bluuebunny/crossref_metadata_2025 huggingface dataset:
LDAK-GBAT: fast and powerful gene-based association testing using summary statistics
Authors: Berrandou Takiy-Eddine , Balding David , Speed Doug
Published: July 2022

We present LDAK-GBAT, a novel tool for gene-based association testing using summary statistics from genome-wide association studies. We first evaluate LDAK-GBAT using ten phenotypes from the UK Biobank. We show that LDAK-GBAT is computationally efficient, taking approximately 30 minutes to analyze imputed data (2.9M common, genic SNPs), and requiring less than 10Gb memory. In total, LDAK-GBAT finds 680 genome-wide significant genes (P≤2.8×10−6), which is at least 25% more than each of five existing tools (MAGMA, GCTA-fastBAT, sumFREGAT-SKAT-O, sumFREGAT-PCA and sumFREGAT-ACAT), and 48% more than found by single-SNP analysis. We then analyze 99 additional phenotypes from the UK Biobank, the Million Veterans Project and the Psychiatric Genetics Consortium. In total, LDAK-GBAT finds 7957 significant genes, which is at least 24% more than the best existing tools, and 42% more than found by single-SNP analysis.
CD19+ B cell numbers predict the increase of anti-SARS CoV2 antibodies in fingolimod-treated and COVID-19-vaccinated patients with multiple sclerosis
Authors: Schiavetti I. , Barcellini L. , Lapucci C. , Tazza F. , Cellerino M. , Capello E. , Franciotta D. , Inglese M. , Sormani M. P. , Uccelli A. , Laroni A.
Published: July 2022

Treatment with fingolimod for multiple sclerosis (MS) reduces the efficacy of COVID-19 vaccination. We evaluated by a multivariate linear regression model whether main lymphocyte subsets and demographic feature correlated to the subsequent increase in anti-SARS-CoV2 antibodies following the third dose of COVID-19 vaccination in fingolimod-treated MS patients. We found that number and proportion of peripheral blood CD19+ B lymphocytes before the third dose of vaccination in MS patients treated with fingolimod, predict the subsequent increase of anti-SARS-CoV2 antibodies (respectively p = 0.013; p = 0.015). This work suggests that evaluating the numbers of CD19+ B cells may be important to identify patients at risk of not producing SARS-CoV-2 antibodies, with possible reduced protection from COVID-19.
Inferring the differences in incubation-period and generation-interval distributions of the Delta and Omicron variants of SARS-CoV-2
Authors: Park Sang Woo , Sun Kaiyuan , Abbott Sam , Sender Ron , Bar-on Yinon , Weitz Joshua S. , Funk Sebastian , Grenfell Bryan T. , Backer Jantien A , Wallinga Jacco , Viboud Cecile , Dushoff Jonathan
Published: July 2022

Estimating the differences in the incubation-period, serial-interval, and generation-interval distributions of SARS-CoV-2 variants is critical to understanding their transmission and control. However, the impact of epidemic dynamics is often neglected in estimating the timing of infection and transmission—for example, when an epidemic is growing exponentially, a cohort of infected individuals who developed symptoms at the same time are more likely to have been infected recently. Here, we re-analyze incubation-period and serial-interval data describing transmissions of the Delta and Omicron variants from the Netherlands at the end of December 2021. Previous analysis of the same data set reported shorter mean observed incubation period (3.2 days vs 4.4 days) and serial interval (3.5 days vs 4.1 days) for the Omicron variant, but the number of infections caused by the Delta variant decreased during this period as the number of Omicron infections increased. When we account for growth-rate differences of two variants during the study period, we estimate similar mean incubation periods (3.8–4.5 days) for both variants but a shorter mean generation interval for the Omicron variant (3.0 days; 95% CI: 2.7–3.2 days) than for the Delta variant (3.8 days; 95% CI: 3.7–4.0 days). We further note that the differences in estimated generation intervals may be driven by the “network effect”—higher effective transmissibility of the Omicron variant can cause faster susceptible depletion among contact networks, which in turn prevents late transmission (therefore shortening realized generation intervals). Using up-to-date generation-interval distributions is critical to accurately estimating the reproduction advantage of the Omicron variant.

