bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disease severity of unvaccinated SARS-CoV-2 positive adults less than 65 years old without comorbidity, in the Omicron period and pre-Omicron periods
Authors: Wahlström Erik , Bruce Daniel , Bennet-Bark Anna M , Walther Sten , Hanberger Håkan , Strålin Kristoffer 
Published: February 2023

AbstractBackgroundThe reduced severity and burden of COVID-19 in 2022 can largely be attributable to vaccination and a shift to Omicron predominance. However, millions of individuals remain unvaccinated. In the present study, we aimed to study disease severity in unvaccinated individuals without risk factors during the Omicron period, compared to pre-Omicron periods.MethodsThis register-based study included all unvaccinated individuals in Sweden aged 18-64 years without comorbidity or care dependency who were SARS-CoV-2 positive between week 45 of 2020 and week 5 of 2022. Variant of concern (VOC) periods were periods with certain VOCs identified in ≥92% of sequenced cases nationwide. Outcomes were hospitalization with a main discharge code of COVID-19; severe illness, defined as high-flow nasal oxygen treatment or intensive care unit admission; and death with COVID-19 as the underlying cause of death on the death certificate.ResultsAmong 788,895 individuals in the overall SARS-CoV-2 positive cohort, both hospitalization and death increased stepwise from the pre-VOC period to the Alpha and Delta periods, and decreased in the Omicron period. Among 15,179 patients hospitalized for COVID-19, the proportions with severe illness and death increased to the Delta period, but in the Omicron period, these outcomes returned to the level of the pre-VOC period.ConclusionIn the Omicron period, compared to pre-Omicron periods, unvaccinated SARS-CoV-2 positive adults <65 years old without comorbidity had reduced proportions of hospitalization and death overall, but similar proportion of severe illness among patients hospitalized for COVID-19. These results support continuous efforts to prevent hospitalizations for COVID-19.
Antifungal activity of the novel compound M451 against phytopathogens
Authors: Tetz V , Kardava K , Krasnov K , Vecherkovskaya M , Tetz G 
Published: February 2023

AbstractPhytopathogenic fungi are the dominant causal agents of plant diseases. Currently available fungicides have significant disadvantages, being insufficiently effective owing to both intrinsic tolerance and the spread of antibiotic resistance accumulating in plant tissues, posing a global threat to public health. Finding a new broad-spectrum fungicide is a challenge for plant protection. We studied the potency of a novel antimicrobial agent, M451, against different phytopathogenic fungi of the phylaAscomycota, Oomycota, andBasidiomycota. M451 exhibited significant antifungal activity with EC50 values ranging from 34 to 145 µg/mL. Analysis of the minimal fungicidal concentration and conidial destruction assay revealed that M451 possesses the highest activity compared with different polyene, azole, and phenylpyrrole antifungals againstFusarium oxysporum. Time-kill analysis revealed that M451 was the only antifungal agent tested that exhibited antifungal activity within 5 min of exposure. Spore production and germination were also significantly inhibited by M451 treatment. Based on the broad spectrum of antifungal effects across different plant pathogens, M451 could be a new chemical fungicide for plant disease management.
Dual orexin/hypocretin receptor antagonism attenuates attentional impairments in an NMDA receptor hypofunction model of schizophrenia
Authors: Maness Eden B. , Blumenthal Sarah A. , Burk Joshua A. 
Published: February 2023

