bluuebunny/crossref_metadata_2025_split huggingface dataset:
DMC1 attenuates RAD51-mediated recombination in Arabidopsis
Authors: Ines Olivier Da , Bazile Jeanne , Gallego Maria E. , White Charles I. 
Published: July 2022

AbstractEnsuring balanced distribution of chromosomes in gametes, meiotic recombination is essential for fertility in most sexually reproducing organisms. The repair of the programmed DNA double strand breaks that initiate meiotic recombination requires two DNA strand-exchange proteins, RAD51 and DMC1, to search for and invade an intact DNA molecule on the homologous chromosome. DMC1 is meiosis-specific, while RAD51 is essential for both mitotic and meiotic homologous recombination. DMC1 is the main catalytically active strand-exchange protein during meiosis, while this activity of RAD51 is downregulated. RAD51 is however an essential cofactor in meiosis, supporting the function of DMC1. This work presents a study of the mechanism(s) involved in this and our results point to DMC1 being, at least, a major actor in the meiotic suppression of the RAD51 strand-exchange activity in plants. Ectopic expression of DMC1 in somatic cells renders plants hypersensitive to DNA damage and specifically impairs RAD51-dependent homologous recombination. DNA damage-induced RAD51 focus formation in somatic cells is not however suppressed by ectopic expression of DMC1. Interestingly, DMC1 also forms damage-induced foci in these cells and we further show that the ability of DMC1 to prevent RAD51-mediated recombination is associated with local assembly of DMC1 at DNA breaks. In support of our hypothesis, expression of a dominant negative DMC1 protein in meiosis impairs RAD51-mediated DSB repair. We propose that DMC1 acts to prevent RAD51-mediated recombination in Arabidopsis and that this down-regulation requires local assembly of DMC1 nucleofilaments.Author SummaryEssential for fertility and responsible for a major part of genetic variation in sexually reproducing species, meiotic recombination establishes the physical linkages between homologous chromosomes which ensure their balanced segregation in the production of gametes. These linkages, or chiasmata, result from DNA strand exchange catalyzed by the RAD51 and DMC1 recombinases and their numbers and distribution are tightly regulated. Essential for maintaining chromosomal integrity in mitotic cells, the strand-exchange activity of RAD51 is downregulated in meiosis, where it plays a supporting role to the activity of DMC1. Notwithstanding considerable attention from the genetics community, precisely why this is done and the mechanisms involved are far from being fully understood. We show here in the plant Arabidopsis that DMC1 can downregulate RAD51 strand-exchange activity and propose that this may be a general mechanism for suppression of RAD51-mediated recombination in meiosis.
Modulation of fibroblasts phenotype by colorectal cancer cells-secreted factors is mostly independent of oncogenic KRAS
Authors: Dias Carvalho Patrícia , Mendonça Susana , Martins Flávia , Oliveira Maria José , Velho Sérgia 
Published: July 2022

ABSTRACTKRAS mutations have been shown to extend their oncogenic effects beyond the cancer cell, influencing the tumor microenvironment components. Herein, we studied the impact of mutant KRAS on the modulation of cancer-associated fibroblasts (CAFs) pro-tumorigenic properties. To do so, we challenged CCD-18Co normal-like colon fibroblasts with control media (DMEM alone and DMEM+rhTGFβ1 media), and conditioned media from control and KRAS silenced colorectal cancer (CRC) cells. Two mutant KRAS CRC cell lines-HCT116 and LS174T, were used. Major pro-tumorigenic fibroblasts phenotypic features, such as α-SMA expression, TGFβ1 and HGF production, extracellular matrix components and metalloproteinases expression, collagen contraction and migration capacities, were analyzed upon fibroblast challenging with cells conditioned media. Our results showed that the mutant KRAS CRC cells-secreted factors are capable of turning normal-like fibroblasts into CAF-like by modulating α-SMA expression, TGFβ1 and HGF production and migration capacity, though in a cell line-specific manner. In this scenario, oncogenic KRAS showed to play a secondary role, regulating only discrete features in each cancer cell-educated fibroblasts. For instance, in HCT116, KRAS impairs fibroblasts migration and in LS174T it promotes α-SMA expression. In summary, our work suggests that mutant KRAS does not play a major role in controlling the CRC cell secreted factors that modulate fibroblasts behavior. This KRAS-independent modulation of fibroblast pro-tumorigenic features is likely to negatively impact the response to KRAS inhibitors, thus standing as a putative mechanism of resistance to KRAS-inhibition, with possible therapeutical relevance.
Cholinergic neuronal responses to probabilistic outcome-predicting stimuli follow a weighed, unsigned prediction error model and anticipate behavioral responses
Authors: Hegedüs Panna , Sviatkó Katalin , Király Bálint , Martínez-Bellver Sergio , Hangya Balázs 
Published: July 2022

