bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Computational Growth and Remodeling Framework for Adaptive and Maladaptive Pulmonary Arterial Hemodynamics
Authors: Szafron Jason M. , Yang Weiguang , Feinstein Jeffrey A. , Rabinovitch Marlene , Marsden Alison L. 
Published: April 2023

AbstractHemodynamic loading is known to contribute to the development and progression of pulmonary arterial hypertension (PAH). This loading drives changes in mechanobiological stimuli that affect cellular phenotypes and lead to pulmonary vascular remodeling. Computational models have been used to simulate mechanobiological metrics of interest, such as wall shear stress, at single time points for PAH patients. However, there is a need for new approaches that simulate disease evolution to allow for prediction of long-term outcomes. In this work, we develop a framework that models the pulmonary arterial tree through adaptive and maladaptive responses to mechanical and biological perturbations. We coupled a constrained mixture theory-based growth and remodeling framework for the vessel wall with a morphometric tree representation of the pulmonary arterial vasculature. We show that non-uniform mechanical behavior is important to establish the homeostatic state of the pulmonary arterial tree, and that hemodynamic feedback is essential for simulating disease time courses. We also employed a series of maladaptive constitutive models, such as smooth muscle hyperproliferation and stiffening, to identify critical contributors to development of PAH phenotypes. Together, these simulations demonstrate an important step towards predicting changes in metrics of clinical interest for PAH patients and simulating potential treatment approaches.
Anin vitroexperimental pipeline to characterize the binding specificity of SARS-CoV-2 neutralizing antibodies
Authors: Atanasoff Kristina E. , Brambilla Luca , Adelsberg Daniel C. , Kowdle Shreyas , Stevens Christian S. , Hung Chuan-Tien , Fu Yanwen , Lim Reyna , Tran Linh , Allen Robert , Andrew Duty J. , Bajic Goran , Lee Benhur , Tortorella Domenico 
Published: April 2023

AbstractThe coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has led to over 760 million cases and >6.8 million deaths worldwide. We developed a panel of human neutralizing monoclonal antibodies (mAbs) targeting the SARS-CoV-2 Spike protein using Harbour H2L2 transgenic mice immunized with Spike receptor binding domain (RBD) (1). Representative antibodies from genetically-distinct families were evaluated for inhibition of replication-competent VSV expressing SARS-CoV-2 Spike (rcVSV-S) in place of VSV-G. One mAb (denoted FG-10A3) inhibited infection of all rcVSV-S variants; its therapeutically-modified version, STI-9167, inhibited infection of all tested SARS-CoV-2 variants, including Omicron BA.1 and BA.2, and limited virus proliferationin vivo(1). To characterize the binding specificity and epitope of FG-10A3, we generated mAb-resistant rcVSV-S virions and performed structural analysis of the antibody/antigen complex using cryo-EM. FG-10A3/STI-9167 is a Class 1 antibody that prevents Spike-ACE2 binding by engaging a region within the Spike receptor binding motif (RBM). Sequencing of mAb-resistant rcVSV-S virions identified F486 as a critical residue for mAb neutralization, with structural analysis revealing that both the variable heavy and light chains of STI-9167 bound the disulfide-stabilized 470-490 loop at the Spike RBD tip. Interestingly, substitutions at position 486 were later observed in emerging variants of concern BA.2.75.2 and XBB. This work provides a predictive modeling strategy to define the neutralizing capacity and limitations of mAb therapeutics against emerging SARS-CoV-2 variants.ImportanceThe COVID-19 pandemic remains a significant public health concern for the global population; development and characterization of therapeutics, especially ones that are broadly effective, will continue to be essential as SARS-CoV-2 variants emerge. Neutralizing monoclonal antibodies remain an effective therapeutic strategy to prevent virus infection and spread with the caveat that they interact with the circulating variants. The epitope and binding specificity of a broadly neutralizing anti-SARS-CoV-2 Spike RBD antibody clone against many SARS-CoV-2 VOC was characterized by generating antibody-resistant virions coupled with cryo-EM structural analysis. This workflow can serve to predict the efficacy of antibody therapeutics against emerging variants and inform the design of therapeutics and vaccines.
Nano-silver and forskolin regulate rice seed germination mediated byOsPIP2-1
Authors: Chen Bingxian , Peng Yuanxuan , Zhang Qi , Chen Zhongjian , Li Hongmei , Liu Jun 
Published: April 2023

