bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clonal phylogenies inferred from bulk, single cell, and spatial transcriptomic analysis of cancer
Authors: Erickson Andrew , Figiel Sandy , Rajakumar Timothy , Rao Srinivasa , Yin Wencheng , Doultsinos Dimitrios , Magnussen Anette , Singh Reema , Poulose Ninu , Bryant Richard J , Cussenot Olivier , Hamdy Freddie C , Woodcock Dan , Mills Ian G , Lamb Alastair D 
Published: February 2023

AbstractEpithelial cancers are typically heterogeneous with primary prostate cancer being a typical example of histological and genomic variation. Prostate cancer is the second most common male cancer in western industrialized countries. Prior studies of primary prostate cancer tumor genetics revealed extensive inter and intra-patient tumor heterogeneity. Recent advances have enabled extensive single-cell and spatial transcriptomic profiling of tissue specimens. The ability to resolve accurate prostate cancer tumor phylogenies at high spatial resolution would provide tools to address questions in tumorigenesis, disease progression, and metastasis. Recent advances in machine learning have enabled the inference of ground-truth genomic single-nucleotide and copy number variant status from transcript data. The inferred SNV and CNV states can be used to resolve clonal phylogenies, however, it is still unknown how faithfully transcript-based tumor phylogenies reconstruct ground truth DNA-based tumor phylogenies. We sought to study the accuracy of inferred-transcript to recapitulate DNA-based tumor phylogenies.We first performed in-silico comparisons of inferred and directly resolved SNV and CNV status, from single cancer cells, from three different cell lines. We found that inferred SNV phylogenies accurately recapitulate DNA phylogenies (entanglement = 0.097). We observed similar results in iCNV and CNV based phylogenies (entanglement = 0.11). Analysis of published prostate cancer DNA phylogenies and inferred CNV, SNV and transcript based phylogenies demonstrated phylogenetic concordance. Finally, a comparison of pseudo-bulked spatial transcriptomic data to adjacent sections with WGS data also demonstrated recapitulation of ground truth (entanglement = 0.35). These results suggest that transcript-based inferred phylogenies recapitulate conventional genomic phylogenies. Further work will need to be done to increase accuracy, genomic, and spatial resolution.
Comparative experimental studies on Trypanosoma isolates in goats and response to diminazene aceturate and isometamidium chloride treatment
Authors: Ayele Abrham , Dagnachew Shimelis 
Published: February 2023

AbstractThe objective of this study was to characterize and compare the clinically visible pathological features and drug resistance patterns of two Trypanosoma isolates from two tsetse infested areas of northwest Ethiopia in experimentally infected goats. From the 37 trypanosome free goats, two goats (trypanosome donors) were used to take trypanosome isolates from naturally infected cattle (one from Jawi and the other from Jabitehenen areas). The remaining thirty five goats were randomly assigned into seven experimental groups, each containing five goats. These groups were again randomly selected, and three of them—Group 1 (JWI-1), Group 2 (JWI-DA), and Group 3 (JWI-ISM)—were inoculated with the Trypanosoma of Jawi isolate. Group-4 (JBI-1), Group-5 (JBI-DA), and Group-6 (JBI-ISM) were inoculated with the Trypanosoma of Jabitehenan isolate. The remaining group, Group 7 (NIC), was under negative control. Each experimental goat received 2 ml of trypanosoma positive blood at the 1×106parasites/ml from donor goats through the jugular vein. Group NIC received 2 mL of sterile water as a negative control. For ten weeks following infection, parameters such as parasitaemia, body weight, PCV, and hemoglobin value were measured once per week. When peak parasitaemia was detected on day 14 of post infection, trypanocidal treatment was administered. Diminazine diaceturate (DA) was given at a dose of 28 mg/kg, and isomethamedium chloride (ISM) was given at a dose of 4 mg/kg. Trypanosomosis was detected on days 5 and 6 of post-infection (Pi) in Jabitehenan and Jawi,T. congolenseisolates from infected groups, respectively. When peak parasitaemia was detected on day 14 of post infection, trypanocidal treatment was administered. 7 mg/kg for Group 2 and Group 5 and 1 mg/kg for Group 3 and Group 6 were the treatment doses for DA and ISM, respectively. All of the infected groups (groups 1 and 4; positive control) had severe clinical signs and recumbence within 27-59 days of infection. The mean PCV, total RBC, and Hgb concentration values of Jabitehenan isolate infected groups were significantly (P<0.05) lower than Jawi isolate infected groups, and severe clinical signs in group 4 occurred earlier than in group 1. These findings point to the presence of inter-isolateT. congolensevariation. Neither of the DA nor ISM treatment groups attained complete recovery, and this shows the presence of disease resistance. A molecular-based study was this study’s limitation, and it is recommended to confirm interisolate differences.
TheWolbachiaWalE1 effector altersDrosophilaendocytosis
Authors: Martin MaryAnn , Newton Irene L.G. 
Published: February 2023