AbstractBasal forebrain cholinergic neurons (BFCNs) play an important role in associative learning, suggesting that BFCNs may participate in processing sensory stimuli that predict future outcomes. However, little is known about how BFCNs respond to outcome-predictive sensory cues and the impact of outcome probabilities on BFCN responses has not been explored. Therefore, we performed bulk calcium imaging and recorded spiking output of identified cholinergic neurons from the basal forebrain of mice performing a probabilistic Pavlovian cued outcome task that allowed us to control the predictive strength of cue stimuli. BFCNs responded strongly to sensory cues predicting likely reward, while little response was observed for cues that were rarely paired with reward. Reward delivery led to the activation of BFCNs, with less expected rewards eliciting a stronger response, while air puff punishments also evoked positive-going responses from BFCNs. We propose that BFCNs differentially weigh predictions of positive and negative reinforcement, reflecting divergent relative salience of forecasting appetitive and aversive outcomes, in accordance with a simple reinforcement learning model of a weighed, unsigned prediction error. Finally, the extent of cholinergic activation after cue stimuli predicted subsequent decision speed, suggesting that the expectation-gated cholinergic firing is instructive to reward-seeking behaviors.
Endogenous μ-opioid – neuropeptide Y Y1 receptor synergy silences chronic postoperative pain
Authors: Nelson Tyler S. , Santos Diogo F. S. , Prasoon Pranav , Gralinski Margaret , Allen Heather N. , Taylor Bradley K. 
Published: July 2022

AbstractTissue injury creates a delicate balance between latent pain sensitization (LS) and compensatory endogenous analgesia. Inhibitory G protein-coupled receptor (GPCR) interactions that oppose LS, including μ-opioid receptor (MOR) and neuropeptide Y Y1 receptor (Y1R) activity, persist in the spinal cord dorsal horn (DH) for months, even after the resolution of normal pain thresholds. Here, we demonstrate that following recovery from surgical incision, a potent endogenous analgesic synergy between MOR and Y1R activity persists within DH interneurons to reduce the intensity and duration of latent postoperative hyperalgesia and ongoing pain. Failure of such endogenous GPCR signaling to maintain LS in remission may underlie the transition from acute to chronic pain states.
Amyotrophic Lateral Sclerosis Proteomic Signature And Treatment With Mesenchymal Stem Cell-derived Extracellular Vesicles
Authors: Varderidou-Minasian Suzy , Pasteuning-Vuhman Svetlana , Timmers Annabel , Altelaar Maarten , Lorenowicz Magdalena J , Pasterkamp R Jeroen 
Published: July 2022

AbstractAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with a lifetime risk of 1:400, primarily affecting upper and lower motor neurons. Unfortunately, there are only two drugs approved to treat ALS, which increase patient survival only by a few months. This highlights the urgent need for developments of new ALS modifying therapies, which have been hampered by high failure rate of new drug candidates during clinical trials.Stem cell therapy is one of the promising approaches that is in development for treating ALS. The beneficial effects of stem cell therapy rely on their paracrine signaling, suggesting extracellular vesicles (EVs) as possible non-cell based therapy. In particular, mesenchymal stem cells (MSCs) contribute to reparative process.To better translate and assess therapeutic potential of MSC-EVs, we combined state of the art induced pluripotent stem cell (iPSC) technologies to obtain patient-derived spinal low motor neurons and a comprehensive proteomic analysis to decipher the proteomic signature.To investigate the key molecular perturbations underlying disease pathology of ALS, a comprehensive proteomic analysis was performed showing mutation-specific and common ALS-specific changes. Mutation-specific effects in ALS motor neurons with hexanucleotide expansion in C9ORF72 exhibit dysregulation inproteins targeting to ERandcytoplasmic translation. In FUS-ALS motor neurons,iron ion homeostasisandcellular response to stressprocesses are affected. In ALS-TDP-43 motor neuronsprotein transportandlocalizationare affected. Common ALS mechanisms such asmRNA splicing, proteasomal ubiquitinandmitochondrial associated processesare dysregulated.Furthermore, we demonstrated these underlying dysregulated mechanisms after treatment with MSC-EVs. More importantly, MSC-EV treatment can restore the protein expression levels impaired in ALS suggesting for future therapeutic potential for ALS.
Optimization of transcription factor genetic circuits
Authors: Frank Steven A. 
Published: July 2022

