bluuebunny/crossref_metadata_2025 huggingface dataset:
From Substrate to Surface: A Turbulence‐Based Model for Gas Transfer Across Sediment‐Water‐Air Interfaces in Vegetated Streams
Authors: Tseng Chien‐Yung , Tinoco Rafael O.
Published: December 2021

Dissolved Oxygen (DO) fluxes across the air‐water and sediment‐water interface (AWI and SWI) are two major processes that govern the amount of oxygen available to living organisms in aquatic ecosystems. Aquatic vegetation generates different scales of turbulence that change the flow structure and affect gas transfer mechanisms at AWI and SWI. A series of laboratory experiments with rigid cylinder arrays to mimic vegetation was conducted in a recirculating race‐track flume with a lightweight sediment bed. 2D Planar Particle Image Velocimetry was used to characterize the flow field under different submergence ratios and array densities to access the effect of vegetation‐generated turbulence on gas transfer. Gas transfer rate across AWI was determined by DO re‐aeration curves. The effective diffusion coefficient for gas transfer flux across SWI was estimated by the difference between near‐bed and near‐surface DO concentrations. When sediment begins to mobilize, near‐bed suspended sediment provides a negative buoyancy term that increases the critical Reynolds number for the surface gas transfer process according to a modified Surface Renewal model for vegetated flows. A new Reynolds number dependence model using near‐bed turbulent kinetic energy as an indicator is proposed to provide a universal prediction for the interfacial flux across SWI in flows with aquatic vegetation. This study provides critical information and useful models for future studies on water quality management and ecosystem restoration in natural water environments such as lakes, rivers, and wetlands.
Force measurement goes to femto-Newton sensitivity of single microscopic particle
Authors: Zhang Xiaohe , Gu Bing , Qiu Cheng-Wei
Published: December 2021

Highly sensitive force measurements of a single microscopic particle with femto-Newton sensitivity have remained elusive owing to the existence of fundamental thermal noise. Now, researchers have proposed an optically controlled hydrodynamic manipulation method, which can measure the weak force of a single microscopic particle with femto-Newton sensitivity.
Exercise rather than fluoxetine promotes oligodendrocyte differentiation and myelination in the hippocampus in a male mouse model of depression
Authors: Tang Jing , Liang Xin , Dou Xiaoyun , Qi Yingqiang , Yang Chunmao , Luo Yanmin , Chao Fenglei , Zhang Lei , Xiao Qian , Jiang Lin , Zhou Chunni , Tang Yong
Published: December 2021

Although selective serotonin reuptake inhibitor (SSRI) systems have been meaningfully linked to the clinical phenomena of mood disorders, 15–35% of patients do not respond to multiple SSRI interventions or even experience an exacerbation of their condition. As we previously showed, both running exercise and fluoxetine reversed depression-like behavior. However, whether exercise reverses depression-like behavior more quickly than fluoxetine treatment and whether this rapid effect is achieved via the promotion of oligodendrocyte differentiation and/or myelination in the hippocampus was previously unknown. Sixty male C57BL/6 J mice were used in the present study. We subjected mice with unpredictable chronic stress (UCS) to a 4-week running exercise trial (UCS + RN) or intraperitoneally injected them with fluoxetine (UCS + FLX) to address these uncertainties. At the behavioral level, mice in the UCS + RN group consumed significantly more sugar water in the sucrose preference test (SPT) at the end of the 7th week than those in the UCS group, while those in the UCS + FLX group consumed significantly more sugar water than mice in the UCS group at the end of the 8th week. The unbiased stereological results and immunofluorescence analyses revealed that running exercise, and not fluoxetine treatment, increased the numbers of CC1+ and CC1+/Olig2+/BrdU+ oligodendrocytes in the CA1 subfield in depressed mice exposed to UCS. Moreover, running exercise rather than fluoxetine increased the level of myelin basic protein (MBP) and the G-ratio of myelinated nerve fibers in the CA1 subfield in the UCS mouse model. Unlike fluoxetine, exercise promoted hippocampal myelination and oligodendrocyte differentiation and thus has potential as a therapeutic strategy to reduce depression-like behaviors induced by UCS.
MiRNA-132/212 regulates tight junction stabilization in blood–brain barrier after stroke
Authors: Yan Haomin , Kanki Hideaki , Matsumura Shigenobu , Kawano Tomohiro , Nishiyama Kumiko , Sugiyama Shintaro , Takemori Hiroshi , Mochizuki Hideki , Sasaki Tsutomu
Published: December 2021

MicroRNA-132/212 has been supposed as a critical gene related to the blood–brain barrier (BBB) protection after stroke, but its regulation pathway including the upstream regulator and downstream targets is still unclear. Herein, we demonstrated the cAMP response element-binding protein (CREB)-regulated transcription coactivator-1 (CRTC1) to be the upstream regulator of miRNA-132/212 using CRTC1 knockout and wild-type mice. CRTC1 deletion led to the reduction of miRNA-132/212 expression in mice brain after ischemic stroke, significantly increased infarct volume, and aggravated BBB permeability with worsening neurological deficits. Furthermore, we identified that miRNA-132 repressed Claudin-1, tight junction-associated protein-1 (TJAP-1), and RNA-binding Fox-1 (RBFox-1) by directly binding to their respective 3′-untranslated regions, which alleviated the ischemic damage by enhancing neuronal survival and BBB integrity. Moreover, the co-culture of endothelial cells with CRTC1-deficient neurons aggravated the cell vulnerability to hypoxia, also supporting the idea that miRNA-132/212 cluster is regulated by CRTC1 and acts as a crucial role in the mitigation of ischemic damage. This work is a step forward for understanding the role of miRNA-132/212 in neurovascular interaction and may be helpful for potential gene therapy of ischemic stroke.
Low immunogenicity of LNP allows repeated administrations of CRISPR-Cas9 mRNA into skeletal muscle in mice
Authors: Kenjo Eriya , Hozumi Hiroyuki , Makita Yukimasa , Iwabuchi Kumiko A. , Fujimoto Naoko , Matsumoto Satoru , Kimura Maya , Amano Yuichiro , Ifuku Masataka , Naoe Youichi , Inukai Naoto , Hotta Akitsu
Published: December 2021

