bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interferon lambda signals in maternal tissues to exert protective and pathologic effects in a gestational-stage dependent manner
Authors: Casazza Rebecca L. , Philip Drake T. , Lazear Helen M. 
Published: January 2022

ABSTRACTInterferon lambda (IFN-λ, type III IFN) is constitutively secreted from human placental cells in culture and reduces Zika virus (ZIKV) transplacental transmission in mice. However, the roles of IFN-λ during healthy pregnancy and in restricting congenital infection remain unclear. Here we used mice lacking the IFN-λ receptor (Ifnlr1-/-) to generate pregnancies lacking either maternal or fetal IFN-λ responsiveness and found that the antiviral effect of IFN-λ resulted from signaling exclusively in maternal tissues. This protective effect depended on gestational stage, as infection earlier in pregnancy (E7 rather than E9) resulted in enhanced transplacental transmission of ZIKV. In Ifnar1-/- dams, which sustain robust ZIKV infection, maternal IFN-λ signaling caused fetal resorption and intrauterine growth restriction. Pregnancy pathology elicited by poly(I:C) treatment also was mediated by maternal IFN-λ signaling, specifically in maternal leukocytes, and also occurred in a gestational stage-dependent manner. These findings identify an unexpected effect of IFN-λ signaling specifically in maternal (rather than placental or fetal) tissues, which is distinct from the pathogenic effects of IFN-αβ (type I IFN) during pregnancy. These results highlight the complexity of immune signaling at the maternal-fetal interface, where disparate outcomes can result from signaling at different gestational stages.IMPORTANCEPregnancy is an immunologically complex situation, which must balance protecting the fetus from maternal pathogens with preventing maternal immune rejection of non-self fetal and placental tissue. Cytokines, such as interferon lambda (IFN-λ), contribute to antiviral immunity at the maternal-fetal interface. We found in a mouse model of congenital Zika virus infection that IFN-λ can have either a protective antiviral effect or cause immune-mediated pathology, depending on the stage of gestation when IFN-λ signaling occurs. Remarkably, both the protective and pathologic effects of IFN-λ occurred through signaling exclusively in maternal immune cells, rather than in fetal or placental tissues, or in other maternal cell types, identifying a new role for IFN-λ at the maternal-fetal interface.
Narrowing gap in regional and age-specific excess mortality in the first year and a half of COVID-19 in Hungary
Authors: Tóth Csaba G. 
Published: January 2022

ABSTRACTIn the first year and a half of the pandemic, the excess mortality in Hungary was 28,400, which was 1,700 lower than the official statistics on COVID-19 deaths. This discrepancy can be partly explained by protective measures instated during the COVID-19 pandemic that decreased the intensity of the seasonal flu outbreak, which caused on average 3,000 deaths per year. Compared to the second wave of the COVID-19 pandemic, the third wave showed a reduction in the differences in excess mortality between age groups and regions. The excess mortality rate for people aged 75+ fell significantly in the third wave, partly due to the vaccination schedule and the absence of a normal flu season. For people aged 40–77, the excess mortality rate rose slightly in the third wave. Between regions, excess mortality was highest in Northern Hungary and Western Transdanubia, and much lower in Central Hungary, where the capital is located. The excess mortality rate for men was almost twice as high as that for women in almost all age groups.
High Sensitivity and NPV for BinaxNOW Rapid Antigen Test in Children at a Mass Testing Site During Prevalent Delta Variant Period
Authors: Sun Kristie J. , Vaeth Mary Jane E. , Robinson Matthew , Elhabashy Maryam , Gupta Ishaan , Purekal Sophia , Hammershaimb E. Adrianne , Peralta Ria , Mitchell Asia , Foyez Maisha , Johnson J. Kristie , Ficke James R , Manabe Yukari C. , Campbell James D. , Callahan Charles W. , Locke Charles F. , Kantsiper Melinda ,   CONQUER COVID Consortium, Siddiqui Zishan K. 
Published: January 2022

