bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual-energy Computed Tomographic Pulmonary Angiography Accurately Estimates Lobar Perfusion Before Lung Volume Reduction for Severe Emphysema
Authors: Jeyin Nidhish , Desai Sujal R. , Padley Simon P.G. , Wechalekar Kshama , Gregg Sima , Sousa Tiago , Shah Pallav L. , Allinson James P. , Hopkinson Nicholas S. , Begum Sofina , Jordan Simon , Kemp Samuel V. , Ridge Carole A.
Published: September 2022

Purpose:

To assess if dual-energy computed tomographic pulmonary angiography (DECTPA) derived lobar iodine quantification can provide an accurate estimate of lobar perfusion in patients with severe emphysema, and offer an adjunct to single-photon emission CT perfusion scintigraphy (SPECT-PS) in assessing suitability for lung volume reduction (LVR).

Materials and Methods:

Patients with severe emphysema (forced expiratory volume in 1 s <49% predicted) undergoing evaluation for LVR between May 2018 and April 2020 imaged with both SPECT-PS and DECTPA were included in this retrospective study. DECTPA perfused blood volume maps were automatically segmented and lobar iodine mass was estimated and compared with lobar technetium (Tc99m) distribution acquired with SPECT-PS. Pearson correlation and Bland-Altman analysis were used for intermodality comparison between DECTPA and SPECT-PS. Univariate and adjusted multivariate linear regression were modelled to ascertain the effect sizes of possible confounders of disease severity, sex, age, and body mass index on the relationship between lobar iodine and Tc99m values. Effective radiation dose and adverse reactions were recorded.

Results:

In all, 123 patients (64.5±8.8 y, 71 men; mean predicted forced expiratory volume in 1 s 32.1 ±12.7%,) were eligible for inclusion. There was a linear relationship between lobar perfusion values acquired using DECTPA and SPECT-PS with statistical significance (P<0.001). Lobar relative perfusion values acquired using DECTPA and SPECT-PS had a consistent relationship both by linear regression and Bland-Altman analysis (mean bias, −0.01, mean r
2 0.64; P<0.0001). Individual lobar comparisons demonstrated moderate correlation (r=0.79, 0.78, 0.84, 0.78, 0.8 for the right upper, middle, lower, left upper, and lower lobes, respectively, P<0.0001). The relationship between lobar iodine and Tc99m values was not significantly altered after controlling for confounders including symptom and disease severity, age, sex, and body mass index.

Conclusions:

DECTPA provides an accurate estimation of lobar perfusion, showing good agreement with SPECT-PS and could potentially streamline preoperative assessment for LVR.
Cardiovascular Imaging in China
Authors: Tang Chun Xiang , Zhou Zhen , Zhang Jia Yin , Xu Lei , Lv Bin
Published: September 2022

The high prevalence and mortality of cardiovascular diseases in China’s large population has increased the use of cardiovascular imaging for the assessment of conditions in recent years. In this study, we review the past 20 years of cardiovascular imaging in China, the increasingly important role played by cardiovascular computed tomography in coronary artery disease and pulmonary embolism assessment, magnetic resonance imaging’s use for cardiomyopathy assessment, the development and application of artificial intelligence in cardiovascular imaging, and the future of Chinese cardiovascular imaging.
Regulatory role of noncoding RNA in sepsis and sepsis-associated organ dysfunction: an updated systematic review
Authors: Zhang Tao , Yang Yu-Hang , Liu Yong-Ping , Zhang Tie-Ning , Yang Ni
Published: September 2022

Background

The exact molecular mechanisms underlying sepsis remain unclear. Accumulating evidence has shown that noncoding RNAs are involved in sepsis and sepsis-associated organ dysfunction (SAOD).

Methods

We performed this updated systematic review focusing mainly on research conducted in the last 5 years regarding noncoding RNAs associated with sepsis and SAOD. The following medical subject headings were used in the PubMed database from October 1, 2016, to March 31, 2022: “microRNA,” “long noncoding RNA,” “circular RNA,” “sepsis,” and/or “septic shock.” Studies investigating the role of noncoding RNAs in the pathogenesis of sepsis and as biomarkers or therapeutic targets in the disease were included. Data were extracted in terms of the role of noncoding RNAs in the pathogenesis of sepsis and their applicability for use as biomarkers or therapeutic targets in sepsis. The quality of the studies was assessed using a modified guideline from the Systematic Review Center for Laboratory animal Experimentation (SYRCLE).

