bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physiological Changes Associated with Copper Sulfate-Induced Emesis in Felines
Authors: Murphey Charles P. , Shulgach Jonathan A. , Amin Pooja R. , Douglas Nerone K. , Bielanin John P. , Sampson Jacob T. , Horn Charles C. , Yates Bill J. 
Published: October 2022

AbstractNausea is a common disease symptom, yet there is no consensus regarding its physiological markers. In contrast, the process of vomiting is well documented as sequential muscular contractions of the diaphragm and abdominal muscles and esophageal shortening. Nausea, like other self-reported perceptions, is difficult to distinguish in preclinical models, but based on human experience emesis is usually preceded by nausea. Here we focused on measuring gastrointestinal and cardiorespiratory changes prior to emesis to provide additional insights into markers for nausea. Felines were instrumented to chronically record heart rate, respiration, and electromyographic (EMG) activity from the stomach and duodenum before and after intragastric delivery of saline or copper sulfate (CuSO4, from 83 to 322 mg). CuSO4is a prototypical emetic test agent that triggers vomiting primarily by action on GI vagal afferent fibers when administered intragastrically. CuSO4infusion elicited a significant increase in heart rate, decrease in respiratory rate, and a disruption of gastric and intestinal EMG activity several minutes prior to emesis. The change in EMG activity was most consistent in the duodenum. Administration of saline did not induce these effects. Increasing the dose of CuSO4did not alter the physiologic changes induced by the treatment. It is postulated that the intestinal EMG activity was related to a retrograde movement of chyme from the intestine to the stomach. These findings suggest that monitoring of intestinal EMG activity, perhaps in combination with heart rate, may provide the best indicator of the onset of nausea following treatments and in disease conditions, including GI disease, associated with emesis.
The PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer
Authors: Armaos Alexandros , Serra François , Núñez-Carpintero Iker , Seo Ji-Heui , Baca Sylvan C. , Gustincich Stefano , Valencia Alfonso , Freedman Matthew L. , Cirillo Davide , Giambartolomei Claudia , Tartaglia Gian Gaetano 
Published: October 2022

AbstractHere we introduce Promoter-ENhancer-GUided Interaction Networks (PENGUIN), a method to uncover protein-protein interaction (PPI) networks at enhancer-promoter contacts. By integrating H3K27ac-HiChIP data and tissue-specific PPI information, PENGUIN enables cluster enhancers-promoter PPI networks (EPINs) and pinpoint actionable factors.Validating PENGUIN in cancer (LNCaP) and benign (LHSAR) prostate cell lines, we observed distinct CTCF-enriched clusters, which identifies diverse chromatin conformations. In LNCaP, we found an EPIN cluster enriched with oncogenes and prostate cancer-associated SNPs. We uncovered a total of 208 SNPs in LNCaP EPINs and used CRISPR/Cas9 knockout and RNAi screens to confirm their relevance.PENGUIN’s application in prostate cancer demonstrates its potential for studying human diseases. The approach allows exploration in different cell types and combinations of GWAS data, offering promising avenues for future investigations. In conclusion, PENGUIN provides valuable insights into the interplay between enhancer-promoter interactions and PPI networks, facilitating the identification of relevant genes and potential intervention targets.
Anticancer and antibacterial activities of secondary bioactive compounds from endosymbiotic bacteria of aphid and their surrounding organisms (Predator and protector)
Authors: Alsufyani Taghreed A. , Al-Otaibi Najwa , Alotaibi Noura J. , M’sakni Nour H , Alghamdi Eman M. 
Published: October 2022