ABSTRACTSARS-CoV-2 continues to develop new, increasingly infectious variants including delta and omicron. We evaluated the efficacy of the Abbott BinaxNOW Rapid Antigen Test against Reverse Transcription Polymerase Chain Reaction (“RT-PCR”) in 1054 pediatric participants presenting to a high-volume Coronavirus Disease 2019 (COVID-19) testing site while the delta variant was predominant. Participants were grouped by COVID-19 exposure and symptom status. RT-PCR demonstrated an overall prevalence of 5.2%. For all participants, sensitivity of the BinaxNOW was 92.7% (95% CI 82.4%-98.0%) and specificity was 98.0% (95% CI 97.0%-98.8%). For symptomatic participants, positive predictive value (PPV) was 72.7% (95% CI 54.5%-86.7%) and negative predictive value (NPV) was 99.2% (95% CI 98.2%-100%). Among asymptomatic participants, PPV was 71.4% (95% CI 53.7%-85.4%) and NPV was 99.7% (95% CI 99.0%-100%). Our reported sensitivity and NPV are higher than other pediatric studies, potentially because of higher viral load from the delta variant, but specificity and PPV are lower.ImportanceThe BinaxNOW rapid antigen COVID-19 test had a sensitivity of nearly 92% in both symptomatic and asymptomatic children when performed at a high-throughput setting during the more transmissible delta variant dominant period. The test may play an invaluable role in asymptomatic screening and keeping children safe in school.
The chronic wound virome: phage diversity and associations with wounds and healing outcomes
Authors: Verbanic Samuel , Deacon John M. , Chen Irene A. 
Published: January 2022

AbstractTwo leading impediments to chronic wound healing are polymicrobial infection and biofilm formation. Recent studies have characterized the bacterial fraction of these microbiomes and have begun to elucidate compositional correlations to healing outcomes. However, the factors that drive compositional shifts are still being uncovered. The virome may play an important role in shaping bacterial community structure and function. Previous work on the skin virome determined that it was dominated by bacteriophages, viruses that infect bacteria. To characterize the virome, we enrolled 20 chronic wound patients presenting at an outpatient wound care clinic in a microbiome survey, collecting swab samples from healthy skin and chronic wounds before and after a single, sharp debridement procedure. We investigated the virome using a virus-like particle enrichment procedure, shotgun metagenomic sequencing, and a k-mer-based, reference-dependent taxonomic classification method. Taxonomic composition, diversity, and associations to covariates are presented. We find that the wound virome is highly diverse, with many phages targeting known pathogens, and may influence bacterial community composition and functionality in ways that impact healing outcomes.ImportanceChronic wounds are an increasing medical burden. These wounds are known to be rich in microbial content, including both bacteria and bacterial viruses (phages). The viruses may play an important role in shaping bacterial community structure and function. We analyzed the virome and bacterial composition of 20 patients with chronic wounds. The viruses found in wounds are highly diverse compared to normal skin, unlike the bacterial composition, where diversity is decreased. These data represent an initial look at this relatively understudied component of the chronic wound microbiome.
Adherence of SARS-CoV-2 delta variant to surgical mask and N95 respirators
Authors: Lorenzo-Leal Ana C. , Vimalanathan Selvarani , Bach Horacio 
Published: January 2022

AbstractThe use of facial protection, including masks and respirators, has been adopted globally due to the COVID-19 pandemic. These products have been demonstrated to be effective in reducing the transmission of the virus. To determine whether or not the virus adheres to masks and respirators, we dissected four respirators and one surgical mask into layers. These individual layers were contaminated with the SARS-CoV-2 delta variant, and its release by vortexing was performed. Samples were used to infect Vero cells, and a plaque assay was used to determine to evaluate the adherence of the virus. Results showed that a cumulative log reduction of the layers reduced the load of the virus six-folds. Our study confirms the effectiveness of facial protection in reducing the transmission and or infection of the virus.
Neurofeedback-guided kinesthetic motor imagery training in Parkinson’s disease: Randomized trial
Authors: Tinaz Sule , Kamel Serageldin , Aravala Sai S. , Elfil Mohamed , Bayoumi Ahmed , Patel Amar , Scheinost Dustin , Sinha Rajita , Hampson Michelle 
Published: January 2022

