bluuebunny/crossref_metadata_2025_split huggingface dataset:
Membrane potential phase shifts differ for excitation vs. inhibition in resonant pyramidal neurons: a computer modeling study
Authors: Kelley Craig , Antic Srdjan D. , Carnevale Nicholas T. , Kubie John L. , Lytton William W. 
Published: March 2023

AbstractRhythmic activity is ubiquitous in neural systems, and impedance analysis has been widely used to examine frequency-dependent responses of neuronal membranes to rhythmic inputs. Impedance analysis assumes the neuronal membrane is a linear system, requiring the use of small signals to stay in a near-linear regime. However, postsynaptic potentials are often large and trigger nonlinear mechanisms. We therefore augmented impedance analysis to evaluate membrane responses in this nonlinear domain, analyzing responses to injected current for subthreshold membrane voltage (Vmemb), suprathreshold spike-blocked Vmemb, and spiking in a validated neocortical pyramidal neuron computer model. Responses in these output regimes were asymmetrical, with different phase shifts during hyperpolarizing and depolarizing half-cycles. Suprathreshold chirp stimulation gave equivocal results due to nonstationarity of response, requiring us to use fixed-frequency sinusoids. Sinusoidal inputs producedphase retreat: action potentials occurred progressively later in cycles of the input stimulus, resulting from adaptation. Conversely, sinusoidal current with increasing amplitude over cycles produced a pattern ofphase advance: action potentials occurred progressively earlier. Phase retreat was dependent onIhandIAHPcurrents; phase advance was modulated by these currents. Our results suggest differential responses of cortical neurons depending on the frequency of oscillatory input in the delta – beta range, which will play a role in neuronal responses to shifts in network state. We hypothesize that intrinsic cellular properties complement network properties and contribute toin vivophase-shift phenomena such as phase precession, seen in place and grid cells, and phase roll, observed in hippocampal CA1 neurons.New & NoteworthyWe augmented electrical impedance analysis to characterize phase shifts between large amplitude current stimuli and nonlinear, asymmetric membrane potential responses. We predict different frequency-dependent phase shifts in response excitation versus inhibition, as well as shifts in spike timing over multiple input cycles, in resonant pyramidal neurons. We hypothesize that these effects contribute to navigation-related phenomena like phase precession and phase roll. Our neuron-level hypothesis complements, rather than falsifies, prior network-level explanations of these phenomena.
Hemispheric decoupling of awareness-related activity in human auditory cortex under informational masking and divided attention
Authors: Dykstra Andrew R. , Gutschalk Alexander 
Published: March 2023

ABSTRACTThe conditions under which sensory stimuli require selective attention to reach awareness is a fundamental question of cognitive neuroscience. We examined this question in the context of audition utilizing M/EEG and a dual-task informational-masking paradigm. Listeners performed a demanding primary task in one ear – detecting isochronous target-tone streams embedded in random multi-tone backgrounds and counting within-stream deviants – and retrospectively reported their awareness of secondary, masker-embedded target streams in the other ear. Irrespective of attention or ear, left-AC activity strongly covaried with target-stream detection starting as early as 50 ms post-stimulus. In contrast, right-AC activity was unmodulated by detection until later, and then only weakly. Thus, under certain conditions, human ACs can functionally decouple, such that one – here, right – is automatic and stimulus-driven while the other – here, left – supports perceptual and/or task demands, including basic perceptual awareness of nonverbal sound sequences.
Transgene Expression in Cultured Cells Using Unpurified Recombinant Adeno-Associated Viral Vectors
Authors: Benyamini Brian , Esbin Meagan N. , Whitney Oscar , Walther Nike , Maurer Anna C. 
Published: March 2023

