bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biology of healthy aging: Biological hallmarks of stress resistance-related and unrelated to longevity in humans
Authors: Badial Komalpreet , Lacayo Patricia , Murakami Shin 
Published: July 2024

AbstractStress resistance is tightly associated with longer and healthier lifespans in various model organisms, including nematodes, fruit flies, and mice. However, we lack a complete understanding of stress resistance in humans, and therefore, we investigated how stress resistance and longevity are interlinked in humans. Using more than 180 databases, we identified 541 human genes associated with stress resistance. The curated gene set is highly enriched with genes involved in cellular response to stress. The Reactome analysis identified 398 biological pathways, narrowed down to 172 pathways, using a medium threshold (p-value < 1 × 10−04). We further summarized into 14 pathway categories, e.g., cellular response to stimuli/stress, DNA repair, gene expression, and immune system. There were overlapping categories between stress resistance and longevity, including gene expression, signal transduction, immune system, and cellular responses to stimuli/stress. The categories include the PIP3-AKT-FOXO and mTOR pathways, known to specify lifespans in the model systems. They also include the accelerated aging syndrome genes (WRN and HGPS/LMNA), while the genes were also involved in non-overlapped categories. Notably, nuclear pore proteins are enriched among the stress resistance pathways and overlap with diverse metabolic pathways. This study suggests that stress resistance is closely linked with longevity pathways, but not entirely identical. While most longevity categories intersect with stress-resistance categories, some do not, particularly those related to cell proliferation and beta-cell development. We also note inconsistencies in pathway terminologies with aging hallmarks reported previously and propose them to be more unified and integral.
Temporal Transcriptomic Profiling of the DevelopingXenopus laevisEye
Authors: Hack Samantha J. , Petereit Juli , Tseng Kelly Ai-Sun 
Published: July 2024

AbstractRetinal progenitor cells (RPCs) are a multipotent and highly proliferative population that give rise to all retinal cell types during organogenesis. Defining their molecular signature is a key step towards identifying suitable approaches to treat visual impairments. Here, we performed RNA-sequencing of whole eyes fromXenopusat three embryonic stages and used differential expression analysis to define the transcriptomic profiles of optic tissues containing proliferating and differentiating RPCs during retinogenesis. Gene Ontology and KEGG pathway analyses showed that genes associated with developmental pathways (including Wnt and Hedgehog signaling) were upregulated during the period of active RPC proliferation in early retinal development (Nieuwkoop Faber st. 24 and 27). Developing eyes had dynamic expression profiles and shifted to enrichment for metabolic processes and phototransduction during RPC progeny specification and differentiation (st. 35). Furthermore, conserved adult eye regeneration genes were also expressed during early retinal development includingsox2,pax6,nrl, and Notch signaling components. The eye transcriptomic profiles presented here span RPC proliferation to retinogenesis and included regrowth-competent stages. Thus, our dataset provides a rich resource to uncover molecular regulators of RPC activity and will allow future studies to address regulators of RPC proliferation during eye repair and regrowth.
Harnessing Dye-induced Photothermal Confinement in Lipid Membranes: A Path to NIR-modulated Artificial Synaptic Vesicles
Authors: Sarker Satya Ranjan , Yamazaki Takeru , Sou Keitaro , Takemura Ichiro , Kurita Yusuke , Nomura Kayoko , Ichimura Mari , Suzuki Takahito , Kai Ayumi , Araki Takumi , Hattori Shinnosuke , Furuyama Taniyuki , Chang Young-Tae , Kiya Taketoshi , Arai Satoshi 
Published: July 2024

