bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined patterns of activity of major neuronal classes underpin a global change in brain state during spontaneous and forced walk inDrosophila
Authors: Aimon Sophie , Cheng Karen Y. , Gjorgjieva Julijana , Grunwald Kadow Ilona C. 
Published: January 2022

AbstractMovement-correlated brain activity has been found across species and brain regions. Here, we used fast whole-brain lightfield imaging in adultDrosophilato investigate the relationship between walk and neuronal activity. We observed brainwide activity that tightly correlated with spontaneous bouts of walk. While imaging specific sets of excitatory, inhibitory, and neuromodulatory neurons highlighted their joint contribution, spatial heterogeneity in forward walk- and turning-induced activity allowed parsing unique responses from subregions and sometimes individual neurons. For example, previously uncharacterized serotonergic neurons were inhibited during walk. While activity onset in some areas preceded walk onset exclusively in spontaneously walking animals, spontaneous and forced walk elicited highly similar activity in most brain regions. These data suggest a major contribution of walk and walk-related sensory or proprioceptive information to brain state. We conclude that walk-related signals induce global but heterogeneous patterns of activity, allowing for local and brain-wide integration of behavioral state into other processes in the brain.
Membrane Stretch Gates NMDA Receptors
Authors: Belin Sophie , Maki Bruce A. , Catlin James , Rein Benjamin A. , Popescu Gabriela K. 
Published: January 2022

AbstractN-Methyl-D-aspartic (NMDA) receptors are excitatory glutamate-gated ion channels. Their activation is essential for the normal development, maintenance, and plasticity of excitatory synapses in the central nervous system. They function as glutamate-gated Ca2+-permeable channels, require glycine as co-agonist, and can be modulated by myriad of diffusible ligands and cellular cues, including mechanical stimuli. Previously, we found that in cultured astrocytes, shear stress initiates NMDA receptor-mediated Ca2+ entry in the absence of added agonists, suggesting that in addition to being mechanosensitive, NMDA receptors may be mechanically activated. Here, we used controlled expression of recombinant receptors and non-invasive on-cell single-channel current recordings to show that gentle membrane stretch can substitute for the neurotransmitter glutamate in gating NMDA receptor currents. Notably, stretch-activated currents preserved the hallmark features of the glutamate-gated currents, including glycine-requirement, large unitary conductance, high Ca2+ permeability, and voltage-dependent Mg2+ blockade. Further, we found that the stretch-gated current required the receptor’s intracellular domain, which may suggest a force-from-filament sensing mechanism. These results are consistent with the hypothesis that mechanical forces can gate NMDA receptor currents even in the absence of synaptic glutamate release, which has important implications for understanding mechanotransduction and the effect of mechanical forces on cells of the central nervous system.HighlightsMembrane stretch gates NMDA receptor currents in the absence of the neurotransmitter glutamate.Stretch-gated currents maintain the characteristic features of glutamate-gated currents, including glycine requirement, Ca2+ permeability, and voltage-dependent Mg2+ block.Gating of NMDA receptor by membrane stretch requires the receptor’s intracellular domain.Mild stretch of neuronal membranes gate native NMDA receptor currents.SummaryMembrane stretch gates NMDA receptor currents in the absence of neurotransmitter. Stretch-gated currents have the biophysical hallmarks of the glutamate-gated currents including requirement for glycine, large Na+ conductance, high Ca2+ permeability, and voltage-dependent Mg2+ block.
ScrepYard: an online resource for disulfide-stabilised tandem repeat peptides
Authors: Liu Junyu , Maxwell Michael , Cuddihy Thom , Crawford Theo , Bassetti Madeline , Hyde Cameron , Undheim Eivind A. B. , Mobli Mehdi 
Published: January 2022