AbstractSecondary metabolites of bacterial origin are a valuable source of diverse molecules with antibacterial and anticancer activities. In the current study, 10 endosymbiotic bacteria were isolated from aphids, aphid predators and ants. Bacterial strains were identified based on the 16S rRNA gene. Crude extracts were prepared from each isolated bacteria and tested for their antibacterial activities using the disk diffusion method. The extracts of three bacterial species;Planococcussp,Klebsiella aerogenes, Enterococcus aviumfromAphis punicae, Chrysoperia carneaandTapinoma magnum, respectively were found to have strong antibacterial activities against one or more of the five pathogenic bacteria tested. The inhibition zones ranged from 10.00± 0.13 to 20.00± 1.11mm with minimum inhibitory concentration (MIC) values ranged from 0.156 mg/mL to 1.25 mg/mL. The notable antibacterial activity was for the crude extract ofK. aerogenesagainstKlebsiella pneumoniaandEscherichia coliat MIC value of 0.156 mg/mL. The cytotoxic activity of the crude extracts varied according to the tested cell line. The most cytotoxic effect was for the extracts ofK. aerogenesandE. aviumat a concentration of 0.16 mg/mL against lung carcinoma epithelial cells (A549) with cell reduction of 79.4% and 67.2%, respectively. Crude extracts ofK. aerogenesandPantoea agglomeransat a concentration of 0.16 mg/mL showed 69.4% and 67.8% cell reduction against human colon cancer (Hct116), respectively. Gas chromatography–mass spectrometry (GC-MS) analysis of three crude extracts revealed the presence of several bioactive secondary metabolites that have been reported previously to possess antibacterial and anticancer properties. To the best of our knowledge, this is the first study to report the biological activities of endosymbiotic bacteria from aphids, aphid predators and ants. The promising data presented in this study opens a new avenue for alternative drugs to overcome the continuous emergence of multidrug-resistant bacteria and to find alternative drugs for traditional cancer therapies.
Understanding Vascular Endothelial Cell Behavior Using a Mechanical Strain Gradient Generated by an Electromagnetic Stretching Device
Authors: Yang Michelle L. , Zuo Catalina , Liu Jiafeng , Man Kun , Zuo Zhenyu , Yang Yong 
Published: October 2022

AbstractCardiovascular diseases cause an estimated 17.9 million deaths globally each year (World Health Organization). Endothelial cells that line the vasculature and the endocardium are subjected to cyclic mechanical stretch. Deviation from physiological stretch can alter the endothelial function, having the risk of atherosclerosis and myocardial infarction. To understand the mechanical stretch effects, cell culture platforms that provide mechanical stretch have been developed. However, most of them have fixed strain and frequency, sometime not in the pathophysiological range. We thus developed a novel, electromagnetically driven, uniaxial stretching device, where cells were grown on a flexible polydimethylsiloxane (PDMS) membrane mounted onto a 3-D printed track. The strain of the membrane was readily controlled by tailoring the track design and the frequency was determined by electromagnetic actuation. Furthermore, the mechanical strain gradient was generated on a PDMS membrane with a tapered thickness. This strain gradient, ranging from 1.5% to 40%, covered both physiological and pathological vascular stretch ranges. When human vascular endothelial cells were subjected to the cyclic stretch, the cells exhibited strain-dependent cell and nuclear orientation and elongation perpendicular to the stretching direction, compared to the random cell and nuclear orientation under the static condition. However, the overstretching led to deviation from the aforementioned orientation and elongation, and impaired the tight junctions, leading to a leaky endothelium. This novel, versatile, cost-effective, pathophysiologically relevant stretching device provides a useful platform for advancement of vascular disease research and treatment.
MDM2 inhibitors, nutlin-3a and navtemadelin, retain efficacy in human and mouse cancer cells cultured in hypoxia
Authors: Clavero Ada Lerma , Boqvist Paula Lafqvist , Ingelshed Katrine , Bosdotter Cecilia , Sedimbi Saikiran , Jiang Long , Wermeling Fredrik , Vojtesek Borivoj , Lane David P. , Kannan Pavitra 
Published: October 2022

AbstractActivation of p53 by small molecule MDM2 inhibitors can induce cell cycle arrest or death in p53 wildtype cancer cells. However, cancer cells exposed to hypoxia can develop resistance to other small molecules, such as chemotherapies, that activate p53. Here, we evaluated whether hypoxia could render cancer cells insensitive to two MDM2 inhibitors with different potencies, nutlin-3a and navtemadlin. Inhibitor efficacy and potency were evaluated under short-term hypoxic conditions in human and mouse cancer cells expressing different p53 genotypes (wild-type, mutant, or null). Treatment of wild-type p53 cancer cells with MDM2 inhibitors reduced cell growth by >75% in hypoxia through activation of the p53-p21 signaling pathway; no inhibitor-induced growth reduction was observed in hypoxic mutant or null p53 cells except at very high concentrations. The concentration of inhibitors needed to induce the maximal p53 response was not significantly different in hypoxia compared to normoxia. However, inhibitor efficacy varied by species and by cell line, with stronger effects at lower concentrations observed in human cell lines than in mouse cell lines grown as 2D and 3D cultures. Together, these results indicate that MDM2 inhibitors retain efficacy in hypoxia, suggesting they could be useful for targeting acutely hypoxic cancer cells.
Quantitative analysis of calcium oxalate monohydrate and dihydrate for elucidating the formation mechanism of calcium oxalate kidney stones
Authors: Maruyama Mihoko , Sawada Koichi P. , Tanaka Yutaro , Okada Atsushi , Momma Koichi , Nakamura Masanori , Mori Ryota , Furukawa Yoshihiro , Sugiura Yuki , Tajiri Rie , Taguchi Kazumi , Hamamoto Shuzo , Ando Ryosuke , Tsukamoto Katsuo , Takano Kazufumi , Imanishi Masayuki , Yoshimura Masashi , Yasui Takahiro , Mori Yusuke 
Published: October 2022