AbstractRecombinant adeno-associated viral vectors (rAAV) can achieve potent and durable transgene expression without integration in a broad range of tissue types, making them a popular choice for gene delivery in animal models and in clinical settings. In addition to therapeutic applications, rAAVs are a useful laboratory tool for delivering transgenes tailored to the researcher’s experimental needs and scientific goals in cultured cells. Some examples include exogenous reporter genes, overexpression cassettes, RNA interference, and CRISPR-based tools including those for genome-wide screens. rAAV transductions are less harmful to cells than electroporation or chemical transfection and moreover do not require any special equipment or expensive reagents to produce. Crude lysates or conditioned media containing rAAVs can be added directly to cultured cells without further purification to transduce many cell types – an underappreciated feature of rAAVs. Here, we provide protocols for basic transgene cassette cloning and demonstrate how to produce and apply crude rAAV preparations to cultured cells. As proof-of-principle, we demonstrate transduction of three cell types that have not yet been reported in rAAV applications. We discuss appropriate uses for crude rAAV preparations, the limitations of rAAVs for gene delivery, and considerations for capsid choice. The simplicity of production, exceedingly low cost, and often potent results make crude rAAV a primary choice for researchers to achieve effective DNA delivery.SummaryRecombinant adeno-associated virus (rAAV) is widely used for clinical and preclinical gene delivery. An underappreciated use for rAAVs is the robust transduction of cultured cells without the need for purification. For researchers new to rAAV, we provide a protocol for transgene cassette cloning, crude vector production, and cell culture transduction.
Development and Feasibility of a Primary Care Provider Training Intervention to Improve Atrial Fibrillation Management
Authors: Daw J. Michael , Armbruster Tiffany , Deyo Zack , Walker Jennifer , Rosman Lindsey A , Sears Samuel F. , Mazzella Anthony J. , Gehi Anil K. 
Published: March 2023

STRUCTURED ABSTRACTBackgroundDisparities in atrial fibrillation (AF) care are partially attributed to inadequate access to providers with specialized training in AF. Primary care providers (PCPs) are often the sole providers of AF care in under-resourced regions.ObjectiveTo create a virtual education intervention for PCPs and evaluate its impact on use of stroke risk reduction strategies in AF patients.MethodsA multi-disciplinary team mentored PCPs on AF management over 6 months using a virtual case-based training format. Surveys of participant knowledge and confidence in AF care were compared pre- and post-intervention. Hierarchical logistic regression modeling was used to evaluate change in stroke risk reduction therapies among patients seen by participants before or after training.ResultsOf 41 participants trained, 49% worked in family medicine, 41% internal medicine, and 10% general cardiology. Participants attended a mean of 14 one-hour sessions. Overall, appropriate use of oral anticoagulation (OAC) therapy (CHA2DS2-VASc score ≥1 men, ≥2 women) increased from 37% to 46% (p<.001) comparing patients seen pre- (n=1739) to post- (n=610) intervention. Factors independently associated with appropriate OAC use included participant training (OR 1.4, p=.002) and participant competence in AF management (by survey). Factors associated with decreased OAC use included patient age (OR 0.8 per 10 years, p=.008), nonwhite race (OR 0.7, p=.028). Provider knowledge and confidence in AF care both improved (p<.001).ConclusionsA virtual case-based PCP training intervention improved use of stroke risk reduction therapy in outpatients with AF. This widely scalable intervention could improve AF care in under-resourced communities.CONDENSED ABSTRACTA virtual educational model was developed for primary care providers to improve competency in AF care in their community. Following a 6-month training intervention, the rate of appropriate oral anticoagulation (OAC) therapy among patients cared for by participating providers increased from 37% to 46% (p<.001). Among participants, knowledge and confidence in AF care improved. These findings suggest a virtual AF training intervention can improve PCP competency in AF care. This widely scalable intervention could help improve AF care in under-resourced communities.
Guidelines for Optimizing Type S Non-Ribosomal Peptide Synthetases
Authors: Abbood Nadya , Effert Juliana , Bozhueyuek Kenan A. J. , Bode Helge B. 
Published: March 2023