AbstractReceptor avidity through multivalency is a highly sought-after property of ligands. While readily available in nature in the form of bivalent antibodies, this property remains challenging to engineer in synthetic molecules. The discovery of several bivalent venom peptides containing two homologous and independently folded domains (in a tandem repeat arrangement) has provided a unique opportunity to better understand the underpinning design of multivalency in multimeric biomolecules, as well as how naturally occurring multivalent ligands can be identified. In previous work we classified these molecules as a larger class termed secreted cysteine-rich repeat-proteins (SCREPs). Here, we present an online resource; ScrepYard, designed to assist researchers in identification of SCREP sequences of interest and to aid in characterizing this emerging class of biomolecules. Analysis of sequences within the ScrepYard reveals that two-domain tandem repeats constitute the most abundant SCREP domain architecture, while the interdomain “linker” regions connecting the ordered domains are found to be abundant in amino acids with short or polar sidechains and contain an unusually high abundance of proline residues. Finally, we demonstrate the utility of ScrepYard as a virtual screening tool for discovery of putatively multivalent peptides, by using it as a resource to identify a previously uncharacterised serine protease inhibitor and confirm its predicated activity using an enzyme assay.
Assessing the response to genomic selection by simulation
Authors: Buntaran Harimurti , Bernal-Vasquez Angela Maria , Gordillo Andres , Wimmer Valentin , Sahr Morten , Piepho Hans-Peter 
Published: January 2022

ABSTRACTThe goal of any plant breeding program is to maximize genetic gain for traits of interest. In classical quantitative genetics, the genetic gain can be obtained from what is known as “Breeder’s equation”. In the past, only phenotypic data was used to compute the genetic gain. The advent of genomic prediction has opened the door to the utilization of dense markers for estimating genomic breeding values or GBV. The salient feature of genomic prediction is the possibility to carry out genomic selection with the assistance of the kinship matrix, hence, improving the prediction accuracy and accelerating the breeding cycle. However, estimates of GBV as such do not provide the full information on the number of entries to be selected as in the classical response to selection. In this paper, we use simulation, based on a fitted mixed model for genomic prediction in a multi-environmental framework, to answer two typical questions of a plant breeder: (1) How many entries need to be selected to have a defined probability of selecting the truly best entry from the population; (2) What is the probability of obtaining the truly best entries when some top-ranked entries are selected.
Long-Term Persistence of IgG Antibodies in recovered COVID-19 individuals at 18 months and the impact of two-dose BNT162b2 (Pfizer-BioNTech) mRNA vaccination on the antibody response
Authors: Puya-Dehgani-Mobaraki  , Wang Chao , Floridi Alessandro , Floridi Emanuela , Zaidi Asiya K 
Published: January 2022

AbstractThis era of emerging variants needs a thorough evaluation of data on the long-term efficacy of immune responses in vaccinated as well as recovered individuals, to understand the overall evolution of the pandemic. In this study, we aimed to assess the dynamics of IgG titers over 18 months in n=36 patients from the Umbria region in Italy, who had a documented history of COVID-19 infection in March 2020, and then compared the impact of two-dose BNT162b2 (Pfizer-BioNTech) vaccination on the antibody titers of these patients with the ones who did not receive any dose of vaccine. This is the longest observation (March 2020-September 2021) for the presence of antibodies against SARS-CoV-2 in recovered individuals along with the impact of 2 dose-BNT162b2 vaccination on the titers. Fixed-effect regression models were used for statistical analysis which could be also used to predict future titer trends. At 18 months, 97% participants tested positive for anti-NCP hinting towards the persistence of infection-induced immunity even for the vaccinated individuals. Our study findings demonstrate that while double dose vaccination boosted the IgG titers in recovered individuals 161 times, this “boost” was relatively short-lived. The unvaccinated recovered individuals, in contrast, continued to show a steady decline but detectable antibody levels. Further studies are required to re-evaluate the timing and dose regimen of vaccines for an adequate immune response in recovered individuals.
An excitatory-inhibitory fronto-cerebellar loop resolves the Stroop effect
Authors: Okayasu Moe , Inukai Tensei , Tanaka Daiki , Tsumura Kaho , Hosono Maho , Shintaki Reiko , Takeda Masaki , Nakahara Kiyoshi , Jimura Koji 
Published: January 2022

