bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Mouse Model forLAMA2-Related Muscular Dystrophy: Analysis of Molecular Pathogenesis and Clinical Phenotype
Authors: Tan Dandan , Liu Yidan , Luo Huaxia , Shen Qiang , Long Xingbo , Xu Luzheng , Liu Jieyu , Zhong Nanbert , Zhang Hong , Xiong Hui
Published: January 2024

Our understanding of the molecular pathogenesis ofLAMA2-related muscular dystrophy (LAMA2-MD) requires improving. Here, we report the phenotype, neuropathology and transcriptomics data (scRNA-seq and bulk RNA-seq) of a newLama2knockout mouse (dyH/dyH) which was created based on the humanLAMA2-MD mutation hotspot region using CRISPR-Cas9. The dyH/dyHmice presented severe phenotype with muscular dystrophy. Mouse brain scRNA-seq showed thatLama2gene was expressed predominantly and specifically in vascular and leptomeningeal fibroblasts and vascular smooth muscle cells, and weakly in astrocytes in wild-type mouse. Laminin α2 expression on the cortical surface was observed with immunofluorescence. In dyH/dyH,Lama2expression was decreased in those cell types, which might be associated with the disruption of gliovascular basal lamina assembly. Additionally, transcriptomic investigation of muscles showed 2020 differentially expressed genes, mainly associated with the impaired muscle cytoskeleton and development. In summary, this study provided potentially useful information for understanding the molecular pathogenesis ofLAMA2-MD.
Morphological Reprogramming of Primary Cilia Length Mitigates the Fibrotic Phenotype in Fibroblasts Across Diverse Fibrotic Conditions
Authors: Verma Priyanka , Yalavarthi Bharat , Bhattacharyya Swati , Khanna Dinesh , Gudjonsson Johann E. , Tsoi Lam C. , Wells Rebecca , Ross Rebecca L , Galdo Natalia Riobo-Del , Galdo Francesco Del , Fortier Sean M. , Teves Maria E. , Varga John , Bhattacharyya Dibyendu
Published: January 2024

Fibrosis is a hallmark of systemic sclerosis (SSc) and many diverse and incurable diseases. Myofibroblast activation, a common cellular phenomenon shared across fibrotic diseases, is marked by actin polymerization known to affect primary cilia (PC) length. We discovered that fibroblasts from diverse fibrotic conditions display significantly reduced PC lengthex vivo.Treatment of healthy fibroblasts with profibrotic TGF-β1 induced PC shortening, while silencingACTA2in SSc skin fibroblasts caused PC elongation. Importantly, we found that PC length is negatively correlated with cellular expression of α-SMA in TGF-β1-stimulated healthy fibroblasts, or pharmacologically de-differentiated myofibroblasts. PC elongation by microtubule polymerization induction in SSc skin fibroblasts using LiCl or the HDAC6 inhibitor tubacin, reversed and mitigated fibrotic responses. Our results implicate a key role for microtubule polymerization in restraining fibrotic responses and suggest that modulation of PC dynamics may represent a potential therapeutic strategy for SSc and other treatment-resistant diseases associated with fibrosis.

Teaser.PC length shortening is a hallmark of fibrosis.
Dynamic parallel transmit diffusion MRI at 7T
Authors: Zhang Minghao , Ding Belinda , Dragonu Iulius , Liebig Patrick , Rodgers Christopher T.
Published: January 2024

Diffusion MRI (dMRI) is inherently limited by SNR. Scanning at 7T increases intrinsic SNR but 7T MRI scans suffer from regions of signal dropout, especially in the temporal lobes and cerebellum. We applied dynamic parallel transmit (pTx) to allow whole-brain 7T dMRI and compared with circularly polarized (CP) pulses in 6 subjects.

Subject-specific 2-spoke dynamic pTx pulses were designed offline for 8 slabs covering the brain. We used vendor-provided B0and B1+mapping. Spokes positions were set using the Fourier difference approach, and RF coefficients optimized with a Jacobi-matrix high-flip-angle optimizer. Diffusion data were analyzed with FSL.