SUMMARYAs timely germination of seeds is crucial to crop yield and quality, the low germination percentage for direct seeding in rice and pre-harvest sprouting during late stage of maturity have extremely adverse effects on rice production. Herein, we found that nano-silver inhibited rice seed germination while forskolin promoted this process. Germination assay showed that 20 μM AgNPs and 0.5 μM forskolin could be the optimal concentrations regulating rice seed germination. At the molecular level, an aquaporin gene,OsPIP2-1, was most highly expressed among those homologous genes during rice seed germination, and was decreased by AgNPs and increased by forskolin. Meanwhile, the activity of α-amylase and its genes expression were also inhibited by AgNPs and promoted by forskolin. Next, the germination percentage ofOsPIP2-1overexpressing seeds was significantly higher than that of wild-type, and that ofOsPIP2-1knockout seeds was dramatically reduced. Furthermore, compared with the wild type, α-amylase activity and the transcription ofOsAmy3CandOsAmy3Ewere increased inOsPIP2-1overexpressing seeds and decreased inOsPIP2-1knockout seeds, indicating thatOsPIP2-1positively regulates α-amylase. Interestingly, seed germination, α-amylase activity and its genes expression inOsPIP2-1overexpressed and knockdout lines could also be inhibited by nano-silver and promoted by forskolin. In conclusion, we propose that nano-silver and forskolin regulated seed germination by modulating the expression ofOsPIP2-1and thus α-amylase. Our results may bring new application of nano-silver and forskolin in rice cultivation.
Comparative genome microsynteny illuminates the fast evolution of nuclear mitochondrial segments (NUMTs) in mammals
Authors: Uvizl Marek , Puechmaille Sebastien J. , Power Sarahjane , Pippel Martin , Carthy Samuel , Haerty Wilfried , Myers Eugene W. , Teeling Emma C. , Huang Zixia 
Published: April 2023

AbstractThe escape of DNA from mitochondria into the nuclear genome (nuclear mitochondrial DNA, NUMT) is an ongoing process. Although pervasively observed in eukaryotic genomes, their evolutionary trajectories in a mammal-wide context are poorly understood. The main challenge lies in the orthology assignment of NUMTs across species due to their fast evolution and chromosomal rearrangements over the past ∼200 million years. To address this issue, we systematically investigated the characteristics of NUMT insertions in 45 mammalian genomes, and established a novel, synteny-based method to accurately predict orthologous NUMTs and ascertain their evolution across mammals. With a series of comparative analyses across taxa, we revealed that NUMTs may originate from non-random regions in mtDNA, tend to locate in transposon-rich and intergenic regions, and unlikely code for functional proteins. Using our synteny-based approach, we leveraged 630 pairwise comparisons of genome-wide microsynteny and predicted the NUMT orthology relationships across 36 mammals. With the phylogenetic patterns of NUMT presence-and-absence across taxa, we constructed the ancestral state of NUMTs given the mammal tree using a coalescent method. We found support on the ancestral node of Fereuungulata within Laurasiatheria, whose subordinal relationships are still controversial. This strongly indicates that NUMT gain-and-loss over evolutionary time provides great insights into mammal evolution. However, we also demonstrated that one should be cautious when using ancestral NUMT trees to infer phylogenetic relationships. This study broadens our knowledge on NUMT insertion and evolution in mammalian genomes and highlights the merit of NUMTs as alternative genetic markers in phylogenetic inference.
Trial participants are frequently excluded based on their symptoms rather than their condition: A systematic review of Cochrane reviews and their component trials
Authors: Stocking Katie , Watson Andrew , Kirkham Jamie J , Wilkinson Jack , Vail Andy 
Published: April 2023