Results

A total of 537 original studies investigated the potential roles of noncoding RNAs in sepsis and SAOD. Experimental studies in the last 5 years confirmed that long noncoding RNAs have important regulatory roles in sepsis and SAOD. However, studies on circRNAs and sepsis remain limited, and more studies should be conducted to elucidate this relationship. Amongst the included studies, the SYRCLE scores ranged from 3 to 7 (an average score of 3.78). Notably, 94 noncoding RNAs were evaluated as potential biomarkers for sepsis, and selective reporting of the sensitivity, specificity, and receiver operating curve was common. A total of 117 studies demonstrated the use of noncoding RNAs as potential therapeutic targets in sepsis and SAOD. At a molecular level, inflammation-related pathways, mitochondrial dysfunction, cell apoptosis, and/or oxidative stress were the most extensively studied.

Conclusion

This review suggests that noncoding RNAs could be good biomarkers and therapeutic candidates for sepsis and SAOD. Prospective, large-scale, and multicenter cohort studies should be performed to evaluate specific noncoding RNAs as biomarkers and test the organ-specific delivery of these regulatory molecules when used as therapeutic targets.
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

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

Background

Dimethyl fumarate (DMF) is an anti-inflammatory drug that has been proposed as a treatment for patients hospitalised with COVID-19

Methods

This 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).

Findings

Between 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.

Interpretation

In adults hospitalised with COVID-19, DMF was not associated with an improvement in clinical outcomes.

Funding

UK 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

Kinases 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

Herpes 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

Despite 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

Genetic 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

Biological 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

Ovarian 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

Mating 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

Bats 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

Representations 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.
Reconstructing the transport cycle in the sugar porter superfamily using coevolution-powered machine learning
Authors: Mitrovic Darko , Comas Sarah Mc , Alleva Claudia , Bonaccorsi Marta , Drew David , Delemotte Lucie
Published: September 2022

Sugar porters represent the largest group of secondary-active transporters. Some members, such as the glucose (GLUT) transporters, are well-known for their role in maintaining blood glucose homeostasis in mammals, with their expression upregulated in many types of cancers. Because only a few sugar porter structures have been determined, mechanistic models have been constructed by piecing together structural states of distantly related proteins. Current GLUT transport models are predominantly descriptive and oversimplified. Here, we have combined coevolution analysis and comparative modeling, to predict structures of the entire sugar porter superfamily in each state of the transport cycle. We have analysed the state-specific contacts inferred from coevolving residue pairs and shown how this information can be used to rapidly generate free-energy landscapes consistent with experimental estimates, as illustrated here for the mammalian fructose transporter GLUT5. By comparing many different sugar porter models and scrutinizing their sequence, we have been able to define the molecular determinants of the transport cycle, which are conserved throughout the sugar porter superfamily. We have also been able to highlight differences leading to the emergence of proton-coupling, validating, and extending the previously proposed latch mechanism. Our computational approach is transferable to any transporter, and to other protein families in general.
Impact of clonal architecture on clinical course and prognosis in patients with myeloproliferative neoplasms
Authors: Luque Paz Damien , Bader Michael S. , Nienhold Ronny , Rai Shivam , Almeida Fonseca Tiago , Stetka Jan , Hao-Shen Hui , Mild-Schneider Gabi , Passweg Jakob R. , Skoda Radek C.
Published: September 2022

