bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of enhanced versus reduced vasodilating treatment on brachial and central blood pressure in patients with chronic kidney disease: a randomized controlled trial
Authors: Khatir Dinah Sherzad , Carlsen Rasmus Kirkeskov , Ivarsen Per , Jespersen Bente , Pedersen Michael , Christensen Kent Lodberg , Buus Niels Henrik 
Published: July 2021

Background:
Blood pressure (BP) control is important in chronic kidney disease (CKD), but a reduction in brachial BP may not mirror changes in central aortic BP (cBP) during antihypertensive medication. We hypothesize that a fall in cBP is better reflected during enhanced vasodilation treatment (EVT) compared with reduced vasodilation treatment (RVT) because of different hemodynamic actions of these interventions.

Methods:
Eighty-one hypertensive CKD stage 3–4 patients (mean measured glomerular filtration rate 36 ml/min per 1.73 m2) were randomized to either EVT based on renin--angiotensin blockade and/or amlodipine or RVT based on nonvasodilating β-blockade (metoprolol). Before randomization and following 18 months of treatment, we performed 24-h ambulatory BP measurements (ABPM) and radial artery pulse wave analysis for estimation of cBP and augmentation index (AIx). Forearm resistance (R
rest) was determined by venous occlusion plethysmography and arterial stiffness by carotid--femoral pulse wave velocity (PWV). Matched healthy controls were studied once for comparison.

Results:
Compared with controls, CKD patients had elevated ABPM, cBP and PWV. Although ABPM remained unchanged from baseline to follow-up in both treatment groups, cBP decreased 4.7/2.9 mmHg (systolic/diastolic) during EVT and increased 5.1/1.5 mmHg during RVT (Δ=9.8/4.4 mmHg, P=0.02 for SBP, P = 0.05 for DBP). At follow-up, the difference between systolic cBP and 24-h ABPM (ΔBPsyst) was negatively associated with heart rate and positively associated with AIx and Rrest (all P < 0.01) but not PWV (P = 0.32).

Conclusion:
In CKD patients, EVT and RVT have opposite effects on cBP and the difference between cBP and ambulatory BP is larger for EVT than RVT.
Precontrast Magnetic Resonance Imaging Findings and Assessment of Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Low- and High-Flow Vascular Malformations
Authors: Berger Sigurd , Andersen Rune , Jakobsen Jarl Åsbjørn , Geier Oliver Marcel , Abildgaard Andreas , Dorenberg Eric 
Published: July 2021

Objectives:
To evaluate magnetic resonance imaging (MRI) findings in vascular malformations by assessing (1) the prevalence of phleboliths and flow voids and (2) dynamic contrast enhancement characteristics in early and delayed contrast phases.

Methods:
Ninety-eight patients (median age 27 years) were included. MRI analyses were performed by 2 radiologists that were blinded to clinical information. Phleboliths and flow-voids were assessed with T1 and short tau inversion recovery. Artery-lesion enhancement time (ALET) was assessed with time-resolved MRI angiography. Contrast accumulation until 15 minutes postinjection was assessed using subtraction techniques based on volumetric interpolated breath-hold examination. Standard statistical methods were applied.

Results:
Eighty-nine patients had low-flow malformations and 9 patients had high-flow malformations. Phleboliths were present in 13.5% of low-flow malformations, and 0% of high-flow malformations (P = .60). Flow voids were observed in 16.9% of low-flow malformations and 55.6% of high-flow malformations (P < .05). Median ALET of low-flow malformations was 9.2 seconds and of high-flow malformations (n = 8) was 0.8 seconds (P < .05). Twenty-one low-flow malformations had ALET that overlapped with ALET of high-flow malformations (≤6.3 seconds). Contrast accumulation between preinjection and 2 minutes postinjection was observed in 97.5% of low-flow malformations and 100% of high-flow malformations, whereas contrast accumulation between 2 and 15 minutes postinjection was observed in 92.6% of low-flow malformations and 62.5% of high-flow malformations (P < .05).

