bluuebunny/crossref_metadata_2025_split huggingface dataset:
ALDA-1 TREATMENT ALLEVIATES LUNG INJURY AFTER CARDIAC ARREST AND RESUSCITATION IN SWINE
Authors: Wu Hongbo , Xu Shanxiang , Diao Mengyuan , Wang Jiangang , Zhang Gongping , Xu Jiefeng 
Published: September 2022

ABSTRACT

Introduction
Alda-1, an aldehyde dehydrogenase 2 (ALDH2) activator, has been shown to protect the lung against a variety of diseases including regional ischemia reperfusion injury, severe hemorrhagic shock, hyperoxia and so on. The present study was designed to investigate the effectiveness of Alda-1 treatment in alleviating lung injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in swine.

Methods
A total of 24 swine were randomized into three groups: 1) Sham (n = 6), 2) CA/CPR (n = 10), and 3) CA/CPR + Alda-1 (n = 8). The swine model was established by 8 min of electrically induced and untreated CA, and then 8 min of manual CPR. A dose of 0.88 mg/kg of Alda-1 was intravenously injected at 5 min after CA/CPR. After CA/CPR, extravascular lung water index (ELWI), pulmonary vascular permeability index (PVPI), and oxygenation index (OI) were regularly evaluated for 4 h. At 24 h after resuscitation, lung ALDH2 activity was detected, and its injury score, apoptosis, and ferroptosis were measured.

Results
After experiencing the same procedure of CA and CPR, five swine in the CA/CPR group and six swine in the CA/CPR + Alda-1 group restored spontaneous circulation. Subsequently, significantly increased ELWI and PVPI, and markedly decreased OI were observed in these two groups compared with the Sham group. However, all of them were gradually improved and significantly better in the swine treated with the Alda-1 compared to the CA/CPR group. Tissue analysis indicated that lung ALDH2 activity was significantly decreased in those swine experiencing the CA/CPR procedure compared with the Sham group; nevertheless, its activity was significantly greater in the CA/CPR + Alda-1 group than in the CA/CPR group. Additionally, lung injury score, and its apoptosis and ferroptosis were significantly increased in the CA/CPR and CA/CPR + Alda-1 groups compared with the Sham group. Likewise, Alda-1 treatment significantly decreased these pathological damages in lung tissue when compared to the CA/CPR group.

Conclusions
Alda-1 treatment was effective to alleviate lung injury after CA/CPR in a swine model, in which the protective role was possibly related to the inhibition of cell apoptosis and ferroptosis. It might provide a novel therapeutic target, and also a feasible therapeutic drug for lung protection after CA/CPR.
Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Authors:   RECOVERY Collaborative Group, Horby Peter W , Peto Leon , Staplin Natalie , Campbell Mark , Pessoa-Amorim Guilherme , Mafham Marion , Emberson Jonathan R , Stewart Richard , Prudon Benjamin , Uriel Alison , Green Christopher A , Dhasmana Devesh J , Malein Flora , Majumdar Jaydip , Collini Paul , Shurmer Jack , Yates Bryan , Baillie J Kenneth , Buch Maya H , Day Jeremy N , Faust Saul N , Jaki Thomas , Jeffery Katie , Juszczak Edmund , Knight Marian , Lim Wei Shen , Montgomery Alan , Mumford Andrew , Rowan Kathryn , Thwaites Guy , Haynes Richard , Landray Martin 
Published: September 2022

SUMMARYBackgroundDimethyl fumarate (DMF) is an anti-inflammatory drug that has been proposed as a treatment for patients hospitalised with COVID-19MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. In this initial assessment of DMF, performed at 27 UK hospitals, eligible and consenting adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF 120mg twice daily for 2 days followed by 240mg twice daily for 8 days, or until discharge if sooner. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale, assessed using a proportional odds model. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).FindingsBetween 2 March 2021 and 18 November 2021, 713 patients were enrolled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients were receiving corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.85-1.46; p=0.42). There was no significant effect of DMF on any secondary outcome. As expected, DMF caused flushing and gastrointestinal symptoms, each in around 6% of patients, but no new adverse effects were identified.InterpretationIn adults hospitalised with COVID-19, DMF was not associated with an improvement in clinical outcomes.FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).
A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer
Authors: Datta Ishwaree , Linkous Benjamin , Odum Tyler , Drew Christian , Taylor Andrew , Vassel Tajah , Bangi Erdem 
Published: September 2022

