bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ciliary ARL13B prevents obesity in mice
Authors: Terry Tiffany T. , Gigante Eduardo D. , Alexandre Coralie M. , Brewer Kathryn M. , Engle Staci E. , Yue Xinyu , Berbari Nicolas F. , Vaisse Christian , Caspary Tamara 
Published: August 2023

AbstractCilia are near ubiquitous small, cellular appendages critical for cell-to-cell communication. As such, they are involved in diverse developmental and homeostatic processes, including energy homeostasis. ARL13B is a regulatory GTPase highly enriched in cilia. Mice expressing an engineered ARL13B variant, ARL13BV358Awhich retains normal biochemical activity, display no detectable ciliary ARL13B. Surprisingly, these mice become obese. Here, we measured body weight, food intake, and blood glucose levels to reveal these mice display hyperphagia and metabolic defects. We showed that ARL13B normally localizes to cilia of neurons in specific brain regions and pancreatic cells but is excluded from these cilia in theArl13bV358A/V358Amodel. In addition to its GTPase function, ARL13B acts as a guanine nucleotide exchange factor (GEF) for ARL3. To test whether ARL13B’s GEF activity is required to regulate body weight, we analyzed the body weight of mice expressing ARL13BR79Q, a variant that lacks ARL13B GEF activity for ARL3. We found no difference in body weight. Taken together, our results show that ARL13B functions within cilia to control body weight and that this function does not depend on its role as a GEF for ARL3. Controlling the subcellular localization of ARL13B in the engineered mouse model, ARL13BV358A, enables us to define the cilia-specific role of ARL13B in regulating energy homeostasis.
Unraveling the Global Proteome and Phosphoproteome of Prostate Cancer Patient-Derived Xenografts
Authors: Sychev Zoi E. , Day Abderrahman , Bergom Hannah E. , Larson Gabrianne , Ali Atef , Ludwig Megan , Boytim Ella , Coleman Ilsa , Corey Eva , Plymate Stephen R. , Nelson Peter S. , Hwang Justin H. , Drake Justin M. 
Published: August 2023

AbstractResistance to androgen deprivation therapies leads to metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform to emergent aggressive variant prostate cancer (AVPC) which has neuroendocrine (NE)-like features. To this end, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models that reflects and retains key features of the tumor from advanced prostate cancer patients. Here we performed proteome and phosphoproteome characterization of 48 LuCaP PDX tumors and identified over 94,000 peptides and 9,700 phosphopeptides corresponding to 7,738 proteins. When we compared 15 NE versus 33 AdCa PDX samples, we identified 309 unique proteins and 476 unique phosphopeptides that were significantly altered and corresponded to proteins that are known to distinguish these two phenotypes. Assessment of protein and RNA concordance from these tumors revealed increased dissonance in transcriptionally regulated proteins in NE and metabolite interconversion enzymes in AdCa.
The interplay of cortical magnification and perceptual load in the visual processing of task-irrelevant biological motion across the visual field
Authors: Tunca Murat Batu , Rezaki Ada Dilek , Nizamoğlu Hilal , Urgen Burcu A. 
Published: August 2023

AbstractPerceptual load theory argues that attention is a limited resource and stimuli cannot be processed if there is insufficient perceptual capacity available. Although attention is known to modulate biological motion processing, whether this modulation differs among different perceptual loads remains unknown. To answer this question, three experiments are conducted in which biological motion is utilized as a task-irrelevant distractor. The first experiment showed that biological motion is processed differently than non-biological motion across different perceptual load conditions. The second experiment investigated the effect of attention on biological motion processing, revealing that higher eccentricities enhance biological motion processing but only when the perceptual load is low. The last experiment investigated the same question but with cortically magnified stimuli. It found that when the stimuli are cortically magnified, the enhancement effect of eccentricity is present regardless of the perceptual load. Overall, the results suggest that perceptual load modulates the processing of task-irrelevant biological motion and interacts with other factors (such as eccentricity) that modulate this processing.
Genetic Dependence and Genetic Diseases
Authors: Li Bin , Bian Wen-Jun , Zhou Peng , Wang Jie , Fan Cui-Xia , Xu Hai-Qing , Yu Lu , He Na , Shi Yi-Wu , Su Tao , Yi Yong-Hong , Liao Wei-Ping 
Published: August 2023