AbstractObjectivesIdentify strategies used in the design of recent randomised controlled trials (RCTs) and their associated Cochrane reviews where patients with the same gynaecological condition present with different symptoms.Study Design and SettingWe searched the Cochrane library (February 2022) for reviews in polycystic ovarian syndrome (PCOS) and endometriosis. Reviews were included if the intervention was intended to treat all condition-specific symptoms. We restricted to trials published since 2012 to consider ‘current’ approaches. For each trial we recorded the number of potentially eligible participants excluded as a direct result of the chosen strategy. For each review we recorded the numbers of RCTs and participants excluded unnecessarily.ResultsThere were 89 distinct PCOS trials in 13 reviews, and 13 Endometriosis trials in 11 reviews. Most trials restricted their eligibility to participants with specific symptoms (55% PCOS, 46% endometriosis). The second most common strategy was to measure and analyse clinical outcomes that were not relevant to all participants (38% PCOS, 31% endometriosis). Reviews excluded 27% of trials based just on outcome data.ConclusionsCurrent gynaecological research is inefficient. Most trials either exclude patients who could benefit from treatment or measure outcomes not relevant to all participants.RegistrationPROSPERO (CRD42022334776)What is new?Key findingsOver a quarter of Cochrane reviews included in this review excluded trials based on the outcomes reported.Typically, recent randomised controlled trials in Polycystic Ovarian Syndrome and Endometriosis trials either exclude patients who could potentially benefit from the treatment given, or measure outcomes of no relevance to some participants.What this adds to what is known?Strategies developed that are employed in the design and measurement of outcomes in gynaecological trials.There are multiple sources of waste in the current gynaecological research landscape. The population of patients available is under-utilised by excluding patients based on the outcomes measured, or alternatively, researchers are measuring outcomes in patients who do not experience the associated symptom(s).What is the implication and what should change now?Gynaecological patients experience heterogeneity in their symptoms and therefore it is crucial to employ appropriate outcome measures in order to reduce research waste. Cochrane Reviews should include all trials which report outcomes that are relevant to the population of interest if the intervention under investigation is deemed to plausibly treat the associated symptom(s).
Ornithine is the central intermediate in the arginine degradative pathway and its regulation inBacillus subtilis
Authors: Warneke Robert , Garbers Tim Benedict , Herzberg Christina , Aschenbrandt Georg , Ficner Ralf , Stülke Jörg 
Published: April 2023

ABSTRACTThe Gram-positive model bacteriumBacillus subtilisis able to utilize a variety of proteinogenic and non proteinogenic amino acids as sources of carbon, energy and nitrogen. The utilization of the amino acids arginine, citrulline and ornithine is catalyzed by enzymes that are encoded in therocABCandrocDEFoperons and by therocGgene. Expression of these genes is under control of the alternative sigma factor SigL. RNA polymerase associated to this sigma factor depends on an ATP-hydrolyzing transcription activator to initiate transcription. The RocR protein acts as transcription activator for therocgenes. In this work, we have studied the contributions of all enzymes of the Roc pathway to the degradation of arginine, citrulline and ornithine. This identified the previously uncharacterized RocB protein as responsible for the conversion of citrulline to ornithine.In vitroassays with the purified enzyme suggest that it acts as a manganese-dependent N-carbamoyl-L-ornithine hydrolase that cleaves citrulline to ornithine and carbamate. So far, the molecular effector that triggers transcription activation by RocR has not been unequivocally identified. Using a combination of transcription reporter assays and biochemical experiments we demonstrate that ornithine is the molecular inducer for RocR activity. Our work suggests that binding of ATP to RocR triggers its hexamerization, and binding of ornithine then allows ATP hydrolysis and activation ofrocgene transcription. Thus, ornithine is the central molecule of therocdegradative pathway as it is the common intermediate of arginine and citrulline degradation and the molecular effector for the transcription regulator RocR.IMPORTANCEAmino acids serve as building blocks for protein biosynthesis in each living cell but can also be used as sources of carbon, energy and nitrogen. In this work we have identified ornithine as the central player in the utilization of arginine, citrulline and ornithine in the Gram-positive bacteriumB. subtilis. Ornithine is the common intermediate after the first steps of arginine and citrulline degradation. We have identified the so far uncharacterized protein RocB as the enzyme responsible for the cleavage of citrulline to ornithine and carbamate. Moreover, we demonstrate that ornithine is the molecular effector that triggers ATPase activity of the transcription factor RocR. Binding of ornithine to RocR and the subsequent hydrolysis of ATP allow a functional interaction with the alternative sigma factor SigL and subsequent transcription activation of all genes of the degradative pathway.
Nucleus accumbens neurons dynamically encode positive and aversive associative learning
Authors: Deseyve Catarina , Domingues Ana Verónica , Carvalho Tawan T. A. , Vieitas-Gaspar Natacha , Pinto Luísa , Sousa Nuno , Coimbra Bárbara , Rodrigues Ana João , Soares-Cunha Carina 
Published: April 2023