AbstractOptical heating coupled with near-infrared (NIR) light and photothermal materials enables thermal confinement within biospecimens, minimizing undesirable thermal damage. Here, we demonstrated that photothermally heating lipid bilayers embedded with a unique phthalocyanine dye (VPc) efficiently perturbs the bilayers, resulting in increased permeability. Notably, microscopic studies revealed that the mechanism causing changes in membrane permeability may not follow the conventional temperature-sensitive liposome model. Furthermore, the heat generated by NIR laser illumination rarely diffused into the surrounding environment, and the dye was located within the bilayers at the molecular level, where it effectively transferred heat to the lipid bilayer. We prepared VPc-embedded liposomes encapsulating acetylcholine (ACh) and demonstrated the NIR laser-triggered release of ACh, creating a concentration jump across a few cells or within a limited single cell region. This method induced Ca2+flux through ACh receptor stimulation in thermally delicate biospecimens such as C2C12 myotubes and theDrosophilabrain.
European Robin Cryptochrome-4a Associates with Lipid Bilayers in an Ordered Manner, Fulfilling a Molecular-Level Condition for Magnetoreception
Authors: Majewska Marta , Hanić Maja , Bartölke Rabea , Schmidt Jessica , Mouritsen Henrik , Koch Karl-Wilhelm , Solov’yov Ilia A. , Brand Izabella 
Published: July 2024

AbstractSince the middle of the 20th century, long-distance avian migration has been known to rely partly on the geomagnetic field. However, the underlying sensory mechanism is still not fully understood. Cryptochrome 4a (ErCry4a), found in European Robin (Erithacus rubecula), a night-migratory songbird has been suggested to be a magnetic sensory molecule. It is sensitive to external magnetic fields via the so-called radical-pair mechanism. ErCry4a is primarily located in the outer segments of the double cone photoreceptor cells in the eye, which contain stacked and highly ordered membranes that could facilitate the anisotropic attachment of ErCry4a needed for magnetic compass sensing. Here, we investigate possible interactions of ErCry4a with a model membrane that mimics the lipid composition of outer segments of vertebrate photoreceptor cells by using experimental and computational approaches. Experimental results show that the attachment of ErCry4a to the membrane could be controlled by the physical state of lipid molecules (average area per lipid) in the outer leaflet of the lipid bilayer. Furthermore, polarization modulation infrared reflection absorption spectroscopy allowed us to determine the conformation, motional freedom, and average orientation of the α- helices in ErCry4a in a membrane-associated state. Atomistic molecular dynamics studies supported the experimental results. A ∼1000 kcal mol−1decrease in the interaction energy as a result of ErCry4a membrane binding was determined compared to cases where no protein binding to the membrane occurred. At the molecular level, the binding seems to involve negatively charged carboxylate groups of the phosphoserine lipids and the C-terminal residues of ErCry4a. Our study reveals a potential direct interaction of ErCry4a with the lipid membrane and discusses how this binding could be an essential step for ErCry4a to propagate a magnetic signal further and thus fulfill a role as a magnetoreceptor.
Inseparable/IER3IP1are essential for cytokinesis inDrosophilaneuroblast and human cells
Authors: Kakade Aishwarya Arun , Gupta Sachin , Varghese Reshmi , Adicherla Harikrishna , Nagarkar-Jaiswal Sonal 
Published: July 2024

AbstractTo unveil the molecular players that maintain neural stem cell homeostasis, we conducted a genetic screen inDrosophilaand isolated an uncharacterized gene that we namedInseparable(Insep).Insepis theDrosophilahomologue of humanIER3IP1, a gene associated with Microcephaly, Epilepsy, and Neonatal Diabetes Syndrome (MEDS-1). We show thatInseploss leads to early larval lethality with small brains and these phenotypes can be rescued by expressing IER3IP1 indicating that their biological function is conserved through evolution. TheInsepdeficient neuroblasts fail to complete cytokinesis and show excessive accumulation of Rab11 vesicles in the cytoplasm. Similarly,IER3IP1depletion in human cells leads to cytokinesis failure and accumulation of Rab11 vesicles. Insep and IER3IP1 localize to Rab11 vesicles and interact with Rab11. The pathogenic mutations in IER3IP1 perturb its localization to Rab11 vesicles and interaction with Rab11. These results suggest that Insep and IER3IP1 work along with Rab11 and may regulate fusion of Rab11 vesicles to the advancing furrow during cytokinesis.
CTCF-DEPENDENT INSULATION OFHoxb13AND THE HETEROCHRONIC CONTROL OF TAIL LENGTH
Authors: Lopez-Delisle Lucille , Zakany Jozsef , Bochaton Célia , Osteil Pierre , Mayran Alexandre , Darbellay Fabrice , Mascrez Bénédicte , Rekaik Hocine , Duboule Denis 
Published: July 2024