AbstractThe human life depends on the function of proteins that are encoded by about twenty-thousand genes. The gene-disease associations in majority genes are unknown and the mechanisms underlying pathogenicity of genes/variants and common diseases remain unclear. We studied how human life depends on the genes, i.e., the genetic-dependence, which was classified as genetic-dependent nature (GDN, vital consequence of abolishing a gene), genetic-dependent quantity (GDQ, quantitative genetic function required for normal life), and genetic-dependent stage (GDS, temporal expression pattern). Each gene differs in genetic-dependent features, which determines the gene-disease association extensively. The GDN is associated with the pathogenic potential/feature of genes and the strength of pathogenicity. The GDQ-damage relation determines the pathogenicity of variants and subsequently the pathogenic genotype, phenotype spectrum, and inheritance of variants. The GDS is mainly associated with the onset age/evolution/outcome and the nature of genetic disorders (disease/susceptibility). The varied and quantitative genetic-dependent feature of genome explains common mild phenotype/susceptibility. The genetic-dependence discloses the mechanisms underlying pathogenicity of gene/variants and common diseases.One sentence summaryGenetic dependent feature differs in genes and determines pathogenicity of genes/variants and the clinical features of genetic diseases.
piikun: An Information Theoretic Toolkit for Analysis and Visualization of Species Delimitation Metric Space
Authors: Sukumaran Jeet , Meila Marina 
Published: August 2023

AbstractBackgroundExisting software for comparison of species delimitation models do not provide a (true) metric or distance functions between species delimitation models, nor a way to compare these models in terms of relative clustering differences along a lattice of partitions.Resultspiikunis a Python package for analyzing and visualizing species delimitation models in an information theoretic framework that, in addition to classic measures of information such as the entropy and mutual information [1], provides for the calculation of the variation of information criterion [2], a true metric or distance function for species delimitation models that is aligned with the lattice of partitions.Conclusionspiikunis available under the MIT license from its public repository (https://github.com/jeetsukumaran/piikun), and can be installed locally using the Python package manager ‘pip’.
Early recovery of proteasome activity in cells pulse-treated with proteasome inhibitors is independent of DDI2
Authors: Ibtisam Ibtisam , Kisselev Alexei F. 
Published: August 2023

AbstractRapid recovery of proteasome activity may contribute to intrinsic and acquired resistance to FDA-approved proteasome inhibitors. Previous studies have demonstrated that the expression of proteasome genes in cells treated with sub-lethal concentrations of proteasome inhibitors is upregulated by the transcription factor Nrf1 (NFE2L1), which is activated by a DDI2 protease. Here, we demonstrate that the recovery of proteasome activity is DDI2-independent and occurs before transcription of proteasomal genes is upregulated but requires protein translation. Thus, mammalian cells possess an additional DDI2 and transcription-independent pathway for the rapid recovery of proteasome activity after proteasome inhibition.
Estimating the reproduction number,R0, from agent-based models of tree disease spread
Authors: Wadkin Laura E , Holden John , Ettelaie Rammile , Holmes Melvin J , Smith James , Golightly Andrew , Parker Nick G , Baggaley Andrew W 
Published: August 2023

AbstractTree populations worldwide are facing an unprecedented threat from a variety of tree diseases and invasive pests. Their spread, exacerbated by increasing globalisation and climate change, has an enormous environmental, economic and social impact. Computational agent-based models are a popular tool for describing and forecasting the spread of tree diseases due to their flexibility and ability to reveal collective behaviours. In this paper we present a versatile agentbased model with a Gaussian infectivity kernel to describe the spread of a generic tree disease through a synthetic treescape. We then explore several methods of calculating the basic reproduction numberR0, a characteristic measurement of disease infectivity, defining the expected number of new infections resulting from one newly infected individual throughout their infectious period. It is a useful comparative summary parameter of a disease and can be used to explore the threshold dynamics of epidemics through mathematical models. We demonstrate several methods of estimatingR0through the agent-based model, including contact tracing, inferring the Kermack-McKendrick SIR model parameters using the linear noise approximation, and an analytical approximation. As an illustrative example, we then use the model and each of the methods to calculate estimates ofR0for the ash dieback epidemic in the UK.
AAontology: An ontology of amino acid scales for interpretable machine learning
Authors: Breimann Stephan , Kamp Frits , Steiner Harald , Frishman Dmitrij 
Published: August 2023