AbstractThe Stroop effect is a well-known behavioral phenomenon in humans that refers to robust interference between language and color information. Although this effect has long been studied, it remains unclear when the interference occurs and how it is resolved in the brain. By manipulating the verbality of stimulus perception and response generation, here we show that the Stroop effect occurs during perception of color-word stimuli and is resolved by a cross-hemispheric, excitatory-inhibitory functional loop involving the lateral prefrontal cortex and cerebellum. Humans performed a Stroop task and a control task in which the stimulus did not contain verbal information, and made a response either vocally or manually. The resolution of Stroop interference involved the lateral prefrontal cortex in the left hemisphere and the cerebellum in the right hemisphere, independently of whether the response was made vocally or manually. In contrast, such cross-hemispheric lateralization was absent during the non-verbal control task. Moreover, the prefrontal cortex amplified cerebellar activity, whereas the cerebellum suppressed prefrontal activity, and these effects were enhanced during interference resolution. These results suggest that this fronto-cerebellar loop involving language and cognitive systems regulates goal-relevant information to resolve the interference occurring during simultaneous perception of a word and color.
Decoding the activated stem cell phenotype of the vividly maturing neonatal pituitary
Authors: Laporte Emma , Hermans Florian , Vriendt Silke De , Vennekens Annelies , Lambrechts Diether , Nys Charlotte , Cox Benoit , Vankelecom Hugo 
Published: January 2022

AbstractThe pituitary represents the endocrine master regulator. In mouse, the gland undergoes vivid maturation immediately after birth. Here, we in detail portrayed the stem cell compartment of neonatal pituitary. Single-cell RNA-sequencing pictured an active gland, revealing proliferative stem as well as hormonal (progenitor) cell populations. The stem cell pool displayed a hybrid epithelial/mesenchymal phenotype, characteristic of development-involved tissue stem cells. Organoid culturing recapitulated the stem cells’ phenotype, interestingly also reproducing their paracrine activity. The pituitary stem cell-activating interleukin-6 (IL-6) advanced organoid growth, although the neonatal stem cell compartment was not visibly affected in IL-6-/- mice, likely due to cytokine family redundancy. Further transcriptomic analysis exposed a pronounced WNT pathway in the neonatal gland, shown to be involved in stem cell activation and to overlap with the (fetal) human pituitary transcriptome. Following local damage, the neonatal gland efficiently regenerates, despite absence of additional stem cell proliferation, or upregulated IL-6 or WNT expression, all in line with the already high stem cell activation status, thereby exposing striking differences with adult pituitary. Together, our study decodes the stem cell compartment of neonatal pituitary, exposing an activated state in the vividly maturing gland. Understanding stem cell activation is key to potential pituitary regenerative prospects.
Genetic control of KRAB-ZFP genes explains distal CpG-site methylation which associates with human disease phenotypes
Authors: Bretherick Andrew D. , Zeng Yanni , Walker Rosie M. , Hayward Caroline , Porteous David J. , Evans Kathryn L. , McIntosh Andrew M. , Kenneth Baillie J. , Haley Chris , Ponting Chris P. 
Published: January 2022

AbstractKrüppel-associated box zinc finger proteins (KRAB-ZFPs) are the largest gene family of transcriptional regulators in higher vertebrates. We have developed a method for inferring these factors’ DNA binding-sites in vivo. We achieved this by combining the genome-wide association of methylation at 573,027 CpG-sites (meQTL) in blood and KRAB-ZFP RNA expression changes (eQTL). This method’s efficacy is clearly demonstrated by showing that the CpG-sites whose methylation is affected by KRAB-ZFP expression changes occur preferentially near KRAB-ZFP binding-sites in the HEK293T cell line. We found such an enrichment to be significant for 31% of factors tested. In addition, we found that binding-sites of many KRAB-ZFPs are significantly enriched (or sometimes depleted) in disease-associated CpG-sites. In total, 9% (11 of 125) of the traits tested, and 14% (32 of 222) of the factors (KRAB-ZFPs and TIF1-beta) tested, were enriched or depleted in one or more trait-factor pairing. Rheumatoid arthritis and human immunodeficiency virus (HIV) infection were associated with the largest number of KRAB-ZFP enrichments. There have been variable reports on the effects on HIV infection dynamics of transcription intermediary factor 1-beta (TIF1-beta, also known as KAP1 or TRIM28), a nuclear corepressor for KRAB-ZFPs. We provide evidence that KRAB-ZFP-independent effects of TIF1-beta are responsible for the decreased methylation of CpG-sites within its binding-sites that is observed in HIV infection. In conclusion, KRAB-ZFPs often affect CpG-site methylation within the proximity of their binding-sites, and CpG-sites within the binding-sites of KRAB-ZFPs are enriched for association with many traits, including rheumatoid arthritis and HIV infection.
A potent alpaca-derived nanobody that neutralizes SARS-CoV-2 variants
Authors: Weinstein Jules B. , Bates Timothy A. , Leier Hans C. , McBride Savannah K. , Barklis Eric , Tafesse Fikadu G. 
Published: January 2022