Genome editing therapy for Duchenne muscular dystrophy (DMD) holds great promise, however, one major obstacle is delivery of the CRISPR-Cas9/sgRNA system to skeletal muscle tissues. In general, AAV vectors are used for in vivo delivery, but AAV injections cannot be repeated because of neutralization antibodies. Here we report a chemically defined lipid nanoparticle (LNP) system which is able to deliver Cas9 mRNA and sgRNA into skeletal muscle by repeated intramuscular injections. Although the expressions of Cas9 protein and sgRNA were transient, our LNP system could induce stable genomic exon skipping and restore dystrophin protein in a DMD mouse model that harbors a humanized exon sequence. Furthermore, administration of our LNP via limb perfusion method enables to target multiple muscle groups. The repeated administration and low immunogenicity of our LNP system are promising features for a delivery vehicle of CRISPR-Cas9 to treat skeletal muscle disorders.
A nanoscale reciprocating rotary mechanism with coordinated mobility control
Authors: Bertosin Eva , Maffeo Christopher M. , Drexler Thomas , Honemann Maximilian N. , Aksimentiev Aleksei , Dietz Hendrik
Published: December 2021

Biological molecular motors transform chemical energy into mechanical work by coupling cyclic catalytic reactions to large-scale structural transitions. Mechanical deformation can be surprisingly efficient in realizing such coupling, as demonstrated by the F1FO ATP synthase. Here, we describe a synthetic molecular mechanism that transforms a rotary motion of an asymmetric camshaft into reciprocating large-scale transitions in a surrounding stator orchestrated by mechanical deformation. We design the mechanism using DNA origami, characterize its structure via cryo-electron microscopy, and examine its dynamic behavior using single-particle fluorescence microscopy and molecular dynamics simulations. While the camshaft can rotate inside the stator by diffusion, the stator’s mechanics makes the camshaft pause at preferred orientations. By changing the stator’s mechanical stiffness, we accelerate or suppress the Brownian rotation, demonstrating an allosteric coupling between the camshaft and the stator. Our mechanism provides a framework for manufacturing artificial nanomachines that function because of coordinated movements of their components.
Pricing indirect emissions accelerates low—carbon transition of US light vehicle sector
Authors: Wolfram Paul , Weber Stephanie , Gillingham Kenneth , Hertwich Edgar G.
Published: December 2021

Large–scale electric vehicle adoption can greatly reduce emissions from vehicle tailpipes. However, analysts have cautioned that it can come with increased indirect emissions from electricity and battery production that are not commonly regulated by transport policies. We combine integrated energy modeling and life cycle assessment to compare optimal policy scenarios that price emissions at the tailpipe only, versus both tailpipe and indirect emissions. Surprisingly, scenarios that also price indirect emissions exhibit higher, rather than reduced, sales of electric vehicles, while yielding lower cumulative tailpipe and indirect emissions. Expected technological change ensures that emissions from electricity and battery production are more than offset by reduced emissions of gasoline production. Given continued decarbonization of electricity supply, results show that a large–scale adoption of electric vehicles is able to reduce CO2 emissions through more channels than previously expected. Further, carbon pricing of stationary sources will also favor electric vehicles.
Molecular basis for redox control by the human cystine/glutamate antiporter system xc−
Authors: Parker Joanne L. , Deme Justin C. , Kolokouris Dimitrios , Kuteyi Gabriel , Biggin Philip C. , Lea Susan M. , Newstead Simon
Published: December 2021

Cysteine plays an essential role in cellular redox homoeostasis as a key constituent of the tripeptide glutathione (GSH). A rate limiting step in cellular GSH synthesis is the availability of cysteine. However, circulating cysteine exists in the blood as the oxidised di-peptide cystine, requiring specialised transport systems for its import into the cell. System xc− is a dedicated cystine transporter, importing cystine in exchange for intracellular glutamate. To counteract elevated levels of reactive oxygen species in cancerous cells system xc− is frequently upregulated, making it an attractive target for anticancer therapies. However, the molecular basis for ligand recognition remains elusive, hampering efforts to specifically target this transport system. Here we present the cryo-EM structure of system xc− in both the apo and glutamate bound states. Structural comparisons reveal an allosteric mechanism for ligand discrimination, supported by molecular dynamics and cell-based assays, establishing a mechanism for cystine transport in human cells.
Improved analyses of GWAS summary statistics by reducing data heterogeneity and errors
Authors: Chen Wenhan , Wu Yang , Zheng Zhili , Qi Ting , Visscher Peter M. , Zhu Zhihong , Yang Jian
Published: December 2021