AbstractBacterial biosynthetic assembly lines, such as non-ribosomal peptide synthetases (NRPS) and polyketide synthases, are often subject of synthetic biology – because they produce a variety of natural products invaluable for modern pharmacotherapy. Acquiring the ability to engineer these biosynthetic assembly lines allows the production of artificial non-ribosomal peptides (NRP), polyketides, and hybrids thereof with new or improved properties. However, traditional bioengineering approaches have suffered for decades from their very limited applicability and, unlike combinatorial chemistry, are stigmatized as inefficient because they cannot be linked to the high-throughput screening platforms of the pharmaceutical industry. Although combinatorial chemistry can generate new molecules cheaper, faster, and in greater numbers than traditional natural product discovery and bioengineering approaches, it does not meet current medical needs because it covers only a limited biologically relevant chemical space. Hence, methods for high-throughput generation of new natural product-like compound libraries could provide a new avenue towards the identification of new lead compounds. To this end, prior to this work, we introduced an artificial synthetic NRPS type, referred to as type S NRPS, to provide a first-of-its-kind bicombinatorial approach to parallelized high-throughput NRP library generation. However, a bottleneck of these first two generations of type S NRPS was a significant drop in production yields. To address this issue, we applied an iterative optimization process that enabled titer increases of up to 55-fold compared to the non-optimized equivalents, restoring them to wild-type levels and beyond.
SARS-CoV-2 infection activates endogenous retroviruses of the LTR69 subfamily
Authors: Arora Ankit , Kolberg Jan Eric , Badarinarayan Smitha Srinivasachar , Munot Daksha , Müller Martin , Sauter Daniel , Bansal Vikas 
Published: March 2023

AbstractAccumulating evidence suggests that endogenous retroviruses (ERVs) play an important role in the host response to infection and the development of disease. By combining RNA- and ChIP-sequencing analyses with RT-qPCR, we show that SARS-CoV-2 infection induces the LTR69 subfamily of ERVs, bothin vitroandin vivo. Using functional assays, we identified one SARS-CoV-2-activated LTR69 locus, termed Dup69, which exhibits enhancer activity and is responsive to the transcription factors IRF3 and p65/RelA. LTR69-Dup69 is located about 500 bp upstream of a long non-coding RNA gene (ENSG00000289418) and within thePTPRN2gene encoding a diabetes-associated autoantigen. Both ENSG00000289418 andPTPRN2showed a significant increase in expression upon SARS-CoV-2 infection. Thus, our study sheds light on the interplay of exogenous with endogenous viruses and helps to understand how ERVs regulate gene expression during infection.
The smallest infectious substructure encoding the prion strain structural determinant revealed by spontaneous dissociation of misfolded prion protein assemblies
Authors: Bohl Jan , Moudjou Mohammed , Herzog Laetitia , Reine Fabienne , Sailler Fiona , Klute Hannah , Halgand Frederic , Van der Rest Guillaume , Boulard Yves , Béringue Vincent , Igel Angelique , Rezaei Human 
Published: March 2023

AbstractIt is commonly accepted that the prion replicative propensity and strain structural determinant (SSD) are encoded in the fold of PrPScamyloid fibril assemblies. By exploring the quaternary structure dynamicity of several prion strains, we revealed that all mammalian prion assemblies exhibit the generic property of spontaneously generating two sets of discreet infectious tetrameric and dimeric species differing significantly by their specific infectivity. By using perturbation approaches such as dilution and ionic strength variation, we demonstrated that these two oligomeric species were highly dynamic and evolved differently in the presence of chaotropic agents. In general, our observations of seven different prion strains from three distinct species highlight the high dynamicity of PrPScassemblies as a common and intrinsic property of mammalian prions. The existence of such small infectious PrPScspecies harboring the SSD indicates that the prion infectivity and the SSD are not restricted only to the amyloid fold but can also be encoded in other alternative quaternary structures. Such diversity in the quaternary structure of prion assemblies tends to indicate that the structure of PrPSccan be divided into two independent folding domains: a domain encoding the strain structural determinant and a second domain whose fold determines the type of quaternary structure that could adopt PrPScassemblies.HighlightsMammalian prion assemblies are highly dynamicPrion assemblies spontaneously disassemble into two infectious oligomersPrion infectivity is not exclusively encoded in the amyloid fibrils’ structureTwo independent folding domains could structure Prion assemblies
LactococcusG423 Ameliorates the Growth Performance of Broilers by Modulation of Gut Microbiota- Metabolites
Authors: Wang Mi , Ma Wei , Wang Chunqiang , Li Desheng , Wang Yuan 
Published: March 2023

