bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted phage hunting to specificKlebsiella pneumoniaeclinical isolates is an efficient antibiotic resistance and infection control strategy
Authors: Ferriol-González Celia , Concha-Eloko Robby , Bernabéu-Gimeno Mireia , Fernández-Cuenca Felipe , Cañada-García Javier E. , García-Cobos Silvia , Sanjuán Rafael , Domingo-Calap Pilar 
Published: January 2024

AbstractKlebsiella pneumoniaeis one of the most threatening multi-drug resistant pathogens today, with phage therapy being a promising alternative for personalized treatments. However, the intrinsic capsule diversity inKlebsiellaspp. poses a substantial barrier to phage host range, complicating the development of broad-spectrum phage-based treatments. Here, we have isolated and genomically characterized phages capable of infecting each of the acquired 77 reference serotypes ofKlebsiellaspp.,including capsular types widespread among high-riskK. pneumoniaeclones causing nosocomial infections. We demonstrated the possibility of isolating phages for all capsular types in the collection, revealing high capsular specificity among taxonomically related phages, in contrast to a few phages that exhibited broad-spectrum infection capabilities. To decipher the determinants of the specificity of these phages, we focused on their receptor-binding proteins, with particular attention to depolymerase domains. We also explored the possibility of designing a broad-spectrum phage cocktail based on phages isolated in reference capsular type strains, and determining the ability to lysate relevant clinical isolates. Interestingly, a combination of 12 phages capable of infecting 60% of the referenceKlebsiellaspp. serotypes was tested on a panel of carbapenem-resistantK. pneumoniaeclinical isolates. Our results suggest that in a highly variable encapsulated bacterial host, phage hunting must be directed to the specificKlebsiellaisolates. This work is a step forward in the understanding of the complexity of phage-host interactions, and highlights the importance of implementing precise and phage-specific strategies to treatK. pneumoniaeinfections worldwide.
A spatial cell atlas of neuroblastoma reveals developmental, epigenetic and spatial axis of tumor heterogeneity
Authors: Patel Anand G. , Ashenberg Orr , Collins Natalie B. , Segerstolpe Åsa , Jiang Sizun , Slyper Michal , Huang Xin , Caraccio Chiara , Jin Hongjian , Sheppard Heather , Xu Ke , Chang Ti-Cheng , Orr Brent A. , Shirinifard Abbas , Chapple Richard H. , Shen Amber , Clay Michael R. , Tatevossian Ruth G. , Reilly Colleen , Patel Jaimin , Lupo Marybeth , Cline Cynthia , Dionne Danielle , Porter Caroline B.M. , Waldman Julia , Bai Yunhao , Zhu Bokai , Barrera Irving , Murray Evan , Vigneau Sébastien , Napolitano Sara , Wakiro Isaac , Wu Jingyi , Grimaldi Grace , Dellostritto Laura , Helvie Karla , Rotem Asaf , Lako Ana , Cullen Nicole , Pfaff Kathleen L. , Karlström Åsa , Jané-Valbuena Judit , Todres Ellen , Thorner Aaron , Geeleher Paul , Rodig Scott J. , Zhou Xin , Stewart Elizabeth , Johnson Bruce E. , Wu Gang , Chen Fei , Yu Jiyang , Goltsev Yury , Nolan Garry P. , Rozenblatt-Rosen Orit , Regev Aviv , Dyer Michael A. 
Published: January 2024

SUMMARYNeuroblastoma is a pediatric cancer arising from the developing sympathoadrenal lineage with complex inter- and intra-tumoral heterogeneity. To chart this complexity, we generated a comprehensive cell atlas of 55 neuroblastoma patient tumors, collected from two pediatric cancer institutions, spanning a range of clinical, genetic, and histologic features. Our atlas combines single-cell/nucleus RNA-seq (sc/scRNA-seq), bulk RNA-seq, whole exome sequencing, DNA methylation profiling, spatial transcriptomics, and two spatial proteomic methods. Sc/snRNA-seq revealed three malignant cell states with features of sympathoadrenal lineage development. All of the neuroblastomas had malignant cells that resembled sympathoblasts and the more differentiated adrenergic cells. A subset of tumors had malignant cells in a mesenchymal cell state with molecular features of Schwann cell precursors. DNA methylation profiles defined four groupings of patients, which differ in the degree of malignant cell heterogeneity and clinical outcomes. Using spatial proteomics, we found that neuroblastomas are spatially compartmentalized, with malignant tumor cells sequestered away from immune cells. Finally, we identify spatially restricted signaling patterns in immune cells from spatial transcriptomics. To facilitate the visualization and analysis of our atlas as a resource for further research in neuroblastoma, single cell, and spatial-omics, all data are shared through the Human Tumor Atlas Network Data Commons atwww.humantumoratlas.org.
Linkers in bitopic agonists shape bias profile among transducers for the dopamine D2 and D3 receptors
Authors: Semeano Ana , Garland Rian , Bonifazi Alessandro , Lee Kuo Hao , Famiglietti John , Zhang Wenqi , Jo Yoon Jae , Battiti Francisco O. , Shi Lei , Newman Amy Hauck , Yano Hideaki 
Published: January 2024