Conclusion:
Our data suggest that phleboliths are infrequent in vascular malformations and that flow voids may be unreliable markers of high-flow malformations. Both high- and low-flow malformations may present with considerable overlap regarding flow dynamics, implying vascular heterogeneity within both malformation types.
Mutations in two SARS-CoV-2 variants of concern reflect two distinct strategies of antibody escape
Authors: Fiedler Sebastian , Denninger Viola , Morgunov Alexey S. , Ilsley Alison , Worth Roland , Meisl Georg , Xu Catherine K. , Piziorska Monika A. , Ricci Francesco , Malik Anisa Y. , Devenish Sean R. A. , Schneider Matthias M. , Kosmoliaptsis Vasilis , Aguzzi Adriano , Iwasaki Akiko , Fiegler Heike , Knowles Tuomas P. J. 
Published: July 2021

AbstractUnderstanding the factors that contribute to antibody escape of SARS-CoV-2 and its variants is key for the development of drugs and vaccines that provide broad protection against a variety of virus variants. Using microfluidic diffusional sizing, we determined the dissociation constant (KD) for the interaction between receptor binding domains (RBDs) of SARS-CoV-2 in its original version (WT) as well as alpha and beta variants with the host-cell receptor angiotensin converting enzyme 2 (ACE2). For RBD-alpha, the ACE2-binding affinity was increased by a factor of ten when compared with RBD-WT, while ACE2-binding of RBD-beta was largely unaffected. However, when challenged with a neutralizing antibody that binds to both RBD-WT and RBD-alpha with low nanomolar KD values, RBD-beta displayed no binding, suggesting a substantial epitope change. In SARS-CoV-2 convalescent sera, RBD-binding antibodies showed low nanomolar affinities to both wild-type and variant RBD proteins—strikingly, the concentration of antibodies binding to RBD-beta was half that of RBD-WT and RBD-alpha, again indicating considerable epitope changes in the beta variant. Our data therefore suggests that one factor contributing to the higher transmissibility and antibody evasion of SARS-CoV-2 alpha and beta is a larger fraction of viruses that can form a complex with ACE2. However, the two variants employ different mechanisms to achieve this goal. While SARS-CoV-2 alpha RBD binds with greater affinity to ACE2 and is thus more difficult to displace from the receptor by neutralizing antibodies, RBD-beta is less accessible to antibodies due to epitope changes which increases the chances of ACE2-binding and infection.
The peroxisomal transporter ABCD3 plays a major role in dicarboxylic fatty acid metabolism
Authors: Ranea-Robles Pablo , Chen Hongjie , Stauffer Brandon , Yu Chunli , Bhattacharya Dipankar , Friedman Scott L. , Puchowicz Michelle , Houten Sander M. 
Published: July 2021

AbstractPeroxisomes metabolize a specific subset of fatty acids, which include dicarboxylic fatty acids (DCAs) generated by ω-oxidation. Data obtained in vitro suggest that the peroxisomal transporter ABCD3 (also known as PMP70) mediates the transport of DCAs into the peroxisome, but in vivo evidence to support this role is lacking. In this study, we studied an Abcd3 KO mouse model generated by CRISPR-Cas9 technology using targeted and untargeted metabolomics, histology, immunoblotting, and stable isotope tracing technology. We show that ABCD3 functions in DCA metabolism and uncover a novel role for this peroxisomal transporter in lipid metabolic homeostasis. The Abcd3 KO mouse presents with lipodystrophy, increased circulating free fatty acids, decreased ketone bodies, enhanced hepatic cholesterol synthesis and decreased hepatic de novo lipogenesis. Moreover, our study suggests that DCAs are metabolized by mitochondrial β-oxidation when ABCD3 is not functional, reflecting the importance of the metabolic compartmentalization and communication between peroxisomes and mitochondria. In summary, this study provides data on the role of the peroxisomal transporter ABCD3 in hepatic lipid homeostasis and DCA metabolism, and the consequences of peroxisomal dysfunction for the liver.
Increased aerosol transmission for B.1.1.7 (alpha variant) over lineage A variant of SARS-CoV-2
Authors: Port Julia R. , Yinda Claude Kwe , Avanzato Victoria A. , Schulz Jonathan E. , Holbrook Myndi G. , van Doremalen Neeltje , Shaia Carl , Fischer Robert J. , Munster Vincent J. 
Published: July 2021

