bluuebunny/crossref_metadata_2025_split huggingface dataset:
FORWARD: A Learning Framework for Logical Network Perturbations to Prioritize Targets for Drug Development
Authors: Sinha Saptarshi , McLaren Ella , Mullick Madhubanti , Singh Siddharth , Boland Brigid S. , Ghosh Pradipta 
Published: July 2024

AbstractDespite advances in artificial intelligence (AI), target-based drug development remains a costly, complex and imprecise process. We introduce F.O.R.W.A.R.D [Framework for Outcome-based Research and Drug Development], a network-based target prioritization approach and test its utility in the challenging therapeutic area of Inflammatory Bowel Diseases (IBD), which is a chronic condition of multifactorial origin. F.O.R.W.A.R.D leverages real-world outcomes, using a machine-learning classifier trained on transcriptomic data from seven prospective randomized clinical trials involving four drugs. It establishes a molecular signature of remission as the therapeutic goal and computes, by integrating principles of network connectivity, the likelihood that a drug’s action on its target(s) will induce the remission-associated genes. Benchmarking F.O.R.W.A.R.D against 210 completed clinical trials on 52 targets showed a perfect predictive accuracy of 100%. The success of F.O.R.W.A.R.D was achieved despite differences in targets, mechanisms, and trial designs. F.O.R.W.A.R.D-driven in-silico phase ’0’ trials revealed its potential to inform trial design, justify re-trialing failed drugs, and guide early terminations. With its extendable applications to other therapeutic areas and its iterative refinement with emerging trials, F.O.R.W.A.R.D holds the promise to transform drug discovery by generating foresight from hindsight and impacting research and development as well as human-in-the-loop clinical decision-making.
Microphysiological system modeling pericyte-induced temozolomide resistance in glioblastoma
Authors: Maity Surjendu , Jewell Christopher , Yilgor Can , Kawakita Satoru , Sharma Saurabh , Gomez Alejandro , Mecwan Marvin , Falcone Natashya , Ermis Menekse , Monirizad Mahsa , Kouchehbaghi Negar Hosseinzadeh , Zehtabi Fatemeh , Khorsandi Danial , Dokmeci Mehmet Remzi , Moniz-Garcia Diogo , Quiñones-Hinojosa Alfredo , Khademhosseini Ali , Jucaud Vadim 
Published: July 2024

AbstractGlioblastoma (GBM) is a malignancy with poor survival and high rates of chemoresistance. Temozolomide (TMZ), the standard-of-care chemotherapy for GBM patients, but GBM cells can be resistant to TMZ, resulting in limited clinical efficacy. Elucidating the complex mechanisms of TMZ chemoresistance in GBM requires novelin vitromodels replicating the complex tumor microenvironment (TME). We present an multicellular 3D GBM model recapitulating the biomechanical characteristics of brain tissues and pericyte-mediated TMZ resistance. The composite hydrogel used to encapsulate GBM spheroids (U87, LN229, and PDM140), pericytes, or GBM spheroids with pericytes, mimics the rheological properties of brain tissues (G’∼800Pa and G”∼100Pa). When untreated, the GBM models remain viable and proliferative for 14 days. PDM140 spheroids were most sensitive to TMZ (IC50=73μM), followed by LN229 (IC50=278μM) and U87 (IC50=446μM). With pericytes, the viability of TMZ-treated GBM spheroids significantly increases by 22.7% for PDM140, 32.5% for LN229, and 22.1% for U87, confirming pericyte-induced GBM chemoresistance responses. The upregulation (380-fold) of C-C motif chemokine ligand 5 (CCL5) in pericytes upon TMZ treatment could explain the chemoresistance responses. This innovative brain-mimicking 3D GBM model represents a novelin vitroplatform for testing the efficacy of TMZ and novel drugs targeting CCL5-mediated chemoresistance pathways in GBM.
Perturbed pediatric serum metabolome in mild and severe dengue disease
Authors: Soma Paul S. , Gullberg Rebekah C. , Graham Barbara , Islam M. Nurul , Balmaseda Angel , Blair Carol D. , Beaty Barry J. , Belisle John T. , Harris Eva , Perera Rushika 
Published: July 2024

