bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterologous Expression of NoxA Confers Aerotolerance in Clostridium sporogenes
Authors: Sadr Sara , Zargar Bahram , Perez Justo , Aucoin Marc , Ingalls Brian 
Published: May 2022

AbstractClostridium is a genus of Gram-positive obligate anaerobic bacteria. Some species of Clostridium, including C. sporogenes, may be of use in bacteria-mediated cancer therapy. Spores of Clostridium are inert in healthy normoxic tissue, but germinate when in the hypoxic regions of solid tumors, causing tumor regression. However, such treatments fail to completely eradicate tumors because of higher oxygen levels rise at the tumor’s outer rim. In this study, we demonstrate that a degree of aerotolerance can be introduced to C. sporogenes by transfer of the noxA gene from C. aminovalericum. NoxA is a water-forming NADH oxidase enzyme. Thus, its activity has no detrimental effect on cell viability. In addition to its potential in cancer treatment, the noxA-expressing strain described here could be used to alleviate challenges related to oxygen sensitivity of C. sporogenes in biomanufacturing.
A Remarkable Adaptive Paradigm Of Heart Performance And Protection Emerges In Response To The Constitutive Challenge Of Marked Cardiac-Specific Overexpression Of Adenylyl Cyclase Type 8
Authors: Tarasov Kirill V. , Chakir Khalid , Riordon Daniel R. , Lyashkov Alexey E. , Ahmet Ismayil , Perino Maria Grazia , Silvester Allwin Jennifa , Zhang Jing , Wang Mingyi , Lukyanenko Yevgeniya O. , Qu Jia-Hua , Barrera Miguel Calvo-Rubio , Juhaszova Magdalena , Tarasova Yelena S , Ziman Bruce , Telljohann Richard , Kumar Vikas , Ranek Mark , Lammons John , Beshkov Rostislav , deCabo Rafael , Jun Seungho , Keceli Gizem , Gupta Ashish , Yang Dongmei , Aon Miguel A. , Adamo Luigi , Morrell Christopher H. , Otu Walter , Carroll Cameron , Chambers Shane , Paolocci Nazareno , Huynh Thanh , Pacak Karel , Weiss Robert G , Field Loren , Sollott Steven J. , Lakatta Edward G 
Published: May 2022

AbstractAdult mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an incessantly increased cAMP-induced cardiac workload (∼30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here we show that despite markedly increased cardiac work, classical cardiac hypertrophy markers were absent in TGAC8, total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8was encased by thicker LV walls harboring an increased number of small cardiac myocytes and a network of small interstitial non-cardiac myocytes, manifesting increased proliferation markers and compared to WT. Protein synthesis, proteosome activity, autophagy, and Nrf-2, Hsp90α, ACC2 protein levels were increased in TGAC8, but LV ATP and phosphocreatine levels in vivo did not differ by genotype. 2,323 transcripts and 2,184 proteins identified in unbiased omics analyses, spanning a wide array of biological processes and molecular functions in numerous cellular compartments differed in TGAC8vs WT; and over 250 canonical signaling pathways characteristic of adaptive survival circuitry of cancers, including PI3K and growth factor signaling, cytokine and T cell receptor signaling, immune responses, ROS scavenging, proliferation, protection from apoptosis, and nutrient sensing, were activated in TGAC8; and compared to WT there was a shift from fatty acid oxidation to increased aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, the adaptive paradigm, that becomes activated in the LV of TGAC8in response to severe chronic, intense AC/PKA/Ca2+signaling embodies many hallmarks of cancer.
Cerebellum Directly Modulates the Substantia Nigra Dopaminergic Activity
Authors: Washburn Samantha , Oñate Maritza , Yoshida Junichi , Vera Jorge , K. B. Ramakrishnan , Khatami Leila , Nadim Farzan , Khodakhah Kamran 
Published: May 2022