AbstractBitopic ligands bind both orthosteric and allosteric or secondary binding sites within the same receptor, often resulting in improvement of receptor selectivity, potency, and efficacy. In particular, for both agonists and antagonists of the dopamine D2 and D3 receptors (D2R and D3R), the primary therapeutic targets for several neurological and neuropsychiatric disorders, bitopic ligand design has proved advantageous in achieving better pharmacological profilesin vitro. Although the two pharmacophores within a bitopic ligand are typically considered the main drivers of conformational change for a receptor, the role of the linker that connects the two has not yet been systematically studied for its relevance in receptor activity profiles.Here, we present a comprehensive analysis of sumanirole and PF592,379-based indole-containing bitopic compounds in agonist activity at D2R and D3R, with a focus on linker chemical space and stereochemistry achieved through testing seven distinct chirally resolved linkers. The current study examines the structure activity relationships (SAR) of these linkers extensively, beyond the conventional level, by characterizing activation of all putative transducers over a 44 min time course. Our multiparametric analysis provides previously unappreciated clarity of linker-dependent effects, highlighting the utility of this applied comprehensive approach and the significance of linker type in the shaping of transducer bias profiles.
A pathologically expanded, clonal lineage of IL-21 producing CD4+ T cells drives Inflammatory neuropathy
Authors: Seyedsadr Maryamsadat , Bang Madison , McCarthy Ethan , Zhang Shirley , Chen Ho-Chung , Mohebbi Mahnia , Hugo Willy , Whitmire Jason K. , Lechner Melissa G. , Su Maureen A. 
Published: January 2024

AbstractInflammatory neuropathies, which include CIDP (chronic inflammatory demyelinating polyneuropathy) and GBS (Guillain Barre Syndrome), result from autoimmune destruction of the peripheral nervous system (PNS) and are characterized by progressive weakness and sensory loss. CD4+ T cells play a key role in the autoimmune destruction of the PNS. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood. Here, we use paired scRNAseq and scTCRseq of peripheral nerves from an inflammatory neuropathy mouse model to identify IL-21 expressing CD4+ T cells that are clonally expanded and multifunctional. These IL-21-expressing CD4+ T cells are comprised of two transcriptionally distinct expanded populations, which express genes associated with Tfh and Tph subsets. Remarkably, TCR clonotypes are shared between these two IL-21-expressing populations, suggesting a common lineage differentiation pathway. Finally, we demonstrate that IL-21 signaling is required for neuropathy development and pathogenic T cell infiltration into peripheral nerves. IL-21 signaling upregulates CXCR6, a chemokine receptor that promotes CD4+ T cell localization in peripheral nerves. Together, these findings point to IL-21 signaling, Tfh/Tph differentiation, and CXCR6-mediated cellular localization as potential therapeutic targets in inflammatory neuropathies.
MATE-Pred: Multimodal Attention-based TCR-Epitope interaction Predictor
Authors: Goffinet Etienne , Mall Raghvendra , Singh Ankita , Kaushik Rahul , Castiglione Filippo 
Published: January 2024