Summary statistics from genome-wide association studies (GWAS) have facilitated the development of various summary data-based methods, which typically require a reference sample for linkage disequilibrium (LD) estimation. Analyses using these methods may be biased by errors in GWAS summary data or LD reference or heterogeneity between GWAS and LD reference. Here we propose a quality control method, DENTIST, that leverages LD among genetic variants to detect and eliminate errors in GWAS or LD reference and heterogeneity between the two. Through simulations, we demonstrate that DENTIST substantially reduces false-positive rate in detecting secondary signals in the summary-data-based conditional and joint association analysis, especially for imputed rare variants (false-positive rate reduced from >28% to <2% in the presence of heterogeneity between GWAS and LD reference). We further show that DENTIST can improve other summary-data-based analyses such as fine-mapping analysis.
Free fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection
Authors: Mistry Jayna J. , Hellmich Charlotte , Moore Jamie A. , Jibril Aisha , Macaulay Iain , Moreno-Gonzalez Mar , Di Palma Federica , Beraza Naiara , Bowles Kristian M. , Rushworth Stuart A.
Published: December 2021

Acute infection is known to induce rapid expansion of hematopoietic stem cells (HSCs), but the mechanisms supporting this expansion remain incomplete. Using mouse models, we show that inducible CD36 is required for free fatty acid uptake by HSCs during acute infection, allowing the metabolic transition from glycolysis towards β-oxidation. Mechanistically, high CD36 levels promote FFA uptake, which enables CPT1A to transport fatty acyl chains from the cytosol into the mitochondria. Without CD36-mediated FFA uptake, the HSCs are unable to enter the cell cycle, subsequently enhancing mortality in response to bacterial infection. These findings enhance our understanding of HSC metabolism in the bone marrow microenvironment, which supports the expansion of HSCs during pathogenic challenge.
Extracellular matrix remodeling through endocytosis and resurfacing of Tenascin-R
Authors: Dankovich Tal M. , Kaushik Rahul , Olsthoorn Linda H. M. , Petersen Gabriel Cassinelli , Giro Philipp Emanuel , Kluever Verena , Agüi-Gonzalez Paola , Grewe Katharina , Bao Guobin , Beuermann Sabine , Hadi Hannah Abdul , Doeren Jose , Klöppner Simon , Cooper Benjamin H. , Dityatev Alexander , Rizzoli Silvio O.
Published: December 2021

The brain extracellular matrix (ECM) consists of extremely long-lived proteins that assemble around neurons and synapses, to stabilize them. The ECM is thought to change only rarely, in relation to neuronal plasticity, through ECM proteolysis and renewed protein synthesis. We report here an alternative ECM remodeling mechanism, based on the recycling of ECM molecules. Using multiple ECM labeling and imaging assays, from super-resolution optical imaging to nanoscale secondary ion mass spectrometry, both in culture and in brain slices, we find that a key ECM protein, Tenascin-R, is frequently endocytosed, and later resurfaces, preferentially near synapses. The TNR molecules complete this cycle within ~3 days, in an activity-dependent fashion. Interfering with the recycling process perturbs severely neuronal function, strongly reducing synaptic vesicle exo- and endocytosis. We conclude that the neuronal ECM can be remodeled frequently through mechanisms that involve endocytosis and recycling of ECM proteins.
Unlucky punches: the vulnerability-stress model for the development of impulse control disorders in Parkinson’s disease
Authors: Theis Hendrik , Probst Catharina , Fernagut Pierre-Olivier , van Eimeren Thilo
Published: December 2021

Impulse-control disorders are commonly observed during dopamine-replacement therapy in Parkinson’s disease, but the majority of patients seems “immune” to this side effect. Epidemiological evidence suggests that a major risk factor may be a specific difference in the layout of the dopaminergic-reinforcement system, of which the ventral striatum is a central player. A series of imaging studies of the dopaminergic system point toward a presynaptic reduction of dopamine-reuptake transporter density and dopamine synthesis capacity. Here, we review current evidence for a vulnerability-stress model in which a relative reduction of dopaminergic projections to the ventral striatum and concomitant sensitization of postsynaptic neurons represent a predisposing (hypodopaminergic) vulnerability. Stress (hyperdopaminergic) is delivered when dopamine replacement therapy leads to a relative overdosing of the already-sensitized ventral striatum. These alterations are consistent with consecutive changes in reinforcement mechanisms, which stimulate learning from reward and impede learning from punishment, thereby fostering the development of impulse-control disorders. This vulnerability-stress model might also provide important insights into the development of addictions in the non-Parkinsonian population.
A class-contrastive human-interpretable machine learning approach to predict mortality in severe mental illness
Authors: Banerjee Soumya , Lio Pietro , Jones Peter B. , Cardinal Rudolf N.
Published: December 2021

