bluuebunny/crossref_metadata_2025 huggingface dataset:
Texture Analysis of Tumor and Peritumoral Tissues Based on 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Hybrid Imaging in Patients With Rectal Cancer
Authors: Orel Valerii E. , Ashykhmin Andrii , Golovko Tetiana , Rykhalskyi Oleksandr , Orel Valerii B.
Published: September 2021

Objective

This study aimed to determine whether texture parameters could be used in differentiation between the tumor and the peritumoral tissues based on hybrid 18F-Fluorodeoxyglucose positron emission tomography/computed tomography imaging for patients with rectal cancer.

Methods

Seven parameters, including heterogeneity, entropy, energy, skewness, kurtosis, standard deviation, and average brightness, were extracted from positron emission tomography/computed tomography scans of 22 patients (12 male and 10 female; mean age, 61 ± 2 years).

Results

The peritumoral tissue had a significantly lower value of the heterogeneity parameter (23%) than the tumor. Tumor size (r = −0.48, P < 0.05) and extramural venous invasion scores (r = 0.64, P < 0.05) correlated with heterogeneity in the peritumoral tissue. There were significant differences (P < 0.05) in the correlation coefficients between men and women.

Conclusions

Therefore, we provided additional quantitative information to differentiate the tumor from the peritumoral tissue and indicated possible application for extramural venous invasion evaluation in rectal cancer.
Disparities in Alzheimer Disease and Mild Cognitive Impairment Among Native Hawaiians and Pacific Islanders
Authors: Smith Maiya , Van Nicholas , Roberts Alyssa , Hosaka Kalei R.J. , Choi So Yung , Viereck Jason , Carrazana Enrique , Borman Pat , Chen John J. , Liow Kore Kai
Published: September 2021

Background:

Previous studies of racial differences in Alzheimer disease (AD) presentation have not included Native Hawaiians and Pacific Islanders (NHPI).

Objective:

To explore the presentation of AD and mild cognitive impairment (MCI) in NHPI.

Method:

We conducted a retrospective review of patient records from Hawaii with a diagnosis of unspecified AD or MCI from September 2000 to September 2019. Variables of interest included age at diagnosis, gender, race, marital status, insurance, comorbidities, and scores on the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA).

Results:

We reviewed the medical records of 598 patients, including 224 Asians, 202 Whites, 87 NHPI, and 85 Other. AD was more dominant than MCI across all of the groups, with the highest percentage in NHPI. Among the mean ages of diagnosis, NHPI were the youngest. Across all groups, a higher proportion of women than men had AD, with the highest female prevalence among NHPI. Hypertension, hyperlipidemia, and type II diabetes were highest among NHPI compared with the other groups. Of individuals with MMSE/MoCA scores, there were significant variations in scores by racial group. The mean MMSE/MoCA score was highest among Whites and lowest among NHPI.

Conclusion:

Compared with other racial groups, NHPI have a higher proportion of AD than MCI at diagnosis, are diagnosed at a younger age, have a higher female prevalence, have more comorbidities that may contribute to AD/MCI onset, and present with lower MMSE scores.
Development of a women empowerment framework to promote voluntary medical male circumcision uptake for HIV prevention in Zimbabwe
Authors: Danda Grace , Mavundla Thandisizwe R , Mudokwenyu- Rawdon Christina
Published: September 2021

Introduction

This study aimed to develop a women empowerment framework to promote Voluntary Medical Male Circumcision (VMMC) uptake for human immune-deficiency virus (HIV) prevention, guided by the following objectives: To explore relevant literature on the role of women in promoting male circumcision uptake; To develop a women empowerment framework to promote male circumcision uptake; To describe the women empowerment framework to promote male circumcision uptake.

Methods

The study used a theory-generation design to explore, describe and develop a women empowerment framework from a broad literature review.

Results

A three-phase approach suitable for the framework development emerged from the literature review. Phase one involved exploring relevant literature on the role of women in male circumcision uptake, using the Population/problem, Intervention, Comparison and Outcome (PICO) method to identify and define the key concepts. Phase 2 adopted and adapted the model by Maibvise and Mavundla in identifying the following concepts: change agents as the health care providers, recipients as the women to influence men eligible for male circumcision, promoting male circumcision uptake and success of the male circumcision program. Phase 3 provided a detailed description of the framework including three key steps of empowerment of women, influencing positive perceptions of men and utilisation of male circumcision services.