Significance

Recent studies suggest that individuals infected with the Omicron variant develop symptoms earlier (shorter incubation period) and transmit faster (shorter generation interval) than those infected with the Delta variant. However, these studies typically neglect population-level effects: when an epidemic is growing, a greater proportion of current cases were infected recently, biasing us toward observing faster transmission events. Accounting for this dynamical bias, we find that Omicron infections from the Netherlands at the end of December 2021 had similar incubation periods, but shorter generation intervals, compared to Delta infections from the same period. Shorter generation intervals of the Omicron variant might be due to its higher effective reproduction number, which can cause faster local susceptible depletion around the contact network.
Oxonium Ion-Guided Ion Mobility-Assisted Glycoproteomics on the timsTOF Pro
Authors: Mukherjee Soumya , Jankevics Andris , Busch Florian , Lubeck Markus , Zou Yang , Kruppa Gary , Heck Albert J. R. , Scheltema Richard A. , Reiding Karli R.
Published: July 2022

Spatial separation of ions in the gas-phase, providing information about their size as collisional cross-sections, can readily be achieved through ion mobility. The timsTOF Pro series combines a trapped ion mobility device with a quadrupole, collision-cell and a time-of-flight analyser to enable the analysis of ions at great speed. Here, we show that the timsTOF Pro is capable of physically separating N-glycopeptides from non-modified peptides and producing high-quality fragmentation spectra, both beneficial for glycoproteomics analyses of complex samples. The glycan moieties enlarge the size of glycopeptides compared to non-modified peptides, yielding a clear cluster in the mobilogram that, next to increased dynamic range from the physical separation of glycopeptides and non-modified peptides, can be used to make an effective selection filter for directing the mass spectrometer to analytes of interest. This new approach was applied to selected glycoproteins, human plasma- and neutrophil-derived glycopeptides. We show that the achieved physical separation, combined with the focussing of the mass spectrometer, allows for improved extraction of information from the samples, even at shorter LC gradients of 15 min. We validated our approach on human neutrophil and plasma samples of known make-up, in which we captured the anticipated glycan heterogeneity (paucimannose, phosphomannose, high mannose, hybrid and complex glycans) from plasma and neutrophil samples at the expected abundances. As the method is compatible with off-the-shelve data acquisition routines and data analysis software, it can readily be applied by any laboratory with a timsTOF Pro and is reproducible as demonstrated by a comparison between two laboratories.
Sex-linked gene traffic underlies the acquisition of sexually dimorphic UV color vision in Heliconius butterflies
Authors: Chakraborty Mahul , Lara Angelica Guadalupe , Dang Andrew , McCulloch Kyle J. , Rainbow Dylan , Carter David , Ngo Luna Thanh , Solares Edwin , Said Iskander , Corbett-Detig Russ , Gilbert Lawrence E. , Emerson J.J. , Briscoe Adriana D.
Published: July 2022

Butterflies have photoreceptor cells that are sensitive to the ultraviolet part of the spectrum due to ultraviolet-sensitive rhodopsin (UVRh), a gene that has been duplicated in the Heliconius genus. In individuals expressing UVRh1 and UVRh2, electrophysiological and behavioral studies demonstrate that these opsin proteins enable discrimination of UV wavelengths. This behavioral trait varies between species, being absent in H. melpomene and limited to females in H. erato. To identify the evolutionary origins of this trait, we first examined UV color vision in H. charithonia, a species related to H. erato in the sara/sapho group. We found that this species also has sexually dimorphic UV color vision. To identify the genetic basis of this trait, we built a reference-grade genome assembly of H. charithonia. We discovered that one duplicate, UVRh1, is present on the W chromosome, making it obligately female-specific. We employed gDNA PCR assays of UVRh1 across the Heliconius genus. In species with sexually dimorphic UVRh1 mRNA expression, UVRh1 gDNA is absent in males, whereas in species with sexually monomorphic UVRh1 mRNA expression, UVRh1 gDNA is found in both sexes. The presence or absence of male UVRh1 expression across the Heliconius phylogeny supports a model where sexual dimorphism was acquired early via movement of a gene duplication to the W-chromosome. We used CRISPR-Cas9 to engineer a deletion in the UVRh1 locus in female H. charithonia and use immunohistochemistry to show that UVRh1 protein expression is absent in mutant tissue, similar to that of males. Our results show that a rare behavioral phenotype, sex-specific UV color vision, was acquired via sex chromosome gene traffic of a duplicated UV rhodopsin.
Inside and outside of virus-like particles HBc and HBc/4M2e: a comprehensive study of the structure
Authors: Egorov V.V. , Shvetsov A.V. , Pichkur E.B. , Shaldzhyan A.A. , Zabrodskaya Ya.A. , Vinogradova D.S. , Nekrasov P.A. , Gorshkov A.N. , Garmay Yu.P. , Kovaleva A.A. , Stepanova L.A. , Tsybalova L. M. , Shtam T.A. , Myasnikov A.G. , Konevega A.L.
Published: July 2022