AbstractEvidence of direct reciprocal connections between the cerebellum and basal ganglia has challenged the long-held notion that these structures function independently. While anatomical studies have suggested the presence of cerebellar projections to the substantia nigra pars compacta (SNc), the nature and function of these connections (Cb-SNc) is unknown. Here we show that the Cb-SNc form monosynaptic glutamatergic synapses with both dopaminergic and non-dopaminergic neurons in the SNc. Optogenetic activation Cb-SNc axons in the SNc rapidly increases SNc activity, elevates striatal dopamine levels, and increases the probability of locomotion. During ongoing behavior, Cb-SNc axons are bilaterally activated prior to ambulation and unilateral lever manipulation. The Cb-SNc axons show prominent activation to water reward, and higher activation for sweet water, suggesting that the pathway also encodes reward value. Thus, the cerebellum directly, rapidly, and effectively modulates basal ganglia dopamine levels and conveys information related to movement initiation, vigor, and possibly reward processing.
Bees differentiate sucrose solution from water at a distance
Authors: Kienitz Melina , Czaczkes Tomer , De Agrò Massimo 
Published: May 2022

AbstractBees are perhaps the most important model for studying complex cognition in invertebrates, showing a variety of impressive abilities. Many experiments employ a training procedure in which the animal associates a characteristic of a “flower” (neutral stimulus) to sucrose solution (positive stimulus) over multiple foraging bouts. We hypothesized that sucrose solution might appear different from water to the bee sensorium, rendering it superfluous for the animal to learn the intended experimental cues. To test this hypothesis, we presented bumblebees simultaneously with 1.6M sucrose and water on artificial flowers. We presented the solutions in three conditions, to identify the most likely recognition mechanism: in drop form, inside cotton-plugged centrifuge tubes, and soaked into raised cigarette filters. The bumblebees chose to contact the sucrose solution significantly more often in all three conditions, confirming their ability to discriminate sucrose from water at a distance, with spectral differences being the most likely mechanism for this differentiation. These results have large implications for the design of training procedures, as the presence of an alternative cue may mask the learning of challenging tasks. This may force us to re-examine much of the literature and unpublished ‘negative results’ on bee cognition: weakening some claims, but strengthening others.
SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly
Authors: Onnis Anna , Andreano Emanuele , Cassioli Chiara , Pantano Elisa , Abbiento Valentina , Marotta Giuseppe , Rappuoli Rino , Baldari Cosima T 
Published: May 2022

AbstractCTL-mediated killing of virally infected or malignant cells is orchestrated at a specialized intercellular junction, the immune synapse (IS). We hypothesized that SARS-CoV-2 may target IS assembly in CTLs to escape killing. We show that primary human CD8+ T cells strongly upregulate the expression of ACE2, the Spike protein receptor, during differentiation to CTLs. CTL pre-incubation with the Wuhan or Omicron Spike variants inhibits IS assembly and function, as shown by defective synaptic accumulation of TCRs and tyrosine phosphoproteins as well as defective centrosome and lytic granule polarisation to the IS, resulting in impaired target cell killing. These defects were reversed by anti-Spike antibodies that interfere with ACE2 binding and were reproduced by ACE2 engagement with Angiotensin-II or an anti-ACE2 antibody, but not by the ACE2 product Ang (1-7). These results highlight a new strategy of immune evasion by SARS-CoV-2 based on the Spike-dependent, ACE2-mediated targeting of the lytic IS to prevent the elimination of infected cells.Summary statementWe report a new mechanism of immune evasion by SARS-CoV-2 based on direct disabling CTLs to form immune synapses through Spike protein binding to ACE2. This mechanism could contribute to the failure of the immune system to control SARS-CoV-2 infection.
Graph-based algorithms for Laplace transformed coalescence time distributions
Authors: Bisschop Gertjan 
Published: May 2022