AbstractBackgroundParkinson’s disease (PD) causes difficulty with maintaining the speed, size, and vigor of movements, especially when they are internally generated. We previously proposed that the insula is important in motivating intentional movement via its connections with the dorsomedial frontal cortex (dmFC). We demonstrated that subjects with PD can increase the right insula-dmFC functional connectivity using fMRI-based neurofeedback (NF) combined with kinesthetic motor imagery (MI). The current study is a randomized clinical trial testing whether NF-guided kinesthetic MI training can improve motor performance and increase task-based and resting-state right insula-dmFC functional connectivity in subjects with PD.MethodsWe assigned nondemented subjects with mild PD (Hoehn & Yahr stage ≤ 3) to the experimental kinesthetic MI with NF (MI-NF, n=22) and active control visual imagery (VI, n=22) groups. Only the MI-NF group received NF-guided MI training (10-12 runs). The NF signal was based on the right insula-dmFC functional connectivity strength. All subjects also practiced their respective imagery tasks at home daily for 4 weeks. Post-training changes in 1) task-based and resting-state right insula-dmFC functional connectivity were the imaging outcomes, and 2) MDS-UPDRS motor exam and motor function scores were the clinical outcomes.ResultsThe MI-NF group did not show significant NF regulation and was not significantly different from the VI group in any of the imaging or clinical outcome measures. The MI-NF group reported subjective improvement in kinesthetic body awareness. There was significant and comparable improvement only in motor function scores in both groups. This improvement correlated with NF regulation of the right insula-dmFC functional connectivity only in the MI-NF group. Both groups showed specific training effects in whole-brain functional connectivity with distinct neural circuits supporting kinesthetic motor and visual imagery (exploratory outcome).ConclusionsThe functional connectivity-based NF regulation was unsuccessful in our cohort with mild PD. However, kinesthetic MI practice by itself or in combination with other imagery techniques is a promising tool in motor rehabilitation in PD.HighlightsParkinson’s disease (PD) causes difficulty with sustained motor performanceInsula and dorsomedial frontal cortex (dmFC) are implicated in motivating movementRegulation of insula-dmFC functional connectivity with neurofeedback (NF) failedMotor imagery practice regardless of NF improved motor function and body awarenessMotor imagery is a promising strategy for motor rehabilitation in PD
Stability of plasma metabolomics over 10 years among women
Authors: Zeleznik Oana A. , Wittenbecher Clemens , Deik Amy , Jeanfavre Sarah , Avila-Pacheco Julian , Rosner Bernard , Rexrode Kathryn M. , Clish Clary B. , Hu Frank B. , Eliassen A. Heather 
Published: January 2022

AbstractBackgroundIn epidemiological studies, samples are often collected long before disease onset or outcome assessment. Understanding the long-term stability of biomarkers measured in these samples is crucial. We estimated within-person stability over 10 years of metabolites and metabolite features (N=5938) in the Nurses’ Health Study (NHS): The primary dataset included 1880 women with 1184 repeated samples donated 10 years apart while the secondary dataset included 1456 women with 488 repeated samples donated 10 years apart.MethodsWe quantified plasma metabolomics using two liquid chromatography mass spectrometry platforms (lipids and polar metabolites) at the Broad Institute (Cambridge, MA). Intra-class correlations were used to estimate long-term stability (10 years) of metabolites and were calculated as the proportion of the total variability (within-person + between-person) attributable to between-person variability. Within-person variability was estimated among participants who donated two blood samples approximately 10 years apart while between-person variability was estimated among all participants.ResultsIn the primary dataset, the median ICC was 0.43 (1st quartile [Q1]: 0.36; 3rd quartile [Q3]: 0.50) among known metabolites and 0.41 (Q1: 0.34; Q3: 0.48) among unknown metabolite features. The most stable (median ICCs: 0.54-0.57) metabolite classes were nucleosides, nucleotides and analogues, phosphatidylcholine plasmalogens, diglycerides, and cholesteryl esters. The least stable (median ICCs: 0.26-0.36) metabolite classes were lysophosphatidylethanolamines, lysophosphatidylcholines and steroid and steroid derivatives. Results in the secondary dataset were similar (Spearman correlation=0.87) to corresponding results in the primary dataset.ConclusionWithin-person stability over 10 years is reasonable for lipid, lipid-related, and polar metabolites, and varies by metabolite class. Additional studies are required to estimate within-person stability over 10 years of other metabolites groups.
Gata2, Nkx2-2 and Skor2 form a transcription factor network regulating development of a midbrain GABAergic neuron subtype with characteristics of REM sleep regulatory neurons
Authors: Kirjavainen Anna , Singh Parul , Lahti Laura , Seja Patricia , Lelkes Zoltan , Makkonen Aki , Kilpinen Sami , Ono Yuichi , Salminen Marjo , Aitta-Aho Teemu , Stenberg Tarja , Molchanova Svetlana , Achim Kaia , Partanen Juha 
Published: January 2022