ABSTRACTIn mammals, tail length is controlled by several genetic determinants, amongst which Hox13 genes located at the posterior extremities of Hox clusters, whose main function are to terminate the extension of the body axis. In this view, the precise timing in the transcriptional activation of these genes may impact upon body length. Unlike other Hox clusters, HoxB lacks all posterior genes between Hoxb9 and Hoxb13, two genes separated by a ca. 70 kb large DNA segment containing an unusually high number of CTCF sites, suggesting it isolates Hoxb13 from the rest of the cluster, thereby delaying its negative impact on trunk extension. We deleted the spacer DNA to induce a potential heterochronic gain of function of Hoxb13 at physiological concentration and observed a shortening of the tail as well as other abnormal phenotypes, which were all rescued by inactivating Hoxb13 in-cis with the deletion. A comparable gain of function was observed in mutant ES cells grown as pseudo-embryos in vitro, which allowed us to examine in details the importance of both the number and the orientation of CTCF sites in the insulating activity of the DNA spacer. A short cassette containing all the CTCF sites was sufficient to insulate Hoxb13 from the rest of HoxB and additional modifications of this CTCF cassette showed that two CTCF sites in convergent orientations are already capable of importantly delaying Hoxb13 activation in these conditions. We discuss the relative importance of genomic distance versus number and orientation of CTCF sites in preventing Hoxb13 to be activated too early during trunk extension and hence to modulate tail length.
IGLoo: Profiling the Immunoglobulin Heavy chain locus in Lymphoblastoid Cell Lines with PacBio High-Fidelity Sequencing reads
Authors: Lin Mao-Jan , Langmead Ben , Safonova Yana 
Published: July 2024

AbstractNew high-quality human genome assemblies derived from lymphoblastoid cell lines (LCLs) provide reference genomes and pangenomes for genomics studies. However, the characteristics of LCLs pose technical challenges to profiling immunoglobulin (IG) genes. IG loci in LCLs contain a mixture of germline and somatically recombined haplotypes, making them difficult to genotype or assemble accurately. To address these challenges, we introduceIGLoo, a software tool that implements novel methods for analyzing sequence data and genome assemblies derived from LCLs.IGLoocharacterizes somatic V(D)J recombination events in the sequence data and identifies the breakpoints and missing IG genes in the LCL-based assemblies. Furthermore,IGLooimplements a novel reassembly framework to improve germline assembly quality by integrating information about somatic events and population structural variantions in the IG loci. We appliedIGLooto study the assemblies from the Human Pangenome Reference Consortium, providing new insights into the mechanisms, gene usage, and patterns of V(D)J recombination, causes of assembly fragmentation in the IG heavy chain (IGH) locus, and improved representation of the IGH assemblies.
Deep Learning-based Modeling for Preclinical Drug Safety Assessment
Authors: Jaume Guillaume , de Brot Simone , Song Andrew H. , Williamson Drew F. K. , Oldenburg Lukas , Zhang Andrew , Chen Richard J. , Asin Javier , Blatter Sohvi , Dettwiler Martina , Goepfert Christine , Grau-Roma Llorenç , Soto Sara , Keller Stefan M. , Rottenberg Sven , del-Pozo Jorge , Pettit Rowland , Le Long Phi , Mahmood Faisal 
Published: July 2024