Conclusions

The identified concepts resulted in development of a women empowerment framework, which can be used as an education and advocacy tool in building the capacity of women in supporting the male circumcision programme to promote uptake. Further research is required to expand the utilisation of the framework in male circumcision healthcare services.
A Deep Transcriptome Meta-Analysis Reveals Sex-based Molecular Differences in Multiple Sclerosis
Authors: Català-Senent José Francisco , Andreu Zoraida , Hidalgo Marta R. , Roig Francisco José , Yanguas-Casás Natalia , Neva-Alejo Almudena , López-Cerdán Adolfo , Soler-Sáez Irene , de la Iglesia-Vayá María , García-García Francisco
Published: September 2021

Background

Multiple sclerosis (MS), a chronic auto-immune, inflammatory, and degenerative disease of the central nervous system, affects both males and females; however, females suffer from a higher risk of developing MS (2-3:1 ratio compared to males). Current knowledge does not allow a precise definition of the sex-based factors influencing MS. Here, we explore the role of sex in MS to identify potential molecular mechanisms underlying sex-based differences that may guide novel therapeutic approaches tailored for males or females.

Methods

We performed a rigorous and systematic review of whole transcriptome studies of MS that included patient information regarding sex in Gene Expression Omnibus and ArrayExpress databases following PRISMA statement guidelines. We analyzed differential gene expression for each selected study and addressed 3 meta-analyses based on genes to evaluate common features and sex bias: the first meta-analysis of 4 nervous tissue studies, a second in 5 blood studies, and a third integrating 9 studies from both tissues. Finally, we performed a gene set analysis on the meta-analyzed differential transcriptomic profiles of the nervous system to study sex-based differences in biological pathways and phenotypes (physiological and pathological states).

Results

After screening 122 publications, the systematic review provided a selection of 9 studies (5 in blood and 4 in nervous tissue) with a total of 474 samples (189 MS females and 109 control females; 82 MS males and 94 control males). The tissue-specific meta-analysis identified the overexpression of KIR2DL3 in blood in females and 13 genes with a sex-based differential expression pattern in the nervous system (7 overexpressed in females: ARL17B, CECR7, CEP78, STMP1, TRAF3IP2-AS1, ZNF117 and ZNF488; and 6 overexpressed in males: IFFO2, LOC401127, NUDT18, RNF10, SLC17A5, and UBXN2B). The two-tissue meta-analysis detected a single gene overexpressed in females (LOC102723701). Functional analyses revealed different altered immune scenarios in females and males. A pro-inflammatory environment and innate immune responses related to myeloid linage predominate in females, while in males, adaptative responses associated with the lymphocyte linage. Additionally, MS females displayed alterations in mitochondrial respiratory chain complexes, purine, and glutamate metabolism, while MS males displayed alterations in stress response to metal ion, amine, and amino acid transport.

Conclusion

We found transcriptomic and functional differences between MS males and females (especially in the immune system), which may support the development of sex-specific treatments. Our study highlights the importance of understanding sex as a variable in MS.
High-Throughput Adaptable SARS-CoV-2 Screening for Rapid Identification of Dominant and Emerging Regional Variants
Authors: Hubler Zita , Song Xiao , Norris Cameron , Jani Mehul , Alouani David , Atchley Maureen , Stempak Lisa , Cherian Sarah , Schmotzer Christine , Sadri Navid
Published: September 2021

Objectives

Emerging SARS-CoV-2 variant strains can be associated with increased transmissibility, more severe disease, and reduced effectiveness of treatments. To improve the availability of regional variant surveillance, we describe a variant genotyping system that is rapid, accurate, adaptable, and able to detect new low-level variants built with existing hospital infrastructure.

Methods

We use a tiered high-throughput SARS-CoV-2 screening program to characterizes variants in a supra-regional health system over 76 days. Combining targeted qPCR and selective sequencing, we screen positive SARS-CoV-2 samples from all hospitals within our health care system for genotyping dominant and emerging variants.

Results

The median turnaround for genotyping was two days using the high-throughput qPCR-based screen, allowing us to rapidly characterize the emerging Delta variant. In our population, the Delta variant is associated with a lower CT value, lower age at infection, and increased vaccine breakthrough cases. Detection of low-level and potentially emerging variants highlights the utility of a tiered approach.

Conclusions

These findings underscore the need for fast, low-cost, high-throughput monitoring of regional viral sequences as the pandemic unfolds and the emergence of SARS-CoV-2 variants increases. Combing qPCR-based screening with selective sequencing allows for rapid genotyping of variants and dynamic system improvement.

Key messages

A tiered approach that uses qPCR-based screening to identify dominant variants and sequencing for unique variants maximizes throughput, turnaround time, and information gleaned from each sample.

In our population, the Delta variant became dominant in less than a month and is associated with lower CT, lower age at infection, and increased breakthrough cases.