AbstractAirborne transmission, a term combining both large droplet and aerosol transmission, is thought to be the main transmission route of SARS-CoV-2. Here we investigated the relative efficiency of aerosol transmission of two variants of SARS-CoV-2, B.1.1.7 (alpha) and lineage A, in the Syrian hamster. A novel transmission caging setup was designed and validated, which allowed the assessment of transmission efficiency at various distances. At 2 meters distance, only particles <5 µm traversed between cages. In this setup, aerosol transmission was confirmed in 8 out of 8 (N = 4 for each variant) sentinels after 24 hours of exposure as demonstrated by respiratory shedding and seroconversion. Successful transmission occurred even when exposure time was limited to one hour, highlighting the efficiency of this transmission route. Interestingly, the B.1.1.7 variant outcompeted the lineage A variant in an airborne transmission chain after mixed infection of donors. Combined, this data indicates that the infectious dose of B.1.1.7 required for successful transmission may be lower than that of lineage A virus. The experimental proof for true aerosol transmission and the increase in the aerosol transmission potential of B.1.1.7 underscore the continuous need for assessment of novel variants and the development or preemptive transmission mitigation strategies.
Svep1 orchestrates distal airway patterning and alveolar differentiation in murine lung development
Authors: Foxworth N , Wells J , Ocaña-Lopez S , Muller S , Bhayani P , Denegre J , Palmer K , Memishian W , McGee T , Murray SA , Donahoe PK , Bult CJ , Loscertales M 
Published: July 2021

AbstractDisruptions in airway branching or alveolar differentiation during lung development can lead to severe respiratory deficiencies and neonatal death. The molecular mechanisms governing branching patterning and early alveolar formation remain elusive. Loss ofSvep1function in mice results in various developmental defects, including lung hypoplasia and perinatal lethality. Our examination of the lungs ofSvep1knockout (Svep1-/-)mouse embryos, bothin vivoandin vitro, revealed thatSvep1mutants exhibit an increase in the number of disorganized distal airway tips and progressively greater disruption of lung lobe morphology over time and saccular development.Svep1interacts with FGF signaling to regulate smooth muscle differentiation and, together withFgf9,guides airway branching patterning. Transcriptomic data from the lungs ofSvep1-/-embryos revealed dysregulated gene expression affecting saccular maturation. Our findings demonstrate thatSvep1is a key extracellular matrix player shaping airway morphology and influencing alveolar fate. These insights offer potential avenues for therapeutic interventions in congenital lung disorders.
Self-supervised contrastive learning for integrative single cell RNA-seq data analysis
Authors: Han Wenkai , Cheng Yuqi , Chen Jiayang , Zhong Huawen , Hu Zhihang , Chen Siyuan , Zong Licheng , King Irwin , Gao Xin , Li Yu 
Published: July 2021

AbstractSingle-cell RNA-sequencing (scRNA-seq) has become a powerful tool to reveal the complex biological diversity and heterogeneity among cell populations. However, the technical noise and bias of the technology still have negative impacts on the downstream analysis. Here, we present a self-supervised Contrastive LEArning framework for scRNA-seq (CLEAR) profile representation and the downstream analysis. CLEAR overcomes the heterogeneity of the experimental data with a specifically designed representation learning task and thus can handle batch effects and dropout events. In the task, the deep learning model learns to pull together the representations of similar cells while pushing apart distinct cells, without manual labeling. It achieves superior performance on a broad range of fundamental tasks, including clustering, visualization, dropout correction, batch effect removal, and pseudo-time inference. The proposed method successfully identifies and illustrates inflammatory-related mechanisms in a COVID-19 disease study with 43,695 single cells from peripheral blood mononuclear cells. Further experiments to process a million-scale single-cell dataset demonstrate the scalability of CLEAR. This scalable method generates effective scRNA-seq data representation while eliminating technical noise, and it will serve as a general computational framework for single-cell data analysis.
Kveik brewing yeasts demonstrate wide flexibility in beer fermentation temperature and flavour metabolite production and exhibit enhanced trehalose accumulation
Authors: Foster Barret , Tyrawa Caroline , Ozsahin Emine , Lubberts Mark , Krogerus Kristoffer , Preiss Richard , van der Merwe George 
Published: July 2021

AbstractTraditional Norwegian Farmhouse ale yeasts, also known as kveik, have captured the attention of the brewing community in recent years. Kveik were recently reported as fast fermenting thermo- and ethanol tolerant yeasts with the capacity to produce a variety of interesting flavour metabolites. They are a genetically distinct group of domesticated beer yeasts of admixed origin with one parent from the “Beer 1” clade and the other unknown. While kveik are known to ferment wort efficiently at warmer temperatures, its range of fermentation temperatures and corresponding flavour metabolites produced, remain uncharacterized. In addition, the characteristics responsible for its increased thermotolerance remain largely unknown. Here we demonstrate variation in kveik strains at a wide range of fermentation temperatures and show not all kveik strains are equal in fermentation performance, flavour metabolite production and stress tolerance. Furthermore, we uncovered an increased capacity of kveik strains to accumulate intracellular trehalose, which likely contributes to its increased thermo- and ethanol tolerances. Taken together our results present a clearer picture of the future opportunities presented by Norwegian kveik yeasts and offer further insight into their applications in brewing.
Functional buffering via cell-specific gene expression promotes tissue homeostasis and cancer robustness
Authors: Lin Hao-Kuen , Cheng Jen-Hao , Wu Chia-Chou , Hsieh Feng-Shu , Dunlap Carolyn , Chen Sheng-hong 
Published: July 2021