AbstractSchizophrenia is a neuropsychiatric condition that is associated with impaired attentional processing and performance. Failure to support increasing attentional load may result, in part, from abnormally overactive basal forebrain projections to the prefrontal cortex, and available antipsychotics often fail to address this issue. Orexin/hypocretin receptors are expressed on corticopetal cholinergic neurons, and their blockade has been shown to decrease the activity of cortical basal forebrain outputs and prefrontal cortical cholinergic neurotransmission. In the present experiment, rats (N = 14) trained in a visual sustained attention task that required discrimination of trials which presented a visual signal from trials during which no signal was presented. Once trained, rats were then co-administered the psychotomimetic N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801: 0 or 0.1 mg/kg, intraperitoneal injections) and the dual orexin receptor antagonist filorexant (MK-6096: 0, 0.1, or 1 mM, intracerebroventricular infusions) prior to task performance across six sessions. Dizocilpine impaired overall accuracy during signal trials, slowed reaction times for correctly-responded trials, and increased the number of omitted trials throughout the task. Dizocilpine-induced increases in signal trial deficits, correct response latencies, and errors of omission were reduced following infusions of the 0.1 mM, but not 1 mM, dose of filorexant. Orexin receptor blockade, perhaps through anticholinergic mechanisms, may improve attentional deficits in a state of NMDA receptor hypofunction.HighlightsSchizophrenia is associated with attentional deficits that may stem from abnormally reactive BF projections to the prefrontal cortexOrexin receptor antagonists decrease acetylcholine release and reduce prefrontal cortical activityThe dual orexin receptor antagonist filorexant alleviated impairments of attention following NMDA receptor blockade
A Theory of Hippocampal Theta Correlations: Extrinsic and Intrinsic Sequences
Authors: Yiu Yuk-Hoi , Leibold Christian 
Published: February 2023

AbstractHippocampal place cell sequences have been hypothesized to serve as diverse purposes as the induction of synaptic plasticity, formation and consolidation of long-term memories, or navigation and planning. During spatial behaviors of rodents, sequential firing of place cells at the theta timescale (known as theta sequences) encodes running trajectories, which can be considered as 1-dimensional behavioral sequences of traversed locations. In a 2-dimensional space, however, each single location can be visited along arbitrary 1-dimensional running trajectories. Thus, a place cell will generally take part in multiple different theta sequences, raising questions about how this 2-dimensional topology can be reconciled with the idea of hippocampal sequences underlying memory of (1-dimensional) episodes. Here, we propose a computational model of cornu ammonis 3 (CA3) and dentate gyrus (DG), where sensorimotor input drives the direction-dependent (extrinsic) theta sequences within CA3 reflecting the 2-dimensional spatial topology, whereas the in-trahippocampal CA3-DG projections concurrently produce intrinsic sequences that are independent of the specific running trajectory. Consistent with experimental data, these intrinsic theta sequences are less prominent in the theta state, but we show that they can nevertheless be detected during theta activity, thereby serving as running-direction independent landmark cues. We hypothesize that the intrinsic sequences largely reflect replay and preplay activity during non-theta states.
Monitoring oligomerization dynamics of individual human neurotensin receptors 1 in living cells and in SMALP nanodiscs
Authors: Spantzel Lukas , Pérez Iván , Heitkamp Thomas , Westphal Anika , Reuter Stefanie , Mrowka Ralf , Börsch Michael 
Published: February 2023

ABSTRACTThe human neurotensin receptor 1 (NTSR1) is a G protein-coupled receptor. The receptor is activated by a small peptide ligand neurotensin. NTSR1 can be expressed in HEK cells by stable transfection. Previously we used the fluorescent protein markers mRuby3 or mNeonGreen fused to NTSR1 for EMCCD-based structured illumination microscopy (SIM) in living HEK cells. Ligand binding induced conformational changes in NTSR1 which triggered the intracellular signaling processes. Recent single-molecule studies revealed a dynamic monomer/dimer equilibrium of this receptor in artificial lipid bilayers. Here we report on the oligomerization state of human NTSR1 from living cells by trapping them into lipid nanodiscs. Briefly, SMALPs (styrene-maleic acid copolymer lipid nanoparticles) were produced directly from the plasma membranes of living HEK293T FlpIn cells. SMALPs with a diameter of 15 nm were soluble and stable. NTSR1 in SMALPs were analyzed by single-molecule intensity measurements one membrane patch at a time using a custom-built confocal anti-Brownian electrokinetic trap (ABEL trap) microscope. We found oligomerization changes before and after stimulation of the receptor with its ligand neurotensin.
Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation of frontostriatal networks
Authors: Magnard Robin , Fouyssac Maxime , Vachez Yvan M. , Cheng Yifeng , Dufourd Thibault , Carcenac Carole , Boulet Sabrina , Janak Patricia H. , Savasta Marc , Belin David , Carnicella Sebastien 
Published: February 2023

ABSTRACTImpulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathological gambling, hypersexuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D2/3receptor agonists, such as pramipexole (PPX). Despite evidence showing that impulsivity is associated with functional alterations in corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucidated. Here we used a hotspot analysis to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (HI), moderately impulsive (MI) or with low levels of impulsivity (LI) in the 5-choice serial reaction time task (5-CSRTT). PPX dramatically reduced impulsivity in HI rats. Assessment of the expression pattern of the two immediate early genes C-fos and Zif268 byin situhybridization subsequently revealed that PPX resulted in a decrease in Zif268 mRNA levels in different striatal regions of both LI and HI rats accompanied by a high impulsivity specific reduction of Zif268 mRNA levels in prelimbic and cingulate cortices. PPX also decreased C-fos mRNA levels in all striatal regions of LI rats, but only in the dorsolateral striatum and nucleus accumbens core (NAc Core) of HI rats. Structural equation modelling further suggested that the anti-impulsive effect of PPX was mainly attributable to the specific downregulation of Zif268 mRNA in the NAc Core. Altogether, our results show that PPX restores impulse control in highly impulsive rats by modulation of limbic frontostriatal circuits.
Cellular iron governs the host response to malaria
Authors: Wideman Sarah K. , Frost Joe N. , Richter Felix C. , Naylor Caitlin , Lopes José M. , Viveiros Nicole , Teh Megan R. , Preston Alexandra E. , White Natasha , Yusuf Shamsideen , Draper Simon J. , Armitage Andrew E. , Duarte Tiago L. , Drakesmith Hal 
Published: February 2023

ABSTRACTMalaria and iron deficiency are major global health problems with extensive epidemiological overlap. Iron deficiency-induced anaemia can protect the host from malaria by limiting parasite growth. On the other hand, iron deficiency can significantly disrupt immune cell function. However, the impact of host cell iron scarcity beyond anaemia remains elusive in malaria. To address this, we employed a transgenic mouse model carrying a mutation in the transferrin receptor (TfrcY20H/Y20H), which limits the ability of cells to internalise iron from plasma. At homeostasisTfrcY20H/Y20Hmice appear healthy and are not anaemic. However,TfrcY20H/Y20Hmice infected withPlasmodium chabaudi chabaudi ASshowed significantly higher peak parasitaemia and body weight loss. We found thatTfrcY20H/Y20Hmice displayed a similar trajectory of malaria-induced anaemia as wild-type mice, and elevated circulating iron did not increase peak parasitaemia. Instead,P. chabaudiinfectedTfrcY20H/Y20Hmice had an impaired innate and adaptive immune response, marked by decreased cell proliferation and cytokine production.Moreover, we demonstrated that these immune cell impairments were cell-intrinsic, asex vivoiron supplementation fully recovered CD4 T cell and B cell function. Despite the inhibited immune response and increased parasitaemia,TfrcY20H/Y20Hmice displayed mitigated liver damage, characterised by decreased parasite sequestration in the liver and an attenuated hepatic immune response. Together, these results show that host cell iron scarcity inhibits the immune response but prevents excessive hepatic tissue damage during malaria infection. These divergent effects shed light on the role of iron in the complex balance between protection and pathology in malaria.
Niche cells regulate primordial germ cell quiescence in response to basement membrane signaling
Authors: McIntyre Daniel C. , Nance Jeremy 
Published: February 2023

AbstractStem cell quiescence, proliferation and differentiation are controlled by interactions with niche cells and a specialized extracellular matrix called the basement membrane (BM). Direct interactions with adjacent BM are known to regulate stem cell quiescence; however, it is less clear how niche BM relays signals to stem cells that it does not contact. Here, we examine how niche BM regulatesC. elegansprimordial germ cells (PGCs), which remain quiescent during embryogenesis. Depleting the BM protein laminin causes embryonic PGCs to proliferate, indicating that laminin functions to maintain PGC quiescence. How laminin signals to the PGCs remains unclear, as somatic niche cells enwrap PGCs and physically exclude them from contacting the BM. Here, we show that, following laminin depletion, gonadal niche cells relay proliferation-inducing signals from the gonadal BM to PGCs via integrin receptors. Mutations disrupting the BM proteoglycan perlecan block PGC proliferation when laminin is depleted, suggesting that laminin functions to inhibit a proliferation-inducing signal originating from perlecan. Our results reveal how BM signals can regulate stem cell quiescence indirectly, by activating niche cell integrin receptors.
Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy
Authors: Kazansky Yaniv , Cameron Daniel , Mueller Helen , Demarest Phillip , Zaffaroni Nadia , Arrighetti Noemi , Zuco Valentina , Kuwahara Yasumichi , Somwar Romel , Ladanyi Marc , Qu Rui , Stanchina Elisa De , Cruz Filemon Dela , Kung Andrew , Gounder Mrinal , Kentsis Alex 
Published: February 2023