AbstractTo survive, individuals must learn to associate cues in the environment with emotionally relevant outcomes. This association is partially mediated by the nucleus accumbens (NAc), a key brain region of the reward circuit that is mainly composed by GABAergic medium spiny neurons (MSNs), that express either dopamine receptor D1 or D2. Recent studies showed that both populations can drive reward and aversion, however, the activity of these neurons during appetitive and aversive Pavlovian conditioning remains to be determined.Here, we investigated the relevance of D1- and D2-neurons in Pavlovian associations, by measuring calcium transients with fiber photometry during appetitive and aversive Pavlovian tasks. Sucrose was used as a positive unconditioned stimulus (US) and foot shock was used as a negative US. We show that during appetitive Pavlovian conditioning, D1- and D2-neurons exhibit a general decrease in activity in response to CS and to US across learning, with dynamic, and partially overlapping, activity responses to CS and US. During the aversive Pavlovian conditioning, D1- and D2-neurons showed an increase in the activity in response to the CS and to the US (shock).Our data supports a synchronous role for D1- and D2-neurons in appetitive and aversion processing.
Mutualism at the leading edge: Insights into the eco-evolutionary dynamics of host-symbiont communities during range expansion
Authors: Martignoni Maria M , Tyson Rebecca C , Kolodny Oren , Garnier Jimmy 
Published: April 2023

AbstractThe evolution of mutualism between host and symbiont communities plays an essential role in maintaining ecosystem function and should therefore have a pro-found effect on their range expansion dynamics. In particular, the presence of mutualistic symbionts at the leading edge of a host-symbiont community should enhance its propagation in space. We develop a theoretical framework that captures the eco-evolutionary dynamics of host-symbiont communities, to investigate how the evolution of resource exchange may shape community structure during range expansion. We consider a community with symbionts that are mutualistic or parasitic to various degrees, where parasitic symbionts receive the same amount of resource from the host as mutualistic symbionts, but at lower cost. The selective advantage of parasitic symbionts over mutualistic ones is strengthened with resource availability (i.e. with host density), promoting mutualism at the range edges, where host density is low, and parasitism in the population core, where host density is higher. This spatial selection also influences the speed of spread. We find that the host growth rate (which depends on the average benefit provided by the symbionts) is maximal at the range edges, where symbionts are more mutualistic, and that host-symbiont communities with high symbiont density at their core (e.g. resulting from more mutualistic hosts) spread faster into new territories. These results indicate that the expansion of host-symbiont communities is pulled by the hosts but pushed by the symbionts, in a unique push-pull dynamic where both the host and symbionts are active and tightly-linked players.
Impairments of motor adaptation in Essential Tremor are linked to movement execution
Authors: Blondiaux Florence , Lebrun Louisien , Hanseeuw Bernard J. , Crevecoeur Frédéric 
Published: April 2023