AbstractAmino acid scales are crucial for protein prediction tasks, many of them being curated in the AAindex database. Despite various clustering attempts to organize them and to better understand their relationships, these approaches lack the fine-grained classification necessary for satisfactory interpretability in many protein prediction problems.To address this issue, we developed AAontology—a two-level classification for 586 amino acid scales (mainly from AAindex) together with an in-depth analysis of their relations—using bag-of-word-based classification, clustering, and manual refinement over multiple iterations. AAontology organizes physicochemical scales into 8 categories and 67 subcategories, enhancing the interpretability of scale-based machine learning methods in protein bioinformatics. Thereby it enables researchers to gain a deeper biological insight. We anticipate that AAontology will be a building block to link amino acid properties with protein function and dysfunctions as well as aid informed decision-making in mutation analysis or protein drug design.
Functional Adaptations of Endogenous Retroviruses to theDrosophilaHost Underlie their Evolutionary Diversification
Authors: Senti Kirsten-Andre , Handler Dominik , Rafanel Baptiste , Kosiol Carolin , Schlötterer Christian , Brennecke Julius 
Published: August 2023

AbstractTransposable elements profoundly affect the biology and evolution of their hosts, yet their own evolutionary dynamics remain poorly understood. Here, we investigate insect endogenous retroviruses (iERVs), a monophyletic group of LTR retrotransposons that have acquired the trait of infectivity, likely through capture of a Baculovirusenvelopegene. InDrosophilaovaries, iERVs with functionalenvelopehave adapted theircis-regulatory sequences to be expressed in any somatic cell type, from where they infect the germline. Strikingly, related retroviruses show distinct expression patterns, indicating niche partitioning. In contrast, all non-infectious iERVs that emerged through secondaryenvelope-loss are specifically expressed in the germline. Co-evolving with iERVs, the genome-protecting piRNA pathway has assimilated iERV promoter and sequence information into piRNA clusters, underscoring the functional significance of iERV expression in somatic niches. We propose that the evolutionary innovation of cell-to-cell infectivity has triggered the adaptive radiation of iERVs through trait diversification and antagonistic virus-host interactions, processes that likely underpin niche-specific expression of endogenous retroviruses in vertebrates as well.
TIM3 is a context-dependent co-regulator of cytotoxic T cell function
Authors: Alamir Hanin , Wong Carissa C.W. , Alsubaiti Amal , Edmunds Grace L. , Grant Tressan , Alsulaimani Safaa , Boyd James , Holland Christopher J. , Morgan David J. , Gallimore Awen M. , Wülfing Christoph 
Published: August 2023

AbstractTIM3 is a co-regulatory receptor that is highly expressed on multiple immune cell types, including on T cells after prolonged exposure to antigen. It marks functionally suppressed cytotoxic T lymphocytes (CTL) in the tumor microenvironment. However, it is unresolved whether TIM3 acts directly on suppressed CTL. Moreover, the nature of TIM3 ligands remains controversial. Paradoxically, TIM3 combines inhibitory function in vivo with costimulatory signaling capability in vitro. Here we have investigated TIM3 in the direct interaction of suppressed murine and human CTL with tumor target cell using spheroids. TIM3 directly inhibited the function of such CTL. TIM3 regulated the ability of suppressed CTL to polarize their cytoskeleton as a required step in cytolysis. Expression of CEACAM1 in cis, on the CTL, blocked TIM3 function, expression of CEACAM1 and galectin9 in trans, on the tumor target cells, enhanced TIM3 function. TIM3 only functioned as an inhibitory receptor on the spheroid-suppressed CTL, not on active CTL in a two-dimensional tissue culture model. These data suggest that TIM3 amplifies T cell function, serving as a co-inhibitory or co-stimulatory receptor depending on the functional context of the T cell it is expressed on.
Optogenetic strategies for optimizing the performance of biosensors of membrane phospholipids in live cells
Authors: Yao Yuanfa , Lou Xiayan , Jin Luhong , Sun Weiyun , Liu Jingfang , Chen Yunyue , Cheng Sunying , Zhao Tengjiao , Ke Shuwei , Zhang Luhao , Xu Yingke , He Lian , Li Hanbing 
Published: August 2023