ABSTRACTKinases are key regulators of cellular signal transduction pathways. Many diseases including cancer are associated with global alterations in protein phosphorylation networks, as a result, kinases are frequent targets of drug discovery efforts. However, target identification and assessment, a critical step in targeted drug discovery which involves identifying essential genetic mediators of disease phenotypes, can be challenging in complex, heterogeneous diseases like cancer where multiple concurrent genomic alterations are common. Drosophila is a particularly useful genetic model system to identify novel regulators of biological processes through unbiased genetic screens. Here, we report two classic genetic modifier screens focusing on the Drosophila kinome to identify kinase regulators in two different backgrounds: KRAS TP53 PTEN APC, a multigenic cancer model that targets four genes recurrently mutated in human colon tumors and KRAS alone, a simpler model that targets one of the most frequently altered pathways in cancer. These screens identified hits that are shared by both models as well as those unique to each one, emphasizing the importance of capturing the genetic complexity of human tumor genome landscapes in experimental models. Our follow-up analysis of two hits from the KRAS only screen suggest that classical genetic modifier screens in heterozygous mutant backgrounds that result in a modest, non-lethal reduction in candidate gene activity in the context of a whole animal —a key goal of systemic drug treatment— may be a particularly useful approach to identify most rate limiting genetic vulnerabilities in disease models as ideal candidate drug targets.
AAV-delivered gene editing for latent genital or orofacial herpes simplex virus infection reduces ganglionic viral load and minimizes subsequent viral shedding in mice
Authors: Aubert Martine , Haick Anoria K. , Strongin Daniel E. , Klouser Lindsay M. , Loprieno Michelle A. , Stensland Laurence , Santo Tracy K. , Huang Meei-Li , Hyrien Ollivier , Stone Daniel , Jerome Keith R. 
Published: September 2022

ABSTRACTHerpes simplex virus (HSV) establishes latency in ganglionic neurons of the peripheral nervous system, from which it can reactivate, causing recurrent disease and possible transmission to a new host. Current anti-HSV therapy does not eliminate latent HSV, and thus is only suppressive rather than curative. We developed a potentially curative approach to latent HSV infection and pathogenesis, based on gene editing using HSV-specific meganucleases delivered by adeno-associated virus (AAV) vectors. Our results demonstrated that a dual meganuclease therapy, composed of two anti-HSV-1 meganucleases delivered by a triple AAV serotype combination (AAV9, AAV-Dj/8, AAV-Rh10), can eliminate up to 97% of latent HSV DNA from ganglia in both ocular and vaginal mouse models of latent HSV infection. Using a novel pharmacological approach to reactivate latent HSV-1 in mice with the bromodomain inhibitor JQ-1, we demonstrated that this reduction in ganglionic viral load leads to a significant reduction of viral shedding from treated vs. control mice, with many treated mice showing no detectable virus shedding. In general, therapy was well tolerated, although dose-ranging studies showed hepatotoxicity at high AAV doses, consistent with previous observations in animals and humans. Also in agreement with previous literature, we observed subtle histological evidence of neuronal injury in some experimental mice, although none of the mice demonstrated observable neurological signs or deficits. These results reinforce the curative potential of gene editing for latent orofacial and genital HSV disease, and provide a framework for additional safety studies before human trials can begin.
The impact of Mmu17 non-Hsa21 orthologous genes in the Ts65Dn mouse model of Down syndrome: the “gold standard” revisited
Authors: Guedj Faycal , Kane Elise , Bishop Lauren A. , Pennings Jeroen L. A. , Herault Yann , Bianchi Diana W. 
Published: September 2022