AbstractFunctional buffering that ensures biological robustness is critical for maintaining tissue homeostasis, organismal survival, and evolution of novelty. However, the mechanism underlying functional buffering, particularly in multicellular organisms, remains largely elusive. Here, we developed an inference index (C-score) for Cell-specific Expression- BUffering (CEBU), whereby functional buffering is mediated via expression of buffering genes in specific cells and tissues in humans. By computing C-scores across 684 human cell lines using genome-wide CRISPR screens and transcriptomic RNA-seq, we report that C- score-identified putative buffering gene pairs are enriched for members of the same duplicated gene family, pathway, and protein complex. Furthermore, CEBU is especially prevalent in tissues of low regenerative capacity (e.g., bone and neuronal tissues) and is weakest in highly regenerative blood cells, linking functional buffering to tissue regeneration. Clinically, the buffering capacity enabled by CEBU can help predict patient survival for multiple cancers. Our results reveal CEBU as a buffering mechanism contributing to tissue homeostasis and cancer robustness in humans.Summary blurbWe unveil a genome-wide functional buffering mechanism, termed Cell-specific Expression Buffering (CEBU), whereby gene expression contributes to functional buffering in specific cell types and tissues. We link CEBU to genetic interactions, tissue homeostasis and cancer robustness.
Different Contribution of the Monkey Prefrontal and Premotor Dorsal Cortex in Decision Making during a Transitive Inference task
Authors: Ramawat S , Mione V , Di Bello F , Bardella G , Genovesio A , Pani P , Ferraina S , Brunamonti E 
Published: July 2021

AbstractSeveral studies have reported similar neural modulations between brain areas of the frontal cortex, such as the dorsolateral prefrontal (DLPFC) and the premotor dorsal (PMd) cortex, in tasks requiring encoding of the abstract rules for selecting the proper action. Here we compared the neuronal modulation of the DLPFC and PMd of monkeys trained to choose the higher rank from a pair of abstract images (target item), selected from an arbitrarily rank-ordered set (A>B>C>D>E>F) in the context of a transitive inference task. Once acquired by trial-and-error, the ordinal relationship between pairs of adjacent images (i.e., A>B; B>C; C>D; D>E; E>F), monkeys were tested in indicating the ordinal relation between items of the list not paired during learning. During these decisions, we observed that the choice accuracy increased and the reaction time decreased as the rank difference between the compared items enhanced. This result is in line with the hypothesis that after learning, the monkeys built an abstract mental representation of the ranked items, where rank comparisons correspond to the items’ position comparison on this representation. In both brain areas, we observed higher neuronal activity when the target item appeared in a specific location on the screen with respect to the opposite position and that this difference was particularly enhanced at lower degrees of difficulty. By comparing the time evolution of the activity of the two areas, we observed that the neural encoding of target item spatial position occurred earlier in the DLPFC than in the PMd.
Regulatory cross-talk supports resistance to Zn intoxication in Streptococcus
Authors: Sullivan Matthew J. , Goh Kelvin G. K. , Ulett Glen C. 
Published: July 2021

