bluuebunny/crossref_metadata_2025_split huggingface dataset:
Perivascular network segmentations derived from high-field MRI and their implications for perivascular and parenchymal mass transport in the rat brain
Authors: Rey Julian A. , Farid Uzair M. , Najjoum Christopher M. , Brown Alec , Magdoom Kulam Najmudeen , Mareci Thomas H. , Sarntinoranont Malisa 
Published: June 2023

AbstractA custom segmentation workflow was applied to ex vivo high-field MR images of rat brains acquired following in vivo intraventricular contrast agent infusion to generate maps of the perivascular spaces (PVS). The resulting perivascular network segmentations enabled analysis of perivascular connections to the ventricles, parenchymal solute clearance, and dispersive solute transport within PVS. Numerous perivascular connections between the brain surface and the ventricles suggest the ventricles integrate into a PVS-mediated clearance system and raise the possibility of cerebrospinal fluid (CSF) return from the subarachnoid space to the ventricles via PVS. Assuming rapid solute exchange between the PVS and CSF spaces primarily by advection, the extensive perivascular network decreased the mean clearance distance from parenchyma to the nearest CSF compartment resulting in an over 21-fold reduction in the estimated diffusive clearance time scale, irrespective of solute diffusivity. This corresponds to an estimated diffusive clearance time scale under 10 min for amyloid-beta which suggests that the widespread distribution of PVS may render diffusion an effective parenchymal clearance mechanism. Additional analysis of oscillatory solute dispersion within PVS indicates that advection rather than dispersion is likely the primary transport mechanism for dissolved compounds greater than 66 kDa in the long (> 2 mm) perivascular segments identified here, although dispersion may be significant for smaller compounds in shorter perivascular segments.
Site-directed mutagenesis of Mycobacterium tuberculosis and functional validation to investigate potential bedaquiline resistance-causing mutations
Authors: Otum Christian C. , Rivière Emmanuel , Barnard Monique , Loubser Johannes , Williams Monique J. , Streicher Elizabeth M. , Van Rie Annelies , Warren Robin M. , Klopper Marisa 
Published: June 2023

AbstractMolecular detection of bedaquiline resistant tuberculosis is challenging as only a small proportion of mutations in candidate bedaquiline resistance genes have been statistically associated with phenotypic resistance. We introduced two mutations, atpE Ile66Val and Rv0678 Thr33Ala, in the Mycobacterium tuberculosis H37Rv reference strain using homologous recombineering or recombination to investigate the phenotypic effect of these mutations. The genotype of the resulting strains was confirmed by Sanger- and whole genome sequencing, and bedaquiline susceptibility was assessed by minimal inhibitory concentration (MIC) assays. The impact of the mutations on protein stability and interactions was predicted using mutation Cutoff Scanning Matrix (mCSM) tools. The atpE Ile66Val mutation did not elevate the MIC above the critical concentration (MIC 0.25–0.5 µg/ml), while the MIC of the Rv0678 Thr33Ala mutant strains (> 1.0 µg/ml) classifies the strain as resistant, confirming clinical findings. In silico analyses confirmed that the atpE Ile66Val mutation minimally disrupts the bedaquiline-ATP synthase interaction, while the Rv0678 Thr33Ala mutation substantially affects the DNA binding affinity of the MmpR transcriptional repressor. Based on a combination of wet-lab and computational methods, our results suggest that the Rv0678 Thr33Ala mutation confers resistance to BDQ, while the atpE Ile66Val mutation does not, but definite proof can only be provided by complementation studies given the presence of secondary mutations.
Ebselen derivatives inhibit SARS-CoV-2 replication by inhibition of its essential proteins: PLpro and Mpro proteases, and nsp14 guanine N7-methyltransferase
Authors: Zmudzinski Mikolaj , Rut Wioletta , Olech Kamila , Granda Jarosław , Giurg Mirosław , Burda-Grabowska Małgorzata , Kaleta Rafał , Zgarbova Michala , Kasprzyk Renata , Zhang Linlin , Sun Xinyuanyuan , Lv Zongyang , Nayak Digant , Kesik-Brodacka Malgorzata , Olsen Shaun K. , Weber Jan , Hilgenfeld Rolf , Jemielity Jacek , Drag Marcin 
Published: June 2023

AbstractProteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. SARS-CoV-2 main protease (Mpro, 3CLpro) and papain-like protease (PLpro) are responsible for viral polyprotein cleavage—a process crucial for viral survival and replication. Recently it was shown that 2-phenylbenzisoselenazol-3(2H)-one (ebselen), an organoselenium anti-inflammatory small-molecule drug, is a potent, covalent inhibitor of both the proteases and its potency was evaluated in enzymatic and antiviral assays. In this study, we screened a collection of 34 ebselen and ebselen diselenide derivatives for SARS-CoV-2 PLpro and Mpro inhibitors. Our studies revealed that ebselen derivatives are potent inhibitors of both the proteases. We identified three PLpro and four Mpro inhibitors superior to ebselen. Independently, ebselen was shown to inhibit the N7-methyltransferase activity of SARS-CoV-2 nsp14 protein involved in viral RNA cap modification. Hence, selected compounds were also evaluated as nsp14 inhibitors. In the second part of our work, we employed 11 ebselen analogues—bis(2-carbamoylaryl)phenyl diselenides—in biological assays to evaluate their anti-SARS-CoV-2 activity in Vero E6 cells. We present their antiviral and cytoprotective activity and also low cytotoxicity. Our work shows that ebselen, its derivatives, and diselenide analogues constitute a promising platform for development of new antivirals targeting the SARS-CoV-2 virus.
Self-regulation of visual word form area activation with real-time fMRI neurofeedback
Authors: Haugg Amelie , Frei Nada , Menghini Milena , Stutz Felizia , Steinegger Sara , Röthlisberger Martina , Brem Silvia 
Published: June 2023

AbstractThe Visual Word Form Area (VWFA) is a key region of the brain’s reading network and its activation has been shown to be strongly associated with reading skills. Here, for the first time, we investigated whether voluntary regulation of VWFA activation is feasible using real-time fMRI neurofeedback. 40 adults with typical reading skills were instructed to either upregulate (UP group, N = 20) or downregulate (DOWN group, N = 20) their own VWFA activation during six neurofeedback training runs. The VWFA target region was individually defined based on a functional localizer task. Before and after training, also regulation runs without feedback (“no-feedback runs”) were performed. When comparing the two groups, we found stronger activation across the reading network for the UP than the DOWN group. Further, activation in the VWFA was significantly stronger in the UP group than the DOWN group. Crucially, we observed a significant interaction of group and time (pre, post) for the no-feedback runs: The two groups did not differ significantly in their VWFA activation before neurofeedback training, but the UP group showed significantly stronger activation than the DOWN group after neurofeedback training. Our results indicate that upregulation of VWFA activation is feasible and that, once learned, successful upregulation can even be performed in the absence of feedback. These results are a crucial first step toward the development of a potential therapeutic support to improve reading skills in individuals with reading impairments.
Preferential rabbit antibody responses to C-termini of NOTCH3 peptide immunogens
Authors: Lee Soo Jung , Gasche Mitchell B. , Burrows Connor J. , Kondepudi Akhil , Zhang Xiaojie , Wang Michael M. 
Published: June 2023

AbstractAntibodies raised in peptide-immunized rabbits have been used in biological research for decades. Although there has been wide implementation of this approach, specific proteins are occasionally difficult to target for multiple reasons. One consideration that was noted in mice is that humoral responses may preferentially target the carboxyl terminus of the peptide sequence which is not present in the intact protein. To shed light on the frequency of preferential rabbit antibody responses to C-termini of peptide immunogens, we present our experience with generation of rabbit antibodies to human NOTCH3. A total of 23 antibodies were raised against 10 peptide sequences of human NOTCH3. Over 70% (16 of 23) of these polyclonal antibodies were determined to be C-terminal preferring: NOTCH3 peptide-reactive antibodies largely targeted the terminating free carboxyl group of the immunizing peptide. The antibodies that preferred C-terminal epitopes reacted weakly or not at all with recombinant target sequences with extension the C-terminus that eliminated the free carboxyl group of the immunogen structure; furthermore, each of these antisera revealed no antibody reactivity to proteins truncated before the C-terminus of the immunogen. In immunocytochemical applications of these anti-peptide antibodies, we similarly found reactivity to recombinant targets that best binding to cells expressing the free C-terminus of the immunizing sequence. In aggregate, our experience demonstrates a strong propensity for rabbits to mount antibody responses to C-terminal epitopes of NOTCH3-derived peptides which is predicted to limit their use against the native protein. We discuss some potential approaches to overcome this bias that could improve the efficiency of generation of antibodies in this commonly utilized experimental paradigm.
Integrated ultrasonographic approach to evaluate fluid responsiveness in critically ill patients
Authors: Innocenti Francesca , Savinelli Caterina , Coppa Alessandro , Tassinari Irene , Pini Riccardo 
Published: June 2023