Machine learning (ML), one aspect of artificial intelligence (AI), involves computer algorithms that train themselves. They have been widely applied in the healthcare domain. However, many trained ML algorithms operate as ‘black boxes’, producing a prediction from input data without a clear explanation of their workings. Non-transparent predictions are of limited utility in many clinical domains, where decisions must be justifiable. Here, we apply class-contrastive counterfactual reasoning to ML to demonstrate how specific changes in inputs lead to different predictions of mortality in people with severe mental illness (SMI), a major public health challenge. We produce predictions accompanied by visual and textual explanations as to how the prediction would have differed given specific changes to the input. We apply it to routinely collected data from a mental health secondary care provider in patients with schizophrenia. Using a data structuring framework informed by clinical knowledge, we captured information on physical health, mental health, and social predisposing factors. We then trained an ML algorithm and other statistical learning techniques to predict the risk of death. The ML algorithm predicted mortality with an area under receiver operating characteristic curve (AUROC) of 0.80 (95% confidence intervals [0.78, 0.82]). We used class-contrastive analysis to produce explanations for the model predictions. We outline the scenarios in which class-contrastive analysis is likely to be successful in producing explanations for model predictions. Our aim is not to advocate for a particular model but show an application of the class-contrastive analysis technique to electronic healthcare record data for a disease of public health significance. In patients with schizophrenia, our work suggests that use or prescription of medications like antidepressants was associated with lower risk of death. Abuse of alcohol/drugs and a diagnosis of delirium were associated with higher risk of death. Our ML models highlight the role of co-morbidities in determining mortality in patients with schizophrenia and the need to manage co-morbidities in these patients. We hope that some of these bio-social factors can be targeted therapeutically by either patient-level or service-level interventions. Our approach combines clinical knowledge, health data, and statistical learning, to make predictions interpretable to clinicians using class-contrastive reasoning. This is a step towards interpretable AI in the management of patients with schizophrenia and potentially other diseases.
Understanding the impact of dog ownership on autistic adults: implications for mental health and suicide prevention
Authors: Barcelos Ana Maria , Kargas Niko , Packham Chris , Mills Daniel S.
Published: December 2021

Mental health problems and suicide are more frequent in autistic adults than general population. Dog ownership can improve human well-being. This study aimed to generate a framework of well-being outcomes for dog-related activities in autistic adults and compare it to the framework generated for a general adult population. Thirty-six autistic dog owners (18–74 years old, 18 males) from diverse UK regions were interviewed and transcripts thematically analysed. 16.7% reported that their dogs prevented them from taking their own lives, mainly due to the dog's affection and the need to care for the animal. Close dog-owner interactions (e.g., cuddling, walking, dog's presence) were the most frequent activities improving emotions/moods and life functioning, whereas routine-like activities (e.g., feeding the animal) particularly enhanced life functioning. Well-being worsening was mainly linked to dog behaviour problems, dog poor health/death and obligations to the dog. Despite some negatives associated with ownership, having a dog could improve the well-being of many autistic adults and assist suicide prevention strategies in this high-risk group. The framework was consistent with that generated previously, indicating its robustness and the potential opportunity to focus on dog-related activities rather than the vague concept of “ownership” when considering the impact of ownership on well-being.
Cardiac myocyte intrinsic contractility and calcium handling deficits underlie heart organ dysfunction in murine cancer cachexia
Authors: Law Michelle L. , Metzger Joseph M.
Published: December 2021

Cachexia is a muscle wasting syndrome occurring in many advanced cancer patients. Cachexia significantly increases cancer morbidity and mortality. Cardiac atrophy and contractility deficits have been observed in patients and in animal models with cancer cachexia, which may contribute to cachexia pathophysiology. However, underlying contributors to decreased in vivo cardiac contractility are not well understood. In this study, we sought to distinguish heart-intrinsic changes from systemic factors contributing to cachexia-associated cardiac dysfunction. We hypothesized that isolated heart and cardiac myocyte functional deficits underlie in vivo contractile dysfunction. To test this hypothesis, isolated heart and cardiac myocyte function was measured in the colon-26 adenocarcinoma murine model of cachexia. Ex vivo perfused hearts from cachectic animals exhibited marked contraction and relaxation deficits during basal and pacing conditions. Isolated myocytes displayed significantly decreased peak contraction and relaxation rates, which was accompanied by decreased peak calcium and decay rates. This study uncovers significant organ and cellular-level functional deficits in cachectic hearts outside of the catabolic in vivo environment, which is explained in part by impaired calcium cycling. These data provide insight into physiological mechanisms of cardiomyopathy in cachexia, which is critical for the ultimate development of effective treatments for patients.
ACP-MHCNN: an accurate multi-headed deep-convolutional neural network to predict anticancer peptides
Authors: Ahmed Sajid , Muhammod Rafsanjani , Khan Zahid Hossain , Adilina Sheikh , Sharma Alok , Shatabda Swakkhar , Dehzangi Abdollah
Published: December 2021

Although advancing the therapeutic alternatives for treating deadly cancers has gained much attention globally, still the primary methods such as chemotherapy have significant downsides and low specificity. Most recently, Anticancer peptides (ACPs) have emerged as a potential alternative to therapeutic alternatives with much fewer negative side-effects. However, the identification of ACPs through wet-lab experiments is expensive and time-consuming. Hence, computational methods have emerged as viable alternatives. During the past few years, several computational ACP identification techniques using hand-engineered features have been proposed to solve this problem. In this study, we propose a new multi headed deep convolutional neural network model called ACP-MHCNN, for extracting and combining discriminative features from different information sources in an interactive way. Our model extracts sequence, physicochemical, and evolutionary based features for ACP identification using different numerical peptide representations while restraining parameter overhead. It is evident through rigorous experiments using cross-validation and independent-dataset that ACP-MHCNN outperforms other models for anticancer peptide identification by a substantial margin on our employed benchmarks. ACP-MHCNN outperforms state-of-the-art model by 6.3%, 8.6%, 3.7%, 4.0%, and 0.20 in terms of accuracy, sensitivity, specificity, precision, and MCC respectively. ACP-MHCNN and its relevant codes and datasets are publicly available at:https://github.com/mrzResearchArena/Anticancer-Peptides-CNN. ACP-MHCNN is also publicly available as an online predictor at:https://anticancer.pythonanywhere.com/.
Ecological adaptation and phylogenetic analysis of microsymbionts nodulating Polhillia, Wiborgia and Wiborgiella species in the Cape fynbos, South Africa
Authors: Mpai Tiisetso , Jaiswal Sanjay K. , Cupido Christopher N. , Dakora Felix D.
Published: December 2021