AbstractAn accurate binding affinity prediction between T-cell receptors and epitopes contributes decisively to develop successful immunotherapy strategies. Some state-of-the-art computational methods implement deep learning techniques by integrating evolutionary features to convert the amino acid residues of cell receptors and epitope sequences into numerical values, while some other methods employ pre-trained language models to summarize the embedding vectors at the amino acid residue level to obtain sequence-wise representations. Here, we propose a highly reliable novel method, MATE-Pred, that performs multi-modal attention-based prediction of T-cell receptors and epitopes binding affinity. The MATE-Pred is compared and benchmarked with other deep learning models that leverage multi-modal representations of T-cell receptors and epitopes. In the proposed method, the textual representation of proteins is embedded with a pre-trained bi-directional encoder model and combined with two additional modalities: a) a comprehensive set of selected physicochemical properties; b) predicted contact maps that estimate the 3D distances between amino acid residues in the sequences. The MATE-Pred demonstrates the potential of multi-modal model in achieving state-of-the-art performance (+8.4% MCC, +5.5% AUC compared to baselines) and efficiently capturing contextual, physicochemical, and structural information from amino acid residues. The performance of MATE-Pred projects its potential application in various drug discovery regimes.
Risking your Tail: Modeling Individual Differences in Risk-sensitive Exploration using Bayes Adaptive Markov Decision Processes
Authors: Shen Tingke , Dayan Peter 
Published: January 2024

AbstractNovelty is a double-edged sword for agents and animals alike: they might benefit from untapped resources or face unexpected costs or dangers such as predation. The conventional exploration/exploitation tradeoff is thus coloured by risk-sensitivity. A wealth of experiments has shown how animals solve this dilemma, for example using intermittent approach. However, there are large individual differences in the nature of approach, and modeling has yet to elucidate how this might be based on animals’ differing prior expectations about reward and threat, and differing degrees of risk aversion. To capture these factors, we built a Bayes adaptive Markov decision process model with three key components: an adaptive hazard function capturing potential predation, an intrinsic reward function providing the urge to explore, and a conditional value at risk (CVaR) objective, which is a contemporary measure of trait risk-sensitivity. We fit this model to a coarse-grain abstraction of the behaviour of 26 animals who freely explored a novel object in an open-field arena (Akiti et al.Neuron110, 2022). We show that the model captures both quantitative (frequency, duration of exploratory bouts) and qualitative (stereotyped tail-behind) features of behavior, including the substantial idiosyncrasies that were observed. We find that “brave” animals, though varied in their behavior, are generally more risk neutral, and enjoy a flexible hazard prior. They begin with cautious exploration, and quickly transition to confident approach to maximize exploration for reward. On the other hand, “timid” animals, characterized by risk aversion and high and inflexible hazard priors, display self-censoring that leads to the sort of asymptotic maladaptive behavior that is often associated with psychiatric illnesses such as anxiety and depression. Explaining risk-sensitive exploration using factorized parameters of reinforcement learning models could aid in the understanding, diagnosis, and treatment of psychiatric abnormalities in humans and other animals.
Proteome profiling of cutaneous leishmaniasis lesions due to dermotropicLeishmania donovaniin Sri Lanka
Authors: Manamperi Nuwani H. , Edirisinghe Nimesha Madhushani , Wijesinghe Harshima , Pathiraja Lakmali , Pathirana Nishantha , Wanasinghe Vishmi Samudika , de Silva Chamalka Gimhani , Abeyewickreme W. , Karunaweera Nadira D. 
Published: January 2024

AbstractCharacterization of the host response in cutaneous leishmaniasis (CL) through proteome profiling has gained limited insights in leishmaniasis research, in comparison to that of the parasite. The primary objective of this study was to comprehensively analyze the proteomic profile of the skin lesions tissues in patients with CL, by mass spectrometry, and subsequent validation of these findings through immunohistochemical methods. Sixty-seven proteins exhibited significant differential expression between tissues of CL lesions and healthy controls (p<0.01), representing numerous enriched biological processes within the lesion tissue, as evident by both the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. Among these, the integrated endoplasmic reticulum stress response (IERSR) emerges as a pathway characterized by the up-regulated proteins in CL tissues compared to healthy skin. Expression of endoplasmic reticulum (ER) stress sensors, inositol-requiring enzyme-1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6) in lesion tissue was validated by immunohistochemistry. In conclusion, proteomic profiling of skin lesions carried out as a discovery phase study revealed a multitude of probable immunological and pathological mechanisms operating in patients with CL in Sri Lanka, which needs to be further elaborated using more in-depth and targeted investigations.Author SummaryCutaneous leishmaniasis (CL), is a skin infection caused by a type of single-celled parasite. These parasites are usually transmitted through the bite of infected sandflies. In Sri Lanka, CL is caused by a parasite type that usually causes a more severe disease form, known as visceral leishmaniasis. Interaction between the parasite and the human host is important in determining the disease outcome and hence, we conducted a study to look at the proteins in the skin lesions of people with CL using a technique called mass spectrometry. We found 67 proteins that were different between CL lesions and healthy skin. These proteins are involved in various processes in the body, and one specific process called the integrated endoplasmic reticulum stress response (IERSR) was more active in CL patients. We confirmed this by studying specific proteins related to stress in the lesion tissue. In conclusion, our study uncovered several potential immune and disease-related mechanisms in CL patients in Sri Lanka. However, more detailed investigations are needed to fully understand these processes.
Recognition and localization of maize leaves in RGB images based on Point-Line Net
Authors: Liu Bingwen , Chang Jianye , Hou Dengfeng , Li Dengao , Ruan Jue 
Published: January 2024