The structure of the core particles of the hepatitis B virus core antigen (HBc) with the insertion of four external domains of the influenza A M2 protein (HBc/4M2e) have been studied using a combination of molecular modeling and cryogenic electron microscopy (cryo-EM). It has also been shown that synthesis of particles occurs inside bacterial cells, but despite the big inner volume of the core shell particle, purified HBc/4M2e do not contain detectable amounts of bacterial proteins. It has been shown that a fragment of the M2e is prone to the formation of amyloid-like fibrils. However, as a part of HBc immunodominant loop M2e domains as repeats, does not exhibit a tendency to aggregation. Full-atom HBc-4M2E model with 3A resolution was obtained by molecular modeling methods based on cryo-EM data.
Comparing children’s night cough with wheeze: phenotypic characteristics, healthcare use and treatment
Authors: Mallet Maria Christina , Mozun Rebeca , Ardura-Garcia Cristina , Pedersen Eva SL , Jurca Maja , Latzin Philipp ,   LUIS study group, Moeller Alexander , Kuehni Claudia E.
Published: July 2022

Population-based studies of children presenting with dry night cough alone compared with those who also wheeze are few and inconclusive.

Luftibus in the school is a population-based study of schoolchildren conducted between 2013–2016 in Zurich, Switzerland. We divided children into four mutually exclusive groups based on reported dry night cough (‘cough’) and wheeze and compared parent-reported symptoms, comorbidities and exposures using multinomial regression, FeNO using quantile regression, spirometry using linear regression and healthcare use and treatments using descriptive statistics.

Among 3457 schoolchildren aged 6–17 years, 294 (9%) reported ‘cough’, 181 (5%) reported ‘wheeze’, 100 (3%) reported ‘wheeze and cough’ and 2882 (83%) were ‘asymptomatic.’ Adjusting for confounders in a multinomial regression, children with ‘cough’ reported more frequent colds, rhinitis and snoring than ‘asymptomatic’ children; children with ‘wheeze’ or ‘wheeze and cough’ more often reported hay fever, eczema and parental histories of asthma. FeNO and spirometry were similar among ‘asymptomatic’ and children with ‘cough,’ while children with ‘wheeze’ or ‘wheeze and cough’ had higher FeNO and evidence of bronchial obstruction. Children with ‘cough’ used healthcare less often than those with ‘wheeze,’ and they attended mainly primary care. Twenty-two children (7% of those with ‘cough’) reported a physician diagnosis of asthma and used inhalers. These had similar characteristics as children with wheeze.

Our representative population-based study suggests only a small subgroup (7%) of schoolchildren reporting dry night cough without wheeze have features typical of asthma, yet the majority (93%) should be investigated for alternative aetiologies, particularly upper airway disease.

Take home message

Our population-based study found children with night cough alone clearly differ from those with wheeze, suggesting different aetiologies and pathophysiology. Yet, a small subgroup (7%) has features of asthma and may benefit from specific work-up.
How long and effective does a mask protect you from an infected person who emits corona virus-laden particles: by implementing physics-based modeling
Authors: Bahrami Flora , Batt Till , Schudel Seraina , Annaheim Simon , He Weidong , Wang Jing , Rossi René M. , Defraeye Thijs
Published: July 2022