SummaryTranscription factors (TFs) affect the expression of mRNAs. In essence, the TFs form a large computation network that controls many aspects of cellular function. This article introduces a computational method to optimize TF networks. The method extends recent advances in artificial neural network optimization. In a simple example, computational optimization discovers a four-dimensional TF network that maintains a circadian rhythm over many days, successfully buffering strong stochastic perturbations in molecular dynamics and entraining to an external day-night signal that randomly turns on and off at intervals of several days. This work highlights the similar challenges in understanding how computational TF and neural networks gain information and improve performance, and in how large TF networks may acquire a tendency for genetic variation and disease.
Critical assessment of the impact of vaccines and waning/boosting of immunity on the burden of COVID-19 in the U.S
Authors: Ngonghala Calistus N. , Asare-Baah Michael 
Published: July 2022

AbstractThe COVID-19 pandemic continues to have a devastating impact on health systems and economies across the globe. Implementing public health measures in tandem with effective vaccination strategies have been instrumental in curtailing the burden of the pandemic. With the three vaccines authorized for use in the U.S. having varying efficacies and waning effects against major COVID-19 strains, understanding the impact of these vaccines on COVID-19 incidence and fatalities is critical. Here, we formulate and use mathematical models to assess the impact of vaccine type, vaccination and booster uptake, and waning of natural and vaccine-induced immunity on the incidence and fatalities of COVID-19 and to predict future trends of the disease in the U.S. when existing control measures are reinforced or relaxed. Results of the study show a 5, 1.8, and 2 times reduction in the reproduction number during the period in which vaccination, first booster, and second booster uptake started, respectively, compared to the previous period. Due to waning of vaccine-induced immunity, vaccinating up to 96% of the U.S. population might be required to attain herd immunity, if booster uptake is low. Additionally, vaccinating and boosting more people from the onset of vaccination and booster uptake, especially with mRNA vaccines (which confer superior protection than the Johnson & Johnson vaccine) would have led to a significant reduction in COVID-19 cases and deaths in the U.S. Furthermore, adopting natural immunity-boosting measures is important in fighting COVID-19 and transmission rate reduction measures such as mask-use are critical in combating COVID-19. The emergence of a more transmissible COVID-19 variant, or early relaxation of existing control measures can lead to a more devastating wave, especially if transmission rate reduction measures and vaccination are relaxed simultaneously, while chances of containing the pandemic are enhanced if both vaccination and transmission rate reduction measures are reinforced simultaneously. We conclude that maintaining or improving existing control measures and boosting with mRNA vaccines are critical in curtailing the burden of the pandemic in the U.S.
Multimodal surveillance of SARS-CoV-2 at a university enables development of a robust outbreak response framework
Authors: Petros Brittany A. , Paull Jillian S. , Tomkins-Tinch Christopher H. , Loftness Bryn C. , DeRuff Katherine C. , Nair Parvathy , Gionet Gabrielle L. , Benz Aaron , Brock-Fisher Taylor , Hughes Michael , Yurkovetskiy Leonid , Mulaudzi Shandukani , Leenerman Emma , Nyalile Thomas , Moreno Gage K. , Specht Ivan , Sani Kian , Adams Gordon , Babet Simone V. , Baron Emily , Blank Jesse T. , Boehm Chloe , Botti-Lodovico Yolanda , Brown Jeremy , Buisker Adam R. , Burcham Timothy , Chylek Lily , Cronan Paul , Desreumaux Valentine , Doss Megan , Flynn Belinda , Gladden-Young Adrianne , Glennon Olivia , Harmon Hunter D. , Hook Thomas V. , Kary Anton , King Clay , Loreth Christine , Marrs Libby , McQuade Kyle J. , Milton Thorsen T. , Mulford Jada M. , Oba Kyle , Pearlman Leah , Schifferli Mark , Schmidt Madelyn J. , Tandus Grace M. , Tyler Andy , Vodzak Megan E. , Bevill Kelly Krohn , Colubri Andres , MacInnis Bronwyn L. , Ozsoy A. Zeynep , Parrie Eric , Sholtes Kari , Siddle Katherine J. , Fry Ben , Luban Jeremy , Park Daniel J. , Marshall John , Bronson Amy , Schaffner Stephen F. , Sabeti Pardis C. 
Published: July 2022