AbstractThe midbrain reticular formation is a mosaic of diverse GABAergic and glutamatergic neurons that have been associated with a variety of functions, including the regulation of sleep. However the molecular characteristics and development of the midbrain reticular formation neurons are poorly understood. As the transcription factor Gata2 is required for the development of all GABAergic neurons derived from the embryonic mouse midbrain, we hypothesized that the genes expressed downstream of Gata2 could contribute to the diversification of GABAergic neuron subtypes in this brain region. Here, we show that Gata2 is indeed required for the expression of several lineage-specific transcription factors in post-mitotic midbrain GABAergic neuron precursors. These include a homeodomain transcription factor Nkx2-2 and a SKI family transcriptional repressor Skor2, which are co-expressed in a restricted group of GABAergic precursors in the midbrain reticular formation. Both Gata2, and Nkx2-2 function is required for the expression of Skor2 in GABAergic precursors. In the adult mouse as well as rat midbrain, the Nkx2-2 and Skor2 expressing GABAergic neurons locate at the boundary of the ventrolateral periaqueductal gray and the midbrain reticular formation, an area shown to contain REM-off neurons regulating REM sleep. In addition to the characteristic localization, the Skor2 positive cells increase their activity upon REM sleep inhibition, send projections to a pontine region associated with sleep control and are responsive to orexins, consistent with the known properties of the midbrain REM-off neurons.
Head-to-tail peptide cyclization: new directions and application to urotensin II and Nrf2
Authors: Karami Yasaman , Murail Samuel , Giribaldi Julien , Lefranc Benjamin , Defontaine Florian , Lesouhaitier Olivier , Leprince Jérôme , de Vries Sjoerd J. , Tufféry Pierre 
Published: January 2022

AbstractBackbone head-to-tail cyclization is one effective strategy to stabilize the conformation of bioactive peptides, preventing enzymatic degradation and improving their bioavailibility. However, very little is known about the requirements to rationally design linkers for the cyclization of linear peptides. Recently, we have shown that large scale data-mining of protein structures can lead to the precise identification of protein loop conformations. Here, we transpose this approach to head-to-tail peptide cyclization. We first show that given a linker sequence and the conformation of the linear peptide, it is possible to accurately predict the cyclized peptide conformation improving by over 1 Å over pre-existing protocols. Secondly, and more importantly, we show that it is possible to elaborate on the information inferred from protein structures to propose effective candidate linker sequences constrained by length and amino acid composition. As experimental validation, we first apply our approach to design linkers for the head-to-tail cyclizations of a peptide derived from Nrf2. The designed cyclized peptide shows a 26-fold increase in binding affinity. We then consider urotensin II, a cyclic peptide already stabilized by a disulfide bond, that exerts a broad array of biological activities. The designed head-to-tail cyclized peptide, the first synthesized bicyclic 14-residue long urotensin II analogue shows an excellent retention of in vitro activity. Overall, we propose the first framework for the rational peptide head-to-tail cyclization and reveal its potential for cyclic peptide-based drug design.
HLJ1 amplifies endotoxin–induced sepsis severity by promoting IL-12 heterodimerization in macrophages
Authors: Luo Wei-Jia , Yu Sung-Liang , Chang Chia-Ching , Chien Min-Hui , Liao Keng-Mao , Chang Ya-Ling , Chuang Ya-Hui , Chen Jeremy J.W. , Yang Pan-Chyr , Su Kang-Yi 
Published: January 2022

AbstractHeat shock protein (HSP) 40 has emerged as a key actor in both innate and adaptive immunity, whereas the role of HLJ1, a molecular chaperone in HSP40 family, in modulating endotoxin–induced sepsis severity is still unclear. Here, we use single-cell RNA sequencing to characterize mouse liver nonparenchymal cell populations under LPS (lipopolysaccharide) stimulation, and show that HLJ1 deletion affected IFN-γ-related gene signatures in distinct immune cell clusters. HLJ1 deficiency also leads to reduced serum levels of IL-12 in LPS-treated mice, contributing to dampened production of IFN-γ in natural killer cells but not CD4+ or CD8+ T cells, and subsequently to improved survival rate. Adoptive transfer of HLJ1-deleted macrophages into LPS-treated mice results in reduced IL-12 and IFN-γ levels and protects the mice from IFN-γ–dependent mortality. In the context of molecular mechanisms, HLJ1 is an LPS-inducible protein in macrophages and converts misfolded IL-12p35 homodimers to monomers, which maintains bioactive IL-12p70 heterodimerization and secretion. This study suggests HLJ1 causes IFN-γ–dependent septic lethality by promoting IL-12 heterodimerization, and targeting HLJ1 has therapeutic potential in inflammatory diseases involving activating IL-12/IFN-γ axis.
Plant peptidoglycan precursor biosynthesis: Conservation between moss chloroplasts and Gram negative bacteria
Authors: Dowson Amanda J. , Lloyd Adrian J. , Cuming Andrew C. , Roper David I. , Frigerio Lorenzo , Dowson Christopher G. 
Published: January 2022

