a fragmented landscape.
Optimal subsidy policy for new energy vehicles based on the influence of multiple factors and consumers' green preference
Authors: Wang Yi , Zhang Zilu , Zhu Meihong 
Published: March 2024

AbstractPolicies concerning subsidies for new energy vehicles and consumers' environmental preferences significantly impact the sales of such vehicles. To investigate the correlation between sales and subsidies or consumers' environmental preferences and to devise optimal subsidy strategies, two Stackelberg game models are constructed based on both monopoly and duopoly markets, with solutions derived for Nash equilibrium points. In order to refine the strategy for subsidy adjustments, two dynamic adjustment models considering bounded rationality are established. Additionally, the process of adjusting subsidies towards Nash equilibrium points is analyzed. Simulations, utilizing actual research data, are performed to assess China's current adjustment strategies. The findings reveal a substitution relationship between consumers' environmental preferences and subsidies. Furthermore, optimal subsidy levels and bounded rational subsidy adjustment strategies are identified. Governments should thoroughly consider consumers' environmental preferences when refining subsidy policies, as it is a crucial factor influencing the development of the new energy vehicle industry.
The dynamics of the flavin, NADPH, and active site loops determine the mechanism of activation of class B flavin‐dependent monooxygenases
Authors: Pierdominici‐Sottile Gustavo , Palma Juliana , Ferrelli María Leticia , Sobrado Pablo 
Published: March 2024

AbstractFlavin‐dependent monooxygenases (FMOs) constitute a diverse enzyme family that catalyzes crucial hydroxylation, epoxidation, and Baeyer–Villiger reactions across various metabolic pathways in all domains of life. Due to the intricate nature of this enzyme family's mechanisms, some aspects of their functioning remain unknown. Here, we present the results of molecular dynamics computations, supplemented by a bioinformatics analysis, that clarify the early stages of their catalytic cycle. We have elucidated the intricate binding mechanism of NADPH and L‐Orn to a class B monooxygenase, the ornithine hydroxylase from known as SidA. Our investigation involved a comprehensive characterization of the conformational changes associated with the FAD (Flavin Adenine Dinucleotide) cofactor, transitioning from the out to the in position. Furthermore, we explored the rotational dynamics of the nicotinamide ring of NADPH, shedding light on its role in facilitating FAD reduction, supported by experimental evidence. Finally, we also analyzed the extent of conservation of two Tyr‐loops that play critical roles in the process.
Identifying the employment effect of county‐city merger in China
Authors: Liu Wenhua , Xie Ting 
Published: March 2024

AbstractThis paper draws upon a quasi‐natural experiment of county‐city mergers in China to examine whether state‐led urbanisation makes a difference in local labour markets. Based on the difference‐in‐differences framework and three waves of data from the China Household Finance Survey, we show that, on the urban fringe, residents' probability of working in nonagricultural sectors increased by 6.69 percentage points after the policy. Residents responded mainly by shifts from the agriculture sector to being self‐employed. The results indicate that, after fringe counties connect to the corresponding big city in substance, residents in peripheral areas could benefit from the positive spillover effect from large cities and gain employment.
A case of surgical treatment for bronchial foreign bodies with obstructive pneumonia
Authors: Yamashita Yuki , Ugajin Motoi , Yanoma Saki , Yamashita Masakatsu , Kani Hisanori 
Published: March 2024

AbstractChildren and older adults are prone to unintentional foreign body aspiration. A 69‐year‐old man with fever and anorexia presented with obstructive pneumonia resulting from foreign body aspiration. Attempts to remove the foreign body using a bronchoscope failed due to its adhesion to the periphery of the bronchus. Although antibiotic therapy did not improve the obstructive pneumonia caused by the bronchial foreign body, surgery enabled an improvement. The surgical specimen showed similar pathological findings as the fine brown granular material observed in root granulomas occurring as a complication following leakage of root canal filling used in the treatment of dental caries. Therefore, the bronchial foreign body may have been a dental filling. Case reports describing surgical improvement of difficult‐to‐remove bronchial foreign bodies with concurrent infection are rare.