AbstractIn patients with acute circulatory failure, we tested the feasibility of the evaluation of the fluid-responsiveness (FR) by a combined approach with echocardiography and lung ultrasound. We enrolled 113 consecutive patients admitted to the Emergency Department High-Dependency Unit of Careggi University-Hospital from January 2015 to June 2020. We assessed: (1) inferior vena cava collapsibility index (IVCCI); (2) the variation of aortic flow (VTIAo) during the passive leg raising test (PLR); (3) the presence of interstitial syndrome by lung ultrasound. FR was defined as an increase in the VTIAo > 10% during PLR or IVCCI ≥ 40%. FR patients were treated with fluid and those non-FR with diuretics or vasopressors. The therapeutic strategy was reassessed after 12 h. The goal was to maintain the initial strategy. Among 56 FR patients, at lung ultrasound, 15 patients showed basal interstitial syndrome and 4 all-lung involvement. One fluid bolus was given to 51 patients. Among 57 non-FR patients, 26 patients showed interstitial syndrome at lung ultrasound (basal fields in 14, all lungs in 12). We administered diuretics to 21 patients and vasopressors to 4 subjects. We had to change the initial treatment plan in 9% non-FR patients and in 12% FR patients (p = NS). In the first 12 h after the evaluation, non-FR patients received significantly less fluids compared to those FR (1119 ± 410 vs 2010 ± 1254 ml, p < 0.001). The evaluation of the FR based on echocardiography and lung ultrasound was associated with the reduction in fluid administration for non-FR patients compared with those FR.
Opposite modulation of functional recovery following contusive spinal cord injury in mice with oligodendrocyte-selective deletions of Atf4 and Chop/Ddit3
Authors: Gao Yonglin , Wei George Z. , Forston Michael D. , Rood Benjamin , Hodges Emily R. , Burke Darlene , Andres Kariena , Morehouse Johnny , Armstrong Christine , Glover Charles , Slomnicki Lukasz P. , Ding Jixiang , Chariker Julia H. , Rouchka Eric C. , Saraswat Ohri Sujata , Whittemore Scott R. , Hetman Michal 
Published: June 2023

AbstractThe integrated stress response (ISR)-activated transcription factors ATF4 and CHOP/DDIT3 may regulate oligodendrocyte (OL) survival, tissue damage and functional impairment/recovery in white matter pathologies, including traumatic spinal cord injury (SCI). Accordingly, in OLs of OL-specific RiboTag mice, Atf4, Chop/Ddit3 and their downstream target gene transcripts were acutely upregulated at 2, but not 10, days post-contusive T9 SCI coinciding with maximal loss of spinal cord tissue. Unexpectedly, another, OL-specific upregulation of Atf4/Chop followed at 42 days post-injury. However, wild type versus OL-specific Atf4−/− or Chop−/− mice showed similar white matter sparing and OL loss at the injury epicenter, as well as unaffected hindlimb function recovery as determined by the Basso mouse scale. In contrast, the horizontal ladder test revealed persistent worsening or improvement of fine locomotor control in OL-Atf4−/− or OL-Chop−/− mice, respectively. Moreover, chronically, OL-Atf−/− mice showed decreased walking speed during plantar stepping despite greater compensatory forelimb usage. Therefore, ATF4 supports, while CHOP antagonizes, fine locomotor control during post-SCI recovery. No correlation between those effects and white matter sparing together with chronic activation of the OL ISR suggest that in OLs, ATF4 and CHOP regulate function of spinal cord circuitries that mediate fine locomotor control during post-SCI recovery.
Platelets from patients with myeloproliferative neoplasms have increased numbers of mitochondria that are hypersensitive to depolarization by thrombin
Authors: Ross David M. , Liang Hai Po Helena , Iqra Zeenet , Whittaker Shane , Tan Chuen Wen , Dale Brian J. , Chen Vivien M. 
Published: June 2023