Comparing whole-brain averages for pTx against CP scans: mean flip angle error improved by 15% for excitation (2-spoke-VERSE 15.7°vsCP 18.4°,P=0.012) and improved by 14% for refocusing (2-spoke-VERSE 39.7°vsCP 46.2°,P=0.008). Computed spin-echo signal standard deviation improved by 14% (2-spoke-VERSE 0.185 vs 0.214 CP,P=0.025). Temporal SNR increased by 5.4% (2-spoke-VERSE 8.47vsCP 8.04, P=0.004) especially in the inferior temporal lobes. Diffusion fitting uncertainty decreased by 6.2% for first fibres (2-spoke VERSE 0.0655 vs CP 0.0703,P<0.001) and 1.3% for second fibers (2-spoke VERSE 0.139vsCP 0.141,P=0.01). In conclusion, dynamic parallel transmit improves the uniformity of 7T diffusion-weighted imaging. In future, less restrictive SAR limits for parallel transmit scans are expected to allow further improvements.
Neural and behavioral dynamics of encoding, production and synchronization with external rhythms in subcortical lesion patients
Authors: Criscuolo Antonio , Schwartze Michael , Nozaradan Sylvie , Kotz Sonja A.
Published: January 2024

Acting in and adapting to a dynamically changing environment necessitates precise encoding of thetimingof unfolding sensory events in our environment, and totimeof our own (re-)actions to them. Cerebellar (CE) and basal ganglia (BG) circuitries play fundamental and complementary roles in timing processes. While the CE seems to encode the precise timing of sensory events (whenan event occurs), the BG engage in generating temporal predictions (whena next event occurs). However, their contributions are rarely investigated in combination, as it is generally difficult to record data from respective patient groups in parallel.

Here we investigated the causal roles of CE and BG in sensory and sensorimotor timing processes. Healthy controls and patients with CE or BG lesions listened to isochronous auditory sequences while their EEG was recorded and later performed a tapping synchronization task. We assessed intra- and inter-individual variabilities, as well as group differences, using event-related responses, delta-band inter-trial phase-coherence and acceleration dynamics while tuning to the stimulation frequency (Sf). CE and BG lesions increased variability in ERP latency and reduced the coherence of delta-band activity. CE but not BG lesions further impacted the stability of delta-band oscillations while tuning to theSf. These findings show a causal link between subcortical lesions and the capacity to encode and synchronize ongoing neural activity with temporal regularities in the acoustic environment, but do not fully dissociate the specific contributions of the BG and the CE to processing sound in isochronous contexts.
The cervical and meningeal lymphatic network as a pathway for retrograde nanoparticle transport to the brain
Authors: Ramos-Zaldívar Héctor M , Polakovicova Iva , Salas-Huenuleo Edison , Yefi Claudia P , Silva David , Jara-Guajardo Pedro , Oyarzún Juan Esteban , Neira-Troncoso Álvaro , Burgos Patricia V. , Cavieres Viviana A. , Arias-Muñoz Eloisa , Martínez Carlos , Riveros Ana L. , Corvalán Alejandro H , Kogan Marcelo J , Andia Marcelo E
Published: January 2024

The meningeal lymphatic vessels have been described as a pathway that transports cerebrospinal fluid and interstitial fluid in a unidirectional manner towards the deep cervical lymph nodes. However, these vessels exhibit anatomical and molecular characteristics typical of initial lymphatic vessels, with the absence of surrounding smooth muscle and few or absent valves. Given its structure, this network could theoretically allow for bidirectional motion. Nevertheless, it has not been assessed as a potential route for nanoparticles to travel from peripheral tissues to the brain. Here we show that extracellular vesicles derived from the B16F10 melanoma cell line, along with superparamagnetic iron oxide nanoparticles, gold nanorods, and Chinese ink nanoparticles can reach the meningeal lymphatic vessels and the brain of C57BL/6 mice after administration within deep cervical lymph nodesin vivo,exclusively through lymphatic structures. Since the functional anatomy of dural lymphatics has been found to be conserved between mice and humans, we expect that our results will encourage further research into the retrograde motion of nanoparticles towards the brain for pharmacological purposes in nanomedicine, as well as to better understand the fluid dynamics in different physiological or neuropathological conditions.
Impact of perinatal maternal docosahexaenoic acid-containing phospholipid synthesis on offspring growth and neurological symptoms
Authors: Kanatani Ayumi , Hishikawa Daisuke , Nagata Katsuyuki , Hamano Fumie , Nakano Kenta , Okamura Tadashi , Shimizu Takao , Shindou Hideo , Nagamatsu Takeshi , Yanagida Keisuke
Published: January 2024