AbstractWe aimed to identify and quantitatively analyze calcium oxalate (CaOx) kidney stones on the order of micrometers, with a focus on the quantitative identification of calcium oxalate monohydrate (COM) and dihydrate (COD). Fourier Transform Infrared (FTIR) spectroscopy, powder X-ray diffraction (PXRD), and microfocus X-ray CT measurements (micro-CT) were performed, and the results were compared. The extended analysis method of the FTIR spectrum, focusing on the 780 cm−1peak, made it possible to achieve a reliable analysis of the COM/COD ratio. We succeeded in the quantitative analysis of COM/COD in the region of 50 × 50 μm by microscopic FTIR for thin sections of kidney stones, and by the micro-CT for bulk samples. The extended analysis method of the FTIR spectrum focusing on the 780 cm−1peak was introduced to analyze the COM/COD ratio. The analysis results based on PXRD measurement with micro sampling, microscopic FTIR analysis of a thin section, and micro-CT observation of a bulk sample of a kidney stone showed roughly consistent results, indicating that all methods can be used complementarily. This quantitative analysis method evaluates the detailed CaOx composition on the preserved stone surface and provides information on the stone formation processes and interactions with organic molecules.
Multigenerational effect of heat stress on theDrosophila melanogastersperm proteome
Authors: Khan Shagufta , Mishra Rakesh K 
Published: October 2022

ABSTRACTThe notion that genes are the sole units of heredity and that a barrier exists between soma and germline has been a major hurdle in elucidating the heritability of traits that were observed to follow a non-Mendelian inheritance pattern. It was only after the conception of epigenetics by Conrad Waddington that the effect of parental environment on subsequent generations via non-DNA sequence-based mechanisms, such as DNA methylation, chromatin modifications, non-coding RNAs and proteins, could be established, now referred to as multigenerational epigenetic inheritance. Despite growing evidence, the male gamete-derived epigenetic factors that mediate the transmission of such phenotypes are seldom explored, particularly in the model organismDrosophila melanogaster. Using the heat stress-induced multigenerational epigenetic inheritance paradigm in a widely used position-effect variegation line ofDrosophila, namedwhite-mottled, we have dissected the effect of heat stress on the sperm proteome in the current study. We demonstrate that multiple successive generations of heat stress at the early embryonic stage results in a significant downregulation of proteins associated with a diverse set of functions, such as translation, chromatin organization, microtubule-based processes, and generation of metabolites and energy, in the sperms. Based on our findings, we propose chromatin-based epigenetic mechanisms, a well-established mechanism for multigenerational effects, as a plausible way of transmitting heat stress memory via the male germline in this case. Moreover, we show that despite these heat stress-induced changes, the life-history traits, such as reproductive fitness and stress tolerance of the subsequent generations, are unaffected, probing the evolutionary relevance of multigenerational epigenetic effects.
Parsing brain-behavior heterogeneity in very preterm born children using integrated similarity networks
Authors: Hadaya Laila , Dimitrakopoulou Konstantina , Vanes Lucy , Kanel Dana , Fenn-Moltu Sunniva , Gale-Grant Oliver , Counsell Serena J , Edwards A David , Saqi Mansoor , Batalle Dafnis , Nosarti Chiara 
Published: October 2022