Polhillia,WiborgiaandWiborgiellaspecies are shrub legumes endemic to the Cape fynbos of South Africa. They have the ability to fix atmospheric N2when in symbiosis with soil bacteria called ‘rhizobia’. The aim of this study was to assess the morpho-physiological and phylogenetic characteristics of rhizobia associated with the nodulation ofPolhillia,WiborgiaandWiborgiellaspecies growing in the Cape fynbos. The bacterial isolates from root nodules consisted of a mixture of fast and intermediate growers that differed in colony shape and size. The isolates exhibited tolerance to salinity (0.5–3% NaCl) and pH (pH 5–10) and different antibiotic concentrations, and could produce 0.51 to 51.23 µg mL−1of indole-3-acetic acid (IAA), as well as solubilize tri-calcium phosphate. The ERIC-PCR results showed high genomic diversity in the rhizobial population and grouped them into two major clusters. Phylogenetic analysis based on 16S rRNA,atpD,glnII,gyrB,nifHandnodCgene sequences revealed distinct and novel evolutionary lineages related to the genusRhizobiumandMesorhizobium, with some of them being very close toMesorhizobium australicum. However, the phylogenetic analysis ofglnIIandnifHgenes of some isolates showed incongruency.
A lab-on-a-chip approach integrating in-situ characterization and reactive transport modelling diagnostics to unravel (Ba,Sr)SO4 oscillatory zoning
Authors: Poonoosamy Jenna , Mahrous Mohamed , Curti Enzo , Bosbach Dirk , Deissmann Guido , Churakov Sergey V. , Geisler Thorsten , Prasianakis Nikolaos
Published: December 2021

The co-precipitation of sulphate minerals such as celestine and barite is widely studied because their formation is ubiquitous in natural and anthropogenic systems. Co-precipitation in porous media results in crystallization of solid solutions yielding characteristics such as oscillatory zoning that are rarely observed in bulk solution or in batch experiments. In the past, the precipitation of compositionally-zoned (Ba,Sr)SO4 crystals was observed post-mortem in macroscopic silica gel counter-diffusion experiments. Their formation was originally explained by the difference in the solubility products of the end-members combined with diffusion-limited transport of solutes to the mineral-fluid interface, while a later study favored the idea of kinetically controlled reactions. With recent advances combining in-operando microfluidic experiments and reactive transport modelling, it is now possible to verify hypotheses on the driving forces of transport-coupled geochemical processes. We developed a “lab on a chip” experiment that enabled the systematic study of the nucleation and growth of oscillatory-zoned (Ba,Sr)SO4 crystals in a microfluidic reactor. The compositions of the solid solutions were determined by in-situ Raman spectroscopy. Our investigation shows (1) that the composition of the nucleating phases can be approximated using classical nucleation theory, (2) that the oscillatory zoning is not solely controlled by the limited diffusional transport of solutes, and (3) that nucleation kinetics plays a major role in the switch between different stoichiometric compositions. The zoning phenomena is governed by the complex interplay between the diffusion of reactants and the crystallization kinetics as well as other factors, e.g. surface tension and lattice mismatch.
Oxytocin enhances neural approach towards social and non-social stimuli of high personal relevance
Authors: Alaerts Kaat , Taillieu Aymara , Daniels Nicky , Soriano Javier R. , Prinsen Jellina
Published: December 2021

Oxytocin (OT) plays a pivotal role in a variety of complex social behaviors by modulating approach-avoidance motivational tendencies, but recently, its social specificity has been challenged. Here, a randomized, double-blind, placebo-controlled study was conducted with forty young adult men, investigating the effect of a single-dose of OT (24 IU) on behavioral and neural approach-avoidance. Frontal alpha asymmetry, indexing neurophysiological approach-avoidance, was obtained from electroencephalographic recordings while participants were presented with a series of pictures, individually rated in terms of personal relevance (i.e., high versus low positive/negative emotional evocativeness) and categorized as social or non-social. Additionally, participants could prolong (approach) or shorten (avoid) the viewing-time of each picture, providing a measure of behavioral approach-avoidance. Intranasal OT enhanced both behavioral and neural approach (increased viewing-time), particularly towards negatively valenced pictures of both social and non-social nature, thus challenging the notion that OT’s effects are specific to social stimuli. Neurally, OT specifically amplified approach-related motivational salience of stimuli that were self-rated to have high personal relevance, but irrespective of their social nature or rated affective valence (positive/negative). Together, these findings provide support to the General Approach-Avoidance Hypothesis of OT, suggesting a role of OT in amplifying the motivational salience of environmental stimuli with high (personal) relevance, but irrespective of their social/non-social nature.