We identified low-level variants, including the variant of interest B.1.621 and a Delta variant with an E484K mutation in our population using existing hospital infrastructure.
Integrative genetic analysis of the amyotrophic lateral sclerosis spinal cord implicates glial activation and suggests new risk genes
Authors: Humphrey Jack , Venkatesh Sanan , Hasan Rahat , Herb Jake T. , de Paiva Lopes Katia , Küçükali Fahri , Byrska-Bishop Marta , Evani Uday S. , Narzisi Giuseppe , Fagegaltier Delphine ,   NYGC ALS Consortium, Sleegers Kristel , Phatnani Hemali , Knowles David A. , Fratta Pietro , Raj Towfique
Published: September 2021

Amyotrophic lateral sclerosis (ALS) is a progressively fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord. We used 380 post-mortem tissue RNA-seq transcriptomes from 154 ALS cases and 49 control individuals from cervical, thoracic, and lumbar spinal cord segments to investigate the gene expression response to ALS. We observed an increase in microglia and astrocyte expression, accompanied by a decrease in oligodendrocytes. By creating a gene co-expression network in the ALS samples, we identify several activated microglia modules that negatively correlate with retrospective disease duration.

We map molecular quantitative trait loci and find several potential ALS risk loci that may act through gene expression or splicing in the spinal cord and assign putative cell-types for FNBP1, ACSL5, SH3RF1 and NFASC. Finally, we outline how repeat expansions that alter splicing of C9orf72 are tagged by common variants, and use this to suggest ATXN3 as a putative risk gene.
Predictive Classification of IBS-subtype: Performance of a 250-gene RNA expression panel vs. Complete Blood Count (CBC) profiles under a Random Forest model
Authors: Robinson Jeffrey
Published: September 2021

In this experiment, an R-script was developed to select the best performing machine learning (ML) predictive classification algorithm for IBS-subtype, and compare the performance of two datasets from the same clinical cohort – 1) The Complete Blood Count (CBC) results, and 2) A 250-gene Nanostring expression panel run on RNA from the “Buffy Coat” fraction. This publicly available data was compiled from open-source repositories and previously published supplementary data. Column labels were reformatted according to “tidy-data” standards. NA values in the data were imputed based on the mean value of the data column. Subject groups included Control (ie. healthy), IBS-D (diarrhea predominant), and IBS-C (constipation predominant) subtypes. These groups had unequal numbers in the original study, and so random re-sampling was used to make the group numbers equal for downstream linear regression-based analyses. The data was randomly split into training and validation subsets, and 5 classification algorithms were tested. Random Forest was clearly the best performing algorithm for both CBC and gene expression panel data, generally with >95% predictive accuracy, without additional tuning. The 250-gene RNA expression panel performed somewhat better than the CBC profile under a Random Forest model, however the CBC profiles had only 13 predictor variables vs. the 250 of the RNA expression panel. Some artifacts may result from the duplication of IBS-D and IBS-C rows from to the group-size balancing method, and so larger and more comprehensive datasets will be obtained for a follow-up analysis. The R-script and reformatted data are published as supplementary material here, and as a component of the ‘AnalyzeBloodworkv1.2’ GitHub repository.
Optimal COVID-19 testing strategy on limited resources
Authors: Tatsuki Onishi , Naoki Honda , Igarashi Yasunobu
Published: September 2021

The last three years have been spent combating COVID-19, and governments have been seeking optimal solutions to minimize the negative impacts on societies. Although two types of testing have been performed for this—follow-up testing for those who had close contact with infected individuals and mass-testing of those with symptoms—the allocation of resources has been controversial. Mathematical models such as the susceptible, infectious, exposed, recovered, and dead (SEIRD) model have been developed to predict the spread of infection. However, these models do not consider the effects of testing characteristics and resource limitations. To determine the optimal testing strategy, we developed a testing-SEIRD model that depends on testing characteristics and limited resources. In this model, people who test positive are admitted to the hospital based on capacity and medical resources. Using this model, we examined the infection spread depending on the ratio of follow-up and mass-testing. The simulations demonstrated that the infection dynamics exhibit an all-or-none response as infection expands or extinguishes. Optimal and worst follow-up and mass-testing combinations were determined depending on the total resources and cost ratio of the two types of testing. Furthermore, we demonstrated that the cumulative deaths varied significantly by hundreds to thousands of times depending on the testing strategy, which is encouraging for policymakers. Therefore, our model might provide guidelines for testing strategies in the cases of recently emerging infectious diseases.
DNA as a Recyclable Natural Polymer
Authors: Liu Weina , Giaveri Simone , Ortiz Daniel , Stellacci Francesco
Published: September 2021