AbstractVery preterm birth (VPT; ≤ 32 weeks’ gestation) is associated with altered brain development and cognitive and behavioral difficulties across the lifespan. However, heterogeneity in outcomes among individuals born VPT makes it challenging to identify those most vulnerable to neurodevelopmental sequelae. Here, we aimed to stratify VPT children into distinct behavioral subgroups and explore between-subgroup differences in neonatal brain structure and function. 198 VPT children (98 females) previously enrolled in the Evaluation of Preterm Imaging study (EudraCT 2009-011602-42) underwent Magnetic Resonance Imaging at term-equivalent age and neuropsychological assessments at 4-7 years. Using an integrative clustering approach, we combined neonatal socio-demographic, clinical factors and childhood socio-emotional and executive function outcomes, to identify distinct subgroups of children based on their similarity profiles in a multidimensional space. We characterized resultant subgroups using domain-specific outcomes (temperament, psychopathology, IQ and cognitively stimulating home environment) and explored between-subgroup differences in neonatal brain volumes (voxel-wise Tensor-Based-Morphometry), functional connectivity (voxel-wise degree centrality) and structural connectivity (Tract-Based-Spatial-Statistics). Results showed two-and three-cluster data-driven solutions. The two-cluster solution comprised a ‘resilient’ subgroup (lower psychopathology and higher IQ, executive function and socio-emotional outcomes) and an ‘at-risk’ subgroup (poorer behavioral and cognitive outcomes). The three-cluster solution showed an additional third ‘intermediate’ subgroup displaying behavioral and cognitive outcomes intermediate between the resilient and at-risk subgroups. The resilient subgroup had the most cognitively stimulating home environment and the at-risk subgroup showed the highest neonatal clinical risk, while the intermediate subgroup showed the lowest clinical but the highest socio-demographic risk. Compared to the intermediate subgroup, the resilient subgroup displayed larger neonatal insular and orbitofrontal volumes and stronger orbitofrontal functional connectivity, while the at-risk group showed widespread white matter microstructural alterations. These findings suggest that risk stratification following VPT birth is feasible and could be used translationally to guide personalized interventions aimed at promoting children’s resilience.
Posteromedial thalamic nucleus activity significantly contributes to perceptual discrimination
Authors: Qi Jia , Ye Changquan , Naskar Shovan , Inácio Ana R. , Lee Soohyun 
Published: October 2022

AbstractHigher-order sensory thalamic nuclei are densely connected with multiple cortical and subcortical areas, yet the role of these nuclei remains elusive. The posteromedial (POm) thalamic nucleus, the higher-order thalamic nucleus in the rodent somatosensory system, is an anatomical hub broadly connected with multiple sensory and motor brain areas, yet weakly responds to passive sensory stimulation and whisker movements. To understand the role of POm in sensory perception, we developed a self-initiated, two-alternative forced-choice task in freely moving mice during active sensing. Using optogenetic and chemogenetic manipulation, we show that POm thalamic nucleus plays a significant role in sensory perception and the projection from the primary somatosensory cortex to POm is critical for the contribution of POm in sensory perception during active sensing.
A Synthetic Dynamic Polyvinyl Alcohol Photoresin for Fast Volumetric Bioprinting of Functional Ultrasoft Hydrogel Constructs
Authors: Qiu Wanwan , Gehlen Jenny , Bernero Margherita , Gehre Christian , Schädli Gian Nutal , Müller Ralph , Qin Xiao-Hua 
Published: October 2022

AbstractTomographic volumetric bioprinting (VBP) enables fast photofabrication of cell-laden hydrogel constructs in one step, addressing the limitations of conventional layer-by-layer additive manufacturing. However, existing biomaterials that fulfill the physicochemical requirements of VBP are limited to gelatin-based photoresins of high polymer concentrations. The printed microenvironments are predominantly static and stiff, lacking sufficient capacity to support 3D cell growth. We here report a dynamic resin based on thiol-ene photo-clickable polyvinyl alcohol (PVA) and thermo-sensitive sacrificial gelatin for fast VBP of functional ultrasoft cell-laden hydrogel constructs within 7-15 seconds. Using gelatin allows VBP of permissive hydrogels with low PVA contents of 1.5%, providing a stress-relaxing environment for fast cell spreading, 3D osteogenic differentiation of embedded human mesenchymal stem cells and matrix mineralization. Additionally, site-specific immobilization of molecules-of-interest inside a PVA hydrogel is achieved by 4D tomographic thiol-ene photopatterning. This technique may enable spatiotemporal control of cell-material interactions and guidedin vitrotissue formation using programmed cell-friendly light. Altogether, this study introduces a synthetic dynamic photoresin enabling fast VBP of functional ultrasoft hydrogel constructs with well-defined physicochemical properties and high efficiency.
Zebrafish anterior segment mesenchyme progenitors are defined by function of tfap2a but not sox10
Authors: Vöcking Oliver , Van Der Meulen K , Patel M.K , Famulski J.K 
Published: October 2022