AbstractDespite many successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome (DS), translation to humans has failed. This raises critical questions about the appropriateness of the Ts65Dn mouse as the “gold standard” for DS research given that it carries, in addition to Mmu16 orthologous genes, triplication of 50 Mmu17 non-orthologous genes that might contribute to the observed brain and behavioral phenotypes. We used the novel Ts66Yah mouse that carries both an extra mini chromosome and the identical segmental Mmu16 trisomy as Ts65Dn, but in which the Mmu17 non-orthologous region was removed using CRISPR/Cas9 technology. We demonstrate that the Ts65Dn exhibits a more severe phenotype throughout the lifespan compared to the Ts66Yah mouse. Several Mmu17 non-orthologous genes were uniquely overexpressed in Ts65Dn embryonic forebrain; this produced major differences in dysregulated genes and pathways. Despite these genome-wide differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in several commonly dysregulated disomic genes and pathways. During the neonatal period, delays in motor development, communication and olfactory spatial memory were observed in both Ts66Yah and Ts65Dn pups but were more pronounced in Ts65Dn. Adult Ts66Yah mice showed working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved. Like the neonates, adult Ts66Yah mice exhibited fewer and milder behavioral deficits when compared to Ts65Dn mice. Our findings suggest that trisomy of the non-orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may be one major reason why preclinical trials that used this model have unsuccessfully translated to human therapies.
Characterization of sub-tropical maize (Zea Mays L.) inbred lines for the variation in kernel row numbers (KRN)
Authors: Mukri Ganapati , Gadag RN , Bhat Jayant S , Nepolean T. , Gupta Navin C , Mittal Shikha , Nithyashree ML , Kumar Ramesh , Pal Digvender 
Published: September 2022

AbstractGenetic dissection of high KRN trait and cob length has been undertaken by several researchers resulting in identification of loci controlling the traits. Further fine mapping of QTLs controlling KRN and cob length and TILLING strategies identified the underlying genes. All these studies are used temperate maize genotypes which are of limited use to researcher in sub-tropical region, and the sub-tropical maize production systems. Present investigation explores the availability of genetic regions responsible for KRN in sub-tropical maize germplasm. A total of 280 subtropical maize germplasm was analyzed for their KRN variation and selected 45 stable lines were subjected to molecular characterization using genes linked to KRN in maize. Diversity analysis was also performed to understand the possible association of character with the KRN gene in deciding its variation in the given population. It was revealed that four genes showed highest probability of influencing KRN traits in these tropical maize inbred lines. The remaining genes not establishing specific pattern of association with high and low KRN genotypes may need further study on its allelic variation.
On biological networks capable of robust adaptation in the presence of uncertainties: A systems-theoretic approach
Authors: Bhattacharya Priyan , Raman Karthik , Tangirala Arun K. 
Published: September 2022

AbstractBiological adaptation, the tendency of every living organism to regulate its essential activities in environmental fluctuations, is a well-studied functionality in systems and synthetic biology. In this work, we present a generic methodology inspired by systems theory to discover the design principles for robust adaptation, perfect and imperfect, in two different contexts: (1) in the presence of deterministic external disturbance and (2) in a stochastic setting. In all the cases, firstly, we translate the necessary qualitative conditions for adaptation to mathematical constraints using the language of systems theory, which we then map back as design requirements for the underlying networks. Thus, contrary to the existing approaches, the proposed methodologies provide an exhaustive set of admissible network structures without resorting to computationally burdensome brute-force techniques. Further, the proposed frameworks do not assume prior knowledge about the particular rate kinetics, thereby validating the conclusions for a large class of biological networks. In the deterministic setting, we show that unlike the incoherent feed-forward network structures (IFFLP), the modules containing negative feedback with buffer action (NFBLB) are robust to parametric fluctuations when a specific part of the network is assumed to remain unaffected. To this end, we propose a sufficient condition for imperfect adaptation and show that adding negative feedback in an IFFLP topology improves the robustness concerning parametric fluctuations. Further, we propose a stricter set of necessary conditions for imperfect adaptation. Turning to the stochastic scenario, we adopt a Wiener-Kolmogorov filter strategy to tune the parameters of a given network structure towards minimum output variance. We show that both NFBLB and IFFLP can be used as a reduced order W-K filter. Further, we define the notion of nearest neighboring motifs to compare the output variances across different network structures. We argue that the NFBLB achieves adaptation at the cost of a variance higher than its nearest neighboring motifs whereas the IFFLP topology produces locally minimum variance while compared with its nearest neighboring motifs. We present numerical simulations to support the theoretical results. Overall, our results present a generic, systematic, and robust framework for advancing the understanding of complex biological networks.
Establishment of porcine ovarian follicles treated with t-BHP for an in vitro aging model
Authors: Shi Peihua , Gao Jinchun , Zhao Shunran , Xia Wei , Li Junjie , Tao Chenyu 
Published: September 2022