AbstractMetals such as copper (Cu) and zinc (Zn) are important trace elements that can effect bacterial cell physiology but can also intoxicate bacteria at high concentrations. Discrete genetic systems for management of Cu and Zn efflux have been described in several bacteria pathogens, including streptococci. However, insight into molecular cross-talk between systems for Cu and Zn management in bacteria that drive metal detoxification, is limited. Here, we describe a biologically consequential cross-system effect of metal management in group B Streptococcus (GBS) governed by the Cu-responsive copY regulator in response to Zn. RNAseq analysis of wild-type (WT) and copY-deficient GBS exposed to metal stress revealed unique transcriptional links between the systems for Cu and Zn detoxification. We show that the Cu-sensing functions of CopY extend beyond Cu, and enable CopY to regulate Cu and Zn stress responses to effect genes involved in central cellular processes, including riboflavin synthesis. CopY also contributed to supporting GBS virulence in vivo following infection of mice. Identification of the Zn resistome of GBS using TraDIS revealed a suite of genes essential for GBS growth in metal stress. Several of the genes identified are novel to systems that support bacterial survival in metal stress, and represent a diversity of mechanisms of microbial metal homeostasis during cell stress. Overall, this study reveals a new and important mechanism of cross-system complexity driven by CopY in bacteria to regulate cell management of metal stress and survival.Author SummaryMetals, such as Cu and Zn, can be used by the mammalian immune system to target bacterial pathogens, and consequently, bacteria have evolved discrete genetic systems that subvert this host-derived antimicrobial response. Systems for Cu and Zn homeostasis are well characterized, including the transcriptional control of sensing and responding to metal stress. Here we have discovered novel features of metal response sytems in Streptococcus that have major implications for pathogenesis and virulence. We show that Streptococcus resists Zn intoxication by utilizing a bona fide Cu regulator, CopY, to maintain cellular metal homeostasis, which enables the bacteria to survive stressful conditions. We identify new genes in Streptococcus that confer resistance to zinc intoxication, including several that have not previously been linked to metal ion homeostasis in any bacterium. The identification of cross-system metal management and new resistance mechanisms enhances our understanding of metal ion homeostasis in bacteria and its effect on pathogenesis.
CIGB-300 synthetic peptide, an antagonist of CK2 kinase activity, as a treatment for Covid-19. A computational biology approach
Authors: Miranda Jamilet , Bringas Ricardo , Fernández-de-Cossio Jorge , Perera Yasser 
Published: July 2021

AbstractDrug repositioning became the first choice for treating Covid-19 patients due to the urgent need to deal with the pandemic. Similarities in the hijacking mechanisms used by SARS-CoV-2 and several type of cancer, suggest the repurposing of cancer drugs to treat Covid-19. CK2 kinase antagonists have been proposed for the treatment of cancer. A recent study in cells infected with SARS-CoV-2 virus found a significant CK2 kinase activity, and the use of a CK2 inhibitor showed antiviral responses. CIGB-300, originally designed as an anticancer peptide, is an antagonist of CK2 kinase activity that binds to CK2 phospho-acceptor sites. Recent preliminary results show an antiviral activity of CIGB-300 versus a surrogate model of coronavirus. Here we present a computational biology study that provides evidences at the molecular level of how CIGB-300 might interfere with SARS-CoV-2 life cycle inside infected human cells. First, from SARS-CoV studies, we infer the potential incidence of CIGB-300 in SARS-CoV-2 interference on immune response. Next, from the analysis of multiple Omics data, we propose the action of CIGB-300 since early stage of viral infections perturbing the virus hijacking of RNA splicing machinery. It was also predicted the interference of CIGB-300 in virus-host interactions responsible for the high infectivity and the particular immune response to SARS-CoV-2 infection. Further, we provide evidences of CIGB-300 attenuation of phenotypes related to muscle, bleeding, coagulation and respiratory disorders.
Synaptic Mechanisms of Top-Down Control in the Non-Lemniscal Inferior Colliculus
Authors: Oberle Hannah M. , Ford Alexander N. , Dileepkumar Deepak , Czarny Jordyn , Apostolides Pierre F. 
Published: July 2021

AbstractCorticofugal projections to evolutionarily ancient, sub-cortical structures are ubiquitous across mammalian sensory systems. These “descending” pathways enable the neocortex to control ascending sensory representations in a predictive or feedback manner, but the underlying cellular mechanisms are poorly understood. Here we combine optogenetic approaches with in vivo and in vitro patch-clamp electrophysiology to study the projection from auditory cortex to the inferior colliculus (IC), a major descending auditory pathway that controls IC neuron feature selectivity, plasticity and auditory perceptual learning. Although individual auditory cortico-collicular synapses were generally weak, IC neurons often integrated inputs from multiple corticofugal axons that generated reliable, tonic depolarizations even during prolonged presynaptic activity. Latency measurements in vivo showed that descending signals reach the IC within 30 ms of sound onset, which in IC neurons corresponded to the peak of synaptic depolarizations evoked by short sounds. Activating ascending and descending pathways at latencies expected in vivo caused a NMDA receptor dependent, supra-linear EPSP summation, indicating that descending signals can non-linearly amplify IC neurons’ moment-to-moment acoustic responses. Our results shed light upon the synaptic bases of descending sensory control, and imply that heterosynaptic cooperativity contributes to the auditory cortico-collicular pathway’s role in plasticity and perceptual learning.