AbstractIn drug development, assessing the toxicity of candidate compounds is crucial for successfully transitioning from preclinical research to early-stage clinical trials. Drug safety is typically assessed using animal models with a manual histopathological examination of tissue sections to characterize the dose-response relationship of the compound – a timeintensive process prone to inter-observer variability and predominantly involving tedious review of cases without abnormalities. Artificial intelligence (AI) methods in pathology hold promise to accelerate this assessment and enhance reproducibility and objectivity. Here, we introduce TRACE, a model designed for toxicologic liver histopathology assessment capable of tackling a range of diagnostic tasks across multiple scales, including situations where labeled data is limited. TRACE was trained on 15 million histopathology images extracted from 46,734 digitized tissue sections from 157 preclinical studies conducted onRattus norvegicus. We show that TRACE can perform various downstream toxicology tasks spanning histopathological response assessment, lesion severity scoring, morphological retrieval, and automatic dose-response characterization. In an independent reader study, TRACE was evaluated alongside ten board-certified veterinary pathologists and achieved higher concordance with the consensus opinion than the average of the pathologists. Our study represents a substantial leap over existing computational models in toxicology by offering the first framework for accelerating and automating toxicological pathology assessment, promoting significant progress with faster, more consistent, and reliable diagnostic processes.Live Demo:https://mahmoodlab.github.io/tox-foundation-ui/
Dynamic integration of cortical activity in the deep layer of the anterolateral superior colliculus
Authors: Sugino Hikaru , Tanno Sho , Yoshida Tatsumi , Isomura Yoshikazu , Hira Riichiro 
Published: July 2024

AbstractThe superior colliculus (SC) receives inputs from various brain regions in a layer- and radial location-specific manner, but whether the SC exhibits location-specific dynamics remains unclear. To address this issue, we recorded the spiking activity of single SC neurons while photoactivating cortical areas in awake head-fixed Thy1-ChR2 rats. We classified 309 neurons that responded significantly into 8 clusters according to the response dynamics. Among them, neurons with monophasic excitatory responses (7–12 ms latency) that returned to baseline within 20 ms were commonly observed in the optic and intermediate gray layers of centromedial and centrolateral SC. In contrast, neurons with complex polyphasic responses were commonly observed in the deep layers of the anterolateral SC. Cross-correlation analysis suggested that the complex pattern could be only partly explained by an internal circuit of the deep gray layer. Our results indicate that medial to centrolateral SC neurons simply relay cortical activity, whereas neurons in the deep layers of the anterolateral SC dynamically integrate inputs from the cortex, SNr, CN, and local circuits. These findings suggest a spatial gradient in SC integration, with a division of labor between simple relay circuits and those integrating complex dynamics.
AI-assisted In-silico Trial for the Optimization of Osmotherapy following Ischaemic Stroke
Authors: Chen Xi , Lu Lei , Józsa Tamás I. , Clifton David A. , Payne Stephen J. 
Published: July 2024

AbstractOver the past few decades, osmotherapy has commonly been employed to reduce intracranial pressure in post-stroke oedema. However, evaluating the effectiveness of osmotherapy has been challenging due to the difficulties in clinical intracranial pressure measurement. As a result, there are no established guidelines regarding the selection of administration protocol parameters. Considering that the infusion of osmotic agents can also give rise to various side effects, the effectiveness of osmotherapy has remained a subject of debate. In previous studies, we proposed the first mathematical model for the investigation of osmotherapy and validated the model with clinical intracranial pressure data. The physiological parameters vary among patients and such variations can result in the failure of osmotherapy. Here, we propose an AI-assisted in-silico trial for further investigation of the optimisation of administration protocols. The proposed deep neural network predicts intracranial pressure evolution over osmotherapy episodes. The effects of the parameters and the choice of dose of osmotic agents are investigated using the model. In addition, clinical stratifications of patients are related to a brain model for the first time for the optimisation of treatment of different patient groups. This provides an alternative approach to tackle clinical challenges with in-silico trials supported by both mathematical/physical laws and patient-specific biomedical information.
Cannabidiol reverses fentanyl-induced addiction and modulates neuroinflammation
Authors: Bhandari Bidhan , Shimaoka Chagas Henrique Izumi , Naeini Sahar Emami , Chagas Pablo Shimaoka , Rogers Hannah M , Gouron Jules , Khan Aruba , Maciel Lívia Maria , Seyyedi Mohammad , MacKinnon Neil J , Khodadadi Hesam , Salles Évila Lopes , Hess David C , Morgan John C , Yu Jack C , Wang Lei P , Baban Babak 
Published: July 2024