Nature has the ability of circularly re-using its components to produce molecules and materials it needs. An example is the ability of most living organisms of digesting proteins they feed off into amino acids and then using such amino acids in the ribosomal synthesis of new proteins. Recently, we have shown that such recycling of proteins can be reproduced outside living organisms. The key proteins’ feature that allows for this type of recycling is their being sequence-defined polymers. Arguably, Nature’s most famous sequence-defined polymer is DNA. Here we show that it is possible starting from sheared calf-DNA to obtain all the four nucleotides as monophosphate-nucleotides (dNMPs). These dNMPs were phosphorylated in a one-pot, multi-enzymes, phosphorylation reaction to generate triphosphate-nucleotides (dNTPs). Finally, we used the dNTPs so achieved (with a global yield of ∼60%) as reagents for PCR (polymerase chain reaction) to produce target DNA strands, and for the diagnose of targeted DNA by quantitative PCR (qPCR). This approach is an efficient, convenient, and environmentally friendly way to produce dNTPs and DNA through recycling according to the paradigm of circular economy.
Cell types and clonal relations in the mouse brain revealed by single-cell and spatial transcriptomics
Authors: Ratz Michael , von Berlin Leonie , Larsson Ludvig , Martin Marcel , Westholm Jakub Orzechowski , La Manno Gioele , Lundeberg Joakim , Frisén Jonas
Published: September 2021

The mammalian brain contains a large number of specialized cells that develop from a thin sheet of neuroepithelial progenitor cells1,2. Recently, high throughput single-cell technologies have been used to define the molecular diversity of hundreds of cell types in the nervous system3,4. However, the lineage relationships between mature brain cells and progenitor cells are not well understood, because transcriptomic studies do not allow insights into clonal relationships and classical fate-mapping techniques are not scalable5,6. Here we showin vivobarcoding of early progenitor cells that enables simultaneous profiling of cell phenotypes and clonal relations in the mouse brain using single-cell and spatial transcriptomics. We reconstructed thousands of clones to uncover the existence of fate-restricted progenitor cells in the mouse hippocampal neuroepithelium and show that microglia are derived from few primitive myeloid precursors that massively expand to generate widely dispersed progeny. By coupling spatial transcriptomics with clonal barcoding, we disentangle migration patterns of clonally related cells in densely labelled tissue sections. Compared to classical fate mapping, our approach enables high-throughput dense reconstruction of cell phenotypes and clonal relations at the single-cell and tissue level in individual animals and provides an integrated approach for understanding tissue architecture.
Activity-dependent organization of prefrontal hub-networks for associative learning and signal transformation
Authors: Agetsuma Masakazu , Sato Issei , Tanaka Yasuhiro R , Carrillo-Reid Luis , Kasai Atsushi , Arai Yoshiyuki , Yoshitomo Miki , Inagaki Takashi , Hashimoto Hitoshi , Nabekura Junichi , Nagai Takeharu
Published: September 2021

Associative learning is crucial for adapting to environmental changes. The encoding of associative learning involves the dorso-medial prefrontal cortex (dmPFC), and is underpinned by interactions within the resident neuronal population. However, the nature of this population coding is poorly understood. Here we developed a pipeline for computational dissection and longitudinal two-photon imaging of neural population activities in the mouse dmPFC during fear-conditioning procedures, enabling us to detect learning-dependent changes in the dmPFC topology. Through regularized regression methods and graphical modeling, we found fear conditioning organized neuronal ensembles encoding conditioned responses (CR), with enhancing their coactivity, functional connectivity, and association with conditioned stimuli (CS). This suggests that fear conditioning drives dmPFC reorganization to generate novel associative circuits for CS-to-CR transformation. Importantly, neurons strongly responding to unconditioned stimuli (US) during conditioning anterogradely became a hub of the CR ensemble. Altogether, we demonstrate learning-dependent dynamic modulation of population coding structured on an activity-dependent hub-network formation within the dmPFC.

Teaser

Optical and computational dissection uncovered how prefrontal cortical networks are rewired to encode new associative memory

Significance statement

Animals learn to adapt to changing environments. Associative learning is one of the simplest types of learning that has been intensively studied over the past century. Recent development in molecular, genetic, and optogenetic methods has enabled the identification of a neural population encoding the associative memory in the brain. However, it remains unclear how information is stored and processed by the neural population to encode and retrieve the associative memory. To investigate the nature of this population coding, we developed an optical and computational dissection method, demonstrating how associative learning drives reorganization of the neural network in the dorso-medial prefrontal cortex and generates novel circuits for associative memory and signal transformation.
Glass Half Full: Preserved Anatomical Bypasses Predict Variance in Language Functions After Stroke
Authors: Erickson B.A. , Kim B. , Deck B.L. , Pustina D. , DeMarco A.T. , Dickens J.V. , Kelkar A.S. , Turkeltaub P.E. , Medaglia J.D.
Published: September 2021

