bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic analysis of sex and age in hepatocellular carcinoma: a SEER study
Authors: Chen Jun , Wang Xiao , Ye Wenyi 
Published: March 2024

Objectives
This study aimed to explore the impact of sex on clinical features and survival among hepatocellular carcinoma (HCC) patients.

Methods
HCC case data from the Surveillance, Epidemiology, and End Results (SEER) database for the period 2010 to 2015 were selected for analysis. Kaplan–Meier curves displayed overall survival. Univariate cox regression examined the prognostic characteristics of individual features, and multivariate Cox regression assessed hazard ratios.

Results
This study comprised 3486 HCC patients, with 2682 males and 804 females. Across all age groups, there was a higher prevalence of males compared to females. Survival curves among female patients showed no significant differences across various age groups. However, among male patients, those under 60 demonstrated notably higher survival rates compared to those aged 60 and above. Regarding various ethnicities, TNM staging systems, tumor sizes, the presence of lung/bone/brain metastases, location in Purchased/Referred Care Delivery Areas, SEER historic stages, tumor grades, and individuals receiving chemotherapy, the proportion of male patients consistently exceeded that of female patients. Within the female patient group, individuals receiving chemotherapy exhibited significantly higher survival rates compared to those who did not. However, the administration of chemotherapy showed no significant impact on the survival rate of male patients. Multivariate Cox regression analysis revealed age, gender, and the administration of chemotherapy key factors influencing the overall survival prognosis.

Conclusion
Age, gender, and the administration of chemotherapy are influential factors in the prognosis of both male and female HCC patients.
Assessing Spns2-dependent S1P Transport as a Prospective Therapeutic Target
Authors: Kharel Y , Huang T , Dunnavant K , Foster D , Souza GMPR , Nimchuk KE , Merchak AR , Pavelec CM , Juskiewicz ZJ , Gaultier A , Abbott SBG , Shin J-B , Isakson BE , Xu W , Leitinger N , Santos WL , Lynch KR 
Published: March 2024

AbstractS1P (sphingosine 1-phosphate) receptor modulator (SRM) drugs interfere with lymphocyte trafficking by downregulating lymphocyte S1P receptors. While the immunosuppressive activity of SRM drugs has proved useful in treating autoimmune diseases such as multiple sclerosis, that drug class is beset by on-target liabilities such as initial dose bradycardia. The S1P that binds to cell surface lymphocyte S1P receptors is provided by S1P transporters. Mice born deficient in one of these, spinster homolog 2 (Spns2), are lymphocytopenic and have low lymph S1P concentrations. Such observations suggest that inhibition of Spns2-mediated S1P transport might provide another therapeutically beneficial method to modulate immune cell positioning. We report here results using a novel S1P transport blocker (STB), SLF80821178, to investigate the consequences of S1P transport inhibition in rodents. We found that SLF80821178 is efficacious in a multiple sclerosis model but – unlike the SRM fingolimod – neither decreases heart rate nor compromises lung endothelial barrier function. Notably, although Spns2 null mice have a sensorineural hearing defect, mice treated chronically with SLF80821178 have normal hearing acuity. STBs such as SLF80821178 evoke a dose-dependent decrease in peripheral blood lymphocyte counts, which affords a reliable pharmacodynamic marker of target engagement. However, the maximal reduction in circulating lymphocyte counts in response to SLF80821178 is substantially less than the response to SRMs such as fingolimod (50% vs. 90%) due to a lesser effect on T lymphocyte sub-populations by SLF80821178. Finally, in contrast to results obtained with Spns2 deficient mice, lymph S1P concentrations were not significantly changed in response to administration of STBs at doses that evoke maximal lymphopenia, which indicates that current understanding of the mechanism of action of S1P transport inhibitors is incomplete.
Particulate matter constituents trigger the formation of extracellular amyloid β and Tau-containing plaques and neurite shorteningin vitro
Authors: Sebastijanović Aleksandar , Camassa Laura Maria Azzurra , Malmborg Vilhelm , Kralj Slavko , Pagels Joakim , Vogel Ulla , Zienolddiny-Narui Shan , Urbančič Iztok , Koklič Tilen , Štrancar Janez 
Published: March 2024