AbstractThe most common intracellular bacterial infection isWolbachia pipientis, a microbe that manipulates host reproduction and is used in control of insect vectors. Phenotypes induced byWolbachiahave been studied for decades and range from sperm-egg incompatibility to male killing. HowWolbachiaalters host biology is less well understood. Previously, we characterized the firstWolbachiaeffector – WalE1, which encodes a synuclein domain at the N terminus. Purified WalE1 sediments with and bundles actin and when heterologously expressed in flies, increasesWolbachiatiter in the developing oocyte. In this work, we first identify the native expression WalE1 byWolbachiainfecting both fly cells and whole animals. WalE1 appears as aggregates, separate fromWolbachiacells. We next show that WalE1 co-immunoprecipitates with the host protein Past1 and that WalE1 manipulates host endocytosis. Yeast expressing WalE1 show deficiency in uptake of FM4-64 dye, and flies harboring mutations inPast1or overexpressing WalE1 are sensitive to AgNO3, a hallmark of endocytosis defects. Finally, we also show thatPast1null flies harbor moreWolbachiaoverall and in late egg chambers. Our results identify interactions between aWolbachiasecreted effector and a host protein and point to yet another important host cell process impinged upon byWolbachia.
The effect of deep brain stimulation on cortico-subcortical networks in Parkinson’s disease patients with freezing of gait: Exhaustive exploration of a basic model
Authors: Popova Mariia , Messé Arnaud , Gulberti Alessandro , Gerloff Christian , Pötter-Nerger Monika , Hilgetag Claus C 
Published: February 2023

ABSTRACTCurrent treatments of Parkinson’s disease (PD) have limited efficacy in alleviating freezing of gait (FoG). In this context, concomitant deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) has been suggested as a potential therapeutic approach. However, the mechanisms underlying this approach are unknown. While the current rationale relies on network-based hypotheses of intensified disinhibition of brainstem locomotor areas to facilitate the release of gait motor programs, it is still unclear how simultaneous high-frequency DBS in two interconnected basal ganglia nuclei affects large-scale cortico-subcortical network activity. Here, we use a basic model of neural excitation, the susceptible-excited-refractory (SER) model, to compare effects of different stimulation modes of the network underlying FoG. We develop a network-based computational framework to compare subcortical DBS targets through exhaustive analysis of the brain attractor dynamics in the healthy, PD and DBS states. We demonstrate the validity of the approach and the superior performance of combined STN+SNr DBS in the normalization of spike propagation flow in the FoG network. The framework aims to move towards a mechanistic understanding of the network effects of DBS and may be applicable to further perturbation-based therapies of brain disorders.AUTHOR SUMMARYParkinson’s disease patients with Freezing of Gait (FoG) may be treated by deep brain stimulation, which produces effects mediated by brain networks. Currently, the approach of combined DBS of the subthalamic nucleus and the substantia nigra pars reticulata is investigated for being particularly beneficial for patients with axial symptoms, but the exact mechanisms of this effect are unknown. Here, we present a network-based computational framework using a basic excitable model that enables us to simulate the complete activity patterns of the brain network involved in FoG. These simulations reveal network mechanisms underlying STN+SNr DBS and its efficacy in alleviating FoG. The proposed framework can capture the influence of the DBS target sites on cortico-subcortical networks and help to identify suitable stimulation targets.
Dissociable contributions of the amygdala and ventral hippocampus to stress-induced changes in defensive behavior
Authors: Pennington Zachary T. , LaBanca Alexa R. , Sompolpong Patlapa , Abdel-Raheim Shereen D. , Ko Bumjin , Wick Zoe Christenson , Feng Yu , Dong Zhe , Francisco Taylor R. , Bacon Madeline E. , Chen Lingxuan , Fulton Sasha L. , Maze Ian , Shuman Tristan , Cai Denise J. 
Published: February 2023