AbstractEssential epigenetic dependencies have become evident in many cancers. Based on the functional antagonism between BAF/SWI/SNF and PRC2 inSMARCB1-deficient sarcomas, we and colleagues recently completed the clinical trial of the EZH2 inhibitor tazemetostat. However, the principles of tumor response to epigenetic therapy in general, and tazemetostat in particular, remain unknown. Using functional genomics of patient tumors and diverse experimental models, we sought to define molecular mechanisms of tazemetostat resistance inSMARCB1-deficient sarcomas and rhabdoid tumors. We found distinct classes of acquired mutations that converge on the RB1/E2F axis and decouple EZH2-dependent differentiation and cell cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest despite EZH2 inhibition, and suggests a general mechanism for effective EZH2 therapy. This also enables us to develop combination strategies to circumvent tazemetostat resistance using cell cycle bypass targeting via AURKB, and synthetic lethal targeting of PGBD5-dependent DNA damage repair via ATR. This reveals prospective biomarkers for therapy stratification, including PRICKLE1 associated with tazemetostat resistance. In all, this work offers a paradigm for rational epigenetic combination therapy suitable for immediate translation to clinical trials for epithelioid sarcomas, rhabdoid tumors, and other epigenetically dysregulated cancers.SignificanceGenomic studies of patient epithelioid sarcomas, rhabdoid tumors, and their cell lines identify mutations converging on a common pathway that is essential for response to EZH2 inhibition. Resistance mutations decouple drug-induced differentiation from cell cycle control. We identify complementary epigenetic combination strategies to overcome resistance and improve durability of response, supporting their investigation in clinical trials.
Genome-wide mining and comparative analysis of microsatellite markers fromOrientia tsutsugamushigenomes
Authors: Panda Subhasmita , Swain Subrat Kumar , Sahu Basanta Pravas , Sarangi Rachita 
Published: February 2023

AbstractMicrosatellite markers, otherwise known as the simple sequence repeats (SSRs), are being used for molecular identification and characterization as well as estimation of evolution pattern of the organism due to their high polymorphic nature. These are tandemly repeated sequences observed almost all organisms and differentially distributed across the genome. Although the primary genome information ofOrientia tsutsugamushi(OT) suggested the repeats hold the 40% entire of its genome, but lack of characteristic of this repeats increase our interest to study more about it. Thus we investigated a genome-wide presence of microsatellites within nine complete genomes within OT and analyzed their distribution pattern, composition and complexity. Thein-silicostudy revealed the genome of OT enrich with microsatellites having a total of 126187 SSR and 10374 cSSR throughout the genome from which 70% and 30% represented within the coding and non coding region respectively. The relative density (RD) and relative abundance (RA) of SSRs were 42-44.43/kb and 6.25-6.59/kb while for cSSRs this value ranged from 7.06-8.1/kb and 0.50-0.55/kb respectively. However, RA and RD were weakly correlate with genome size and incidence microsatellites. The mononucleotide repeats (54.55%) were prevalent over di- (33.22%), tri- (11.88%), tetra- (0.27%), penta- (0.02%), hexanucleotide (0.04%) repeats, with poly (A/T) richness over poly (G/C). Motif composition of cSSRs revealed that maximum cSSRs were made up of two microsatellites having unique duplication pattern such as AT-x-AT, CG-x-CG. More numbers microsatellites represented within the coding region provides an insight into the genome plasticity that may interfere for gene regulation to mitigate with host-pathogen interaction and evolution of the species.
Innate receptors with high specificity for HLA class I–peptide complexes
Authors: Sim Malcolm J. W. , Brennan Paul , Wahl Katherine L. , Lu Jinghua , Rajagopalan Sumati , Sun Peter D. , Long Eric O. 
Published: February 2023