The severity of post-stroke aphasia is related to damage to white matter connections. However, neural signaling can route not only through direct connections, but also along multi-step network paths. When brain networks are damaged by stroke, paths can bypass around the damage to restore communication. The shortest network paths between regions could be the most efficient routes for mediating bypasses. We examined how shortest-path bypasses after left hemisphere strokes were related to language performance. Regions within and outside of the canonical language network could be important in aphasia recovery. Therefore, we innovated methods to measure the influence of bypasses in the whole brain.

Distinguishing bypasses from all residual shortest paths is difficult without pre-stroke imaging. We identified bypasses by finding shortest paths in subjects with stroke that were longer than those observed in the average network of the most reliably observed connections in age-matched controls. We tested whether features of those bypasses predicted scores in four orthogonal dimensions of language performance derived from a factor analysis of a battery of language tasks. The features were the length of each bypass in steps, and how many bypasses overlapped on each individual direct connection. We related these bypass features to language factors using grid-search cross-validated Support Vector Regression, a technique that extracts robust relationships in high-dimensional data analysis.

We discovered that the length of bypasses reliably predicted variance in lexical production (R2= .576) and auditory comprehension scores (R2= .164). Bypass overlaps reliably predicted variance in Lexical Production scores (R2 = .247). The predictive elongation features revealed that bypass efficiency along the dorsal stream and ventral stream were most related to Lexical Production and Auditory Comprehension, respectively. Among the predictive bypass overlaps, increased bypass routing through the right hemisphere putamen was negatively related to lexical production ability.
Mapping interindividual dynamics of innate immune response at single-cell resolution
Authors: Kumasaka Natsuhiko , Rostom Raghd , Huang Ni , Polanski Krzysztof , Meyer Kerstin B. , Patel Sharad , Boyd Rachel , Gomez Celine , Barnett Sam N. , Panousis Nikolaos I , Schwartzentruber Jeremy , Ghoussaini Maya , Lyons Paul A. , Calero-Nieto Fernando J. , Göttgens Berthold , Barnes Josephine L. , Worlock Kaylee B. , Yoshida Masahiro , Nikolic Marko Z. , Stephenson Emily , Reynolds Gary , Haniffa Muzlifah , Marioni John , Stegle Oliver , Hagai Tzachi , Teichmann Sarah A.
Published: September 2021

Common genetic variants modulate the cellular response to viruses and are implicated in a range of immune pathologies, including infectious and autoimmune diseases. The transcriptional antiviral response is known to vary between infected cells from a single individual, yet how genetic variants across individuals modulate the antiviral response (and its cell-to-cell variability) is not well understood. Here, we triggered the antiviral response in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-seq. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), the first statistical approach designed to identify dynamic eQTLs across a transcriptional trajectory of cell populations, without aggregating single-cell data into pseudo-bulk. This allows us to uncover the underlying architecture and variability of antiviral response across responding cells, and to identify more than two thousands eQTLs modulating the dynamic changes during this response. Many of these eQTLs colocalise with risk loci identified in GWAS of infectious and autoimmune diseases. As a case study, we focus on a COVID-19 susceptibility locus, colocalised with the antiviral OAS1 splicing QTL. We validated it in blood cells from a patient cohort and in the infected nasal cells of a patient with the risk allele, demonstrating the utility of GASPACHO to fine-map and functionally characterise a genetic locus. In summary, our novel analytical approach provides a new framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution.
Biochemical characterisation of human transglutaminase 4
Authors: Csobán-Szabó Zsuzsa , Bécsi Bálint , El Alaoui Saïd , Fésüs László , Korponay-Szabó Ilma Rita , Király Róbert
Published: September 2021

Transglutaminases are protein modifying enzymes involved in physiological and pathological processes with potent therapeutic possibilities. Human TG4, also called prostate transglutaminase, is frequently associated with pathological symptoms and particularly with cancer invasiveness. Although rodent TG4 is well characterised, bio-chemical characteristics of human TG4 that could help the understanding of its way of action are not published. First, we analysed proteomics databases and found that TG4 protein is present in human tissues beyond the prostate. Then, we studied in vitro the transamidase activity of human TG4 and its regulation using the microtiter plate method. Human TG4 has low transamidase activity which prefers slightly acidic pH and a reducing environment. It is enhanced by submicellar concentrations of SDS suggesting that membrane proximity is an important regulatory event. Human TG4 does not bind GTP as tested by GTP-agarose and BODIPY-FL-GTPγS binding, and its proteolytic activation by dispase or when expressed in AD-293 cells was not observed either. We identified several potential human TG4 glutamine donor substrates in the AD-293 cell extract by biotin-pentylamine incorporation and mass spectrometry. Several of these potential substrates are involved in cell-cell interaction, adhesion and proliferation, suggesting that human TG4 could become an anticancer therapeutic target.
Azacytidine targeting SARS-CoV-2 viral RNA as a potential treatment for COVID-19
Authors: Lin Xian , Ke Xianliang , Xia Lin , Zhang Tianying , Xiong Hualong , Zhao Binghai , Liu Wen , Chen Quanjiao , Tang Chong
Published: September 2021