Clinical Trial Number: The study design was registered at ClinicalTrials.gov (NCT04443647; 23/06/2020; https://clinicaltrials.gov/ct2/show/NCT04443647).
Genetic and immunologic features of recurrent stage I lung adenocarcinoma
Authors: Kratz Johannes R. , Li Jack Z. , Tsui Jessica , Lee Jen C. , Ding Vivianne W. , Rao Arjun A. , Mann Michael J. , Chan Vincent , Combes Alexis J. , Krummel Matthew F. , Jablons David M.
Published: December 2021

Although surgery for early-stage lung cancer offers the best chance of cure, recurrence still occurs between 30 and 50% of the time. Why patients frequently recur after complete resection of early-stage lung cancer remains unclear. Using a large cohort of stage I lung adenocarcinoma patients, distinct genetic, genomic, epigenetic, and immunologic profiles of recurrent tumors were analyzed using a novel recurrence classifier. To characterize the tumor immune microenvironment of recurrent stage I tumors, unique tumor-infiltrating immune population markers were identified using single cell RNA-seq on a separate cohort of patients undergoing stage I lung adenocarcinoma resection and applied to a large study cohort using digital cytometry. Recurrent stage I lung adenocarcinomas demonstrated higher mutation and lower methylation burden than non-recurrent tumors, as well as widespread activation of known cancer and cell cycle pathways. Simultaneously, recurrent tumors displayed downregulation of immune response pathways including antigen presentation and Th1/Th2 activation. Recurrent tumors were depleted in adaptive immune populations, and depletion of adaptive immune populations and low cytolytic activity were prognostic of stage I recurrence. Genomic instability and impaired adaptive immune responses are key features of stage I lung adenocarcinoma immunosurveillance escape and recurrence after surgery.
Cut-off value of D. pteronyssinus specific IgE in double negative patients Der p 1 and Der p 2 and its clinical repercussion
Authors: Letrán Antonio , García Ignacio , Espinazo-Romeu Marisa , Moreno-Aguilar Carmen , Moreno Francisco
Published: December 2021

Accessibility to more precise diagnostic techniques such as component resolved diagnostics (CRD), provides us with an important advance in diagnostic aspects as well as treatment. The subject of this study aims to better understand the profiles of sensitization to Der p 1, Der p 2 and Der p 23 and to know to what extent their use could help us in optimizing the decision-making for their treatment with Specific Immunotherapy. Cross-sectional study of subjects older than 5 years, diagnosed with allergy to HDM using skin prick test and sIgE, with symptoms of rhinitis and/or asthma. Total and specific IgE was determined to D. pteronyssinus, nDer p 1, rDer p 2 and rDer p 23 using ImmunoCAP. 240 patients were recruited (97.1% rhinitis and 46.25% rhinitis and asthma). Four different phenotypes were observed: positive or negative for sIgE nDer p 1 and/or IgE rDer p 2. 17% of these patients sIgE were double negative for Der p 1 and Der p 2 (increasing with age and with significantly lower sIgE levels than the rest of the groups). Using ROC curves, value less than 2.18 KUA/L for D. pteronyssinus sIgE gave us a sensitivity and specificity of 0.882 and 0.985, respectively, to double negative IgE nDer p 1 and IgE rDer p 2 group. Despite positive SPT and sIgE to D. pteronyssinus, 17% of the studied population is IgE nDer p 1 and IgE rDer p 2 double negative, with a cut-off value of 2.18 KU/L, which is very relevant for taking of decisions in prescription of AIT. The double positive population sIgE nDer p 1 and IgE rDer p 2 is associated with asthma compared to the other groups and this does not seem to be influenced by IgE rDer p 23.
Single neonatal irradiation induces long-term gene expression changes in the thyroid gland, which may be involved in the tumorigenesis
Authors: Fujimoto Nariaki , Matsuu-Matsuyama Mutsumi , Nakashima Masahiro
Published: December 2021

Exposure to ionizing radiation in childhood has been recognized as a risk factor for thyroid cancer. We previously demonstrated that neonatal X-irradiation induced specific deformation of the thyroid follicles. Here, we further analyzed this model to understand the possible relationship with thyroid carcinogenesis. Wistar rats were subjected to cervical X-irradiation at different ages of 1–8 weeks old and at different doses of 1.5–12 Gy. For tumor promotion, rats were fed with an iodine-deficient diet (IDD). In cervically X-irradiated neonatal rats, the size of thyroid follicles decreased, accompanied by an increase in the number of TUNEL-positive cells. Fas and Lgals3 mRNA levels increased, while Mct8 and Lat4 expressions decreased. The co-administration of IDD induced the proliferation and the upregulation in Lgals3 expression, resulting in thyroid adenoma development at 28 weeks post-exposure. Our data demonstrated that single neonatal X-irradiation induced continuous apoptotic activity in the thyroid with the long-term alternation in Fas, Mct8, Lat4, and Lgals3 mRNA expressions. Some of these changes were similar to those induced by IDD, suggesting that neonatal X-irradiation may partially act as a thyroid tumor promoter. These radiation-induced thyroidal changes may be enhanced by the combined treatment with IDD, resulting in the early development of thyroid adenoma.
DNA barcoding of medicinal orchids in Asia
Authors: Raskoti Bhakta Bahadur , Ale Rita
Published: December 2021