AbstractThe spike glycoprotein of SARS-CoV-2 engages with human angiotensin-converting enzyme 2 (ACE2) to facilitate infection. Here, we describe an alpaca-derived heavy chain antibody fragment (VHH), saRBD-1, that disrupts this interaction by competitively binding to the spike protein receptor-binding domain. We further generated an engineered bivalent nanobody construct engineered by a flexible linker, and a dimeric Fc conjugated nanobody construct. Both multivalent nanobodies blocked infection at picomolar concentrations and demonstrated no loss of potency against emerging variants of concern including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Epsilon (B.1.427/429), and Delta (B.1.617.2). saRBD-1 tolerates elevated temperature, freeze-drying, and nebulization, making it an excellent candidate for further development into a therapeutic approach for COVID-19.
Enterococcus faecalis antagonizes Pseudomonas aeruginosa growth in polymicrobial biofilms
Authors: Zhu Tan Casandra Ai , Lam Ling Ning , Biukovic Goran , Soh Eliza Ye-Chen , Toh Xiao Wei , Lemos José A. , Kline Kimberly A. 
Published: January 2022

ABSTRACTEnterococcus faecalis is often co-isolated with Pseudomonas aeruginosa in polymicrobial biofilm-associated infections of wounds and the urinary tract. As a defense strategy, the host innately restricts iron availability at infection sites. Despite their co-prevalence, the polymicrobial interactions of these two pathogens in iron- restricted conditions, such as those found in the host, remains unexplored. Here we show that E. faecalis inhibits P. aeruginosa growth within biofilms when iron is restricted. E. faecalis lactate dehydrogenase (ldh1) gives rise to L-lactate production during fermentative growth. We find that E. faecalis ldh1 mutant fails to inhibit P. aeruginosa growth. Additionally, we demonstrate that ldh1 expression is induced in iron-restricted conditions, resulting in increased lactic acid exported and consequently, a reduction in pH. Together, our results suggest that E. faecalis synergistically inhibit P. aeruginosa growth by decreasing environmental pH and L-lactate-mediated iron chelation. Overall, this study highlights that the microenvironment in which the infection occurs is important for understanding its pathophysiology.IMPORTANCEMany infections are polymicrobial and biofilm-associated in nature. Iron is essential for many metabolic processes and plays an important role in controlling infections, where the host restricts iron as a defense mechanism against invading pathogens. However, polymicrobial interactions between pathogens are underexplored in iron- restricted conditions. Here, we explore the polymicrobial interactions between commonly co-isolated E. faecalis and P. aeruginosa within biofilms. We find that E. faecalis modulates the microenvironment by exporting lactic acid which further chelates already limited iron, and also lowers the environmental pH to antagonize P. aeruginosa growth in iron-restricted conditions. Our findings provide insights into polymicrobial interactions between pathogens in an infection-relevant condition and how manipulating the microenvironment can be taken advantage of to better control infections.
SARS-CoV-2 Delta variant induces enhanced pathology and inflammatory responses in K18-hACE2 mice
Authors: Lee Katherine S. , Wong Ting Y. , Russ Brynnan P. , Horspool Alexander M. , Miller Olivia A. , Rader Nathaniel A. , Givi Jerome P. , Winters Michael T. , Wong Zeriel YA. , Cyphert Holly A. , Denvir James , Stoilov Peter , Barbier Mariette , Roan Nadia R. , Amin Md. Shahrier , Martinez Ivan , Bevere Justin R. , Damron F. Heath 
Published: January 2022