Mothers provide essential nutrients, including docosahexaenoic acid (DHA), an omega-3 fatty acid, during the perinatal period. DHA deficiency in perinatal mothers is linked to developmental abnormalities, especially in the central nervous system of the offspring; however, its specific impact on distinct events in fetal and neonatal brain development and prospective brain functions remains incompletely understood. We demonstrated using mice lackingAgpat3, a gene encoding the enzyme that synthesizes DHA-containing phospholipids (DHA-PLs), that maternal DHA-PL synthesis significantly contributes to the maternal– offspring DHA supply during the fetal period but not in infancy. Selective modulation of DHA-PL levels during fetal and postnatal periods inAgpat3-knockout mice showed that fetal stage-specific insufficiency in maternal DHA-PL supply potentially influences the neuropsychiatric phenotype in adult mice without affecting postnatal tissue DHA-PL levels, weight gain, and brain expansion. Collectively, enhancing maternal DHA-PL synthesis during pregnancy may help prevent prospective neuropsychiatric abnormalities in the offspring.
Psilocybin Promotes Cell-Type-Specific Changes in the Orbitofrontal Cortex Revealed by Single-Nucleus RNA-seq
Authors: Huang Ziran , Wei Xiaoyan , Wang Yihui , Tian Jing , Dong Jihui , Liang Bo , Lu Lin , Zhang Wen
Published: January 2024

Recent clinical breakthroughs hold great promise for the application of psilocybin in the treatments of psychological disorders, such as depression, addiction, and obsessive-compulsive disorder. Psilocybin is a psychedelic whose metabolite, psilocin, is a 5-HT2Areceptor agonist. Nevertheless, the underlying mechanisms for the effects of psilocybin on the brain are not fully illustrated, and cell type-specific and circuit effects of psilocybin are not fully understood. Here, we combined single-nucleus RNA-seq with functional assays to study the long-term effects of psilocybin on the orbitofrontal cortex (OFC), a brain region vulnerable to psychological disorders such as depression. We showed that a single dose of psilocybin induced long-term genetic and functional changes in neurons of the OFC, and excitatory and inhibitory neurons collectively reduced circuit activity of the brain region. Knockdown of 5-HT2Areceptor in deep layer excitatory neurons abated psilocybin-induced functional changes and the anti-depressant effect. Together, these results showed the cell type-specific mechanisms of psilocybin and shed light on the brain region difference in the effect of psychedelics.
Concerted neuron-astrocyte gene expression declines in aging and schizophrenia
Authors: Ling Emi , Nemesh James , Goldman Melissa , Kamitaki Nolan , Reed Nora , Handsaker Robert E. , Genovese Giulio , Vogelgsang Jonathan S. , Gerges Sherif , Kashin Seva , Ghosh Sulagna , Esposito John M. , French Kiely , Meyer Daniel , Lutservitz Alyssa , Mullally Christopher D. , Wysoker Alec , Spina Liv , Neumann Anna , Hogan Marina , Ichihara Kiku , Berretta Sabina , McCarroll Steven A.
Published: January 2024

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a striking relationship between people’s cortical neurons and cortical astrocytes. We used single-nucleus RNA-seq to analyze the prefrontal cortex of 191 human donors ages 22-97 years, including healthy individuals and persons with schizophrenia. Latent-factor analysis of these data revealed that in persons whose cortical neurons more strongly expressed genes for synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the Synaptic Neuron- and-Astrocyte Program (SNAP). In schizophrenia and aging – two conditions that involve declines in cognitive flexibility and plasticity1,2– cells had divested from SNAP: astrocytes, glutamatergic (excitatory) neurons, and GABAergic (inhibitory) neurons all reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy persons of similar age, may underlie many aspects of normal human interindividual differences and be an important point of convergence for multiple kinds of pathophysiology.
Effect of Pressure on the Conformational Landscape of HumanγD-crystallin from Replica Exchange Molecular Dynamics Simulations
Authors: Kacirani Arlind , Uralcan Betül , Domingues Tiago S. , Haji-Akbari Amir
Published: January 2024

