bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biofabrication of nanocomposite-based scaffolds containing human bone extracellular matrix for the differentiation of skeletal stem and progenitor cells
Authors: Kim Yang-Hee , Kanczler Janos M , Lanham Stuart , Rawlings Andrew , Roldo Marta , Tozzi Gianluca , Dawson Jonathan I. , Cidonio Gianluca , Oreffo Richard O.C 
Published: April 2023

AbstractAutograft or metal implants are routinely used in skeletal repair but can fail to provide a long-term clinical resolution, emphasising the need for a functional biomimetic tissue engineering alternative. An attractive sustainable opportunity for tissue regeneration would be the application of human bone waste tissue for the synthesis of a material ink for 3D bioprinting of skeletal tissue.The use of human bone extracellular matrix (bone-ECM) offers an exciting potential for the development of an appropriate micro-environment for human bone marrow stromal cells (HBMSCs) to proliferate and differentiate along the osteogenic lineage. Extrusion-based deposition was mediated by the blending of human bone-ECM (B) with nanoclay (L, Laponite®) and alginate (A) polymer, to engineer a novel material ink (LAB). The inclusion of nanofiller and polymeric material increased the rheological, printability, and drug retention properties and, critically, the preservation of HBMSCs viability upon printing. The composite human bone-ECM-based 3D constructs containing vascular endothelial growth factor (VEGF) enhanced vascularisation following implantation in anex vivochick chorioallantoic membrane (CAM) model. Addition of bone morphogenetic protein-2 (BMP-2) with HBMSCs further enhanced vascularisation together with mineralisation after only 7 days.The current study demonstrates the synergistic combination of nanoclay with biomimetic materials, (alginate and bone-ECM) to support the formation of osteogenic tissue bothin vitroandex vivoand offers a promising novel 3D bioprinting approach to personalised skeletal tissue repair.Graphical AbstractEngineering nanoclay-based bone ECM novel bioink for bone regeneration. Human bone trabecular tissue was demineralised, decellularised and blended with nanoclay (Laponite®) and alginate after digestion. The resulting ink was investigated for printability following rheological and filament fusion investigation. The microstructural arrangement of the blends was examined together with viability and functionality of bioprinted HBMSCs. Finally, the ability of the novel blend to support drug release ex vivo in a CAM model was determined confirming the potential of the bone ECM ink to support bone formation.
A statistical framework for quantifying the nuclear export rate of influenza viral mRNAs
Authors: Miura Michi , Kiuchi Naho , Lau Siu-Ying , Mok Bobo Wing-Yee , Ushirogawa Hiroshi , Naito Tadasuke , Chen Honglin , Saito Mineki 
Published: April 2023

AbstractInfluenza A virus transcribes viral mRNAs from the eight segmented viral genome when it infects. The kinetics of viral transcription, nuclear export of viral transcripts, and their potential variation between the eight segments are poorly characterised. Here we introduce a statistical framework for estimating the nuclear export rate of each segment from a snapshot ofin situmRNA localisation. This exploits the cell-to-cell variation at a single time point observed by an imaging-basedin situtranscriptome assay. Using our model, we revealed the variation in the mRNA nuclear export rate of the eight viral segments. Notably, the two influenza viral antigens hemagglutinin and neuraminidase were the slowest segments in the nuclear export, suggesting the possibility that influenza A virus uses the nuclear retention of viral transcripts to delay the expression of antigenic molecules. Our framework presented in this study can be widely used for investigating the nuclear retention of nascent transcripts produced in a transcription burst.
Independently evolved pollution resistance in four killifish populations is largely explained by few variants of large effect
Authors: Miller Jeffrey T. , Clark Bryan W. , Reid Noah M. , Karchner Sibel I. , Roach Jennifer L. , Hahn Mark E. , Nacci Diane , Whitehead Andrew 
Published: April 2023