ABSTRACTBackgroundSevere stress can produce multiple persistent changes in defensive behavior relevant to psychiatric illness. While much is known about the circuits supporting stress-induced associative fear, how stress-induced circuit plasticity supports non-associative changes in defensive behavior remains unclear.MethodsMice were exposed to an acute severe stressor, and subsequently, both associative and non-associative defensive behavioral responses were assessed. A mixture of local protein synthesis inhibition, pan-neuronal chemogenetic inhibition, and projection-specific chemogenetic inhibition were utilized to isolate the roles of the basolateral amygdala (BLA) and ventral hippocampus (vHC) to the induction and expression of associative and non-associative defensive behavioral changes.ResultsStress-induced protein synthesis in the BLA was necessary for enhancements in stress sensitivity but not enhancements in anxiety-related behaviors, whereas protein synthesis in the vHC was necessary for enhancements in anxiety-related behavior but not enhancements in stress sensitivity. Like protein synthesis, neuronal activity of the BLA and vHC were found to differentially support the expression of these same defensive behaviors. Additionally, projection-specific inhibition of BLA-vHC connections failed to alter these behaviors, indicating that these defensive behaviors are regulated by distinct BLA and vHC circuits. Lastly, contributions of the BLA and vHC to stress sensitivity and anxiety-related behavior were independent of their contributions to associative fear.ConclusionsStress-induced plasticity in the BLA and vHC were found to support dissociable non-associative behavioral changes, with BLA supporting enhancements in stress sensitivity and vHC supporting increased anxiety-related behavior. These findings demonstrate that independent BLA and vHC circuits are critical for stress-induced defensive behaviors, and that differential targeting of BLA and vHC circuits may be needed in disease treatment.
Airway secretory cell-derived p63+progenitors contribute to alveolar regeneration after sterile lung injury
Authors: Lv Zan , Liu Zixin , Liu Kuo , Pu Wenjuan , Li Yan , Zhao Huan , Xi Ying , Vaughan Andrew E. , Gillich Astrid , Zhou Bin 
Published: February 2023

AbstractLung injury activates epithelial stem or progenitor cells for alveolar repair and regeneration. However, the origin and fate of injury-induced progenitors are poorly defined. Here, we report that p63-expressing progenitors emerge upon bleomycin-induced lung injury. These p63+progenitors proliferate rapidly and differentiate into alveolar type 1 (AT1) and type 2 (AT2) cells through distinct trajectories. Dual recombinase-mediated sequential genetic lineage tracing reveals that p63+progenitors originate from airway secretory cells and subsequently generate alveolar cells. Functionally, p63 activation is required for efficient alveolar regeneration from secretory cells. Our study identifies a secretory cell-derived p63+progenitor that contributes to alveolar repair, indicating a potential therapeutic avenue for lung regeneration after injury.
Mutual regulation of transcriptomes between pneumocytes and fibroblasts mediates alveolar regeneration
Authors: Yao Yiwen , Miethe Sarah , Kattler Kathrin , Walter Jörn , Schneider-Daum Nicole , Herr Christian , Garn Holger , Ritzmann Felix , Bals Robert , Beisswenger Christoph 
Published: February 2023