SummaryGenetic studies associate killer-cell immunoglobulin-like receptors (KIR) and their HLA class I ligands with a variety of human diseases. The basis for these associations, and the relative contribution of inhibitory and activating KIR to NK cell responses are unclear. As KIR binding to HLA-I is peptide-dependent, we performed systematic screens totaling over 3,500 specific interactions to determine the specificity of five KIR for peptides presented by four HLA-C ligands. Inhibitory KIR2DL1 was largely peptide sequence agnostic, binding approximately 60% of hundreds of HLA-peptide complexes tested. Inhibitory KIR2DL2, KIR2DL3, and activating KIR2DS1 and KIR2DS4 bound only 10%, down to 1% of HLA-peptide complexes tested, respectively. Activating KIR2DS1, previously described as weak, had high binding affinity for HLA-C with high peptide sequence specificity. Our data revealed MHC-restricted peptide recognition by germ-line encoded NK receptors and imply that NK cell responses can be shaped by HLA-I bound immunopeptidomes in the context of disease or infection.
Coherence-based interhemispheric EEG functional connectivity changes in distinct frequency bands during eyes open meditation
Authors: Pradeep Kumar G , Sharma Kanishka , Adarsh A , Manvi Amrutha , Ramajayam G , Ramakrishnan A G 
Published: February 2023

AbstractMeditation is a self-regulatory process practiced primarily to reduce stress, manage emotions and mental health. The objective was to study the information exchange between symmetric electrodes across the hemispheres during meditation using functional connectivity (FC) measures. We investigate the changes in the coherence between EEG electrode pairs during the meditation practiced by long-term Brahmakumaris Rajyoga meditators with open eyes and during listening to music by controls as the comparable task. Two distinct FC measures derived from coherency, namely, magnitude squared coherence (MSC) and imaginary part of coherency (ICoh) are used to study the changes in interhemispheric coherence. During baseline conditions, higher MSC is found in meditators in frontocentral and centroparietal regions and higher |ICoh| globally in higher beta and gamma bands than controls. Further, in meditators, the MSC significantly increases in higher theta and alpha bands in the frontal and parietal regions and |ICoh| significantly decreases across all regions and bands except in the alpha band during meditation. However, the control subjects with no knowledge of meditation show no change in theta or alpha MSC or |ICoh| during the music session. Distinct patterns of changes are observed with the two FC measures in different frequency bands during meditation in the meditators and music-listening session in the control subjects indicating varied information processing between the right and left hemispheres and differences in the FC measures used. We found increased MSC and decreased |ICoh| between the frontal electrodes implying increased self-awareness in meditators. The MSC between the occipital electrodes in meditators is less than the controls in baseline condition indicating a possible modified visual information processing in Rajyoga meditators due to the long-term practice of meditation with open eyes. Overall, the changes in MSC indicate increased functional integration during meditation supporting the hypothesis of cortical integration theory.
Plain language in Mauritius: an empirical study of legal communication in Mauritius
Authors: Beebeejaun Ambareen 
Published: February 2023

Purpose
Irrespective of various forms of language existent worldwide, it is still imperative that recipients of professional legal advice be communicated in clear terms to avoid a chaotic situation and to better fulfil obligations and enjoy the rights to which they are entitled to appropriately. As such, the objectives of this paper are twofold: firstly, this paper aims to assess the extent to which clients of the legal profession prefer plain over traditional legal language in Mauritius, a country using a myriad of languages, and secondly, to suggest recommendations for the legal stakeholders in Mauritius regarding guidelines and mechanisms on plain language provisions.

Design/methodology/approach
This study will use a desk-based research methodology by analysing existing literature on the importance of plain language in legal writing. In addition, an empirical study will be conducted to gather information on clients’ preferences in legal communication.

Findings
The responses were received on a complete anonymous basis, and it was found that in general, clients of the legal profession in Mauritius are more at ease when law practitioners use simple, direct and straightforward terms, sentences structured in active voice rather than passive voice or the use of legal jargons or complicated words. These clients also prefer when their legal advisers explain the legal meaning or interpretation in a document or agreement even if these advices may be longer than shorter sentences with only the legal jargons.

Originality/value
At present, there are few literature on the researched topic and this study will be among the first academic writings on the effectiveness of using plain language in legal documentation in Mauritius. The study is carried out with the aim of combining a large amount of empirical, theoretical and factual information that can be of use to various stakeholders and not only to academics.