Myeloproliferative neoplasms (MPNs) are caused by a somatic gain-of-function mutation in one of three “disease driver” genes JAK2, MPL or CALR. About half of MPN patients also carry additional somatic mutations that modify the clinical course. The order of acquisition of these gene mutations has been proposed to influence the phenotype and evolution of the disease. We studied 50 JAK2-V617F-positive MPN patients who carried at least one additional somatic mutation and determined the clonal architecture of their hematopoiesis by sequencing DNA from single cell derived colonies. In 22 of these patients we also side-by-side applied Tapestri single-cell DNA sequencing (scDNAseq) with cells from the same blood sample. The clonal architectures derived by the two methods showed good overall concordance. scDNAseq showed higher sensitivity for mutations with low variant allele fraction, but had more difficulties distinguishing between heterozygous and homozygous mutations. By unsupervised analysis of clonal architecture data from all 50 MPN patients we defined 4 distinct clusters that differed by the order of acquisition of the mutations, and the complexity of the subclonal structure. Cluster 4, characterized by more complex subclonal structure without a preferred order of acquisition, correlated with reduced overall survival, and in multivariate analysis represented a risk factor independent of the MPN subtype or the age at diagnosis. Our results suggest that deciphering the clonal architecture in patients with MPN that carry multiple gene mutations can improve the molecular prognostic stratification that until now was primarily based on the number and type of gene mutations.
Analysis of sex differential genes at whole genome level reveals their organ-and chromosome-dependent expressions, regulations, and interactions
Authors: Ma Jiamin , Wang Lishi , Yuan Gang , Fernando Chrishan , Yao Lan , Dong Wei , Tian Cheng , Bukiya Anna , Jablonski Monica M. , Feng Helin , Li Daniel Z. , Lu Lu , Jiao Yan , Ji Jiafu , Wang Gang , Gu Weikuan
Published: September 2022

Males and females possess genomes that are almost identical but differ in morbidity, prevalence, severity, response to therapies and mortality of many diseases. We comprehensively analyzed gene expression data in seven tissues from BXD recombinant inbred (RI) mouse strains. We found that there were considerable differences in the numbers and functions among different tissues and between autosomal and sex chromosomes. Among sex differential genes, those on autosomal chromosomes mainly function to regulate metabolic pathways related to their host organs, while those on sex chromosomes mainly regulate nuclear proteins required for DNA replication or transcription during early development. Kidney possessed the fewest sex differential genes on sex chromosomes. The sexually dimorphic genes expressed on X chromosomes were all related to perception, while genes on the autosomal chromosomes were related to metabolism. These patterns of gene expression do not translate into similarity of protein structures, rather they are grouping with function.
Gene regulatory changes underlie developmental plasticity in respiration and aerobic performance in highland deer mice
Authors: Schweizer Rena M. , Ivy Catherine M. , Natarajan Chandrasekhar , Scott Graham R. , Storz Jay F. , Cheviron Zachary A.
Published: September 2022

Phenotypic plasticity can play an important role in the ability of animals to tolerate environmental stress, but the nature and magnitude of plastic responses are often specific to the developmental timing of exposure. Here, we examine changes in gene expression in the diaphragm of highland deer mice (Peromyscus maniculatus) in response to hypoxia exposure at different stages of development. In highland deer mice, developmental plasticity in diaphragm function may mediate changes in several respiratory traits that influence aerobic metabolism and performance under hypoxia. We generated RNAseq data from diaphragm tissue of adult deer mice exposed to 1) life-long hypoxia (before conception to adulthood), 2) post-natal hypoxia (birth to adulthood), 3) adult hypoxia (6-8 weeks only during adulthood), or 4) normoxia. We found five suites of co-regulated genes that are differentially expressed in response to hypoxia, but the patterns of differential expression depend on the developmental timing of exposure. We also identified four transcriptional modules that are associated with important respiratory traits. Many of the genes in these transcriptional modules bear signatures of altitude-related selection, providing an indirect line of evidence that observed changes in gene expression may be adaptive in hypoxic environments. Our results demonstrate the importance of developmental stage in determining the phenotypic response to environmental stressors.
Protection of homologous and heterologous boosters after primary schemes of rAd26-rAd5, ChAdOx1 nCoV-19 and BBIBP-CorV during the Omicron outbreak in adults of 50 years and older in Argentina: a test-negative case-control study
Authors: González Soledad , Olszevicki Santiago , Gaiano Alejandra , Salazar Martín , Regairaz Lorena , Varela Baino Ana Nina , Barkel Erika , Varela Teresa , González Martínez Veronica V. , Pesci Santiago , Marín Lupe , Irassar Juan Ignacio , Ceriani Leticia , Garcia Enio , Kreplak Nicolás , Estenssoro Elisa , Marsico Franco
Published: September 2022

Objectives

To estimate the protection against laboratory-confirmed SARS-CoV-2 infection, hospitalisations, and death after homologous or heterologous third-dose (booster) in individuals with primary vaccination schemes with rAd26-rAd5, ChAdOx1nCoV-19, BBIBP-CorV or heterologous combinations, during the period of Omicron BA.1 predominance.