AbstractAlveolar type 2 (AT2) and club cells are part of the stem cell niche of the lung and their differentiation is required for pulmonary homeostasis and tissue regeneration. A disturbed crosstalk between fibroblasts and epithelial cells contributes to the loss of lung structure in chronic lung diseases. Therefore, it is important to understand how fibroblasts and lung epithelial cells interact during regeneration. Here we analyzed the interaction of fibroblasts and the alveolar epithelium modelled in air-liquid interface cultures. Single-cell transcriptomics showed that co-cultivation with fibroblasts leads to increased expression of type 2 markers in pneumocytes, activation of regulons associated with maintenance of alveolar type 2 cells, and trans-differentiation of club cells towards pneumocytes. This was accompanied by an intensified transepithelial barrier. Vice versa, activation of NFκB pathways and the CEBPB regulon as well as the expression of IL-6 and other differentiation factors (e.g. FGFs) were increased in fibroblasts co-cultured with epithelial cells. Recombinant IL-6 enhanced epithelial barrier formation. Therefore, in our co-culture model, regulatory loops were identified by which lung epithelial cells mediate regeneration and differentiation of the alveolar epithelium in a cooperative manner with the mesenchymal compartment.
Plants cultivated for ecosystem restoration can evolve towards a domestication syndrome
Authors: Conrady Malte , Lampei Christian , Bossdorf Oliver , Hölzel Norbert , Michalski Stefan , Durka Walter , Bucharova Anna 
Published: February 2023

AbstractThe UN Decade on Ecosystem Restoration calls for upscaling restoration efforts, but many terrestrial restoration projects are constrained by seed availability. To overcome these constraints, wild plants are increasingly propagated on farms to produce seeds for restoration projects. During on-farm propagation, the plants face non-natural conditions with different selection pressures, and they might evolve adaptations to cultivation that parallel those of agricultural crops, which could be detrimental to restoration efforts. To test this, we compared traits of 19 species grown from wild-collected seeds to those from their farm-propagated offspring of up to four cultivation generations, produced by two European seed growers, in a common garden experiment. We found that some plants rapidly evolved across cultivated generations towards increased size and reproduction, lower within-species variability, and more synchronized flowering. In one species, we found evolution towards less seed shattering. These trait changes are typical signs of the crop domestication syndrome, and our study demonstrates that it can also occur during cultivation of wild plants, within only few cultivated generations. However, there was large variability between cultivation lineages, and the observed effect sizes were generally rather moderate, which suggests that the detected evolutionary changes are unlikely to compromise farm-propagated seeds for ecosystem restoration. To mitigate the potential negative effects of unintended selection, we recommend to limit the maximum number of generations the plants can be cultivated without replenishing the seed stock from new wild collections.Significance StatementGlobally upscaling demands for native seeds for ecosystem restoration can be covered by agricultural seed propagation. Yet, agricultural practice can unintentionally select for specific traits and reduce adaptive variability, which could affect plant performance once sown back to the wild. We show, across 19 wild species, two seed producers and up to four consecutive cultivated generations, that some plants under cultivation evolved higher vigor, reduced adaptive variability, synchronized flowering and in one case, reduced seed shattering. Yet, there were substantial differences among cultivation lineages, with negligible changes in most, and large changes only in a few cases. Substantial unintended evolution in cultivation is thus rather an exception than the rule.
Damage activatesEVG1to suppress vascular differentiation during regeneration inArabidopsis thaliana
Authors: Mazumdar Shamik , Zhang Ai , Musseau Constance , Anjam Muhammad Shahzad , Marhavy Peter , Melnyk Charles W. 
Published: February 2023