The COVID-19 pandemic is a global health disaster. Moreover, emerging mutated virus strains present an even greater challenge for existing vaccines and medications. One possible solution is to design drugs based on the properties of virus epigenome, which are more common among coronaviruses.

Here, we reported an FDA-approved drug for myelodysplastic syndrome, azacytidine (5Aza), limited virus infection and protected mice against SARS-CoV-2. We demonstrated that this antiviral effect is related to 5Aza incorporation into viral RNA, which disrupt m5C RNA methylation modification profile. This work suggests that targeting viral epigenomes is a viable therapeutic strategy, potentially opening new pathways for treating COVID-19.
Real-time visualization of mRNA synthesis during memory formation in live animals
Authors: Lee Byung Hun , Shim Jae Youn , Moon Hyungseok C. , Kim Dong Wook , Kim Jiwon , Yook Jang Soo , Kim Jinhyun , Park Hye Yoon
Published: September 2021

Memories are thought to be encoded in populations of neurons called memory trace or engram cells. However, little is known about the dynamics of these cells because of the difficulty in real-time monitoring of them over long periods of timein vivo. To overcome this limitation, we present a genetically-encoded RNA indicator (GERI) mouse for intravital chronic imaging of endogenousArcmRNA—a popular marker for memory trace cells. We used our GERI to identifyArc-positive neurons in real time without the delay associated with reporter protein expression in conventional approaches. We found that theArc-positive neuronal populations rapidly turned over within two days in the hippocampal CA1 region, whereas ∼4% of neurons in the retrosplenial cortex (RSC) consistently expressedArcfollowing contextual fear conditioning and repeated memory retrievals. Dual imaging of GERI and a calcium indicator in CA1 of mice navigating a virtual reality environment revealed that only the population of neurons expressingArcduring both encoding and retrieval exhibited relatively high calcium activity in a context-specific manner. Thisin vivoRNA imaging approach opens the possibility of unraveling the dynamics of the neuronal population underlying various learning and memory processes.

One Sentence Summary

Live-animal imaging ofArcmRNA reveals the dynamics and activity of memory trace cells during memory encoding and retrieval.
Signal neutrality, scalar property, and collapsing boundaries as consequences of a learned multi-timescale strategy
Authors: Manneschi Luca , Gicante Guido , Del Giudice Paolo , Vasilaki Eleni
Published: September 2021

We postulate that three fundamental elements underlie a decision making process: perception of time passing, information processing in multiple timescales and reward maximisation. We build a simple reinforcement learning agent upon these principles that we train on a random dot-like task. Our results, similar to the experimental data, demonstrate three emerging signatures. (1) Signal neutrality: insensitivity to the signal coherence in the interval preceding the decision. (2) Scalar property: the mean of the response times varies widely for different signal coherences, yet the shape of the distributions stays almost unchanged. (3) Collapsing boundaries: the “effective” decision-making boundary changes over time in a manner reminiscent of the theoretical optimal. Removing the perception of time or the multiple timescales from the model does not preserve the distinguishing signatures. Our results suggest an alternative explanation for signal neutrality. We propose that it is not part of motor planning. It is part of the decision-making process and emerges from information processing on multiple timescales.
Analysing pneumococcal invasiveness using Bayesian models of pathogen progression rates
Authors: Løchen Alessandra , Truscott James E. , Croucher Nicholas J.
Published: September 2021