AbstractExtracting information on the selective and demographic past of populations that is contained in samples of genome sequences requires a description of the distribution of the underlying genealogies. Using the Laplace transform, this distribution can be generated with a simple recursive procedure, regardless of model complexity. Assuming an infinite-sites mutation model, the probability of observing specific configurations of linked variants within small haplotype blocks can be recovered from the Laplace transform of the joint distribution of branch lengths. However, the repeated differentiation required to compute these probabilities has proven to be a serious computational bottleneck in earlier implementations.Here, I show that the state space diagram can be turned into a computational graph, allowing efficient evaluation of the Laplace transform by means of a graph traversal algorithm. This general algorithm can, for example, be applied to tabulate the likelihoods of mutational configurations in non-recombining blocks. This work provides a crucial speed up for existing composite likelihood approaches that rely on the joint distribution of branch lengths to fit isolation with migration models and estimate the parameters of selective sweeps. The associated software is available as an open-source Python library, agemo.
Drosophila embryos spatially sort their nutrient stores to facilitate their utilization
Authors: Kilwein Marcus D. , Johnson Matthew R. , Thomalla Jonathon M. , Mahowald Anthony , Welte Michael A. 
Published: May 2022

AbstractAnimal embryos are provisioned by their mothers with a diverse nutrient supply critical for development. In Drosophila, the three most abundant nutrients (triglycerides, proteins, and glycogen) are sequestered in distinct storage structures, lipid droplets (LDs), yolk vesicles (YVs) and glycogen granules (GGs). Using transmission electron microscopy as well as live and fixed-sample fluorescence imaging, we find that all three storage structures are dispersed throughout the egg but are then spatially allocated to distinct tissues by gastrulation: LDs largely to the peripheral epithelium, YVs and GGs to the central yolk cell. To confound the embryo’s ability to sort its nutrients, we employ mutants in Jabba and Mauve to generate LD:GG or LD:YV compound structures. In these mutants, LDs are missorted to the yolk cell and their turnover is delayed. Our observations demonstrate dramatic spatial nutrient sorting in early embryos and provide the first evidence for its functional importance.
The Batten disease protein CLN3 is important for stress granules dynamics and translational activity
Authors: Relton Emily L. , Roth Nicolas J. , Yasa Seda , Kaleem Abuzar , Hermey Guido , Lefrancois Stephane , McCormick Peter J. , Locker Nicolas 
Published: May 2022

AbstractThe assembly of membrane-less organelles such as stress granules (SGs) is emerging as central in helping cells rapidly respond and adapt to stress. Following stress sensing, the resulting global translational shutoff leads to the condensation of stalled mRNAs and proteins into SGs. By reorganising cytoplasmic contents, SGs can modulate RNA translation, biochemical reactions and signalling cascades to promote survival until the stress is resolved. While mechanisms for SG disassembly are not widely understood, the resolution of SGs is important for maintaining cell viability and protein homeostasis. Mutations that lead to persistent of aberrant SGs are increasingly associated with neuropathology and a hallmark of several neurodegenerative diseases. Mutations inCLN3are causative of juvenile neuronal ceroid lipofuscinosis (JNCL), a rare neurodegenerative disease affecting children.CLN3encodes a transmembrane lysosomal protein implicated in autophagy, endosomal trafficking, metabolism, and response to oxidative stress. Using a HeLa KO model, we now show that CLN3KOis associated with an altered metabolic profile, reduced global translation, and altered stress signalling. We further demonstrate that loss of CLN3 results in perturbations in SG dynamics, resulting in assembly and disassembly defects, and altered expression of the key SG nucleating factor G3BP1. With a growing interest in SG-modulating drugs for the treatment of neurodegenerative diseases, novel insights into the molecular basis of CLN3 Batten disease may reveal avenues for disease-modifying treatments for this debilitating childhood disease.
Automated optimisation of solubility and conformational stability of antibodies and proteins
Authors: Rosace Angelo , Bennett Anja , Oeller Marc , Mortensen Mie M. , Sakhnini Laila , Lorenzen Nikolai , Poulsen Christian , Sormanni Pietro 
Published: May 2022