AbstractOvarian aging is closely associated with low female fertility. Excessive oxidative stress can induce ovarian senescence and follicular atresia, thereby reducing reproductive performance. In this study, intact antral follicles of pigs were treated with tert-butyl hydroperoxide (t-BHP) to simulate aging stimulation conditions. The results showed that 200 μM t-BHP induced the senescence-related phenotype of antral follicles, which was time-dependent and changed significantly after 6 h of treatment. t-BHP can induce an increase in reactive oxygen species (ROS) and senescence mediated by Caspase-3, P53, Foxo1, and SOD. Senescence-associated β-galactosidase (SA-β-Gal) staining revealed an increase in the number of positive cells. Enzyme-linked immunosorbent assays (ELISA) showed that the level of reactive oxygen species increased, and that the ratio of progesterone (P4) to estradiol (E2) increased. Finally, the findings of this study showed that the relative expression levels of Caspase-3, P53, Foxo1 mRNA, and protein increased, while the relative expression levels of SOD decreased. In conclusion, treatment with 200 μM of t-BHP effectively induced follicular senescence at 6 h. Therefore, the in vitro treatment of follicles with 200 μM t-BHP for 6 h may be a feasible in vitro culture model to simulate ovarian senescence in gilts.
Mating strategies in Caenorhabditis elegans populations are determined by male developmental history
Authors: Al-Saadi Rose S. , Luo Jintao , Nichitean Alexandra M. , Wagner Nikolaus R. , Portman Douglas S. , Hall Sarah E. 
Published: September 2022

ABSTRACTMating strategies, whether sexual or asexual, confer unique costs and benefits to populations and species that facilitate evolutionary processes. In wild isolates of Caenorhabditis elegans, mating strategies are dependent on developmental history. Outcrossing levels significantly increase when one or both parents have transiently passed through the stress-resistant dauer diapause stage. However, the molecular mechanisms of how life history alters mating strategies have not been systematically explored. Sex-specific responses to pheromones are a major driver of mating behaviors in C. elegans. We demonstrated previously that postdauer hermaphrodites exhibit a decreased avoidance of the pheromone ascr#3 due to the downregulation of the osm-9 TRPV channel gene in postdauer ADL neurons. Thus, we hypothesized that altered responses to pheromones in postdauer animals could contribute to increased outcrossing. We conducted mating assays using wild type N2 Bristol, as well as daf-3/co-SMAD and mut-16/Mutator strains that fail to downregulate osm-9 in postdauer hermaphrodite ADL neurons. First, we show that the outcrossing level of N2 Bristol correlated with the developmental history of males, and that postdauer males exhibited an increased ability to detect mates via pheromones compared to continuously developed males. In addition, DAF-3 plays a critical role in postdauer males to regulate mating, while playing a more minor role in hermaphrodites. Furthermore, the mut-16 strain exhibited negligible outcrossing, and attempts to rescue the outcrossing phenotype resulted in transgenerational sterility due to germline defects. Together, our results suggest a model whereby mating strategy is driven by developmental history under combinatorial control of TGF-β and RNAi pathways.
Bat pluripotent stem cells reveal unique entanglement between host and viruses
Authors: Déjosez Marion , Marin Arturo , Hughes Graham M. , Morales Ariadna E. , Godoy-Parejo Carlos , Gray Jonathan , Qin Yiren , Singh Arun A. , Xu Hui , Juste Javier , Ibáñez Carlos , White Kris M. , Rosales Romel , Francoeur Nancy J. , Sebra Robert P. , Alcock Dominic , Puechmaille Sébastien J. , Pastusiak Andrzej , Frost Simon D.W. , Hiller Michael , Young Richard A. , Teeling Emma C. , García-Sastre Adolfo , Zwaka Thomas P. 
Published: September 2022