AbstractUniversities are particularly vulnerable to infectious disease outbreaks and are also ideal environments to study transmission dynamics and evaluate mitigation and surveillance measures when outbreaks occur. Here, we introduce a SARS-CoV-2 surveillance and response framework based on high-resolution, multimodal data collected during the 2020-2021 academic year at Colorado Mesa University. We analyzed epidemiological and sociobehavioral data (demographics, contact tracing, and wifi-based co-location data) alongside pathogen surveillance data (wastewater, random, and reflexive diagnostic testing; and viral genomic sequencing of wastewater and clinical specimens) to characterize outbreak dynamics and inform policy decisions. We quantified group attributes that increased disease risk, and highlighted parallels between traditional and wifi-based contact tracing. We additionally used clinical and environmental viral sequencing to identify cryptic transmission, cluster overdispersion, and novel lineages or mutations. Ultimately, we used distinct data types to identify information that may help shape institutional policy and to develop a model of pathogen surveillance suitable for the future of outbreak preparedness.
Prevalence and factors associated with antigen test positivity following SARS-CoV-2 infection among healthcare workers in Los Angeles
Authors: Adamson Paul C. , Currier Judith S. , Uslan Daniel Z. , Garner Omai B. 
Published: July 2022

AbstractSurges of SARS-CoV-2 infections among healthcare workers (HCWs) have led to critical staffing shortages. From January 4 to February 4, 2022, we implemented a return-to-work antigen testing program for HCWs and 870 HCWs participated. Antigen test positivity was 60.5% for those ≤5 days from symptom onset or positive PCR and 47.4% were positive at day 7. Antigen positivity was associated with receiving a booster vaccination and being ≤6 days from symptom onset or PCR test, but not age or a symptomatic infection. Rapid antigen testing can be a useful tool to guide return-to-work and isolation precautions for HCWs following infection.
Weevil carbohydrate intake triggers endosymbiont proliferation: a trade-off between host benefit and endosymbiont burden
Authors: Dell’Aglio Elisa , Lacotte Virginie , Peignier Sergio , Rahioui Isabelle , Benzaoui Fadéla , Vallier Agnès , Silva Pedro Da , Desouhant Emmanuel , Heddi Abdelaziz , Rebollo Rita 
Published: July 2022

AbstractNutritional symbioses between insects and intracellular bacteria (endosymbionts) are a major force of adaptation, allowing animals to colonize nutrient-poor ecological niches. Many beetles feeding on tyrosine-poor substrates rely on a surplus of aromatic amino acids produced by bacterial endosymbionts. This surplus of aromatic amino acids is crucial for the biosynthesis of a thick exoskeleton, the cuticle, which is made of a matrix of chitin with proteins and pigments built from tyrosine-derived molecules, providing an important defensive barrier against biotic and abiotic stress. Other endosymbiont-related advantages for beetles include faster development and improved fecundity. The association betweenSitophilus oryzaeandSodalis pierantoniusendosymbiont represents a unique case study among beetles: endosymbionts undergo an exponential proliferation in young adults concomitant with the cuticle tanning, then they are fully eliminated. While endosymbiont clearance, as well as total endosymbiont titer, are host-controlled processes, the mechanism triggering endosymbiont exponential proliferation remains poorly understood. Here, we show that endosymbiont exponential proliferation relies on host carbohydrate intake, unlike the total endosymbiont titer or the endosymbiont clearance, which are under host genetic control. Remarkably, insect fecundity was preserved, and the cuticle tanning was achieved, even when endosymbiont exponential proliferation was experimentally blocked, except in the context of a severely unbalanced diet. Moreover, a high endosymbiont titer coupled with nutrient shortage, dramatically impacted host survival, revealing possible environment-dependent disadvantages for the host, likely due to the high energy cost of exponentially proliferating endosymbionts.Abstract ImportanceBeetles thriving on tyrosine-poor diet sources often develop mutualistic associations with endosymbionts able to synthesize aromatic amino acids. This surplus of aromatic amino acids is used to reinforce the insect’s protective cuticle. An exceptional feature of theSitophilus oryzae/Sodalis pierantoniusinteraction is the exponential increase in endosymbiotic titer observed in young adult insects, in concomitance with cuticle biosynthesis. Here, we show that host carbohydrate intake triggers endosymbiont exponential proliferation, even in conditions that lead to the detriment of the host survival. In addition, when hosts thrive on a balanced diet, endosymbiont proliferation is dispensable for several host fitness traits. The endosymbiont exponential proliferation is therefore dependent on the nutritional status of the host, and its consequences on host cuticle biosynthesis and survival depend on food quality and availability.
A Novel Regioselective Approach to Cyclize Phage-Displayed Peptides in Combination with Epitope-Directed Selection to Identify a Potent Neutralizing Macrocyclic Peptide for SARS-CoV-2
Authors: Hampton J. Trae , Lalonde Tyler J. , Tharp Jeffery M. , Kurra Yadagiri , Alugubelli Yugendar R. , Roundy Christopher M. , Hamer Gabriel L. , Xu Shiqing , Liu Wenshe Ray 
Published: July 2022