AbstractPlant phenotype detection plays a crucial role in understanding and studying plant biology, agriculture, and ecology. It involves the quantification and analysis of various physical traits and characteristics of plants, such as plant height, leaf shape, angle, number, and growth trajectory. By accurately detecting and measuring these phenotypic traits, researchers can gain insights into plant growth, development, stress tolerance, and the influence of environmental factors. Among these phenotypic information, the number of leaves and growth trajectory of the plant are more accessible. Nonetheless, obtaining these information is labor-intensive and financially demanding. With the rapid development of computer vision technology and artificial intelligence, using maize field images to fully analyze plant-related information such as growth trajectory and number of leaves can greatly eliminate repetitive labor work and enhance the efficiency of plant breeding. However, the application of deep learning methods still faces challenges due to the serious occlusion problem and complex background of field plant images. In this study, we developed a deep learning method called Point-Line Net, which is based on the Mask R-CNN frame-work, to automatically recognize maize field images and determine the number and growth trajectory of leaves and roots. The experimental results demonstrate that the object detection accuracy (mAP) of our Point-Line Net can reach 81.5%. Moreover, to describe the position and growth of leaves and roots, we introduced a new lightweight “keypoint” detection branch that achieved 33.5 using our custom distance verification index. Overall, these findings provide valuable insights for future field plant phenotype detection, particularly for the datasets with dot and line annotations.
Self-balanced regulation by the long non-coding RNALockdon the cell cycle progression of cortical neural progenitor cells through counteractingcisandtransroles
Authors: Qi Shaojun , Zheng Jiangli , Shen Qin 
Published: January 2024

AbstractNeural stem/progenitor cells (NSPCs) undergo active proliferation and exit the cell cycle upon precise regulation to produce differentiated progenies in order. Long non-coding RNAs (lncRNAs) have emerged as critical players in the developmental processes of NSPCs; however, relatively few have been shown to regulate the cell cyclein vivodirectly. Here, we identified an NSPC-expressed lncRNALockd(lncRNA downstream ofCdkn1b) in the developing forebrain. Usingin vivoloss of function models by premature termination ofLockdtranscription via knockin polyadenylation signals or shRNA-mediated knockdown ofLockd(Lockd-KD), we show thatLockdis required for proper cell cycle progression of cortical NSPCs and the production of TBR2+intermediate neural progenitor cells during cortical development. Interestingly, a comparison of genetic profiling in the two models reveals thatLockdpromotes the expression of two counteracting cell cycle-related genes,Cdkn1b in cisandCcnd1 in trans. Overexpression ofCcnd1orCdkn1b-KD can rescue the cellular phenotypes of reduced cycling progenitors inLockd-KD. Our results imply that lncRNA could act through distinctcisandtransmechanisms to achieve a self-balanced function.
IN VITRO5-LOX INHIBITORY POTENTIAL AND ANTIOXIDANT ACTIVITY OF NEW ISOXAZOLE DERIVATIVES
Authors: Alam Waqas , Khan Haroon , Jan Muhammad Saeed , Daglia Maria 
Published: January 2024