Growing popularity of herbal medicine has increased the demand of medicinal orchids in the global markets leading to their overharvesting from natural habitats for illegal trade. To stop such illegal trade, the correct identification of orchid species from their traded products is a foremost requirement. Different species of medicinal orchids are traded as their dried or fresh parts (tubers, pseudobulbs, stems), which look similar to each other making it almost impossible to identify them merely based on morphological observation. To overcome this problem, DNA barcoding could be an important method for accurate identification of medicinal orchids. Therefore, this research evaluated DNA barcoding of medicinal orchids in Asia where illegal trade of medicinal orchids has long existed. Based on genetic distance, similarity-based and tree-based methods with sampling nearly 7,000 sequences from five single barcodes (ITS, ITS2,matK,rbcL,trnH-psbAand their seven combinations), this study revealed that DNA barcoding is effective for identifying medicinal orchids. Among single locus, ITS performed the best barcode, whereas ITS + matKexhibited the most efficient barcode among multi-loci. A barcode library as a resource for identifying medicinal orchids has been established which contains about 7,000 sequences of 380 species (i.e. 90%) of medicinal orchids in Asia.
In-vitro propagation and phytochemical profiling of a highly medicinal and endemic plant species of the Himalayan region (Saussurea costus)
Authors: Khan Ajmal , Shah Azhar Hussain , Ali Niaz
Published: December 2021

Efficient protocols for callus induction and micro propagation ofSaussurea costus(Falc.) Lipsch were developed and phytochemical diversity of wild and in-vitro propagated material was investigated. Brown and red compact callus was formed with frequency of 80–95%, 78–90%, 70–95% and 65–80% from seeds, leaf, petiole and root explants, respectively. MS media supplemented with BAP (2.0 mgL−1), NAA (1.0 mgL−1) and GA3 (0.25 mgL−1) best suited for multiple shoot buds initiation (82%), while maximum shoot length was formed on media with BAP (1.5 mgL−1), NAA (0.25 mgL−1) and Kinetin (0.5 mgL−1). Full strength media with IAA (0.5 mgL−1) along with IBA (0.5 mgL−1) resulted in early roots initiation. Similarly, maximum rooting (87.57%) and lateral roots formation (up to 6.76) was recorded on full strength media supplemented with BAP (0.5 mgL−1), IAA (0.5 mgL−1) and IBA (0.5 mgL−1). Survival rate of acclimatized plantlets in autoclaved garden soil, farmyard soil, and sand (2:1:1) was 87%. Phytochemical analysis revealed variations in biochemical contents i.e. maximum sugar (808.32 µM/ml), proline (48.14 mg/g), ascorbic acid (373.801 mM/g) and phenolic compounds (642.72 mgL−1) were recorded from callus cultured on different stress media. Nonetheless, highest flavenoids (59.892 mg/g) and anthocyanin contents (32.39 mg/kg) were observed in in-vitro propagated plants. GC–MS analysis of the callus ethyl acetate extracts revealed 24 different phytochemicals. The variability in secondary metabolites of both wild and propagated plants/callus is reported for the first time for this species. This study may provide a baseline for the conservation and sustainable utilization ofS. costuswith implications for isolation of unique and pharmacologically active compounds from callus or regenerated plantlets.
Post-translational modifications by SIRT3 de-2-hydroxyisobutyrylase activity regulate glycolysis and enable nephrogenesis
Authors: Perico Luca , Morigi Marina , Pezzotta Anna , Corna Daniela , Brizi Valerio , Conti Sara , Zanchi Cristina , Sangalli Fabio , Trionfini Piera , Buttò Sara , Xinaris Christodoulos , Tomasoni Susanna , Zoja Carlamaria , Remuzzi Giuseppe , Benigni Ariela , Imberti Barbara
Published: December 2021

Abnormal kidney development leads to lower nephron number, predisposing to renal diseases in adulthood. In embryonic kidneys, nephron endowment is dictated by the availability of nephron progenitors, whose self-renewal and differentiation require a relatively repressed chromatin state. More recently, NAD+-dependent deacetylase sirtuins (SIRTs) have emerged as possible regulators that link epigenetic processes to the metabolism. Here, we discovered a novel role for the NAD+-dependent deacylase SIRT3 in kidney development. In the embryonic kidney, SIRT3 was highly expressed only as a short isoform, with nuclear and extra-nuclear localisation. The nuclear SIRT3 did not act as deacetylase but exerted de-2-hydroxyisobutyrylase activity on lysine residues of histone proteins. Extra-nuclear SIRT3 regulated lysine 2-hydroxyisobutyrylation (Khib) levels of phosphofructokinase (PFK) andSirt3deficiency increased PFK Khib levels, inducing a glycolysis boost. This altered Khib landscape inSirt3−/−metanephroi was associated with decreased nephron progenitors, impaired nephrogenesis and a reduced number of nephrons. These data describe an unprecedented role of SIRT3 in controlling early renal development through the regulation of epigenetics and metabolic processes.
Quantitative mismatch between empirical temperature-size rule slopes and predictions based on oxygen limitation
Authors: Einum Sigurd , Bech Claus , Kielland Øystein Nordeide
Published: December 2021