AbstractAn accumulation of evidence suggests that peptidoglycan, consistent with a bacterial cell wall, is synthesised around the chloroplasts of many photosynthetic eukaryotes, from glaucophyte algae to land plants at least as evolved as pteridophyte ferns, but the biosynthetic pathway has not been demonstrated. We employed mass spectrometry and enzymology in a twofold approach to characterize the synthesis of peptidoglycan in chloroplasts of the moss Physcomitrium (Physcomitrella) patens. To drive the accumulation of peptidoglycan pathway intermediates, P.patens was cultured with the antibiotics phosphomycin, D-cycloserine and carbenicillin, which inhibit key peptidoglycan pathway proteins in bacteria. Mass spectrometry of the TCA-extracted moss metabolome revealed elevated levels of five of the predicted intermediates from UDP-GlcNAc through to the UDP-MurNAc-D,L-diaminopimelate (DAP)-pentapeptide.Most Gram negative bacteria, including cyanobacteria, incorporate meso-diaminopimelate (D,L-DAP) into the third residue of the stem peptide of peptidoglycan, as opposed to L-lysine, typical of most Gram positive bacteria. To establish the specificity of D,L-DAP incorporation into the P.patens precursors, we analysed the recombinant protein, UDP-MurNAc-tripeptide ligase (MurE), from both P.patens and the cyanobacterium Anabaena sp. strain PCC 7120. Both ligases incorporated D,L-DAP in almost complete preference to L-Lys, consistent with the mass spectrophotometric data, with catalytic efficiencies similar to previously documented Gram negative bacterial MurE ligases. We discuss how these data accord with the conservation of active site residues common to DL-DAP-incorporating bacterial MurE ligases and of the probability of a horizontal gene transfer event within the plant peptidoglycan pathway.
Autophagy and evasion of immune system by SARS-CoV-2. Structural features of the Non-structural protein 6 from Wild Type and Omicron viral strains interacting with a model lipid bilayer. †
Authors: Bignon Emmanuelle , Marazzi Marco , Grandemange Stéphanie , Monari Antonio 
Published: January 2022

The viral cycle of SARS-CoV-2 is based on a complex interplay with the cellular machinery, which is mediated by specific proteins eluding or hijacking the cellular defense mechanisms. Among the complex pathways called by the viral infection autophagy is particularly crucial and is strongly influenced by the action of the non-structural protein 6 (Nsp6) interacting with the endoplasmic reticulum membrane. Importantly, differently from other non-structural proteins Nsp6 is mutated in the recently emerged Omicron variant, suggesting a possible different role of autophagy. In this contribution we explore, for the first time, the structural property of Nsp6 thanks to long-time scale molecular dynamic simulations and machine learning analysis, identifying the interaction patterns with the lipid membrane. We also show how the mutation brought by the Omicron variant may indeed modify some of the specific interactions, and more particularly help anchoring the viral protein to the lipid bilayer interface.Electronic Supplementary Information (ESI) availableAnalysis protein of the secondary structure and of the specific lipid/amino acid interactions. RMSF per amino acid. Distribution of the distance between the center of mass of the 89 to 99 α-helix and the center of the lipid bilayer. Analysis of the behavior of the 195 to 207 α-helix. See DOI: 10.1039/x0xx00000x
Nanometer-Resolution Long-term Tracking of Single Cargos Reveals Dynein Motor Mechanisms
Authors: Peng Chunte Sam , Zhang Yunxiang , Liu Qian , Marti G. Edward , Huang Yu-Wen Alvin , Südhof Thomas C. , Cui Bianxiao , Chu Steven 
Published: January 2022

AbstractCytoplasmic dynein is essential for intracellular transport, but because of its complexity, we still do not fully understand how this 1.5 megadalton protein works. Here, we used novel optical probes that enable single-particle tracking (SPT) of individual cargos transported by dynein motors in live neurons over 900μm. Analyses using the Fluctuation Theorem (FT) showed that the number of dynein molecules switches between 1-5 motors during the transport. Clearly resolved single-molecular steps revealed that the dwell times between individual steps were accurately described by an enzymatic cycle dominated by two equal and thermally-activated rate constants. Based on these data, we propose a new molecular model whereby each step requires the hydrolysis of 2 ATPs. The model is consistent with extensive structural, single-molecule and biochemical measurements.