ABSTRACTThe genetic architecture of phenotypic traits can affect the mode and tempo of trait evolution. Human-altered environments can impose strong natural selection, where successful evolutionary adaptation requires swift and large phenotypic shifts. In these scenarios, theory predicts the influence of few adaptive variants of large effect, but empirical studies that have revealed the genetic architecture of rapidly evolved phenotypes are rare, especially for populations inhabiting polluted environments.Funduluskillifish have repeatedly evolved adaptive resistance to extreme pollution in urban estuaries. Prior studies, including genome scans for signatures of natural selection, have revealed some of the genes and pathways important for evolved pollution resistance, and provide context for the genotype-phenotype association studies reported here. We created multiple quantitative trait locus (QTL) mapping families using progenitors from four different resistant populations, and genetically mapped variation in sensitivity (developmental perturbations) following embryonic exposure to a model toxicant PCB-126. We found that a few large-effect QTL loci accounted for resistance to PCB- mediated developmental toxicity. QTLs harbored candidate genes that govern the regulation of aryl hydrocarbon receptor (AHR) signaling, where some (but not all) of these QTL loci were shared across all populations, and some (but not all) of these loci showed signatures of recent natural selection in the corresponding wild population. Some strong candidate genes for PCB resistance inferred from genome scans in wild populations were identified as QTL, but some key candidate genes were not. We conclude that rapidly evolved resistance to the developmental defects normally caused by PCB-126 is governed by few genes of large effect. However, other aspects of resistance beyond developmental phenotypes may be governed by additional loci, such that comprehensive resistance to PCB-126, and to the mixtures of chemicals that distinguish urban estuaries more broadly, may be more genetically complex.
SynDISCO: A Mechanistic Modeling-Based Framework for Predictive Prioritization of Synergistic Drug Combinations Directed at Cell Signaling Networks
Authors: Shin Sung-Young , Nguyen Lan K. 
Published: April 2023

AbstractThe widespread development of resistance to cancer monotherapies has prompted the need to identify combinatorial treatment approaches that circumvent drug resistance and achieve more durable clinical benefit. However, given the vast space of possible combinations of existing drugs, the inaccessibility of drug screens to candidate targets with no available drugs, and the significant heterogeneity of cancers, exhaustive experimental testing of combination treatments remains highly impractical. There is thus an urgent need to develop computational approaches that complement experimental efforts and aid the identification and prioritization of effective drug combinations. Here, we provide a practical guide to SynDISCO, a computational framework that leverages mechanistic ODE modeling to predict and prioritize synergistic combination treatments directed at signaling networks. We demonstrate the key steps of SynDISCO and its application to the EGFR-MET signaling network in triple negative breast cancer as an illustrative example. SynDISCO is, however, a network- and cancer-independent framework, and given a suitable ODE model of the network of interest, it could be leveraged to discover cancer-specific combination treatments.
Experimental validation of computational models for the prediction of phase distribution during multi-channel transcranial alternating current stimulation
Authors: Lee Sangjun , Shirinpour Sina , Alekseichuk Ivan , Perera Nipun , Linn Gary , Schroeder Charles E. , Falchier Arnaud Y. , Opitz Alexander 
Published: April 2023

AbstractTranscranial alternating current stimulation (tACS) is a widely used noninvasive brain stimulation (NIBS) technique to affect neural activity. Neural oscillations exhibit phase-dependent associations with cognitive functions, and tools to manipulate local oscillatory phases can affect communication across remote brain regions. A recent study demonstrated that multi-channel tACS can generate electric fields with a phase gradient or traveling waves in the brain. Computational simulations using phasor algebra can predict the phase distribution inside the brain and aid in informing parameters in tACS experiments. However, experimental validation of computational models for multi-phase tACS is still lacking. Here, we develop such a framework for phasor simulation and evaluate its accuracy usingin vivorecordings in nonhuman primates. We extract the phase and amplitude of electric fields from intracranial recordings in two monkeys during multi-channel tACS and compare them to those calculated by phasor analysis using finite element models. Our findings demonstrate that simulated phases correspond well to measured phases (r = 0.9). Further, we systematically evaluated the impact of accurate electrode placement on modeling and data agreement. Finally, our framework can predict the amplitude distribution in measurements given calibrated tissues’ conductivity. Our validated general framework for simulating multi-phase, multi-electrode tACS provides a streamlined tool for principled planning of multi-channel tACS experiments.
Tree-based QTL mapping with expected local genetic relatedness matrices
Authors: Link Vivian , Schraiber Joshua G. , Fan Caoqi , Dinh Bryan , Mancuso Nicholas , Chiang Charleston W.K. , Edge Michael D. 
Published: April 2023