AbstractHigh-performance biosensors play a crucial role in elucidating the intricate spatiotemporal regulatory roles and dynamics of membrane lipids. However, enhancing their sensitivity and substrate-detecting capabilities remains a significant challenge. Here, we presented optogenetic-based strategies to optimize phospholipid biosensors. These strategies involved pre-sequestering unbound probes in the cell nucleus to minimize background signals in the cytoplasm. These stored probes could be released from the nucleus in response to blue light according to experimental requirements. Furthermore, we employed optically-controlled phase separation to generate punctate probes that amplified signals and facilitated the visualization of phospholipids in cells. These improved phospholipid biosensors hold great potential for enhancing our understanding of the spatiotemporal dynamics and regulatory roles of membrane lipids in live cells and this methodological insights might be valuable for developing other high-performance biosensors.
Comparing auditory and visual aspects of multisensory working memory using bimodally matched feature patterns
Authors: Turpin Tori , Uluç Işıl , Kotlarz Parker , Lankinen Kaisu , Mamashli Fahimeh , Ahveninen Jyrki 
Published: August 2023

AbstractWorking memory (WM) reflects the transient maintenance of information in the absence of external input, which can be attained via multiple senses separately or simultaneously. Pertaining to WM, the prevailing literature suggests the dominance of vision over other sensory systems. However, this imbalance may be stemming from challenges in finding comparable stimuli across modalities. Here, we addressed this problem by using a balanced multisensory retro-cue WM design, which employed combinations of auditory (ripple sounds) and visuospatial (Gabor patches) patterns, adjusted relative to each participant’s discrimination ability. In three separate experiments, the participant was asked to determine whether the (retro-cued) auditory and/or visual items maintained in WM matched or mismatched the subsequent probe stimulus. In Experiment 1, all stimuli were audiovisual, and the probes were either fully mismatching, only partially mismatching, or fully matching the memorized item. Experiment 2 was otherwise same as Experiment 1, but the probes were unimodal. In Experiment 3, the participant was cued to maintain only the auditory or visual aspect of an audiovisual item pair. In two of the three experiments, the participant matching performance was significantly more accurate for the auditory than visual attributes of probes. When the perceptual and task demands are bimodally equated, auditory attributes can be matched to multisensory items in WM at least as accurately as, if not more precisely than, their visual counterparts.
Evaluating vaccine-elicited antibody activities againstNeisseria gonorrhoeae:cross-protective responses elicited by the 4CMenB meningococcal vaccine
Authors: Gray Mary C. , Thomas Keena S. , Lamb Evan R. , Werner Lacie M. , Connolly Kristie L. , Jerse Ann E. , Criss Alison K. 
Published: August 2023

AbstractThe bacterial pathogenNeisseria gonorrhoeaeis an urgent global health problem due to increasing numbers of infections, coupled with rampant antibiotic resistance. Vaccines against gonorrhea are being prioritized to combat drug-resistantN. gonorrhoeae.Meningococcal serogroup B vaccines such as 4CMenB are predicted by epidemiology studies to cross-protect individuals from natural infection withN. gonorrhoeaeand elicit antibodies that cross-react withN. gonorrhoeae.Evaluation of vaccine candidates for gonorrhea requires a suite of assays for predicting efficacy in vitro and in animal models of infection, including the role of antibodies elicited by immunization. Here we present assays to evaluate antibody functionality after immunization: antibody binding to intactN. gonorrhoeae,serum bactericidal activity, and opsonophagocytic killing activity using primary human neutrophils (polymorphonuclear leukocytes). These assays were developed with purified antibodies againstN. gonorrhoeaeand used to evaluate serum from mice that were vaccinated with 4CMenB or given alum as a negative control. Results from these assays will help prioritize gonorrhea vaccine candidates for advanced preclinical to early clinical study and will contribute to identifying correlates and mechanisms of immune protection againstN. gonorrhoeae.
Retinoid X Receptor activation prevents diabetic retinopathy in murine models
Authors: Dorofeeva Iuliia , Zhylkibayev Assylbek , Saltykova Irina V. , Atigadda Venkatram , Adhikari Bibek , Gorbatyuk Oleg , Grant Maria B. , Gorbatyuk Marina 
Published: August 2023