The disease burden attributable to opportunistic pathogens depends on their prevalence in asymptomatic colonisation and the rate at which they progress to cause symptomatic disease. Increases in infections caused by commensals can result from the emergence of “hyperinvasive” strains. Such pathogens can be identified through quantifying progression rates using matched samples of typed microbes from disease cases and healthy carriers. This study describes Bayesian models for analysing such datasets, implemented in an RStan package (https://github.com/nickjcroucher/progressionEstimation). The models converged on stable fits that accurately reproduced observations from meta-analyses of Streptococcus pneumoniae datasets. The estimates of invasiveness, the progression rate from carriage to invasive disease, in cases per carrier per year correlated strongly with the dimensionless values from meta-analysis of odds ratios when sample sizes were large. At smaller sample sizes, the Bayesian models produced more informative estimates. This identified historically rare but high-risk S. pneumoniae serotypes that could be problematic following vaccine-associated disruption of the bacterial population. The package allows for hypothesis testing through model comparisons with Bayes factors. Application to datasets in which strain and serotype information were available for S. pneumoniae found significant evidence for within-strain and within-serotype variation in invasiveness. The heterogeneous geographical distribution of these genotypes is therefore likely to contribute to differences in the impact of vaccination in between locations. Hence genomic surveillance of opportunistic pathogens is crucial for quantifying the effectiveness of public health interventions, and enabling ongoing meta-analyses that can identify new, highly invasive variants.

Author summary

Opportunistic pathogens are microbes that are commonly carried by healthy hosts, but can occasionally cause severe disease. The progression rate quantifies the risk of such a pathogen transitioning from a harmless commensal to causing a symptomatic infection. The incidence of infections caused by opportunistic pathogens can rise with the emergence of “hyperinvasive” strains, which have high progression rates. Therefore methods for calculating progression rates of different pathogen strains using surveillance data are crucial for rapidly identifying emerging infectious disease threats. Existing methods typically measure progression rates relative to the overall mix of microbes in the population, but these populations can vary substantially between locations and times, making the outputs challenging to combine across studies. This work presents a new method for estimating progression rates from surveillance data that generates values useful for modelling pathogen populations, even from relatively small sample sizes.
The genomic signatures of natural selection in admixed human populations
Authors: Cuadros Espinoza Sebastian , Laval Guillaume , Quintana-Murci Lluis , Patin Etienne
Published: September 2021

Admixture has been a pervasive phenomenon in human history, shaping extensively the patterns of population genetic diversity. There is increasing evidence to suggest that admixture can also facilitate genetic adaptation to local environments, i.e., admixed populations acquire beneficial mutations from source populations, a process that we refer to as adaptive admixture. However, the role of adaptive admixture in human evolution and the power to detect it are poorly characterized. Here, we use extensive computer simulations to evaluate the power of several neutrality statistics to detect natural selection in the admixed population, accounting for background selection and assuming different admixture scenarios. We show that two statistics based on admixture proportions, Fadm and LAD, show high power to detect mutations that are beneficial in the admixed population, whereas iHS and FST falsely detect neutral mutations that have been selected in the source populations only. By combining Fadm and LAD into a single statistic, we scanned the genomes of 15 worldwide, admixed populations for signatures of adaptive admixture. We confirm that lactase persistence and resistance to malaria have been under adaptive admixture in West Africa and in Madagascar, North Africa and South Asia, respectively. Our approach also uncovers new cases of adaptive admixture, including the APOL1/MYH9 locus in the Fulani nomads and PKN2 in East Indonesians, involved in resistance to infection and metabolism, respectively. Collectively, our study provides new evidence that adaptive admixture has occurred in multiple human populations, whose genetic history is characterized by periods of isolation and spatial expansions resulting in increased gene flow.

Author summary

Adaptive introgression, i.e., the acquisition of adaptive traits through hybridization with another species, is a well-documented phenomenon in evolution. Conversely, adaptive admixture, i.e., the acquisition of adaptive traits through admixture between populations of the same species, is poorly described. In this study, we evaluate the importance of adaptive admixture in human recent evolutionary history. We first determine the expected signatures of adaptive admixture on patterns of genomic diversity, using realistic simulations. We then identify the methods that are the most powerful to detect such molecular signatures. Finally, by using the methods identified as the most powerful, we search for cases of adaptive admixture in the genomes of 15 admixed populations from around the globe. We find evidence that adaptive admixture has occurred in several populations from Northeast Africa, Southeast Asia and Oceania. This study suggests that admixture has indeed facilitated human genetic adaptation, particularly at genes involved in metabolism and resistance against pathogens.
Tolerance of Pseudomonas Strain to the 2,4-D Herbicide through a Peroxidase System
Authors: de Oliveira Elizangela Paz , da Silva Rovida Amanda Flávia , Martins Juliane Gabriele , Veiga Pileggi Sônia Alvim , Schemczssen-Graeff Zelinda , Pileggi Marcos
Published: September 2021