0.AbstractEssential tremor (ET) is a neurological disorder characterized by involuntary oscillations of the limbs. Previous studies have hypothesized that ET was a cerebellar disorder and reported impairments in motor adaptation. However, recent advances have highlighted that motor adaptation involved several components linked to anticipation and control, all dependent on cerebellum, and the specific alteration of adaptation of ET has not been identified. To address this question we investigated behavioural markers of adaptation in ET patients (n=20) and age-matched healthy volunteers (n=20) in saccadic and upper limb adaptation tasks, probing compensation for target jumps and for velocity-dependent force fields, respectively. We found that both groups adapted their movements to the novel contexts, however, ET patients adapted to a lesser extent compared to healthy volunteers. Importantly, we decomposed movements into components linked to anticipation, preserved here, and real-time execution, which were responsible for the adaptation deficit. Altogether, our results suggest that execution deficits may be a specific functional consequence of the alteration of neural pathways associated with ET.Significance StatementWe tested Essential Tremor patients’ adaptation abilities in classical tasks including saccadic adaptation to target jumps and reaching adaptation to force field disturbances. Patients’ adaptation was present but impaired in both tasks. Interestingly, the deficits were mainly present during movement execution, while the anticipatory components of movements were similar to healthy volunteers. These findings reinforce the hypothesis of a cerebellar origin for essential tremor and details the motor adaptation impairments previously found in this disorder.
Regulating microbiome metabolic stability for stable indigenous liquor fermentation
Authors: Tan Yuwei , Zhu Yang , Wijffels René H. , Scott William T. , Xu Yan , Martins dos Santos Vitor 
Published: April 2023

AbstractBackgroundRegulating microbial metabolic stability is an ever-challenging goal in the food industry to ensure the productivity and quality of fermented foods. The microbiome underlying traditional Chinese liquor fermentation is such a representative microbiome metabolism that is affected by many dynamic abiotic/biotic factors. The complex microbial activities bring beneficial qualities (complex and rich aroma profiles,etc.) to the fermented product, but can also cause unstable fermentation outcomes. Here, we designed a three-step experiment (abiotic regulation; biotic regulation; lab-scale validation) to explore which factors cause unstable fermentation outcomes and how to regulate microbiome metabolic functional stability accordingly.ResultsWe found that 30.5% industrial fermentation of traditional Chinese liquor outcomes could be precisely predicted by initial abiotic factors. We could ensure the stability of partial fermentation batches by regulating the initial ratio of acidity to reducing sugar, moisture, and starch. Furthermore, in two representative unpredictable fermentation batches (named batch A and batch B), we found that unstable fermentation outcomes occurred even with similar initial abiotic factors after a dynamic three-phase fermentation. Unstable fermentation batches showed fluctuations in microbial community assembly that affected fermentation stability by altering the beneficial distribution (metabolic flux) of redundant metabolic pathways between yeasts and Lactobacilli. The metabolism of batch B was more stable than that of batch A due to the consistent overexpression of a specific set of bacterial metabolic genes. In repeated feed-batch fermentation processes, the difference in metabolic functional stability between the two batches was amplified 9.02 times. Batch B had significantly lower microbiome metabolic fluctuations than batch A, with higher robustness and lower complexity of the metabolic functional network. Moreover, we found that adjusting the initial microbial inoculation ratio could regulate both the metabolic beneficial distribution and temporal metabolic fluctuations of the microbiome to appropriately reduce the instability caused by biotic factors.ConclusionsThis study demonstrates that rationally regulating initial parameters and microbial inoculation ratio is a practical strategy to optimize indigenous liquor fermentation. The stable microbial beneficial distribution and high metabolic robustness are essential to obtain the ideal microbiome metabolic stability. Our study provides insights and shows the feasibility of enhancing metabolic functional stability through initial conditions in dynamic microbial ecosystems.