AbstractPreviously, the RXR agonist UAB126 demonstrated therapeutic potential to treat obese mice by controlling blood glucose levels (BGL) and altering the expression of genes associated with lipid metabolism and inflammatory response. The purpose of the study was to assess UAB126 effect in progression of diabetic retinopathy (DR) in rodent models of Type1 diabetes (T1D), streptozotocin-induced, and Type2 diabetes (T2D), the db/db mice. UAB126 treatment was delivered either by oral gavage for 6 weeks or by topical application of eye drops for 2 weeks. At the end of the treatment, the retinal function of diabetic mice was assessed by electroretinography (ERG), and their retinal tissue was harvested for protein and gene expression analyses. Bone-marrow cells were isolated and differentiated into bone marrow-derived macrophages (BMDMs). The glycolysis stress test and the 2-DG glucose uptake analysis were performed. Our results demonstrated that in the UAB126-treated diabetic BMDMs, the ECAR rate and the 2-DG uptake were improved as compared to untreated diabetic BMDMs. In UAB126-treated diabetic mice, hyperglycemia was reduced and associated with the preservation of ERG amplitudes and enhanced AMPK activity. Retinas from diabetic mice treated with topical UAB126 demonstrated an increase in Rxr and Ppar, and expression of genes associated with lipid metabolism. Altogether, our data indicate that RXR activation is beneficial to preclinical models of DR.
Identification of omega-3 oxylipins in human milk-derived extracellular vesicles with pro-resolutive actions in gastrointestinal inflammation
Authors: Gómez-Ferrer Marta , Amaro-Prellezo Elena , Albiach-Delgado Abel , Ten-Domenech Isabel , Kuligowski Julia , Sepúlveda Pilar 
Published: August 2023

ABSTRACTPremature infants (PIs) are at risk of suffering necrotizing enterocolitis (NEC), and infants consuming human milk (HM) show a lower incidence than infants receiving formula. The composition of HM has been studied in depth, but the lipid content of HM-derived small extracellular vesicles (HM sEVs) remains unexplored. We isolated HM sEVs from HM samples and analyzed their oxylipin content using liquid chromatography coupled to mass spectrometry, which revealed the presence of anti-inflammatory oxylipins. We then examined the efficacy of a mixture of these oxylipins in combating inflammation and fibrosis, in vitro and and in a murine model of inflammatory bowel disease (IBD). HM-related sEVs contained higher concentrations of oxylipins derived from docosahexaenoic acid, an omega-3 fatty acid. Three anti-inflammatory oxylipins, 14-HDHA, 17-HDHA, and 19,20-DiHDPA (ω3 OXLP), demonstrated similar efficacy to HM sEVs in preventing cell injury, inducing re-epithelialization, mitigating fibrosis, and modulating immune responses. Both ω3 OXLP and HM sEVs effectively reduced inflammation in IBD-model mice, preventing colon shortening, infiltration of inflammatory cells and tissue fibrosis. Incorporating this unique cocktail of oxylipins into fortified milk formulas might reduce the risk of NEC in PIs and also provide immunological and neurodevelopmental support.
Reconstitution of ORP-mediated lipid exchange process coupled to PI(4)P metabolism
Authors: Fuggetta Nicolas , Rigolli Nicola , Magdeleine Maud , Seminara Agnese , Drin Guillaume 
Published: August 2023

AbstractLipid distribution in the eukaryotic cells depends on tight couplings between lipid transfer and lipid metabolism. Yet these couplings remain poorly described. Notably, it is unclear to what extent lipid exchangers of the OSBP-related proteins (ORPs) family, coupled to PI(4)P metabolism, contribute to the formation of sterol and phosphatidylserine gradient between the endoplasmic reticulum (ER) and other cell regions. To address this question, we have examinedin vitrothe activity of Osh4p, a representative ORP, between Golgi mimetic membranes in which PI(4)P is produced by a PI 4-kinase and ER mimetic membranes in which PI(4)P is hydrolyzed by the phosphatase Sac1p. Using quantitative, real-time assays, we demonstrate that Osh4p creates a sterol gradient between the two membranes by sterol/PI(4)P exchange as soon as a PI(4)P gradient is generated at this interface following ATP addition, and define how much PI(4)P must be synthesized for this process. Then, using a kinetic model supported by ourin vitrodata, we estimate to what extent PI(4)P metabolism can drive lipid transfer in cells. Finally, we show that Sec14p, by transferring phosphatidylinositol between membranes, can support the synthesis of PI(4)P and the creation of a sterol gradient by Osh4p. These results indicate to what extent ORPs, under the control of PI(4)P metabolism, can distribute lipids in the cell.