AbstractIntroductionAir pollution is an environmental factor associated with Alzheimer’s disease, characterized by decreased cognitive abilities and memory. The limited models of sporadic Alzheimer’s disease fail to replicate all pathological hallmarks of the disease, making it challenging to uncover potential environmental causes. Environmentally driven models of Alzheimer’s disease are thus timely and necessary.MethodsWe used live-cell confocal fluorescent imaging combined with high-resolution stimulated emission depletion (STED) microscopy to follow the response of neuron-like cells to nanomaterial exposure. Here, we report that a high dose ratein vitroexposure of neuron-like cells to particulate matter constituents reproduces neurodegenerative phenotype, including extracellular amyloid-β containing plaques and decreased neurite length.ResultsConsistent with the existingin vivoresearch, we observed detrimental effects, specifically a substantial reduction in neurite length and formation of amyloid beta plaques, after exposure to iron oxide and diesel exhaust particles. Conversely, after exposure to engineered cerium oxide nanoparticles, the lengths of neurites were maintained, and almost no extracellular amyloid beta plaques were formed.DiscussionAlthough the exact mechanism behind this effect remains to be explained, the high dose ratein vitromodel, comprising wild-type neuron-like cells, could serve as an alternative environmentally driven model of Alzheimer’s disease.Abstract FigureGraphical abstractHigh dose ratein vitroexposure of neuron-like cells to particulate matter constituents, like diesel exhaust and iron oxide nanoparticles, reproduces neurodegenerative phenotype, including extracellular amyloid-β-containing plaques and reduction in neurite length and density.
Pitfalls and windfalls of detecting demographic declines using population genetics in long-lived species
Authors: Clark Meaghan I. , Fitzpatrick Sarah W. , Bradburd Gideon S. 
Published: March 2024

AbstractDetecting recent demographic changes is a crucial component of species conservation and management, as many natural populations face declines due to anthropogenic habitat alteration and climate change. Genetic methods allow researchers to detect changes in effective population size (Ne) from sampling at a single timepoint. However, in species with long lifespans, there is a lag between the start of a decline in a population and the resulting decrease in genetic diversity. This lag slows the rate at which diversity is lost, and therefore makes it difficult to detect recent declines using genetic data. However, the genomes of old individuals can provide a window into the past, and can be compared to those of younger individuals, a contrast that may help reveal recent demographic declines. To test whether comparing the genomes of young and old individuals can help infer recent demographic bottlenecks, we use forward-time, individual-based simulations with varying mean individual lifespans and extents of generational overlap. We find that age information can be used to aid in the detection of demographic declines when the decline has been severe. When average lifespan is long, comparing young and old individuals from a single timepoint has greater power to detect a recent (within the last 50 years) bottleneck event than comparing individuals sampled at different points in time. Our results demonstrate how longevity and generational overlap can be both a hindrance and a boon to detecting recent demographic declines from population genomic data.
Beyond enumeration: Phenotype independent “labeling-capture-release” process enabling precise detection of circulating tumour cells and downstream applications
Authors: Lao Zhiqi , Ren Xiaoxue , Zhuang Dehua , Xie Lingxia , Zhang Yucong , Li Wei , Jiang Zhenyou , Chen Yue , Li Penghui , Tong Liping , Chu Paul K. , Wang Huaiyu 
Published: March 2024

AbstractAlthough strategies for circulating tumor cells (CTCs) enrichment have been proposed, the practical effects of clinical CTCs detection are far from satisfactory. Generally, the methodologies for CTCs detection aim at naturally occurring targets, but misdetection/interferences are prevalent due to the diverse phenotypes and subpopulations of CTCs with high heterogeneity. Herein, a CTCs isolation system based on the “labeling-capture-release” process is demonstrated for precise and high-efficient enrichment of CTCs from clinical blood samples. The mechanism which is based on abnormal glyco-metabolism of tumor cells including CTCs can be utilized for the surface decoration of CTCs with artificial azido groups. With the aid of bio-orthogonal plates designed with DBCO- and disulfide groups and exploiting the anti-fouling effects, the cells labeled with azido groups can be capturedviaa copper-free click reaction and released in a non-destructive manner during subsequent disulfide reduction. The technique is demonstrated to label multiple different types of tumor cells with the EpCAM+/- phenotypes and adherent/suspended status, and all the epithelial/interstitial/hybrid phenotypes of CTCs can be separated from clinical blood samples from 25 patients with 10 different cancer types. Moreover, our strategy is superior to the clinically approved CTCs detection system from the perspective of broad-spectrum and accurate recognition of heterogeneous CTCs. The capturing efficiency of this isolation system is over 80% and the release efficiency exceeds 90%. Most of the released CTCs survive with maintained glycolytic activity thus boding well for downstream applications such as drug susceptibility tests using viable CTCs.
Network medicine informed multi-omics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis
Authors: Yu Mucen , Xu Jielin , Dutta Ranjan , Trapp Bruce , Pieper Andrew A. , Cheng Feixiong 
Published: March 2024

AbstractAmyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. To date, the challenge to establishing effective treatment for ALS remains formidable, partly due to inadequate translation of existing human genetic findings into actionable ALS-specific pathobiology for subsequent therapeutic development. This study evaluates the feasibility of network medicine methodology via integrating human brain-specific multi-omics data to prioritize drug targets and repurposable treatments for ALS. Using human brain-specific genome-wide quantitative trait loci (x-QTLs) under a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in various known ALS pathobiological pathways, including regulation of T cell activation, monocyte differentiation, and lymphocyte proliferation. Specifically, we leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on brain-specific expression quantitative trait loci (QTL) (eQTL), protein QTLs (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Applying network proximity analysis of predicted ALS-associated gene-coding targets and existing drug-target networks under the human protein-protein interactome (PPI) model, we identified a set of potential repurposable drugs (including Diazoxide, Gefitinib, Paliperidone, and Dimethyltryptamine) for ALS. Subsequent validation established preclinical and clinical evidence for top-prioritized repurposable drugs. In summary, we presented a network-based multi-omics framework to identify potential drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.
Neural Correlates of Different Randomization Tasks
Authors: Guseva Maja , Bogler Carsten , Allefeld Carsten , Ziya Ece Büşra , Haynes John-Dylan 
Published: March 2024

AbstractIn some cases, when we are making decisions, the available choices can appear to be equivalent. When this happens, our choices appear not to be constrained by external factors and instead we can believe to be selecting “randomly”. Furthermore, randomness is sometimes even explicitly required by task conditions such as in random sequence generation (RSG) tasks. This is a challenging task that involves the coordination of multiple cognitive processes, which can include the inhibition of habitual choice patterns and monitoring of the running choice sequence.It has been shown that random choices are strongly influenced by the way they are instructed. This raises the question whether the brain mechanisms underlying random selection also differ between different task instructions. To assess this, we measured brain activity while participants were engaging in three different variations of a sequence generation task: Based on previous work, participants were instructed to either (1) “generate a random sequence of choices”, (2) “simulate a fair coin toss”, or (3) “choose freely”.Our results reveal a consistent frontoparietal activation pattern that is shared across all tasks. Specifically, increased activity was observed in bilateral inferior and right middle frontal gyrus, left pre-supplementary motor area, bilateral inferior parietal lobules and portions of anterior insular cortex in both hemispheres. Activity in the mental coin toss condition was higher in right dorsolateral prefrontal cortex, left (pre-) supplementary motor area, a portion of right inferior frontal gyrus, bilateral superior parietal lobules and bilateral anterior insula. Additionally, our multivariate analysis revealed a distinct region in the right frontal pole to be predictive of the outcome of choices, but only when randomness was explicitly instructed.These results emphasize that different randomization tasks involve both shared and unique neural mechanisms. Thus, even seemingly similar randomization behavior can be produced by different neural pathways.
Behavior and alpha-band oscillations reveal cross-modal interactions between chemosensory and auditory processing
Authors: Klatt Laura-Isabelle , Hucke Christine 
Published: March 2024