AbstractIntroductionFentanyl and non-pharmaceutical fentanyl use have been the leading causes of opioid-induced death worldwide. Being 50 times stronger than heroin and 100 times stronger than morphine, fentanyl is a potent opioid with overdoses causing over 250,000 deaths since 2018 in the US alone. The treatment of fentanyl addiction is a complex process and a clinical challenge. There is a dire need to find other innovative and alternative modalities in the fight against fentanyl crisis.Increasing evidence suggests a correlation between neuroinflammation and symptoms of drug abuse, opening up the possibility of immunoregulatory agents as therapy for fentanyl addiction as well as a other opioid-induced addiction.Cannabidiol (CBD) is a non-opioid, relatively safe, non-psychoactive phyto-cannabinoid produced by cannabis plants. Importantly, recent reports have documented benefits of CBD in the treatment and management of complications related to opioid withdrawal.We investigated if inhaled CBD could reverse the fentanyl addiction and whether the CBD treatment could ameliorate the addiction symptoms by regulating neuroinflammatory signals and re-establishing the homeostasis in CNS.MethodWe used a fentanyl-induced conditioned place preference (CPP) model in mouse to test whether inhaled CBD could reverse the fentanyl addiction and ameliorate the adversarial symptoms. By employing a combination of flow cytometry as well as behavioral tests, we further assessed the impact of fentanyl addiction on cells and neuroinflammatory signals in CNS and we measured the effects of CBD in the treatment of addiction symptoms and inflammatory signals.ResultsOur findings suggest that CBD inhalation could be used effectively in the treatment of fentanyl addiction. CBD mitigated the excessive fentanyl-induced neuroinflammatory responses and decreased cellular stress and senescence.Conclusioninhaled CBD could alleviate the fentanyl addiction and regulate neuroinflammatory responses. This novel approach is non-invasive, accessible, effective, and warrants further, translational and research.
Correlation between religiosity and family functioning among secondary school students in high-risk residing areas and factors associated with substance use
Authors: Aziz Noor Adnin binti Ab , Wahab Suzaily , Sutan Rosnah binti , Baharom Muhammad Adib , Azmi Amirul Danial , Asmai Siti Azirah binti 
Published: July 2024

AbstractIntroductionSubstance use in adolescents poses a complex societal challenge that undermines nation-building and socioeconomic growth. Religiosity refers to a person’s religious beliefs, habits, and involvement in religious activities. Family functioning refers to the overall health and operation of a family unit, which includes communication, emotional bonding, support, roles, and behavioral control. Both aspects play a significant impact in determining substance use in adolescents. This study is to assess the correlation between religiosity, and family functioning, and to determine factors associated with substance use among adolescents in secondary schools in high-risk areas.MethodsA cross-sectional study was conducted among 312 adolescents from selected secondary schools in substance use hotspot areas in Northern Malaysia. Alcohol, Smoking, and Substance Involvement Screening Tool-Lite (ASSIST-Lite), Family Adaptation and Cohesion Scale version IV (FACES-IV), and Hatta Islamic Religiosity Scale (HIRS) were used as instruments.ResultsThe prevalence of substance use among adolescents was 9.6%(n=30). Most of the users used a single substance (76.7%; n=23) and only (23.3%; n=7) used multiple substances. The mean age was 14.13 years (SD:0.67), and the majority were Malays (99.0%; n=309) with a background in Muslim religion. Adolescent substance use was significantly associated with gender (16.3% in males and 6.3% in females) and having a recent family history of substance use (16.8%). A negative correlation was found between substance use and family functioning; balanced flexibility (rs=-0.12; P=<0.05), family communication (rs=-0.12; P=<0.05), and family satisfaction (rs=-0.15; P=<0.01). There was a positive correlation between substance use and chaotic family (rs=0.12; P=<0.05). Regression analysis reveals that only male adolescents and a recent family history of substance use were significant predictors of substance use. Family satisfaction was the only significant protective factor. There was no significant association between substance use and religiosity (rs=-0.01; P= 0.83).ConclusionsThese findings can assist policymakers, healthcare professionals and schools develop interventions to reduce substance use, especially in high-risk communities, and increase adolescents’ well-being in general.