ABSTRACT5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors are highly attractive. In this research the previously synthesized isoxazole derivatives has been investigated against 5-Lox inhibitory and antioxidant in vitro assay. The percent inhibition forC3were 89.93±1.73, 85.94±0.91, 81.90±1.32, 77.51±0.59 and 74.80±1.41 at various concentrations with IC50of 8.47 µM. The investigated compoundsC5also exhibited good 5-LOX inhibitory effect. The non-significant percent inhibition forC5were demonstrated as 91.30±1.42, 87.78±0.45, 84.44±0.86, 79.72±1.89 and 75.29±1.64 at various concentration (1000-62.5 µg/ml). The IC50demonstrated forC5was 10.48. Among the 10 synthesized compounds, the potential 5-LOX inhibitory effect was reported forC6. The most potent compound which showed excellent free radical scavenging effect wasC3with different percent inhibitions of 92.51±0.62, 87.65±0.70, 82.25±0.55, 79.37±0.69 and 75.72±0.51 having IC50value of 10.96 µM. The next most potent antioxidant activity was reported forC5which non-significantly showed free radical scavenging effect. The DPPH percent inhibition reported forC5was 92.63±0.64, 88.45±0.55, 83.53±0.41, 79.42±0.46 and 76.10±0.64 at different ranges of (1000, 500, 250, 125 and 62.5 µg/mL) concentrations, respectively. The IC50value observed forC5was 13.12 µM. CompoundC6also showed potent dose dependent antioxidant effect with IC50value of 18.87 µM having percent inhibition of 91.63±0.55, 88.45±0.49, 83.53±0.45, 78.42±0.66 and 73.72±0.64 at concentration 1000-62.5 µg/mL respectively.Among the tested compounds,C6was found most potent which showed significant 5-LOX percent inhibition assay and also reported the minimum IC50value comparable to the reference drug. Thein vitro5-Lox enzymes inhibition assays ofC5andC3also showed non-significant percent inhibition and good potency next toC6. We concluded that amongst the investigated designed molecules theC3was found best potent and showed significant dose dependent antioxidant activity against DPPH screening. The IC50value reported forC3was found good as compared to standard drug. Moreover,C5andC6also showed excellent free radical scavenging effect against DPPH assay.
Mathematical model for rod outer segment dynamics during retinal detachment and reattachment
Authors: Annan William Ebo , Asamani Emmanuel O.A. , White Diana 
Published: January 2024

AbstractRetinal detachment (RD) is the separation of the neural layer from the retinal pigmented epithelium thereby preventing the supply of nutrients to the cells within the neural layer of the retina. In vertebrates, primary photoreceptor cells consisting of rods and cones undergo daily renewal of their outer segment through the addition of disc-like structures and shedding of these discs at their distal end. When the retina detaches, the outer segment of these cells begins to degenerate and, if surgical procedures for reattachment are not done promptly, the cells can die and lead to blindness. The precise effect of RD on the renewal process is not well understood. Additionally, a time frame within which reattachment of the retina can restore proper photoreceptor cell function is not known. Focusing on rod cells, we propose a mathematical model to clarify the influence of retinal detachment on the renewal process. Our model simulation and analysis suggest that RD stops or significantly reduces the formation of new discs and that an alternative removal mechanism is needed to explain the observed degeneration during RD. Sensitivity analysis of our model parameters points to the disc removal rate as the key regulator of the critical time within which retinal reattachment can restore proper photoreceptor cell function.
Roles of the
Tcs¯0(2900)0
and
D0*(2300)
in the process
B−→Ds+K−π−
Authors: Lyu Wen-Tao , Lyu Yun-He , Duan Man-Yu , Li De-Min , Chen Dian-Yong , Wang En 
Published: January 2024

Motivated by the recent LHCb observations of Tcs¯0(2900)0 and Tcs¯0(2900)++ in the processes B0→D¯0Ds+π− and B+→D−Ds+π+, we have investigated the decay B−→Ds+K−π− by taking into account the contributions from the S-wave vector-vector interactions, and the S-wave Ds+K− interactions. Our results show that the Ds+K− invariant mass distribution has an enhancement structure near the threshold, associated with the D0*(2300), which is in good agreement with the Belle measurements. We have also predicted the Ds+π− invariant mass distribution and the Dalitz plot, which show the significant signal of the Tcs¯0(2900). With the same formalism, the Ds−Ks0 invariant mass distribution of the process B0→Ds−Ks0π+ measured by Belle could be well reproduced, and the peak of Tcs¯0(2900) is expected to be observed around 2900 MeV in the Ds−π+ invariant mass distribution. Our results could be tested by the Belle II and LHCb experiments in the future.

Published by the American Physical Society
2024