AbstractThrombosis is one of the cardinal manifestations of myeloproliferative neoplasms (MPN). The mechanisms leading to a prothrombotic state in MPN are complex and remain poorly understood. Platelet mitochondria play a role in platelet activation, but their number and function have not been extensively explored in MPN to date. We observed an increased number of mitochondria in platelets from MPN patients compared with healthy donors. MPN patients had an increased proportion of dysfunctional platelet mitochondria. The fraction of platelets with depolarized mitochondria at rest was increased in essential thrombocythemia (ET) patients and the mitochondria were hypersensitive to depolarization following thrombin agonist stimulation. Live microscopy showed a stochastic process in which a higher proportion of individual ET platelets underwent mitochondrial depolarization and after a shorter agonist exposure compared to healthy donors. Depolarization was immediately followed by ballooning of the platelet membrane, which is a feature of procoagulant platelets. We also noted that the mitochondria of MPN patients were on average located nearer the platelet surface and we observed extrusion of mitochondria from the platelet surface as microparticles. These data implicate platelet mitochondria in a number of prothrombotic phenomena. Further studies are warranted to assess whether these findings correlate with clinical thrombotic events.
Improvement of retinal function in Alzheimer disease-associated retinopathy by dietary lysophosphatidylcholine-EPA/DHA
Authors: Sugasini Dhavamani , Park Jason C. , McAnany J. Jason , Kim Tae-Hoon , Ma Guangying , Yao Xincheng , Antharavally Babu , Oroskar Anil , Oroskar Asha A. , Layden Brian T. , Subbaiah Papasani V. 
Published: June 2023

AbstractAlzheimer disease (AD) is the most prevalent cause of dementia in the elderly. Although impaired cognition and memory are the most prominent features of AD, abnormalities in visual functions often precede them, and are increasingly being used as diagnostic and prognostic markers for the disease. Retina contains the highest concentration of the essential fatty acid docosahexaenoic acid (DHA) in the body, and its deficiency is associated with several retinal diseases including diabetic retinopathy and age related macular degeneration. In this study, we tested the hypothesis that enriching retinal DHA through a novel dietary approach could ameliorate symptoms of retinopathy in 5XFAD mice, a widely employed model of AD. The results show that 5XFAD mice have significantly lower retinal DHA compared to their wild type littermates, and feeding the lysophosphatidylcholine (LPC) form of DHA and eicosapentaenoic acid (EPA) rapidly normalizes the DHA levels, and increases retinal EPA by several-fold. On the other hand, feeding similar amounts of DHA and EPA in the form of triacylglycerol had only modest effects on retinal DHA and EPA. Electroretinography measurements after 2 months of feeding the experimental diets showed a significant improvement in a-wave and b-wave functions by the LPC-diet, whereas the TAG-diet had only a modest benefit. Retinal amyloid β levels were decreased by about 50% by the LPC-DHA/EPA diet, and by about 17% with the TAG-DHA/EPA diet. These results show that enriching retinal DHA and EPA through dietary LPC could potentially improve visual abnormalities associated with AD.
Reconfigurable biconcave lens antenna based on plasma technology
Authors: Sadeghikia Fatemeh , Zafari Kazem , Dorbin Mohammad-Reza , Himdi Mohamed , Horestani Ali Karami 
Published: June 2023

AbstractThis article is focused on the application of plasma technology for the development of microwave lens antennas with electronically controllable radiation gain. With this aim, the analytical background and design procedure for designing a biconcave lens based on plasma dielectric material are presented. The procedure is used to design a plasma lens antenna with a pyramidal horn feed. The effect of switching the designed lens ON and OFF on the radiation gain of the lens antenna is investigated. It is also shown that the plasma frequency of the lens can be used to dynamically adjust the radiation gain. A one-dimensional version of the proposed plasma lens operating at 10 GHz has been developed to validate the concept. Experimentally measured characteristics of a fabricated prototype of the lens antenna based on commercially available fluorescent lamps confirm the presented design procedure and numerical results. The results also show that changing the plasma frequency of the lens can be used to adjust the radiation gain of the proposed lens antenna.
Longitudinal torsional vibrations of the chain drive system of mine scraper conveyor
Authors: Lu Jinnan , Yang Runkun , Mao Jun , Xie Chunxue 
Published: June 2023