ABSTRACTThis study aimed to explore whetherLactococcusG423 could ameliorate growth performance of broilers by modulation of gut microbiota-metabolites based on the 16S ribosomal RNA (rRNA) and liquid chromatography-mass spectrometry (LC-MS). A total of 640 one-day-old AA broilers were randomly divided into 4 groups (Control (CON), Lac_L, Lac_H, and ABX). Average daily gain (ADG), average daily feed intake (ADFI), and feed conversion ratio (FCR) were calculated on the 42nd day. The ileum content was harvested and immediately frozen in liquid nitrogen for 16S rRNA and LC-MS analyses. Then, the results of 16S rRNA analysis were confirmed by quantitative polymerase chain reaction (qPCR). Compared with the CON group, ADG significantly increased in the Lac_H group (P<0.05), and survival rate significantly decreased in the Lac_H, Lac_H, and ABX groups (allP<0.05). A significant difference in microbial diversity was found among the four groups. Compared with the CON group, the abundance rates ofFirmicutes and Lactobacillusin the Lac_H group were significantly risen (P<0.05). The global and overview maps and membrane transport in the Lac_L, Lac_H, and ABX groups significantly changed versus those in the CON group (P<0.05). The results of LC-MS demonstrated thatLactococcuscould significantly improve the levels of some metabolites (6-hydroxy-5-methoxyindole glucuronide, 9,10-DiHOME, carbamazepine-O-quinone, N-Acetyl-L-phenylalanine, and kynurenine), and these metabolites were involved in 5 metabolic pathways. Among them, the pathways of linoleic acid metabolism, phenylalanine metabolism, and pentose and glucuronate interconversions significantly changed (P<0.05).Lactococcusimproved wight and survival rate of broilers through the gut microbiota, regulating the pathways of amino acid metabolism, lipid metabolism, bile acid metabolism, and carbohydrate metabolism. However, antibiotics may negatively influence the gut microbiota.IMPORTANCEImprovements in the growth rate of broiler chickens can be achieved through dietary manipulation of the naturally occurring bacterial populations while mitigating the withdrawal of antibiotic growth promoters.Lactococcusis industrially cruciallactic acid bacteria, can be incorporated into the diets of chickens to improve their growth performance. This study investigated the key mechanisms behind this progression and pinpointedLactococcusimproved wight and survival rate of broilers through the gut microbiota, regulating the pathways of amino acid metabolism, lipid metabolism, bile acid metabolism, and carbohydrate metabolism.
The timing of confidence computations in human prefrontal cortex
Authors: Xue Kai , Zheng Yunxuan , Rafiei Farshad , Rahnev Dobromir 
Published: March 2023

AbstractKnowing when confidence computations take place is critical for building mechanistic understanding of the neural and computational bases of metacognition. Yet, even though substantial amount of research has focused on revealing the neural correlates and computations underlying human confidence judgments, very little is known about the timing of confidence computations. Subjects judged the orientation of a briefly presented visual stimulus and provided a confidence rating regarding the accuracy of their decision. We delivered single pulses of transcranial magnetic stimulation (TMS) at different times after stimulus presentation. TMS was delivered to either dorsolateral prefrontal cortex (DLPFC) in the experimental group or to vertex in the control group. We found that TMS to DLPFC, but not to vertex, led to increased confidence in the absence of changes to accuracy or metacognitive ability. Critically, equivalent levels of confidence increase occurred for TMS delivered between 200 and 500 ms after stimulus presentation. These results suggest that confidence computations occur during a broad window that begins before the perceptual decision has been fully made and thus provide important constraints for theories of confidence generation.
Inhibition of sensory neuron driven acute, inflammatory, and neuropathic pain using a humanised chemogenetic system
Authors: Perez-Sanchez Jimena , Middleton Steven J. , Pattison Luke A. , Hilton Helen , Awadelkareem Mosab Ali , Zuberi Sana R. , Renke Maria B. , Hu Huimin , Yang Xun , Clark Alex J. , St Ewan , Smith John , Bennett David L. 
Published: March 2023