AbstractDengue viruses (DENVs) are the most prevalent arboviruses affecting humans. Four billion people are at risk of infection and this burden is rapidly increasing due to geographic expansion of the mosquito vector. Infection with any of the four serotypes of DENV can result in a self-limiting disease but debilitating febrile illness (DF), and some infections progress to severe disease with manifestations such as hemorrhage and shock. DENV infection drives the metabolic state of host cells for viral benefit and induces a host-immune response that has metabolic implications that link to disease. In this study, a dynamic metabolic response to DENV infection and disease was measured in 535 pediatric patient sera using liquid chromatography-mass spectrometry. The metabolome was interrogated to discover biochemical pathways and identify key metabolites perturbed in severe dengue disease. A biomarker panel of thirty-two perturbed metabolites was utilized to classify DF, and severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) with high sensitivity and specificity equating to a balanced accuracy of 96.9%. Some metabolites that were structurally confirmed here belong to important biochemical pathways of omega-3 and omega-6 fatty acids, sphingolipids, purines, and tryptophan metabolism. A previously reported trend between serotonin and platelets in DHF patients has been expanded upon here to reveal a major depletion of serotonin, but not platelets, in DSS patients. This study differentiated and classified DF and DHF/DSS using a serum metabolic biomarker panel based on perturbed biochemical pathways that have potential implications for severe dengue disease.One sentence summary:Metabolic biomarkers distinguish dengue hemorrhagic fever and dengue shock syndrome from dengue fever and lend insight to severe disease pathology
SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1
Authors: Dong Fangyuan , He Kang , Zhang Shan , Song Kaiyuan , Jiang Luju , Hu LiPeng , Li Qing , Zhang Xue-Li , Zhang Naiqi , Li Bo-Tai , Zhu Li-Li , Li Jun , Feng Mingxuan , Gao Yunchen , Chen Jie , Hu Xiaona , Wang Jiaofeng , Jiang Chongyi , Zhu Helen He , Da Lin-Tai , Ji Jianguang , Bao Zhijun , Jiang Shu-Heng 
Published: July 2024

AbstractAlthough there is growing appreciation for effective repurposing of selective serotonin reuptake inhibitors (SSRIs) for cancer therapy, particularly hepatocellular carcinoma (HCC), efforts are hampered by limited knowledge of their molecular targets and mechanism of action. Global inverse gene-expression profiling method, drug affinity responsive target stability assay, and in silico molecular docking analysis was performed to identify the targets of SSRIs. Murine subcutaneous, orthotopic models, and patient-derived xenograft were employed to explore the therapeutic effects and underlying mechanisms of SSRIs in HCC. The clinical relevance of SSRI use was verified with real world data. SSRIs exhibit significant anti-HCC effects independent of their known target serotonin reuptake transporter. The glucose transporter 1 (GLUT1) is identified as a new target of SSRIs. Citalopram binds to and antagonizes GLUT1, resulting in reduced glycolytic flux and ATP generation. Mutant GLUT1 in the binding site E380 of citalopram compromises the inhibitory effects of citalopram on the Warburg effect and tumor growth. In preclinical models, citalopram dampens the growth kinetics of GLUT1highliver tumors and displays a synergistic effect with anti-PD-1 therapy. Retrospective analysis of health records found that SSRIs use is associated with a lower risk of metastasis among HCC patients. Our study reveals an unprecedented role of SSRIs in cancer metabolism, and establishes a rationale for repurposing SSRIs as potential anticancer drugs for HCC.
The first complete mitochondrial genome of tjaku□a (Great Desert Skink,Liopholis kintorei)
Authors: Thuo David , Wallace Jesse , Keogh J. Scott , Macgregor Nicholas A. , Goumas Margarita , Swan Shaeleigh , Guest Tracey , Doerr Erik D. , Paltridge Rachel , Kenny Jeremy , Merson Samuel D. , Joseph Leo 
Published: July 2024

AbstractThe complete mitochondrial genome (mitogenome) of the tjaku□a,Liopholis kintoreiwas obtained using next-generation sequencing, making it the first recorded mitogenome of the genusLiopholisand theTiliquini. The mitogenome is 16,844bp in length with a base composition of A (31.7%), T (24.4%), G (14.6%), and C (29.3%) and a G + C content of 43.9%. The genome contains 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes (12S and 16S), and three non-coding fragments, consisting of the putative control region and two mitochondrially encoded heavy strand origin of replication region (OriH). The gene order is identical to that of typical skink mitogenomes. This genomic resource will provide valuable information for genetic studies of this genus and contribute to the growing collection of mitogenomes within the family Scincidae.
Sensory dependencies rapidly and autonomously yield generalizable representations in recurrent cortical-like networks
Authors: Rongala Udaya B. , Jörntell Henrik 
Published: July 2024