SARS-CoV-2 spreads via droplets, aerosols, and smear infection. From the beginning of the COVID-19 pandemic, using a facemask in different locations was recommended to slow down the spread of the virus. To evaluate facemasks’ performance, masks’ filtration efficiency is tested for a range of particle sizes. Although such tests quantify the blockage of the mask for a range of particle sizes, the test does not quantify the cumulative amount of virus-laden particles inhaled or exhaled by its wearer. In this study, we quantify the accumulated viruses that the healthy person inhales as a function of time, activity level, type of mask, and room condition using a physics-based model. We considered different types of masks, such as surgical masks and filtering facepieces (FFPs), and different characteristics of public places such as office rooms, buses, trains, and airplanes. To do such quantification, we implemented a physics-based model of the mask. Our results confirm the importance of both people wearing a mask compared to when only one wears the mask. The protection time before the healthy wearer has an infection risk of 50% reduces by 80% if only one wears the facemask instead of both people. The protection time is further reduced if the infected person starts to cough or increases the activity level by 85% and 99%, respectively. Results show the leakage of the mask can considerably affect the performance of the mask. For the surgical mask, the apparent filtration efficiency reduces by 75% with such a leakage, which cannot provide sufficient protection despite the high filtration efficiency of the mask. The facemask model presented provides key input in order to evaluate the protection of masks for different conditions in public places. The physics-based model of the facemask is provided as an online application.
Artificial Intelligence (AI)-based Chatbots in Promoting Health Behavioral Changes: A Systematic Review
Authors: Aggarwal Abhishek , Tam Cheuk Chi , Wu Dezhi , Li Xiaoming , Qiao Shan
Published: July 2022

Background

Artificial-Intelligence (AI)-based chatbots can offer personalized, engaging, and on-demand health-promotion interventions. This systematic review evaluates the feasibility, efficacy, and intervention characteristics of AI-chatbots in promoting health-behavior change.

Methods

A comprehensive search was conducted in seven bibliographic databases (PubMed, IEEE Xplore, ACM Digital Library, PsychoINFO, Web of Science, EMBASE, and JMIR publications) for empirical articles published from 1980 to 2022 that evaluated feasibility and/or efficacy of AI-chatbots for behavioral change. The screening, extraction, and analyses of identified articles followed the PRISMA guidelines.

Results

Of the 15 included studies, majority studies (n=11) reported high usability, acceptability and engagement, and some evidence on feasibility of AI-chatbots. Selected studies demonstrated high efficacy in promoting healthy lifestyles (n=6), smoking cessation (n=4), treatment/medication adherence (n=2), and reduction in substance misuse (n=1). Behavioral change theories and/or expert consultation were used to develop behavioral change strategies of AI-chatbots, including goal setting, monitoring, real-time reinforcement/feedback, and on- demand support. Real-time user-chatbot interaction data, such as user preferences and behavioral performance, were collected on the chatbot platform to identify ways of providing personalized services. The AI-chatbots demonstrated potential for scalability by deployment through accessible devices and platforms (e.g., smartphones and messenger). Participants also reported that AI-chatbots offered a non-judgmental space for communicating sensitive information. However, the reported results need to be interpreted with caution because of moderate to high risk of internal validity, insufficient description of AI-techniques, and limitation for generalizability.

Conclusion

AI-chatbots have demonstrated efficacy of health-behavior change interventions among large and diverse population; however, future studies need to adopt robust RCTs to establish definitive conclusions.
Parental acceptance of and preferences for administration of routine varicella vaccination in the UK: a study to inform policy
Authors: Sherman Susan M. , Lingley-Heath Nicola , Lai Jasmine , Sim Julius , Bedford Helen
Published: July 2022

Objectives

To explore acceptability of and preferences for the introduction of varicella vaccination to the UK childhood immunisation schedule.

Design

We conducted an online cross-sectional survey exploring parental attitudes towards vaccines in general, and varicella vaccine specifically, and their preferences for how the vaccine should be administered.

Participants

596 parents (76.3% female, 23.3% male, mean age 33.4 years) whose youngest child was aged 0-5 years.

Main outcome measures

Willingness to accept the vaccine for their child and preferences for how the vaccine should be administered (in combination with the MMR vaccine [MMRV], on the same day as the MMR vaccine but as a separate injection [MMR+V], on a separate additional visit).

Results

74.0% of parents (95% CI 70.2% to 77.5%) were extremely/somewhat likely to accept a varicella vaccine for their child if one became available, 18.3% (95% CI 15.3% to 21.8%) were extremely/somewhat unlikely to accept it and 7.7% (95% CI 5.7% to 10.2%) were neither likely nor unlikely. Reasons provided by parents likely to accept the vaccine included protection from complications of chickenpox, trust in the vaccine/healthcare professionals, and wanting their child to avoid their personal experience of chickenpox. Reasons provided by parents who were unlikely included chickenpox not being a serious illness, concern about side effects, and believing it is preferable to catch chickenpox as a child rather than as an adult. A combined MMRV vaccination or additional visit to the surgery were preferred over an additional injection at the same visit.