In ectotherms, adult body size commonly declines with increasing environmental temperature, a pattern known as the temperature-size rule. One influential hypothesis explaining this observation is that the challenge of obtaining sufficient oxygen to support metabolism becomes greater with increasing body size, and more so at high temperatures. Yet, previous models based on this hypothesis do not account for phenotypic plasticity in the physiology of organisms that counteracts oxygen limitation at high temperature. Here, we model the predicted strength of the temperature-size response using estimates of how both the oxygen supply and demand is affected by temperature when allowing for phenotypic plasticity in the aquatic ectotherm Daphnia magna. Our predictions remain highly inconsistent with empirical temperature-size responses, with the prior being close to one order of magnitude stronger than the latter. These results fail to provide quantitative support for the hypothesis that oxygen limitation drives temperature-size clines in aquatic ectotherms. Future studies into the role of oxygen limitation should address how the strength of the temperature-size response may be shaped by evolution under fluctuating temperature regimes. Finally, our results caution against applying deterministic models based on the oxygen limitation hypothesis when predicting future changes in ectotherm size distributions under climate change.
The PRY/SPRY domain of pyrin/TRIM20 interacts with β2-microglobulin to promote inflammasome formation
Authors: Samukawa Sei , Yoshimi Ryusuke , Kirino Yohei , Nakajima Hideaki
Published: December 2021

Pyrin/TRIM20 is expressed in the neutrophils and monocytes/macrophages and regulates caspase-1 activation and interleukin-1β maturation. Although the mutations in the PRY/SPRY domain of pyrin cause familial Mediterranean fever (FMF), the mechanism of how mutated pyrin provokes excessive inflammation in FMF patients is not well understood. The present study investigated the role of pyrin/TRIM20 in inflammation and the pathogenesis of FMF. β2-Microglobulin (β2MG) was identified as the novel pyrin ligand binding to the PRY/SPRY domain by yeast two-hybrid screenings and co-immunoprecipitation analysis. β2MG was co-localized with pyrin not only in the HEK293 cells overexpressing these proteins but also in the monosodium urate-stimulated human neutrophils in the speck-like structures. The pyrin–β2MG interaction triggered the binding of pyrin and proline–serine–threonine phosphatase interacting protein 1 (PSTPIP1) and then the subsequent recruitment of apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). Caspase-1 p20 subunit, produced by pyrin inflammasome, also interacted with the pyrin PRY/SPRY domain and inhibited the pyrin–β2MG interaction. FMF-associated pyrin mutation M694V did not affect pyrin–β2MG interaction but weakened this inhibition. Our findings suggest that β2MG functions as the pyrin ligand inducing pyrin inflammasome formation and that the FMF-associated pyrin mutations weakened negative feedback of caspase-1 p20 subunit.
Validation of reference genes for quantitative real-time PCR in chemical exposed and at different age’s brackish water flea Diaphanosoma celebensis
Authors: Lee Young-Mi , Cho Hayoung , Kim Ryeo-Ok , In Soyeon , Kim Se-Joo , Won Eun-Ji
Published: December 2021

Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), a primary approach for evaluating gene expression, requires an appropriate normalization strategy to confirm relative gene expression levels by comparison, and rule out variations that might occur in analytical procedures. The best option is to use a reference gene whose expression level is stable across various experimental conditions to compare the mRNA levels of a target gene. However, there is limited information on how the reference gene is differentially expressed at different ages (growth) in small invertebrates with notable changes such as molting. In this study, expression profiles of nine candidate reference genes from the brackish water flea, Diaphanosoma celebensis, were evaluated under diverse exposure to toxicants and according to growth. As a result, four different algorithms showed similar stabilities of genes for chemical exposures in the case of limited conditions using the same developmental stage (H2A was stable, whereas Act was fairly unstable in adults), while the results according to age showed a significantly different pattern in suite of candidate reference genes. This affected the results of genes EcRA and GST, which are involved in development and detoxification mechanisms, respectively. Our finding is the first step towards establishing a standardized real-time qRT-PCR analysis of this environmentally important invertebrate that has potential for aquatic ecotoxicology, particularly in estuarine environments.
Perceived chronic stress influences the effect of acute stress on cognitive flexibility
Authors: Knauft Katherine , Waldron Alexander , Mathur Mishali , Kalia Vrinda
Published: December 2021

Executive functions are cognitive processes that facilitate goal-directed behavior by enabling us to direct and control our thoughts. Cognitive flexibility is an executive function characterized by the ability to mentally shift between rules, strategies, or tasks. Several studies have reported that acute (brief) stress impairs cognitive flexibility. Even though an individual’s perception of their chronic stress levels is shown to influence effects of future stressors, the interactive effect of acute and perceived chronic stress on cognitive flexibility is not known. We conducted two experiments to address this gap. In both studies, perceived chronic stress was measured using the Perceived Stress Scale. Acute stress was induced using the Cold Pressor Test. Number of perseverative errors on the Wisconsin Card Sorting Test was used as an indicator of cognitive flexibility. In Study 2, we also measured salivary alpha amylase as a marker of the physiological stress response. Data from our two studies are consistent with the hypothesis that an individual’s perception of their chronic stress level may impact the effect of acute stress on perseveration. In Study 1, we observed a significant interaction between acute and perceived chronic stress on perseverative errors, such that only individuals who reported high levels of perceived chronic stress prior to acute stress exposure showed no change in perseveration following the acute stress manipulation. This effect did not differ based on participant sex. In Study 2, we found a similar interaction effect of acute and perceived chronic stress on perseverative errors in an all-woman sample. After identifying salivary alpha amylase responders and non-responders, we observed a strong, negative correlation between perceived chronic stress and perseverative errors amongst the responders only. Our data highlight the value in studying salivary alpha amylase in response to acute stress exposure. Additionally, perceived chronic stress emerged as a key variable in the relationship between acute stress and cognitive flexibility. Overall, our work suggests that future research interested in interrogating moderators in the relationship between acute stress and cognition would benefit from inclusion of measures of chronic stress.