ABSTRACTThe anterior segment is a critical component of the visual system. Developing independent of the retina, the AS relies partially on cranial neural crest cells (cNCC) as its earliest progenitors. The cNCCs are thought to first adopt a periocular mesenchyme (POM) fate and subsequently target to the AS upon formation of the rudimentary retina. AS targeted POM is termed anterior segment mesenchyme (ASM). However, it remains unknown when and how the switch from cNCC to POM or POM to ASM takes place. As such, we sought to visualize the timing of these transitions and identify the regulators of this process using the zebrafish embryo model. Using two color fluorescencein situhybridization, we tracked cNCC and ASM target gene expression from 12-24hpf. In doing so, we identified atfap2aandfoxc1aco-expression at 16hpf, identifying the earliest ASM to arrive at the AS. Interestingly, expression of two other key regulators of NCC,foxD3andsox10was not associated with early ASM. Functional analysis of tfap2a, foxd3 and sox10 revealed that tfap2a and foxd3 are both critical regulators of ASM specification and AS formation while sox10 was dispensable for either specification or development of the AS. Using genetic knockout lines, we show that in the absence of tfap2a or foxD3 function ASM cells are not specified, and subsequently the AS is malformed. Conversely, sox10 genetic mutants or CRISPR Cas9 injected embryos displayed no defects in ASM specification, migration or the AS. Lastly, using transcriptomic analysis, we show that GFP+ cNCCs derived from Tg[foxd3:GFP] and Tg[foxc1b:GFP] share expression profiles consistent with ASM development whereas cNCCs isolated from Tg[sox10:GFP] exhibit expression profiles associated with vasculogenesis, muscle function and pigmentation. Taken together, we identify the earliest stage of anterior segment mesenchyme (ASM) specification to be approximately 16hpf and involve tfap2a/foxc1a positive cNCCs.
High bacillary burden and the ESX-1 type VII secretion system promote MHC class I presentation byMycobacterium tuberculosisinfected macrophages to CD8 T-cells
Authors: Mott Daniel , Yang Jason , Baer Christina , Papavinasasundaram Kadamba , Sassetti Christopher M. , Behar Samuel M. 
Published: October 2022

AbstractMycobacterium tuberculosis(Mtb) subverts host defenses to persist in macrophages despite immune pressure. CD4 T-cells can recognize macrophages infected with a single bacillusin vitro. Under identical conditions, CD8 T-cells inefficiently recognize infected macrophages and fail to restrict Mtb growth, although they can inhibit Mtb growth during high burden intracellular infection. We show that high intracellular Mtb numbers cause macrophage death, leading other macrophages to scavenge cellular debris and cross-present the TB10.4 antigen to CD8 T-cells. Presentation by infected macrophages requires Mtb to have a functional ESX-1 type VII secretion system. These data indicate that phagosomal membrane damage and cell death promote class I MHC presentation of the immunodominant antigen TB10.4 by macrophages. Although this mode of antigen-presentation stimulates cytokine production that we presume would be host beneficial; killing of uninfected cells could worsen immunopathology. We suggest that shifting the focus of CD8 T-cell recognition to uninfected macrophages would limit the interaction of CD8 T-cells with infected macrophages and impair CD8 T-cell mediated resolution of tuberculosis.
Structural and molecular biology of Acheta domesticus segmented densovirus, the first parvovirus to harbor a bipartite genome
Authors: Penzes Judit J. , Pham Hanh T. , Chipman Paul , Smith Emmanuel W. , McKenna Robert , Tijssen Peter 
Published: October 2022

AbstractParvoviruses (familyParvoviridae) are defined by their linear monopartite ssDNA genome, T=1 icosahedral capsid, and distinct structural (VP) and non-structural (NS) protein expression cassettes within their genome. Here, we report the first parvovirus with a segmented genome, Acheta domesticus segmented densovirus (AdSDV), a house cricket (Acheta domesticus) pathogen. The AdSDV harbors its NS and VP cassettes on two separate segmented genomes. Its VP segment acquired a phospholipase A2-encoding gene via inter-subfamily recombination, which is absent from its capsid. The AdSDV evolved a transcription profile in response to its multipartite replication strategy that has diverged from itsBrevihamaparvovirusancestors. Furthermore, AdSDV assembles three capsid populations, which package one genome segment per particle. The cryoEM structures of these three capsids (2.3 to 3.3 Å resolution) reveal a genome packaging mechanism, which differs from other parvoviruses. This study provides a new perspective on ssDNA genome segmentation and on the plasticity of parvovirus biology.