HumanγD-crystallin belongs to a crucial family of proteins known as crystallins located in fiber cells of the human lens. Since crystallins do not undergo any turnover after birth, they need to possess remarkable thermodynamic stability. However, their sporadic misfolding and aggregation, triggered by environmental perturbations or genetic mutations, constitute the molecular basis of cataracts, which is the primary cause of blindness in the globe according to the World Health Organization. Here, we investigate the impact of high pressure on the conformational landscape of the wild-type HγD-crystallin using replica exchange molecular dynamics simulations augmented with principal component analysis. We find pressure to have a modest impact on global measures of protein stability, such as root mean square displacement and radius of gyration. Upon projecting our trajectories along the first two principal components from Pca, however, we observe the emergence of distinct free energy basins at high pressures. By screening local order parameters previously shown or hypothesized as markers of HγD-crystallin stability, we establish correlations between a tyrosine-tyrosine aromatic contact within the N-terminal domain and the protein’s end-to-end distance with projections along the first and second principal components, respectively. Furthermore, we observe the simultaneous contraction of the hydrophobic core and its intrusion by water molecules. This exploration sheds light on the intricate responses of HγD-crystallin to elevated pressures, offering insights into potential mechanisms underlying its stability and susceptibility to environmental perturbations, crucial for understanding cataract formation.
Tolerance thresholds underlie responses to DNA damage during germline development
Authors: Jansen Gloria , Gebert Daniel , Kumar Tharini Ravindra , Simmons Emily , Murphy Sarah , Teixeira Felipe Karam
Published: January 2024

Selfish DNA modules like transposable elements (TEs) are particularly active in the germline, the lineage that passes genetic information across generations. New TE insertions can disrupt genes and impair the functionality and viability of germ cells. However, we find that inP-Mhybrid dysgenesis inDrosophila, a sterility syndrome triggered by theP-element DNA transposon, germ cells harbour unexpectedly few new TE insertions, despite accumulating DNA double-strand breaks (DSBs) and inducing cell cycle arrest. Using an engineered CRISPR-Cas9 system, we show that generating DSBs at silencedP-elements or other non-coding sequences is sufficient to induce germ cell loss independently of gene disruption. Indeed, we demonstrate that both developing and adult mitotic germ cells are sensitive to DSBs in a dosage-dependent manner. Following the mitotic-to-meiotic transition, however, germ cells become more tolerant to DSBs, completing oogenesis regardless of the accumulated genome damage. Our findings establish DNA damage tolerance thresholds as crucial safeguards of genome integrity during germline development.
Strata use in a canopy-beetle community of a lowland Neotropical rainforest in southern Venezuela
Authors: Kirmse Susan
Published: January 2024

The stratification in tropical rainforests is well pronounced. This strongly impacts the distribution of arthropods. As part of a larger beetle survey in the northern part of the Amazonian rainforest, I analyze the characteristics of beetle species shared between the canopy and the understory. Linking the strata use of adult beetles in the complex structure of tropical rainforests with their ecological characteristics may uncover causes of the differences in diversity between vertical layers. Seventy out of a total of 862 beetle species in 45 families sampled on 23 canopy-tree species were collected also in the understory. Beetle families represented with most species in the canopy and ground samples comprise Curculionidae, Chrysomelidae, and Carabidae. In Elateridae and Scarabaeidae, the proportion of shared species between both strata amounted to ≥ 20%. In contrast, the species-rich families (≥ 20 canopy species) Cerambycidae, Mordellidae, and Buprestidae did not comprise species sampled in both strata. Adult feeding requirements and larval substrates are discussed as main reasons for the differences in strata use between these beetle families. In addition, different climatic conditions between the exposed canopy and the more uniform understory might cause a migration of adult beetles between both strata and thus, result in intermixing of beetle species from different strata within the forest.
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

Klebsiella 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

Neuroblastoma 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

Bitopic 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

Inflammatory 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

An 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

Novelty 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

Characterization 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 Summary

Cutaneous 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

Plant 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

Neural 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

5-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

Retinal 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.
Heavy quark drag and diffusion coefficients in the prehydrodynamic QCD plasma
Authors: Du Xiaojian
Published: January 2024

Kinetic and chemical equilibrations play important roles in the formation of the quark-gluon plasma (QGP) in relativistic heavy-ion collisions (HICs). These processes further influence the production of hard and electromagnetic probes in HICs, in particular, the thermalization of heavy quarks, which are produced at an extremely early time before the formation of the QGP. I calculate the drag and diffusion coefficients of heavy quarks in the prehydrodynamic quantum chromodynamic (QCD) plasma with the state-of-the-art QCD effective kinetic theory (EKT) solver. The time, momentum, and angular dependencies of these coefficients for gluon and quark contributions are presented separately, showing the effects of isotropization and chemical equilibration from the QCD plasma. I also provide a simple formula to estimate the heavy quark drag and diffusion coefficients, as well as its energy loss, within the prehydrodynamic plasma at different coupling strengths based on the attractor theory. Finally, I discuss the validity of these estimations with leading-order calculations and leading-logarithmic rescaling factors.