AbstractTo deeply analyse the dynamic characteristics of the scraper conveyor during operation, the mechanical characteristics of the coupled longitudinal and torsional vibrational modes under excitation by cargo loading are studied. Based on the Kelvin‒Voigt model and the point-by-point tension method, a model of the coupled longitudinal and torsional vibrations of the scraper chain drive system is established. Then the functional program is constructed and the numerical simulation is carried out. Finally, the correctness of the model is verified by comparison with experiments. The research results reveal the torsional vibration characteristics of the scraper chain drive system under two different working conditions, light load and medium load, and determine the influence area of the torsional vibration of the scraper. The results of this analysis provide a theoretical basis for the subsequent optimization of the scraper parameters, the prediction of scraper chain drive system failure, and the calculation to give an early warning before failure occurs.
Autocatalytic flow chemistry
Authors: Galanics Csenge , Sintár Virág , Szalai István 
Published: June 2023

AbstractAutocatalysis is a crucial process of nonequilibrium self-organization in nature and is assumed to play a role in the origin of life. The essential dynamical phenomena of an autocatalytic reaction network are bistability and the development of propagating front when combined with diffusion. The presence of bulk fluid motion may widen the range of emerging behavior in those systems. Many aspects of the dynamics of autocatalytic reactions in a continuous flow have already been studied, especially the shape and dynamics of the chemical front and the influence of the chemical reactions on hydrodynamic instabilities. This paper aims to provide experimental evidence of bistability and related dynamical phenomena, such as excitability and oscillations in autocatalytic reactions performed in a tubular flow reactor, where the flow is laminar and advection is the dominating transport process. We show that the linear residence time ramp may result in the simultaneous appearance of different dynamic states along the length of the pipe. Therefore, long tubular reactors offer a unique opportunity to quickly explore the dynamics of reaction networks. These findings enhance our understanding of nonlinear flow chemistry and its role in natural pattern formation.
A real-world data validation of the value of early-stage SIR modelling to public health
Authors: Liu Taoran , Huang Jian , He Zonglin , Zhang Yin , Yan Ni , Zhang Casper J. P. , Ming Wai-Kit 
Published: June 2023

AbstractPerformance of Susceptible-Infected-Recovered (SIR) model in the early stage of a novel epidemic may be hindered by data availability. Additionally, the traditional SIR model may oversimplify the disease progress, and knowledge about the virus and transmission is limited early in the epidemic, resulting in a greater uncertainty of such modelling. We aimed to investigate the impact of model inputs on the early-stage SIR projection using COVID-19 as an illustration to evaluate the application of early infection models. We constructed a modified SIR model using discrete-time Markov chain to simulate daily epidemic dynamics and estimate the number of beds needed in Wuhan in the early stage of COVID-19 epidemic. We compared eight scenarios of SIR projection to the real-world data (RWD) and used root mean square error (RMSE) to assess model performance. According to the National Health Commission, the number of beds occupied in isolation wards and ICUs due to COVID-19 in Wuhan peaked at 37,746. In our model, as the epidemic developed, we observed an increasing daily new case rate, and decreasing daily removal rate and ICU rate. This change in rates contributed to the growth in the needs of bed in both isolation wards and ICUs. Assuming a 50% diagnosis rate and 70% public health efficacy, the model based on parameters estimated using data from the day reaching 3200 to the day reaching 6400 cases returned a lowest RMSE. This model predicted 22,613 beds needed in isolation ward and ICU as on the day of RWD peak. Very early SIR model predictions based on early cumulative case data initially underestimated the number of beds needed, but the RMSEs tended to decline as more updated data were used. Very-early-stage SIR model, although simple but convenient and relatively accurate, is a useful tool to provide decisive information for the public health system and predict the trend of an epidemic of novel infectious disease in the very early stage, thus, avoiding the issue of delay-decision and extra deaths.
In-plane gate graphene transistor with epitaxially grown molybdenum disulfide passivation layers
Authors: Tsai Po-Cheng , Huang Chun-Wei , Chang Shoou-Jinn , Chang Shu-Wei , Lin Shih-Yen 
Published: June 2023

AbstractWe demonstrate in-plane gate transistors based on the molybdenum disulfide (MoS2)/graphene hetero-structure. The graphene works as channels while MoS2 functions as passivation layers. The weak hysteresis of the device suggests that the MoS2 layer can effectively passivate the graphene channel. The characteristics of devices with and without removal of MoS2 between electrodes and graphene are also compared. The device with direct electrode/graphene contact shows a reduced contact resistance, increased drain current, and enhanced field-effect mobility. The higher field-effect mobility than that obtained through Hall measurement indicates that more carriers are present in the channel, rendering it more conductive.