SummaryThe perceived location of a sound can be mislocated towards a spatially discordant but temporally synchronous visual stimulus. This is referred to as the spatial ventriloquist effect. However, whether chemosensory cues can similarly bias sound localization remains largely unaddressed. Hence, the present EEG study adopted a dynamic sound localization paradigm with concurrent bimodal odorant stimulation. Participants heard sequences of sounds varying in location. After each sound, participants made a two-alternative forced choice localization judgment (left vs. right). Critically, in a subset of occasions, but unbeknown to the participants, the sounds originated from a central location. Furthermore, in the first half of the sequence, sound presentation could be accompanied by a task-irrelevant, trigeminally potent odorant in the left, right, or both nostril(s). Auditory-only trials and birhinal stimulation served as controls. For central sounds in the second half of the sequence, the proportion of right-ward responses increased with right-nostril stimulation but decreased with left-nostril stimulation relative to the control conditions, showing an after-effect of odorant stimulation for ambiguous sound cues. This odorant-induced localization bias diminished with increasing spatial discernability of the sounds. On the contrary, alpha power lateralization, a correlate of auditory spatial attention, was most susceptible to odorant stimulation when the spatial disparity between the senses was largest, as reflected in diminished alpha lateralization for incongruent chemosensory-sound stimulation. No such effect was present in a multivariate decoding analysis of alpha power. We discuss the present findings in light of cross-modal interactions and a proposed common attentional control system between the senses.
Immediate glucose signaling transmitted via the vagus nerve in gut-brain neural communication
Authors: Yamada Serika , Natsubori Akiyo , Harada Kazuki , Tsuboi Takashi , Monai Hiromu 
Published: March 2024

SummarySucrose consumption is influenced by certain gut-brain signaling mechanisms. Among these, one pathway involves neuropod cells, which form synaptic connections with the vagus nerve, leading to the immediate activation of central dopaminergic pathways. This study explored the role of the frontal cortex in its process. We found that the vagus nerve’s immediate activation is mediated by the sodium-glucose cotransporter 1 (SGLT1) of neuropod cells after the intragastric glucose injection in mice. Also, we showed that the involvement of both astrocytes and neurons in the frontal cortex via D2 and D1 dopamine receptors, respectively, by in vivo Ca2+imaging. Finally, we revealed that psychological stress, which induces a reduction in sucrose preference, significantly diminishes the activation levels of both the vagus nerve and the frontal cortex. These findings highlight the role of a comprehensive gut-brain network in modulating sucrose preference, involving neuropod cells, the vagus nerve, and the frontal cortex.Graphical abstract
MegaKG: Toward an explainable knowledge graph for early drug development
Authors: Dong Jianqiang , Liu Junwu , Wei Yifan , Huang Peilin , Wu Qiong 
Published: March 2024

ABSTRACTIn biomedical research, the utilization of Knowledge Graph (KG) has proven valuable in gaining deep understanding of various processes. In this study, we constructed a comprehensive biomedical KG, named as MegaKG, by integrating a total of 23 primary data sources, which finally consisted of 188, 844 nodes/entities and 9, 165, 855 edges/relations after stringent data processing. Such a massive KG can not only provide a holistic view of the entities of interest, but also generate insightful hypotheses on unknown relations by applying AI computations. We focused on the interplay of the key elements in drug development, such as genes, diseases and drugs, and aimed to facilitate practical applications that could benefit early drug development in industries. More importantly, we placed much emphasis on the exploitability of the predictions generated by MegaKG. This may greatly help researchers to assess the feasibility or design appropriate downstream validation experiments, making AI techniques more than just black-box models. In this regard, NBFNet was adopted, which combines the advantages of both traditional path-based methods and more recently developed GNN-based ones. Performance evaluation experiments indicated superior results by MegaKG. We also conducted real case studies to validate its practical utility in various scenarios, including target prediction, indication extension and drug repurposing. All these experiments highlighted the potential of MegaKG as a valuable tool in driving innovation and accelerating drug development in pharmaceutical industry.
The Hyaluronan Synthase isoforms direct distinct patterns of fibroblast activation linked to fibrosis progression versus resolution following renal ischaemia
Authors: Grigorieva Irina , Midgley Adam , Brown Charlotte , Chevez Gilda , Williams Aled , Manetta-Jones Dominic , Bowen Timothy , Chan Deva , Plaas Anna , Chevez Rafael , Steadman Robert , Khalid Usman , Meran Soma 
Published: March 2024