Published by the American Physical Society
2024
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
Exclusive production of
Tcc−
in hadron-hadron ultraperipheral collisions
Authors: Wang Xiaopeng , Xie Yaping , Huang Yin , Chen Xurong
Published: January 2024

Understanding the production mechanisms and utilizing them as probes to investigate the structure of exotic states represent some of the most actively studied research areas in particle physics. In this study, we present a theoretical analysis of the charmed meson Tcc− in the γp→D+Tcc−Λc+ and γγ→D+Tcc−D*0 reactions, considering Tcc+ as a DD* molecule. The differential cross section and total cross section for the photoproduction of Tcc− in the

γ

p

→

D

+

T

c

c

−

Λ

c

+

and γγ→D+Tcc−D*0 reactions are presented for nucleus-nucleus (nucleon-nucleon) ultraperipheral collisions at HL-LHC and RHIC, respectively. Taking into account the integrated luminosity per typical run and the luminosity of photons from the nucleus (nucleon), we observe a significant event count for Tcc− production in p−p ultraperipheral collisions at HL-LHC.

Published by the American Physical Society
2024
Spectroscopically resolved resonant interatomic Coulombic decay in photoexcited large He nanodroplets
Authors: Ben Ltaief L. , Sishodia K. , Richter R. , Bastian B. , Asmussen J. D. , Mandal S. , Pal N. , Medina C. , Krishnan S. R. , von Haeften K. , Mudrich M.
Published: January 2024

Interatomic Coulombic decay (ICD) processes play a crucial role in weakly bound complexes exposed to intense or high-energy radiation. Using large helium nanodroplets, we demonstrate that ICD is efficient even when the droplets are irradiated by weak synchrotron radiation at relatively low photon energies. Below the ionization threshold, resonant excitation of multiple centers efficiently induces resonant ICD as previously observed for intense pulses [A. C. LaForge , ]. More surprisingly, we observe ICD even above the ionization threshold due to recombination of photoelectrons and ions into excited states which subsequently decay by ICD. This demonstrates the importance of secondary processes, in particular electron scattering and recombination, in inducing ICD in extended condensed phase systems. High-resolution ICD electron spectra in combination with coincidence imaging of electrons and ions reveal the relaxation dynamics of highly excited and ionized weakly bound nanosystems.

Published by the American Physical Society
2024
Magnon-magnon coupling mediated by topological edge states
Authors: Pan H. , An Z. H. , Hu C.-M.
Published: January 2024

The topology of the photonic bath shows excellent potential to engineer the intriguing interaction properties between light and matter. Here, we study the dielectric resonator array with a zigzag geometry, an analogy of the Su-Schrieffer-Heeger model equipped with peculiar freedom to manipulate the nearest-neighbor coupling strength by the internal interaction. A staggered coupling strength of s-type pillar modes is experimentally achieved via the photonic spin-orbit coupling by employing the zigzag dielectric resonator chain. As a result, we observe that the robust edge states of the zigzag chains manifest themselves with linear polarization for an even number of dielectric resonators but elliptical polarization for an odd number. In addition, by coupling magnons to the topological waveguide, we observe resonant magnon–magnon–edge-state coupling, whose coupling strength is topologically protected. More broadly, our work shows that topological waveguide-QED systems may provide the potential for synthesis and study of many-body states with attractive long-range interaction.

Published by the American Physical Society
2024
Game-theoretical approach to minimum entropy productions in information thermodynamics
Authors: Fujimoto Yuma , Ito Sosuke
Published: January 2024

In a situation where each player has control over the transition probabilities of each subsystem, we game-theoretically analyze the optimization problem of minimizing both the partial entropy production of each subsystem and a penalty for failing to achieve a given state transition. In the regime of linear irreversible thermodynamics, we obtain the Nash equilibrium solution of the probability flow and calculate each partial entropy production for this solution. We find a trade-off such that a partial entropy production should be larger if we want the other partial entropy production to be smaller. The total entropy production can be minimized if each subsystem equally shares the penalty. We identify that this trade-off is due to the interacting contribution of the probability flow and discuss a possible biological validity for chemotaxis.

Published by the American Physical Society
2024