Design

Retrospective, test-negative, case-control study, with matched analysis.

Setting

Province of Buenos Aires, Argentina, between 12/1/21-4/1/21.

Participants

422,144 individuals ≥50 years who had received two or three doses of COVID-19 vaccines and were tested for SARS-CoV-2.

Main outcome measures: Odds ratios of confirmed SARS-CoV-2 infection, hospitalisations and death after administering different boosters, compared to a two-dose primary scheme.

Results

Of 221,933(52.5%) individuals with a positive test, 190,884(45.2%) had received a two-dose vaccination scheme and 231,260(54.8%) a three-dose scheme. The matched analysis included 127,014 cases and 180,714 controls.

The three-dose scheme reduced infections (OR 0.81[0.80-0.83]) but after 60 days protection dropped (OR 1.04[1.01-1.06]). The booster dose decreased the risk of hospitalisations and deaths after 15-59 days (ORs 0.28[0.25-0.32] and 0.25[0.22-0.28] respectively), which persisted after administration for 75[66-89] days.

Administration of a homologous booster after a primary scheme with vectored-vaccines provided low protection against infections (OR 0.94[0.92-0.97] and 1.05[1.01-1.09] before and after 60 days). Protection against hospitalisations and death was significant (OR 0.30[0.26-0.35] and 0.29[0.25-0.33] respectively) but decreased after 60 days (OR 0.59[0.47-0.74] and 0.51[0.41- 0.64] respectively).

The inoculation of a heterologous booster after a primary course with ChAdOx1 nCoV-19, rAd26-rAd5, BBIBP-CorV, or heterologous schemes, offered some protection against infection (OR 0.70[0.68-0.71]), which decreased after 60 days (OR 1.01[0.98-1.04]). The protective effect against hospitalisations and deaths (OR 0.26[0.22-0.31] and 0.22[0.18-0.25] respectively) was clear and persisted after 60 days (OR 0.43[0.35-0.53] and 0.33[0.26-0.41]).

Conclusions

This study shows that, during Omicron predominance, heterologous boosters provide an enhanced protection and longer effect duration against COVID-19-related hospitalisations and death in individuals older than 50, compared to homologous boosters.
Separation of the effects of small intestinal microbiome-diet interactions on human gut hormone secretion
Authors: Rienzi Sara C. Di , Danhof Heather A. , Huerta Juan , Britton Robert A.
Published: September 2022

Microbial regulation of gut hormones is a potential mechanism by which the gut microbiome acts on systemic physiology. However, there are limited systems that permit study of how small intestinal microbes and diet modulate gut hormone secretion. Here we present the platformCulturing andApplication ofMicrobes onIntestinalOrganoids (CAMIO) and demonstrate its usage in studying the effects of diet and microbes on gut hormones. We validate that CAMIO supports long-term cultivation of a small intestinal microbiome in different dietary sugars and show that CAMIO permits measurement of gut hormones released from jejunal organoids in response to products of the small intestinal communities. In doing so, we observe differential secretion of ghrelin, PP, and PYY according to whether the microbial communities were grown in glucose-fructose versus sucrose or trehalose. We expect CAMIO to be useful in mechanistically understanding how diet and microbes collectively regulate gut hormones.
Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes
Authors: Zhu Han , Wang Gaowei , Nguyen-Ngoc Kim-Vy , Kim Dongsu , Miller Michael , Goss Georgina , Kovsky Jenna , Harrington Austin R. , Saunders Diane , Melton Rebecca , Powers Alvin C. , Preissl Sebastian , Spagnoli Francesca M. , Gaulton Kyle J. , Sander Maike
Published: September 2022

Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, CDX2+ pre-β-cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro β-cell maturation and identify sex hormones as drivers of β-cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem cell-derived islets and a framework for manipulating cell identities and maturity.
Biophysical and Structural Characterization of a Viral Genome Packaging Motor
Authors: Prokhorov Nikolai S. , Davis Christal R. , Maruthi Kashyap , Yang Qin , Woodson Michael , White Mark A. , Miller Lohra M. , Jarrold Martin F. , Catalano Carlos E. , Morais Marc C.
Published: September 2022

Like many dsDNA viruses, bacteriophage λ replicates its genome as a concatemer consisting of multiple copies of covalently linked dsDNA genomes. To encapsidate a single genome within a nascent procapsid, λ must: 1) find its own dsDNA amongst the multitude of host nucleic acids; 2) identify the genomic start site; 3) cut the DNA; 4) bring the excised DNA to a procapsid; 5) translocate DNA into the capsid; 6) cut DNA again at a packaging termination site, 7) disengage from the newly filled capsid; and 8) bring the remainder of the genomic concatemer to fill another empty procapsid. These disparate genome processing tasks are carried out by a single virus-encoded enzyme complex called terminase. While it has been shown that λ terminase initially forms a tetrameric complex to cut DNA, it is not clear whether the same configuration translocates DNA. Here, we describe biophysical and initial structural characterization of a λ terminase translocation complex. Analytical ultracentrifugation (AUC) and small angle X-ray scattering (SAXS) indicate that between 4 and 5 protomeric subunits assemble a cone-shaped terminase complex with a maximum dimension of ∼230 and radius of gyration of ∼72 Å. Two-dimensional classification of cryoEM images of λ terminase are consistent with these dimensions and show that particles assume a preferred orientation in ice. The orientations appear to be end-on, as terminase rings resemble a starfish with approximate pentameric symmetry. While ∼5-fold symmetry is apparent, one of the five “arms” appears partially displaced with weaker more diffuse density in some classes, suggesting flexibility and/or partial occupancy. Charge detection mass spectrometry (CDMS) is consistent with a pentameric complex, with evidence that one motor subunit is weakly bound. Kinetic analysis indicates that the complex hydrolyzes ATP at a rate comparable to the rates of other phage packaging motors. Together with previously published data, these results suggest that λ terminase assembles conformationally and stoichiometrically distinct complexes to carry out different genome processing tasks. We propose a “symmetry resolution” pathway to explain how terminase transitions between these structurally and functionally distinct states.
Cell cycle dynamics and window of MUTE action during the terminal division of stomata and ramification of its loss-of-function on the cell cycle of an uncommitted precursor
Authors: Zuch Daniel T. , Herrmann Arvid , Kim Eun-Deok , Torii Keiko U.
Published: September 2022

Plants develop in the absence of cell migration. As such, cell division and differentiation need to be coordinated for functional tissue formation. Cellular valves on the plant epidermis, stomata, are generated through a stereotypical sequence of cell division and differentiation events. In Arabidopsis, three master-regulatory transcription factors, SPEECHLESS (SPCH), MUTE, and FAMA sequentially drive initiation, proliferation, and differentiation of stomata. Among them, MUTE switches the cell cycle mode from proliferative asymmetric division to terminal symmetric division and orchestrates the execution of the single symmetric division event. However, it remains unclear to what extent MUTE regulates the expression of cell cycle genes through the symmetric division and whether MUTE accumulation itself is gated by the cell cycle. Here, we show that MUTE directly upregulates the expression of cell cycle components throughout the terminal cell cycle phases of a stomatal precursor, not only the core cell cycle engines but also checkpoint regulators. Time-lapse live imaging using the multi-color cell cycle indicator PlaCCI revealed that MUTE accumulates up to the early G2 phase, whereas its successor and direct target, FAMA, accumulates at late G2 through terminal mitosis. In the absence of MUTE, meristemoids fail to differentiate, and their G1 phase elongates as they reiterate asymmetric divisions. Combined, our work provides the framework of cell cycle and master regulatory transcription factors to coordinate a single symmetric cell division, and suggests a mechanism for the eventual cell cycle arrest of an uncommitted stem-cell-like precursor at the G1 phase.