AbstractPlants possess remarkable regenerative abilities to formde novovasculature after damage and in response to pathogens that invade and withdraw nutrients. To look for common factors that affect vascular formation upon stress, we searched forArabidopsis thalianagenes differentially expressed duringAgrobacteriuminfection, nematode infection and plant grafting. One such gene was cell-wall associated and highly induced by all three stresses. Mutations in it enhanced ectopic xylem formation in Vascular cell Induction culture System Using Arabidopsis Leaves (VISUAL) and enhanced graft formation and was thus namedENHANCER OF VISUAL AND GRAFTING 1(EVG1). Mutatedevg1inhibited cambium development and callus formation yet promoted tissue attachment, syncytium size, phloem reconnection and xylem formation.evg1affected abscisic acid and cell wall responses and was itself down regulated by ABA. We found mutations in a receptor-like gene,RLP44, had the same regeneration phenotype asEVG1mutations including enhancing VISUAL and grafting.evg1andrlp44mutants affected the expression of many genes in common including those important for successful regeneration and vascular formation. We propose thatEVG1integrates information from cutting, wounding or parasitism stresses and functions withRLP44to suppress vascular differentiation during regeneration.
Financing innovation in agri-food industries: an analysis of the Italian micro, small and medium enterprises
Authors: Paoloni Mauro , Tutino Marco , Paoloni Niccolò , Santolamazza Valentina 
Published: February 2023

PurposeThis work aims to investigate the current financial structure of Italian agri-food micro, small and medium enterprises (MSMEs) to understand how MSMEs face innovation challenges, which are also required to support sustainable development.Design/methodology/approachTo reach the goal, an empirical longitudinal analysis is performed on a sample of Italian agri-food firms. In detail, to highlight the changes in the use of financial sources between 2013 and 2019, a descriptive ratio analysis is carried out on the data extracted by the AIDA database. In addition, statistical analyses were performed, including t-tests and U Mann–Whitney. Finally, a fixed-effects model is created to analyse the panel data. To ensure homogeneity, the sub-sectors of production and transformation are separately considered.FindingsThe financial structure analysis shows an increase in the equity percentage in the funding sources, attributable to an attempt to compensate for the reduction of banks' funding. However, even though this change has not compromised firms' profitability, the undercapitalisation of companies is still present. Therefore, more equity investments are required to support the innovation process.Originality/valueThe value of the present research is to highlight the choice of using new alternative financing sources instead of traditional banks' credit to implement sustainable and innovative development Italian agri-food sector (AFS). This choice is forced by reducing finance from banks and other financial institutions because of the credit crunch. This issue is even more relevant, considering that MSMEs have structural financial problems but have to fulfil the mission of pursuing innovation in the same way as large companies. Therefore, this paper expands the literature on agri-food, delving into an issue typical of MSMEs and combining agri-food with the need for innovation.
A process mining impacts framework
Authors: Mamudu Azumah , Bandara Wasana , Leemans Sander J.J. , Wynn Moe Thandar 
Published: February 2023

PurposeProcess mining (PM) specialises in extracting insights from event logs to facilitate the improvement of an organisation's business processes. Industry trends show the proliferation and continued growth of PM techniques. To address the minimal attention given to developing empirically supported frameworks to assess the nature of impact in the PM domain, this study proposes a framework that identifies the key categories of PM impacts and their interrelationships.Design/methodology/approachThe qualitatively derived framework is built, re-specified and validated from a diverse collection of 62 PM case reports. With multiple rounds of coding supported by coder corroborations, inductively extracted concepts relating to impact from a first set of 12 case reports were grouped into themes and sub-themes to derive an a-priori framework by adopting the balanced scorecard as a theoretical lens. Concepts from the remaining 50 case reports were deductively grouped to re-specify and validate the proposed PM impacts framework. Further analysis identified interrelationships between impacts, which extends our understanding of the identified PM impacts.FindingsThe proposed framework captures PM impacts in four main categories: (a) impact on the process, (b) customer impact, (c) financial impact, and (d) impact on innovation and learning. The authors extended this analysis to identify the interrelationships between these categories, which vividly demonstrates how impact on the process mediates the attainment of the other three impact types.Originality/valueThe need for a deeper understanding of PM impacts within the context of contemporary PM practice is addressed by this work. The PM impacts framework provides a classification of PM impacts into four categories with 19 subcategories. It also identifies direct, moderating and mediating relationships between categories and subcategories whilst highlighting the role of impact on the process as a precursor to the other types of PM impact.