Conclusions

Most parents would accept a varicella vaccination. These findings highlight parents’ preferences for varicella vaccine administration, information needed to inform vaccine policy and practice and development of a communication strategy.
Discovering and Validating Neoantigens by Mass Spectrometry-based Immunopeptidomics and Deep Learning
Authors: Tran Ngoc Hieu , Peng Chao , Lei Qingyang , Xin Lei , Lang Jingxiang , Zhang Qing , Li Wenting , Miao Haofei , Wu Ping , Qiao Rui , Qin Haiming , Bu Dongbo , Zhang Haicang , Yu Chungong , Liu Xiaolong , Zhang Yi , Shan Baozhen , Li Ming
Published: July 2022

Neoantigens are promising targets for cancer immunotherapy but their discovery remains challenging, mainly due to the sensitivity of current technologies to detect them and the specificity of our immune system to recognize them. In this study, we addressed both of those problems and proposed a new approach for neoantigen identification and validation from mass spectrometry (MS) based immunopeptidomics. In particular, we developed DeepNovo Peptidome, ade novosequencing-based search engine that was optimized for HLA peptide identification, especially non-canonical HLA peptides. We also developed DeepSelf, a personalized model for immunogenicity prediction based on the central tolerance of T cells, which could be used to select candidate neoantigens from non-canonical HLA peptides. Both tools were built on deep learning models that were trained specifically for HLA peptides and for the immunopeptidome of each individual patient. To demonstrate their applications, we presented a new MS-based immunopeptidomics study of native tumor tissues from five patients with cervical cancer. We applied DeepNovo Peptidome and DeepSelf to identify and prioritize candidate neoantigens, and then performedin vitrovalidation of autologous neoantigen-specific T cell responses to confirm our results. Our MS-basedde novosequencing approach does not depend on prior knowledge of genome, transcriptome, or proteome information. Thus, it provides an unbiased solution to discover neoantigens from any sources.
Application of Passive Head Motion to Generate Defined Accelerations at the Heads of Rodents
Authors: Maekawa Takahiro , Sakitani Naoyoshi , Ryu Youngjae , Takashima Atsushi , Murase Shuhei , Fink Julius , Nagao Motoshi , Ogata Toru , Shinohara Masahiro , Sawada Yasuhiro
Published: July 2022

Exercise is widely recognized as effective for various diseases and physical disorders, including those related to brain dysfunction. However, molecular mechanisms behind the beneficial effects of exercise are poorly understood. Many physical workouts, particularly those classified as aerobic exercises such as jogging and walking, produce impulsive forces at the time of foot contact with the ground. Therefore, it was speculated that mechanical impact might be implicated in how exercise contributes to organismal homeostasis. For testing this hypothesis on the brain, a custom-designed passive head motion (hereafter referred to as PHM) system was developed that can generate vertical accelerations with controlled and defined magnitudes and modes and reproduce mechanical stimulation that might be applied to the heads of rodents during treadmill running at moderate velocities, a typical intervention to test the effects of exercise in animals. By using this system, it was demonstrated that PHM recapitulates the serotonin (5-hydroxytryptamine, hereafter referred to as 5-HT) receptor subtype 2A (5-HT2A) signaling in the prefrontal cortex (PFC) neurons of mice. This work provides detailed protocols for applying PHM and measuring its resultant mechanical accelerations at rodents’ heads.

The present protocol describes a custom-designed passive head motion system, which reproduces mechanical accelerations at rodents’ heads generated during their treadmill running at moderate velocities. It allows dissecting mechanical factors/elements from the beneficial effects of physical exercise.
DMC1 attenuates RAD51-mediated recombination in Arabidopsis
Authors: Ines Olivier Da , Bazile Jeanne , Gallego Maria E. , White Charles I.
Published: July 2022

Ensuring 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 Summary

Essential 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

KRAS 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

Basal 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

Tissue 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

Amyotrophic 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

Transcription 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

The 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

Universities 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

Surges 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

Nutritional 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 Importance

Beetles 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

Using 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

Lipid 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

Complex 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 Summary

A DNA-based chemical network mathematically mimics the sensing of cold by a biological neuron.