AbstractHyperexcitability in sensory neurons is known to underlie many of the maladaptive changes associated with persistent pain. Chemogenetics has shown promise as a means to suppress such excitability, yet chemogenetic approaches suitable for human applications are needed. PSAM4-GlyR is a modular system based on the human α7 nicotinic acetylcholine and glycine receptors, which responds to inert chemical ligands and the clinically-approved drug, varenicline. Here, we demonstrated the efficacy of this channel in silencing both mouse and human sensory neurons by the activation of large shunting conductances after agonist administration. Virally-mediated expression of PSAM4-GlyR in mouse sensory neurons produced behavioural hyposensitivity upon agonist administration, which was recovered upon agonist washout. Importantly, stable expression of the channel led to similar reversible behavioural effects even after 10 months of viral delivery. Mechanical and spontaneous pain readouts were also ameliorated by PSAM4-GlyR activation in acute and joint pain inflammation models. Furthermore, suppression of mechanical hypersensitivity generated by a spared nerve injury model of neuropathic pain was also observed upon activation of the channel. Effective silencing of behavioural hypersensitivity was reproduced in a human model of hyperexcitability and clinical pain: PSAM4-GlyR activation decreased the excitability of human induced pluripotent stem-cell-derived sensory neurons and spontaneous activity due to a gain of function NaV1.7 mutation causing inherited erythromelalgia. Our results demonstrate the contribution of sensory neuron hyperexcitability to neuropathic pain and the translational potential of an effective, stable and reversible human-based chemogenetic system for the treatment of pain.
Spatiotemporal analysis of SARS-CoV-2 infection reveals an expansive wave of monocyte-derived macrophages associated with vascular damage and virus clearance in hamster lungs
Authors: Bagato Ola , Balkema-Buschmann Anne , Todt Daniel , Weber Saskia , Gömer André , Qu Bingqian , Miskey Csaba , Ivics Zoltan , Mettenleiter Thomas C. , Finke Stefan , Brown Richard J. P. , Breithaupt Angele , Ushakov Dmitry S. 
Published: March 2023

AbstractFactors of the innate immune response to SARS-CoV-2 in the lungs are pivotal for the ability of the host to deal with the infection. In humans, excessive macrophage infiltration is associated with disease severity. Using 3D spatiotemporal analysis of optically cleared hamster lung slices in combination with virological, immunohistochemical and RNA sequence analyses, we visualized the spread of SARS-CoV-2 through the lungs and the rapid anti-viral response in infected lung epithelial cells, followed by a wave of monocyte-derived macrophage (MDM) infiltration and virus elimination from the tissue. These SARS-CoV-2 induced innate immune processes are closely related to the onset of necrotizing inflammatory and consecutive remodelling responses in the lungs, which manifests as extensive cell death, vascular damage, thrombosis, and cell proliferation. Here we show that MDM are directly linked to virus clearance, and appear in connection with tissue injury and blood vessel damage. Rapid initiation of prothrombotic factor upregulation, tissue repair and alveolar cell proliferation results in tissue remodelling, which is followed by fibrosis development despite a decrease in inflammatory and anti-viral activities. Thus, although the hamsters are able to resolve the infection following the MDM influx and repair lung tissue integrity, longer-term alterations of the lung tissues arise as a result of concurrent tissue damage and regeneration processes.
State of university-industry collaboration in quantity surveying profession in Nigeria
Authors: Alli Morufu Abolaji , Dada Joshua Oluwasuji 
Published: March 2023

PurposeUniversity-industry collaboration (UIC) is a symbiosis relationship, brought about through knowledge and resource sharing, with the attendant benefits of innovation and technological advancement. The purpose of this paper is to investigate the state of UIC in quantity surveying profession in Nigeria with a view to ascertaining the situation and chatting the way forward.Design/methodology/approachUsing quantitative survey research approach, primary data were collected through the administration of structured questionnaires on quantity surveying academia and practitioners. A total of 126 respondents were sampled: 52 university lecturers and 74 quantity surveying firms. Of these, 32 university lecturers (61.54%) and 34 quantity surveying firms (45.95%) provided valid responses. In all, this amounts to 52.38% response rate. The quantitative data obtained were analysed using mean score, frequency distribution, percentage and Mann Whitney test.FindingsThe findings show that collaboration is very strong in the areas of student industrial placement and research cooperation between students and academic researchers. However, collaboration in the areas of funding and staff exchange was found to be lagging behind.Practical implicationsThe findings indicate strong collaboration areas (student industrial placement and research cooperation) to be sustained as well as weak areas (funding and staff exchange) to be critically looked into.Originality/valueThe paper represents the first research to empirically assess the state of UIC in quantity surveying profession in Nigeria. In addition, it shows the areas where efforts should be concentrated in maximizing the benefit of UIC.