AbstractThe COVID-19 pandemic has been fueled by novel variants of concern (VOC) that have increased transmissibility, receptor binding affinity, and other properties that enhance disease. The goal of this study is to characterize unique pathogenesis of the Delta VOC strain in the K18-hACE2-mouse challenge model. Challenge studies suggested that the lethal dose of Delta was higher than Alpha or Beta strains. To characterize the differences in the Delta strain’s pathogenesis, a time-course experiment was performed to evaluate the overall host response to Alpha or Delta variant challenge. qRT-PCR analysis of Alpha- or Delta- challenged mice revealed no significant difference between viral RNA burden in the lung, nasal wash or brain. However, histopathological analysis revealed high lung tissue inflammation and cell infiltration following Delta- but not Alpha-challenge at day 6. Additionally, pro-inflammatory cytokines were highest at day 6 in Delta-challenged mice suggesting enhanced pneumonia. Total RNA-sequencing analysis of lungs comparing infected to uninfected mice revealed that Alpha-challenged mice have more total genes differentially activated, conversely, Delta-challenged mice have a higher magnitude of differential gene expression. Delta-challenged mice have increased interferon-dependent gene expression and IFN-γ production compared to Alpha. Analysis of TCR clonotypes suggested that Delta challenged mice have increased T-cell infiltration compared to Alpha challenged. Our data suggest that Delta has evolved to engage interferon responses in a manner that may enhance pathogenesis. Thein vivoandin silicoobservations of this study underscore the need to conduct experiments with VOC strains to best model COVID-19 when evaluating therapeutics and vaccines.ImportanceThe Delta variant of SARS-CoV-2 is known to be more transmissible and cause severe disease in human hosts due to mutations in its genome that are divergent from previous variants of concern (VOC). Our study evaluates the pathogenesis of Delta in the K18-hACE2 mouse model compared to the Alpha VOC. We observed that relative to Alpha, Delta challenge results in enhanced inflammation and tissue damage with stronger antiviral responses. These observations provide insight into Delta’s unique pathogenesis.
Loss of Y in leukocytes as a risk factor for critical COVID-19 in men
Authors: Bruhn-Olszewska Bożena , Davies Hanna , Sarkisyan Daniil , Juhas Ulana , Rychlicka-Buniowska Edyta , Wójcik Magdalena , Horbacz Monika , Jąkalski Marcin , Olszewski Paweł , Westholm Jakub O. , Smialowska Agata , Wierzba Karol , Naluai Åsa Torinsson , Jern Niklas , Andersson Lars-Magnus , Järhult Josef D. , Filipowicz Natalia , Janson Eva Tiensuu , Rubertsson Sten , Lipcsey Miklós , Gisslén Magnus , Hultström Michael , Frithiof Robert , Dumanski Jan P. 
Published: January 2022

AbstractCOVID-19 shows an unexplained, strong male bias for severity and mortality. Loss of Y (LOY) in myeloid cells is a risk factor candidate in COVID-19 because of associations with many age-related diseases and its effect on transcription of immune genes. We report the highest levels of LOY in cells that are crucial for the development of severe COVID-19 phenotype, such as low-density neutrophils, granulocytes, and monocytes reaching 46%, 32%, and 29%, respectively, from men with critical COVID-19 (n=139). LOY in sorted subpopulations of leukocytes correlated with increased thrombocyte count, thromboembolic events, invasive mechanical ventilation and a history of vessel disease. In recovered patients, LOY decreased in whole blood and peripheral blood mononuclear cells. Moreover, sc-RNA-seq analysis of CD14+ monocytes from 30 COVID-19 males and 34 controls revealed pervasive transcriptional downregulation in LOY-cells, notably affecting HLA class I and II genes important for antigen presentation. The data support a link between LOY and emergency myelopoiesis as well as the role of LOY in modulation of COVID-19 severity. Our results might also be relevant for other viral infections showing similar male bias.
Serum extracellular vesicles trace COVID-19 progression and immune responses
Authors: Wai Yim Kevin Ho , Borgoni Simone , Chahwan Richard 
Published: January 2022

ABSTRACTCoronavirus disease 2019 (COVID-19) has transformed very quickly into a world pandemic with severe and unexpected consequences on human health. Concerted efforts to generate better diagnostic and prognostic tools have been ongoing. Research, thus far, has primarily focused on the virus itself or the direct immune response to it. Here, we propose extracellular vesicles (EVs) from serum liquid biopsies as a new and unique modality to unify diagnostic and prognostic tools for COVID-19 analyses. EVs are a novel player in intercellular signaling particularly influencing immune responses. We herein show that innate and adaptive immune EVs profiling, together with SARS-CoV-2 Spike S1+EVs provide a novel signature for COVID-19 infection. It also provides a unique ability to trace the co-existence of viral and host cell signatures to monitor affected tissues and severity of the disease progression. And provide a phenotypic insight into COVID-associated EVs.