AbstractBiologics, such as antibodies and enzymes, are crucial in research, biotechnology, diagnostics, and therapeutics. Often, biologics with suitable functionality are discovered, but their development is impeded by developability issues. Stability and solubility are key biophysical traits underpinning developability potential, as they determine aggregation, correlate with production yield and polyspecificity, and are essential to access parenteral and oral delivery. While advances for the optimisation of individual traits have been made, the co-optimization of multiple traits remains highly problematic and time-consuming, as mutations that improve one property often negatively impact others. In this work, we introduce a fully automated computational strategy for the simultaneous optimisation of conformational stability and solubility, which we experimentally validate on six antibodies, including two approved therapeutics. Our results on 42 designs demonstrate that the computational procedure is highly effective at improving developability potential, while not affecting antigen-binding.We make the method available as a webserver atwww-cohsoftware.ch.cam.ac.uk
Statistical significance and biological relevance: The case ofNosema ceranaeand honey bee colony losses in winter
Authors: Schüler Vivian , Liu Yuk-Chien , Gisder Sebastian , Horchler Lennart , Groth Detlef , Genersch Elke 
Published: May 2022

AbstractManaged and wild insect pollinators play a key role in ensuring that mankind is adequately supplied with food. Among the pollinating insects, the managed Western honey bee providing about 90% of commercial pollination is of special importance. Hence, diseases as well as disease causing pathogens and parasites that threaten honey bees, have become the focus of many research studies. The ectoparasitic miteVarroa destructortogether with deformed wing virus (DWV) vectored by the mite have been identified as the main contributors to colony losses, while the role of the microsporidiumNosema ceranaein colony losses is still controversially discussed. In an attempt to solve this controversy, we statistically analyzed a unique data set on honey bee colony health comprising data on mite infestation levels,Nosemaspp. infections and winter losses continuously collected over 15 years. We used various statistical methods to investigate the relationship between colony mortality and the two pathogens,V. destructorandN. ceranae. Our multivariate statistical analysis confirmed thatV. destructoris the major cause of colony winter losses. When using cumulative data sets, we also found a significant relationship betweenN. ceranaeinfections and colony losses. However, determining the effect size revealed that this statistical significance was of low biological relevance, because the deleterious effects ofN. ceranaeinfection are normally masked by the more severe effects ofV. destructoron colony health and therefore only detectable in the few colonies that are not infested with mites or are infested at low levels.
Quantification and statistical modeling of Chromium-based single-nucleus RNA-sequencing data
Authors: Kuo Albert , Hansen Kasper D. , Hicks Stephanie C. 
Published: May 2022

ABSTRACTIn complex tissues containing cells that are difficult to dissociate, single-nucleus RNA-sequencing (snRNA-seq) has become the preferred experimental technology over single-cell RNA-sequencing (scRNA-seq) to measure gene expression. To accurately model these data in downstream analyses, previous work has shown that droplet-based scRNA-seq data are not zero-inflated, but whether droplet-based snRNA-seq data follow the same probability distributions has not been systematically evaluated. Using pseudo-negative control data from nuclei in mouse cortex sequenced with the 10x Genomics Chromium system, we found that snRNA-seq data follow a negative binomial distribution, suggesting that parametric statistical models applied to scRNA-seq are transferable to snRNA-seq. Furthermore, we found that the quantification choices in adapting quantification mapping strategies from scRNA-seq to snRNA-seq can play a significant role in downstream analyses and biological interpretation. In particular, reference transcriptomes that do not include intronic regions result in significantly smaller library sizes and incongruous cell type classifications. We also confirmed the presence of a gene length bias in snRNA-seq data, which we show is present in both exonic and intronic reads, and investigate potential causes for the bias.
Increased GABA transmission to GnRH neurons after intrahippocampal kainic acid injection in mice is sex-specific and associated with estrous cycle disruption
Authors: Ingram Robbie J. , Leverton Leanna K. , Daniels Victoria C. , Li Jiang , Christian-Hinman Catherine A. 
Published: May 2022