AbstractUnderstanding the genetic basis of complex phenotypes is a central pursuit of genetics. Genome-wide Association Studies (GWAS) are a powerful way to find genetic loci associated with phenotypes. GWAS are widely and successfully used, but they face challenges related to the fact that variants are tested for association with a phenotype independently, whereas in reality variants at different sites are correlated because of their shared evolutionary history. One way to model this shared history is through the ancestral recombination graph (ARG), which encodes a series of local coalescent trees. Recent computational and methodological breakthroughs have made it feasible to estimate approximate ARGs from large-scale samples. Here, we explore the potential of an ARG-based approach to quantitative-trait locus (QTL) mapping, echoing existing variance-components approaches. We propose a framework that relies on the conditional expectation of a local genetic relatedness matrix given the ARG (local eGRM). Simulations show that our method is especially beneficial for finding QTLs in the presence of allelic heterogeneity. By framing QTL mapping in terms of the estimated ARG, we can also facilitate the detection of QTLs in understudied populations. We use local eGRM to identify a large-effect BMI locus, theCREBRFgene, in a sample of Native Hawaiians in which it was not previously detectable by GWAS because of a lack of population-specific imputation resources. Our investigations can provide intuition about the benefits of using estimated ARGs in population- and statistical-genetic methods in general.
An Ecological Study on the Associations of County-Based Credit Ratings with Age-Adjusted Mortality Rates in Michigan
Authors: Rogers John P , Dempsey Tyler J 
Published: April 2023

AbstractThe objective of this study was to examine the association and implications between 21 Michigan county-specific credit ratings and age-adjusted mortality rates averaged across six quarters of county-specific data. Pearson’s regression analysis was performed and indicated that county credit ratings were significantly associated with average age-adjusted county mortality rates (r = 0.7715, p = 0.0000421), with lower county credit ratings corresponding to higher average age-adjusted county mortality rates. The results indicate that county credit ratings are associated with negative public health outcomes specific to that county, which the investigators propose mechanistically relates difficulty of local governments ascertaining low-cost funding for community health, infrastructure, and economic development projects.
Neural encoding of multiple motion speeds in visual cortical area MT
Authors: Huang Xin , Ghimire Bikalpa , Chakrala Anjani Sreeprada , Wiesner Steven 
Published: April 2023