AbstractHow do biological brains become operational so quickly? Here we introduce a ‘neuromorphic’ learning strategy that mimics the strategies of animals in early development. It consists of continual random activations of the body, which is a mechanically coupled system with rich, dynamic intrinsic sensor dependencies. Using a dynamic model of biological skin tissue with distributed sensors, we trained small, recurrent networks designed to emulate a primordial cortex with excitatory and inhibitory neurons and simultaneous independent learning in both types of synapses. Continual random activations of the skin, without resetting the network state, led to rapid acquisition of remarkably generalizable representations with emergent predictive capability. The network could separate inputs and solve a kinematics task it had never encountered, even when substantial parts of the sensor population were removed. This strategy of learning the dominant regularities in dynamic sensory information can explain efficient learning of complex operation in the brain.
Clarifying misconceptions of biomolecular condensate formation
Authors: Hosamane Nidhi , Hartman McKayla , Dubach J. Matthew 
Published: July 2024

AbstractBiomolecular condensates are liquid-like phase separations of disordered proteins and other molecules within cells. These membrane-less organelles are essential in critical cellular processes and are aberrant in myriad disease. Yet, the thermodynamics of condensate formation are not entirely understood, thus the mechanisms of condensate function remain elusive. Two assumptions about biomolecular condensates are that they form through liquid-liquid phase separation (LLPS) and require multivalent interactions. Here, we show results and propose thermodynamic frameworks that suggest these assumptions are not always correct. We demonstrate that condensation does not follow canonical LLPS and that liquid-like phase separation can arise from monovalent interactions. These results clarify the mechanism of condensate thermodynamics to reframe our understanding of condensates in cellular function and disease.
Dynamic regulation of H2A.Zub and H3K27me3 by ambient temperature in plant cell fate determination
Authors: Zhu Kehui , Zhao Long , Lu Fangfang , Lin Xuelei , He Chongsheng , Wagner Doris , Xiao Jun 
Published: July 2024

AbstractCrucial to plant development, ambient temperature triggers intricate mechanisms enabling adaptive responses to temperature variations. The precise coordination of chromatin modifications in shaping cell fate under diverse temperatures remains elusive. Our study, integrating comprehensive transcriptome, epigenome profiling and genetics, unveils that lower ambient temperature (16°C) restores developmental defects caused by H3K27me3 loss in PRC2 mutants by specifically depositing H2A.Zub at ectopically expressed embryonic genes, such asABI3andLEC1. This deposition leads to re-silencing of these genes and compensates for H3K27me3 depletion. PRC1-mediated H2A.Zub and PRC2-catalyzed H3K27me3 play roles in silencing transcription of these embryonic genes for post-germination development. Low temperature decelerates H2A.Z turnover at specific loci likely by attenuating the interaction between TOE1 and H2A.Z chaperone, sustaining repression of embryonic genes and alleviating requirement for PRC2-H3K27me3 at post-germination stage. Our findings offer mechanistic insights into the cooperative epigenetic layers facilitating plants adaptation to varying environmental temperatures.
Clinical Relevance of Computationally Derived Tubular Features: Spatial Relationships and the Development of Tubulointerstitial Scarring in MCD/FSGS
Authors: Fan Fan , Liu Qian , Zee Jarcy , Ozeki Takaya , Demeke Dawit , Yang Yingbao , Farris Alton B. , Wang Bangcheng , Shah Manav , Jacobs Jackson , Mariani Laura , Lafata Kyle , Rubin Jeremy , Chen Yijiang , Holzman Lawrence , Hodgin Jeffrey B. , Madabhushi Anant , Barisoni Laura , Janowczyk Andrew 
Published: July 2024