ABSTRACTBackgroundThe stroma plays a key role during renal development and in regeneration after injury. However, following injury, the stroma expands driving progressive fibrosis. Hyaluronan (HA) is a glycosaminoglycan that is absent in healthy kidney stroma but highly expressed in disease. To understand strategies to modulate stromal HA towards therapeutic advantage, this study compares HA and HA Synthase (HAS) enzyme expression in kidney development, health, disease, and recovery.MethodsRats underwent ischaemia reperfusion injury (IRI) with/without ischaemic preconditioning (IPC) and kidneys histologically analysed. Kidneys from C57BL/6 embryos and HAS1/3-/-mice were also analysed and parallel mechanistic cell studies performed using primary human fibroblasts.ResultsIn health, stromal HA was absent from the renal cortex. HAS1 was expressed in some epithelial cells, whilst HAS2 was not expressed. Following IRI there was increased stromal HA in areas of chronic fibrosis, alongside increased HAS2 (but not HAS1) expression. In contrast, during development prominent stromal HA matrices were evident in areas of tubular generation, with strong HAS1 (not HAS2) expression. Following IPC+IRI, stromal HA and HAS2 were attenuated; whilst HAS1+cells expanded but were distinct from α-SMA+myofibroblasts. Cell studies demonstrated that HAS1+fibroblasts had a functionally distinct phenotype, with enhanced migration and FAP expression but attenuated α-SMA, EDA-FN and COL1A1 expression, whereas HAS2+fibroblasts demonstrated a classic α-SMA+contractile myofibroblast phenotype with high EDA-FN and COL1A1.ConclusionsHA is a key regulator of stromal fibroblast heterogeneity, with HAS1 and HAS2 defining phenotypically distinct populations that may influence divergent renal outcomes following injury.SIGNIFICANCE STATEMENTHyaluronan (HA) is a matrix glycosaminoglycans that is absent in healthy kidney cortex but demonstrates increased expression in the renal stroma during progressive fibrosis. This study makes comparisons of HA accumulation, localisation, and HA Synthase (HAS) protein expression during kidney development, in health, following ischaemic kidney injury and during renal recovery. The study identifies that different HAS isoenzymes (HAS1 and HAS2) mediate distinct functional fibroblast phenotypesin vitroand are localised in distinct stromal localisations and cell sub-populationsin vivo. The data provides interesting insights into HA dependent regulation of fibroblast stromal heterogeneity and identifies thenovelfinding that HAS1 defines cell populations that are associated with kidney recovery following ischaemic injury and are protective against progressive renal fibrosis.
Large-scale RNA-seq mining reveals ciclopirox triggers TDP-43 cryptic exons
Authors: Sinha Irika R. , Sandal Parker S. , Burns Grace D. , Mallika Aswathy Peethambaran , Irwin Katherine E. , Cruz Anna Lourdes F. , Wang Vania , Rodríguez Josué Llamas , Wong Philip C. , Ling Jonathan P. 
Published: March 2024

AbstractNuclear clearance and cytoplasmic aggregation of TDP-43 in neurons, initially identified in ALS-FTD, are hallmark pathological features observed across a spectrum of neurodegenerative diseases. We previously found that TDP-43 loss-of-function leads to the transcriptome-wide inclusion of deleterious cryptic exons in brains and biofluids post-mortem as well as during the presymptomatic stage of ALS-FTD, but upstream mechanisms that lead to TDP-43 dysregulation remain unclear. Here, we developed a web-based resource (SnapMine) to determine the levels of TDP-43 cryptic exon inclusion across hundreds of thousands of publicly available RNA sequencing datasets. We established cryptic exon inclusion across a variety of human cells and tissues to provide ground truth references for future studies on TDP-43 dysregulation. We then explored studies that were entirely unrelated to TDP-43 or neurodegeneration and found that ciclopirox olamine (CPX), an FDA-approved antifungal, can trigger the inclusion of TDP-43-associated cryptic exons in a variety of mouse and human primary cells. CPX induction of cryptic exon occurs via heavy metal toxicity and oxidative stress, suggesting that similar vulnerabilities could play a role in neurodegeneration. Our work demonstrates how diverse datasets can be linked through common biological features and underscores that public archives of sequencing data represent a vastly underutilized resource with tremendous potential for uncovering novel insights into complex biological mechanisms and diseases.