ABSTRACTSegmenting objects from each other and their background is critical for vision. The speed at which objects move provides a salient cue for segmentation. However, how the visual system represents and differentiates multiple speeds is largely unknown. Here we investigated the neural encoding of multiple speeds of overlapping stimuli in the primate visual cortex. We first characterized the perceptual capacity of human and monkey subjects to segment spatially overlapping stimuli moving at different speeds. We then determined how neurons in the motion-sensitive, middle-temporal (MT) cortex of macaque monkeys encode multiple speeds. We made a novel finding that the responses of MT neurons to two speeds of overlapping stimuli showed a robust bias toward the faster speed component when both speeds were slow (≤ 20°/s). The faster-speed bias occurred even when a neuron had a slow preferred speed and responded more strongly to the slower component than the faster component when presented alone. The faster-speed bias emerged very early in neuronal response and was robust over time and to manipulations of motion direction and attention. As the stimulus speed increased, the faster-speed bias changed to response averaging. Our finding can be explained by a modified divisive normalization model, in which the weights for the speed components are proportional to the responses of a population of neurons elicited by the individual speeds. Our results suggest that the neuron population, referred to as the weighting pool, includes neurons that have a broad range of speed preferences. As a result, the response weights for the speed components are determined by the stimulus speeds and invariant to the speed preferences of individual neurons. Our findings help to define the neural encoding rule of multiple stimuli and provide new insight into the underlying neural mechanisms. The faster-speed bias would benefit behavioral tasks such as figure-ground segregation if figural objects tend to move faster than the background in the natural environment.
Latent taste diversity revealed by a vertebrate-wide catalogue of T1R receptors
Authors: Nishihara Hidenori , Toda Yasuka , Kuramoto Tae , Kamohara Kota , Goto Azusa , Hoshino Kyoko , Okada Shinji , Kuraku Shigehiro , Okabe Masataka , Ishimaru Yoshiro 
Published: April 2023

AbstractTaste is a vital chemical sense for feeding behavior. In mammals, the umami and sweet taste receptors are composed of three members of the taste receptor type 1 (T1R/TAS1R) family: T1R1, T1R2, and T1R3. Because their functional homologs exist in teleosts, only threeTAS1Rgenes generated by gene duplication are believed to have been inherited from the common ancestor of bony vertebrates. Here, we report five previously uncharacterizedTAS1Rmembers in vertebrates, namedTAS1R4,5,6,7, andTAS1Rcf, through a genome-wide survey of diverse taxa. ForTAS1R2andTAS1R3, mammalian and teleost fish genes were found to be paralogous. Phylogenetic analysis suggests that the bony vertebrate ancestor had nineTAS1Rsdue to multiple gene duplications, and someTAS1Rs were lost independently in each lineage; ultimately, mammals and teleosts have retained only threeTAS1Rs, whereas other lineages have retained moreTAS1Rs. Functional assays and expression analysis in non-teleost fishes suggest that the novel T1Rs form heterodimers in taste receptor cells and contribute to the recognition of a broad range of ligands such as essential amino acids, including branched-chain amino acids, which were not previously considered as T1R ligands. These results highlight an unexpected diversity of taste sensations in both modern and the ancestors of vertebrates. The complex evolution of the taste receptor family might have enabled vertebrates to adapt to diverse habitats on Earth.
Measuring human cerebral blood flow and brain function with fiber-based speckle contrast optical spectroscopy system
Authors: Kim Byungchan , Zilpelwar Sharvari , Sie Edbert J. , Marsili Francesco , Zimmermann Bernhard , Boas David A. , Cheng Xiaojun 
Published: April 2023

AbstractCerebral blood flow (CBF) is an important indicator of brain health and function. Diffuse correlation spectroscopy (DCS) is an optical technique that enables non-invasive and continuous bedside monitoring of human CBF. However, traditional DCS consisting of a few channels has relatively low signal-to-noise ratio (SNR), preventing measurements at long source detector separations (SDS) with increased sensitivity to cerebral rather than extracerebral blood flow. Here we developed a fiber-based speckle contrast optical spectroscopy (SCOS) system and the corresponding data analysis pipeline to measure CBF variations. We show that SCOS outperforms traditional DCS by more than an order of magnitude in SNR with comparable financial cost. We also demonstrated human brain function measurements during a cognitive task at an SDS of 33mm. This technology will establish the foundation for devices that use spatial speckle statistics to non-invasively monitor human CBF, leading to a new functional neuroimaging approach for cognitive neuroscience.
piTracer - Automatic reconstruction of molecular cascades for the identification of synergistic drug targets
Authors: Gomari Daniel , Achkar Iman W. , Benedetti Elisa , Tabling Jan , Halama Anna , Krumsiek Jan 
Published: April 2023