ABSTRACTBackgroundVisual scoring of tubular damage has limitations in capturing the full spectrum of structural changes and prognostic potential. We investigate if computationally quantified tubular features can enhance prognostication and reveal spatial relationships with interstitial fibrosis.MethodsDeep-learning and image-processing-based segmentations were employed in N=254/266 PAS-WSIs from the NEPTUNE/CureGN datasets (135/153 focal segmental glomerulosclerosis and 119/113 minimal change disease) for: cortex, tubular lumen (TL), epithelium (TE), nuclei (TN), and basement membrane (TBM). N=104 pathomic features were extracted from these segmented tubular substructures and summarized at the patient level using summary statistics. The tubular features were quantified across the biopsy and in manually segmented regions of mature interstitial fibrosis and tubular atrophy (IFTA), pre-IFTA and non-IFTA in the NEPTUNE dataset. Minimum Redundancy Maximum Relevance was used in the NEPTUNE dataset to select features most associated with disease progression and proteinuria remission. Ridge-penalized Cox models evaluated their predictive discrimination compared to clinical/demographic data and visual-assessment. Models were evaluated in the CureGN dataset.ResultsN=9 features were predictive of disease progression and/or proteinuria remission. Models with tubular features had high prognostic accuracy in both NEPTUNE and CureGN datasets and increased prognostic accuracy for both outcomes (5.6%-7.7% and 1.6%-4.6% increase for disease progression and proteinuria remission, respectively) compared to conventional parameters alone in the NEPTUNE dataset. TBM thickness/area and TE simplification progressively increased from non- to pre- and mature IFTA.ConclusionsPreviously under-recognized, quantifiable, and clinically relevant tubular features in the kidney parenchyma can enhance understanding of mechanisms of disease progression and risk stratification.
Reduced functional fungal communities in two species of sloths (Bradypus variegatusandCholoepus hoffmanni) suggest a link to slow digestion
Authors: Chaverri Priscila , Escudero-Leyva Efraín , Mora-Rojas Darling , Calvo-Obando Andrea , González Mariana , Escalante-Campos Esteban , Mesén-Porras Esteve , Wicki-Emmenegger Daniela , Rojas-Gätjens Diego , Avey-Arroyo Judith , Campos-Hernández Mariana , Castellón Erick , Moreira-Soto Andrés , Drexler Jan Felix , Chavarría Max 
Published: July 2024

AbstractSloths, with their ruminant-like digestive systems, possess the slowest digestion among mammals due to their low metabolic rate, minimal food intake, and extremely low-energy diet. However, no comprehensive studies have characterized the sloth’s gut microbiota, including fungi, and their role in digestion. This study hypothesized that effective plant fiber-degrading fungi (e.g., Neocallimastigomycota) would be scarce in the sloth’s gut. The aim was to describe the gut microbiota of three-toed (Bradypus variegatus) and two-toed (Choloepus hoffmanni) sloths to understand their link to slow digestion. Microbial composition and functionality were analyzed using shotgun metagenomics, metatranscriptomics, fungal metabarcoding (ITS 1 and 2 nrDNA), and cellulose degradation analysis. Microbial communities were dominated by bacteria (92–97%), followed by viruses (1–7%). Fungi accounted for only 0.06–0.5% of metagenomic reads and 0.1% of transcripts. Functional analysis revealed minimal CAZy abundance (1.7–1.9% in metagenomes, 0.2% in metatranscriptomes), with no fungal CAZys or glycoside hydrolases detected. Neocallimastigomycota had negligible abundance in metagenomic data and was absent in metatranscriptomic or ITS metabarcoding data.Bradypus variegatusshowed overall lower CAZy abundance and fungal presence compared toCholoepus hoffmanni. Lastly, cellulose degradation analyses revealed that only ∼5–35% of the intake was digested. This study highlights the unique microbial ecosystem in sloths’ guts, showing minimal presence of plant fiber-degrading anaerobic fungi and limited microbial CAZys, aligning with their slow digestion and low metabolic rate, thus enhancing our understanding of their digestive efficiency and metabolic adaptations.
Genetic basis of state-dependent courtship sounds in inbred mice
Authors: Na SaeYeon , Ryoo Jia , Ko Chang Bum , Park Seahyung , Kim Daesoo 
Published: July 2024