AbstractBats have evolved features unique amongst mammals, including flight, laryngeal echolocation, and certain species have been shown to have a unique immune response that may enable them to tolerate viruses such as SARS-CoVs, MERS-CoVs, Nipah, and Marburg viruses. Robust cellular models have yet to be developed for bats, hindering our ability to further understand their special biology and handling of viral pathogens. To establish bats as new model study species, we generated induced pluripotent stem cells (iPSCs) from a wild greater horseshoe bat (Rhinolophus ferrumequinum) using a modified Yamanaka protocol. Rhinolophids are amongst the longest living bat species and are asymptomatic carriers of coronaviruses, including one of the viruses most closely related to SARS-CoV-2. Bat induced pluripotent stem (BiPS) cells were stable in culture, readily differentiated into all three germ layers, and formed complex embryoid bodies, including organoids. The BiPS cells were found to have a core pluripotency gene expression program similar to that of other species, but it also resembled that of cells attacked by viruses. The BiPS cells produced a rich set of diverse endogenized viral sequences and in particular retroviruses. We further validated our protocol by developing iPS cells from an evolutionary distant bat species Myotis myotis (greater mouse-eared bat) non-lethally sampled in the wild, which exhibited similar attributes to the greater horseshoe bat iPS cells, suggesting that this unique pluripotent state evolved in the ancestral bat lineage. Although previous studies have suggested that bats have developed powerful strategies to tame their inflammatory response, our results argue that they have also evolved mechanisms to accommodate a substantial load of endogenous viral sequences and suggest that the natural history of bats and viruses is more profoundly intertwined than previously thought. Further study of bat iPS cells and their differentiated progeny should advance our understanding of the role bats play as virus hosts, provide a novel method of disease surveillance, and enable the functional studies required to ascertain the molecular basis of bats’ unique traits.
Overlapping Neural Representations for Dynamic Visual Imagery and Stationary Storage in Spatial Working Memory
Authors: Günseli Eren , Foster Joshua J. , Sutterer David W. , Todorova Lara , Vogel Edward K. , Awh Edward 
Published: September 2022

AbstractRepresentations in working memory need to be flexibly transformed to adapt to our dynamic environment and variable task demands. Recent work has demonstrated that activity in the alpha frequency band enables precise decoding of visual information during both perception and sustained storage in working memory. Extant work, however, has focused exclusively on the representation of static visual images. Here we used EEG recordings to examine whether alpha-band activity supports the dynamic transformation of representations in spatial working memory using an imagery task that required the active shifting of a stored position to a new position. In line with recent findings, a common format of alpha-band activity precisely tracked both the initial position stored in working memory as well as the transformed position, with the latter emerging approximately 800-1200 ms following an auditory cue to “rotate” to a new position. Moreover, the time course of this transformation of alpha activity predicted between-subject differences in manual reaction time to indicate the new position (Experiment 1), as well as within-subject variations in saccade latency in a speeded version of the task (Experiment 2). Finally, cross-training analyses revealed robust generalization of alpha-band reconstruction of working memory contents before and after mental transformation. These findings demonstrate that alpha activity tracks dynamic transformations of representations in spatial working memory, and that the format of this activity is preserved across the initial and transformed memory representations. These findings highlight a new approach for measuring voluntary shifts in online memory representations and show common representational formats during dynamic mental imagery and the maintenance of static representations in working memory.