ABSTRACTUsing the regioselective cyanobenzothiazole condensation reaction with the N-terminal cysteine and the chloroacetamide reaction with an internal cysteine, a phage-displayed macrocyclic 12-mer peptide library was constructed and subsequently validated. Using this library in combination with iterative selections against two epitopes from the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein, macrocyclic peptides that strongly inhibit the interaction between the Spike RBD and ACE2, the human host receptor of SARS-CoV-2, were identified. The two epitopes were used instead of the Spike RBD to avoid selection of nonproductive macrocyclic peptides that bind RBD but do not directly inhibit its interactions with ACE2. Antiviral tests against SARS-CoV-2 showed that one macrocyclic peptide is highly potent against viral reproduction in Vero E6 cells with an EC50 value of 3.1 μM. The AlphaLISA-detected IC50 value for this macrocyclic peptide was 0.3 μM. The current study demonstrates that two kinetically-controlled reactions toward N-terminal and internal cysteines, respectively, are highly effective in the construction of phage-displayed macrocyclic peptides, and the selection based on the SARS-CoV-2 Spike epitopes is a promising methodology in the identification of peptidyl antivirals.
A membrane sensing mechanism couples local lipid metabolism to protein degradation at the inner nuclear membrane
Authors: Lee Shoken , Merta Holly , Rodríguez Jake W. Carrasquillo , Bahmanyar Shirin 
Published: July 2022

SummaryLipid composition is a determinant of organelle identity; however, whether the inner nuclear membrane (INM) domain of the endoplasmic reticulum (ER) harbors a unique lipid chemistry that contributes to its identity is not known. Here, we demonstrate that a unique INM lipid environment enriched in diacylglycerol protects the nucleo-cytoskeletal linker Sun2 from local degradation by the ubiquitin-proteasome system. A membrane binding amphipathic helix in the nucleoplasmic domain of Sun2 senses INM lipids and is essential to its protein stability. We show that the protein phosphatase CTDNEP1 localizes to the INM to maintain a distinct INM lipid environment necessary for Sun2 accumulation through regulation of the phosphatidic acid phosphatase lipin 1. Thus, the INM lipid environment sculpts the INM proteome via direct lipid-protein interactions that regulate protein stability, which has broad implications for mechanisms of diseases associated with the nuclear envelope.
Neural coding of temperature with a DNA-based spiking chemical neuron
Authors: Lobato-Dauzier N. , Baccouche A. , Gines G. , Lévi T. , Rondelez Y. , Fujii T. , Kim S. H. , Aubert-Kato N. , Genot A.J. 
Published: July 2022

AbstractComplex organisms perceive their surroundings with sensory neurons which encode physical stimuli into spikes of electrical activities. The past decade has seen reports of DNA-based chemical neurons that mimic artificial neural networks with chemical reactions. Yet, they lack the physical sensing and temporal coding of sensory biological neurons. Here we report a thermosensory chemical neuron based on DNA and enzymes that spikes with chemical activity when exposed to cold. Surprisingly, this chemical neuron shares deep mathematical similarities with a toy model of a cold nociceptive neuron: they follow a similar bifurcation route between rest and oscillations and avoid artefacts associated with canonical bifurcations (such as irreversibility, damping or untimely spiking). We experimentally demonstrate this robustness by encoding - digitally and analogically - thermal messages into chemical waveforms. This chemical neuron could pave the way for implementing in DNA the third generation of neural network models (spiking networks), and opens the door for associative learning.One-Sentence SummaryA DNA-based chemical network mathematically mimics the sensing of cold by a biological neuron.