ABSTRACTPatients with epilepsy develop reproductive endocrine comorbidities at a rate higher than that of the general population. Clinical studies have identified disrupted luteinizing hormone (LH) release patterns in patients of both sexes, suggesting potential epilepsy-associated changes in hypothalamic gonadotropin-releasing hormone (GnRH) neuron function. In previous work, we found that GnRH neuron firing is increased in diestrous females and males in the intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy. Notably, GABAA receptor activation is depolarizing in adult GnRH neurons. Therefore, here we tested the hypothesis that increased GnRH neuron firing in IHKA mice is associated with increased GABAergic drive to GnRH neurons. When ionotropic glutamate receptors (iGluRs) were blocked to isolate GABAergic postsynaptic currents (PSCs), no differences in PSC frequency were seen between GnRH neurons from control and IHKA diestrous females. In the absence of iGluR blockade, however, GABA PSC frequency was increased in GnRH neurons from IHKA females with disrupted estrous cycles, but not saline-injected controls nor IHKA females without estrous cycle disruption. GABA PSC amplitude was also increased in IHKA females with disrupted estrous cycles. These findings suggest the presence of an iGluR-dependent increase in feed-forward GABAergic transmission to GnRH neurons specific to IHKA females with comorbid cycle disruption. In males, GABA PSC frequency and amplitude were unchanged but PSC duration was reduced. Together, these findings suggest that increased GABA transmission helps drive elevated firing in IHKA females on diestrus and indicate the presence of a sex-specific hypothalamic mechanism underlying reproductive endocrine dysfunction in IHKA mice.HIGHLIGHTSIncreased GABA transmission to GnRH neurons in IHKA mouse model of epilepsyIncreased GABA transmission is dependent on upstream glutamate signalingIncreased GABA transmission only seen in females with disrupted estrous cyclesPotential sex-specific mechanism for reproductive endocrine dysfunction in epilepsy
Quadrangular Space Syndrome: A Systematic Review of Surgical and Medical Therapeutic advances
Authors: Charmode Sundip , Sharma Shelja , Kushwaha Sudhir , Mehra Simmi , Philip Shalom , Janagal Ranjna , Amrutiya Pratik 
Published: May 2022

AbstractThe Axillary Nerve (AXN) and Posterior Circumflex Humeral Artery (PCHA) are compressed in quadrangular space syndrome (QSS), which can be treated with conservative approaches or surgical decompression in recalcitrant instances. There are no clear guidelines for determining which surgical method is optimal for treating QSS and other disorders that mirror QSS. The goal of this study is to grade and review past, current, and planned medicinal and surgical care modalities for QSS. PROSPERO was used to submit the review protocol (ID: 332766). To identify recent advances in the methods/techniques of medical and surgical management of QSS, PubMed and Medline databases were searched until March 2022 for publications, including case studies, case reports, and review articles, using Medical Subject Headings (MeSH) terms like quadrilateral space syndrome, surgical management, and medical management. Throughout the study, all the authors scrupulously followed a well-developed registered review process and the risk of bias in systematic reviews (ROBIS) guidance tool. Data on proposed medical and surgical management methods/techniques was compiled, and each was analyzed based on the underlying neuro-vascular systems. There were 88 items found in the first search. Following applying the inclusion and exclusion criteria, 16 papers were chosen for synthesis in the review study after a thorough assessment. Three studies (conservative and advanced) focused on medical care of QSS, while 12 articles (prior, current, and newer) focused on surgical management of QSS. Only four of the 15 studies reviewed proposed different surgical approaches/techniques for surgical decompression in QSS. There were two regularly used surgical procedures discovered, one anterior/delto-pectoral and the other posterior/scapular. The anterior route is more technically straightforward and can be employed for surgical QSS decompression.
Improved antibody-specific epitope prediction using AlphaFold and AbAdapt
Authors: Xu Zichang , Davila Ana , Wiamowski Jan , Teraguchi Shunsuke , Standley Daron M. 
Published: May 2022

AbstractAntibodies recognize their cognate antigens with high affinity and specificity, but the prediction of binding sites on the antigen (epitope) corresponding to a specific antibody remains a challenging problem. To address this problem, we developed AbAdapt, a pipeline that integrates antibody and antigen structural modeling with rigid docking in order to derive antibody-antigen specific features for epitope prediction. In this study, we assess the impact of integrating the state-of-the-art protein modeling method AlphaFold with the AbAdapt pipeline and demonstrate significant improvement in the prediction of antibody-specific epitope residues.