AbstractCancer cells frequently undergo metabolic reprogramming as a mechanism of resistance against chemotherapeutic drugs. Metabolomic profiling provides a direct readout of metabolic changes and can thus be used to identify these tumor escape mechanisms. Here, we introduce piTracer, a computational tool that uses multi-scale molecular networks to identify potential combination therapies from pre- and post-treatment metabolomics data. We first demonstrate piTracer’s core ability to reconstruct cellular cascades by inspecting well-characterized molecular pathways and previously studied associations between genetic variants and metabolite levels. We then apply a new gene ranking algorithm on differential metabolomic profiles from human breast cancer cells after glutaminase inhibition. Four of the automatically identified gene targets were experimentally tested by simultaneous inhibition of the respective targets and glutaminase. Of these combination treatments, two were be confirmed to induce synthetic lethality in the cell line. In summary, piTracer integrates the molecular monitoring of escape mechanisms into comprehensive pathway networks to accelerate drug target identification. The tool is open source and can be accessed athttps://github.com/krumsieklab/pitracer.
Cell cycle regulation of the psoriasis associated geneCCHCR1by transcription factor E2F1
Authors: Ling Yick Hin , Chen Yingying , Leung Kwok Nam , Chan King Ming , Liu Wing Keung 
Published: April 2023

AbstractThe coiled-coil alpha-helical rod protein 1 (CCHCR1) was first identified as a candidate gene in psoriasis and has lately been associated with COVID-19 susceptibility. Located within P-bodies and centrosomes, its exact cellular role and transcriptional control remain largely unknown. Here, we showed thatCCHCR1shares a bidirectional promoter with its neighboring gene,TCF19. This bidirectional promoter is activated by the G1/S-regulatory transcription factor E2F1, and both genes are co-induced during the G1/S transition of the cell cycle. A luciferase reporter assay suggests that the short intergenic sequence, only 287 bp in length, is sufficient for the G1/S induction of both genes, but the expression ofCCHCR1is further enhanced by the presence of exon 1 from bothTCF19andCCHCR1. This research uncovers the transcriptional regulation of theCCHCR1gene, offering new perspectives on its function. These findings contribute to the broader understanding of diseases associated with CCHCR1 and may serve as a foundational step for future research in these vital medical fields.
C. elegansmales optimize mate-choice decisions via sex-specific responses to multimodal sensory cues
Authors: Luo Jintao , Barrios Arantza , Portman Douglas S. 
Published: April 2023

SUMMARYFor sexually reproducing animals, selecting optimal mates is essential for maximizing reproductive fitness. Because the nematodeC. elegansreproduces mostly by self-fertilization, little is known about its mate-choice behaviors. While several sensory cues have been implicated in males’ ability to recognize hermaphrodites, achieving an integrated understanding of the ways males use these cues to assess relevant characteristics of potential mates has proven challenging. Here, we use a choice-based social-interaction assay to explore the ability ofC. elegansmales to make and optimize mate choices. We find that males use a combination of volatile sex pheromones (VSPs), ascaroside pheromones, surface-bound chemical cues, and other signals to robustly assess a variety of features of potential mates. Specific aspects of mate choice are communicated by distinct signals: the presence of a sperm-depleted, receptive hermaphrodite is likely signaled by VSPs, while developmental stage and sex are redundantly specified by ascaroside pheromones and surface-associated cues. Ascarosides also signal nutritional information, allowing males to choose well-fed over starved mates, while both ascarosides and surface-associated cues cause males to prefer virgin over previously mated hermaphrodites. The male-specificity of these behavioral responses is determined by both male-specific neurons and the male state of sex-shared circuits, and we reveal an unexpected role for the sex-shared ASH sensory neurons in male attraction to endogenously produced hermaphrodite ascarosides. Together, our findings lead to an integrated view of the signaling and behavioral mechanisms by which males use diverse sensory cues to assess multiple features of potential mates and optimize mate choice.