AbstractCourtship behaviors consist of two phases, namely the appetitive and consummatory states. Despite the long history of the concept, few studies have been done regarding the genetic contribution on those two different phases. Male mice are known to produce distinct ultrasonic vocalizations (USVs) as they progress through courtship states1-14, and these courtship sounds also show strain-specific differences15-18. Here, we delved into USV syllable patterns emitted during specific courtship actions using inbred mouse strains and their progeny: C57BL/6J (B6) mice, 129S4/SvJae (129) mice, and their second filial generation (F2) offspring of mixed genetic backgrounds. B6, 129, and F2 mice generated similar USV syllables during mounting behavior. In contrast, B6 and 129 mice showed different USV syllable patterns during body and anogenital sniffing behavior, and the USV syllable usage of F2 mice in this courtship state diverged according to the degree of genetic similarity with B6 or 129 mice. From these results, we propose that differential selection pressures19-20favored diversity in appetitive behavior but conservation in consummatory behaviors.
Hyper-Raman scattering from the LO modes of perovskite ferroelectric relaxors
Authors: Al-Zein A. , Hehlen B. 
Published: July 2024

Hyper-Raman scattering is used to study the temperature dependence of the longitudinal optic (LO) modes of three prototypical ferroelectric relaxors in a broad temperature range from 20 to 800 K. The three LO bands observed in all spectra of the three materials are linked to the three transverse optic (TO) modes in cubic relaxors where LOi is linked to TOi, with i = 1 to 3. The Last, Slater, and Axe eigenvector pictures of the TO modes are consistent with our observations on LO1, LO2, and LO3, respectively. Within this framework, the splitting of LO2 would mostly be linked to a structural disorder on the site while the strength of an anomaly of LO1 near the freezing temperature Tf relies on the ability of the material to develop a long-range ordering. Moreover, the more pronounced the splitting, the more important the structural disorder and the lower the value of the dielectric constant.

Published by the American Physical Society
2024
Combining business process management and lean manufacturing to improve information and documentation flows: a case study
Authors: Calçado Rodrigo , Ávila Liliana , Rosa Maria J. 
Published: July 2024

PurposeThe objective of this work is to demonstrate how the use of a business process management (BPM) methodology reinforced with the use of lean manufacturing (LM) tools and practices enhances information and documentation flows.Design/methodology/approachFor this purpose, a case study on a large wind blade manufacturing company is described, in which BPM and LM were combined to improve information and documentation flows associated to the process of quality inspections and quality controls.FindingsThe joint use of BPM and LM strongly contributed to the improvement of information and documentation flows. The BPM lifecycle can be used to guide the entire improvement process, while LM tools can be used to act at specific points with an emphasis in the process analysis and implementation phases. Thus, LM complements a BPM approach leading to significant process improvements.Practical implicationsThe results show that LM can be used to support some phases of the BPM lifecycle. Furthermore, LM can contribute to identify lean waste in information and documentation flows associated to quality management processes and help in the selection of methods and tools to support process improvements.Originality/valueThis study is one of the first reporting the use of LM tools and practices as complementary to the BPM methodology to support the improvement of information and documentation flows associated to quality management in a large manufacturing company. This research enriches the literature by presenting empirical evidence that these two continuous improvement approaches are not incompatible in their objectives and visions and can complement each other.
The holding pattern of the worker Bs: how bifurcation of consciousness impacts female academic career progression
Authors: Sharafizad Fleur , Brown Kerry , Jogulu Uma , Omari Maryam , Gander Michelle 
Published: July 2024

PurposeThis paper examines an identified but unexplored career gap evidenced at a mid-level classification in the academic career path for women in Australia. This career-stalling effect or holding pattern, is examined to determine underlying causes of career trajectory interruption.Design/methodology/approachGuided by the epistemological stance of standpoint theory, this exploratory abductive study employs a novel arts-based method, draw, write, reflect, to access experiences that may be difficult to convey verbally. The obtained drawings and reflections were thematically analysed.FindingsDrawing on Bourdieu’s concept of illusio this article finds support for female academics’ bifurcated consciousness. Results demonstrate how opposing social role prescriptions result in the deliberate avoidance of work-life conflict, a nuanced lack of confidence in work tasks in combination with other, often competing responsibilities, and the uneven distribution of administrative duties known as “academic housework”, which combine to stall careers. Female academics feel pressure to prioritise their domestic role and eschew career progression.Research limitations/implicationsDespite the small sample size, the findings provide rich career narratives and experiences of female academics in Australia providing additional impetus for increased gender equity efforts.Originality/valueThis study is the first to explore the previously unidentified holding pattern for female academics in Australia. Findings suggest there is a range of previously unexplored impediments resulting in a gendered stalling at a mid-level classification interrupting female academic career progression.