Herbicides are widely used in agricultural practices for preventing the proliferation of weeds that compete with crops for survival. Upon reaching soil and water, herbicides can damage nontarget organisms, such as bacteria, which need an efficient defense mechanism to tolerate the stress induced by herbicides. 2,4-Dichlorophenoxyacetic acid (2,4-D) is a herbicide that exerts increased oxidative stress among bacterial communities that consequently witness an increased toxicity in their microenvironments. Bacterial isolates were obtained from the biofilm of water that was contaminated with 2,4-D. This biofilm originated from the tanks containing washing water from the packaging of different pesticides, including 2,4-D. Moreover, several isolates were sensitive to biofilm toxicity; however, they remained alive in the presence of 2,4-D. The Pseudomonas sp. CMA-7.3 was selected because of its tolerance against biofilm agrochemicals. Therefore, the objective of this study is to evaluate the antioxidative response system of the Pseudomonas sp. CMA-7.3. This study also analyzed poorly evaluated enzymes, such as superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and guaiacol peroxidase GPX, in the bacterial systems. The toxic effects of 2,4-D on bacteria were evaluated using mechanisms indicating oxidative stress, such as growth curve, cell viability, peroxide, and malondialdehyde. The Pseudomonas sp. CMA-7.3 was an efficient response system against the activity of antioxidant enzymes such as SOD, CAT, APX, and GPX in balancing the production of H2O2, even at high doses as 25x the field dose of the herbicide, thereby proving the toxicity of 2,4-D for this strain and showing the ability of the strain to tolerate 2,4-D. The adaptation of this microorganism to herbicide exposure is truly relevant for improving future metabolic studies on bacterial communities. The strain showed a great potential in the application and developmental prospects of a new product in the bioremediation process of environments contaminated by these herbicides.
Dual perspective proteomics infectome profiling discoversSalmonellatype III secretion system effector functions in macrophages
Authors: Geddes-McAlister J. , Sukumaran A. , Vogt S.L. , Rowland J.L. , Woodward S.E. , Muselius B. , Gee L. , Roach E.J. , Khursigara C.M. , Raupach B. , Finlay B.B. , Meissner F.
Published: September 2021

Intracellular bacterial pathogens have evolved sophisticated infection strategies, including the release and secretion of virulence factors to interfere with host cell functions and to perturb immune responses. ForSalmonella entericaserovar Typhimurium (S. Typhimurium), the type III secretion systems encoded onSalmonellapathogenicity islands (SPI) 1 and 2 mediates invasion of the bacterium into innate immune cells and regulates bacterial replication and survival within the hostile environment of the host, respectively. Here, we explore the temporal and strain-specific dual perspective response of both the host and pathogen during cellular infection via quantitative proteomics. We report time- and pathogenicity island-specific expression and secretion of infection-associated proteins (i.e., SL1344_1263, SL1344_3112, SL1344_1563, and YnhG) and regulated immune response proteins in macrophage, including Cd86, Cd40, Casp4, C3, IL-1α, and Cd69). Through intracellular macrophage andin vivomurine models of infection, we reveal a role in virulence for three of the bacterial proteins (SL1344_1263, SL1344_1563, and YnhG), defining their importance as novel T3SS effectors. We characterize the temporal intra- and extracellular production of the effectors and identify their interaction networks in host cells, representing inhibitory and stimulatory pathways mounted by invading bacterial pathogens.

Author Summary

The relationship between a host and pathogen is intricate, and regulation of the host immune response correlates with the progressive timing of infection and tailored responses to the pathogen. Relying on detection and quantification of protein-level changes using mass spectrometry-based proteomics, we explore the production of known and novel effectors bySalmonelladuring intracellular survival within macrophage. Our results portray a role for these effectors in bacterial virulence using anin vivomurine model of infection, and we define a dynamic network of interaction between the effectors and host proteins. These interactions reveal opportunity for drug design to disrupt modulation of the host by the invading bacterium as a new strategy for combatting infection. Our approach is dynamic and universal, with the power to alter therapeutic discovery against infectious diseases.
CellRegMap: A statistical framework for mapping context-specific regulatory variants using scRNA-seq
Authors: Cuomo Anna S.E. , Heinen Tobias , Vagiaki Danai , Horta Danilo , Marioni John C. , Stegle Oliver
Published: September 2021

Single cell RNA sequencing (scRNA-seq) enables characterizing the cellular heterogeneity in human tissues. Technological advances have enabled the first population-scale scRNA-seq studies in hundreds of individuals, allowing to assay genetic effects with single-cell resolution. However, existing strategies to perform genetic analyses using scRNA-seq remain based on principles established for bulk RNA-seq. In particular, current methods depend on a priori definitions of discrete cell types, and hence cannot assess allelic effects across subtle cell types and cell states. To address this, we propose Cell Regulatory Map (CellRegMap), a statistical framework to test for and quantify genetic effects on gene expression in individual cells. CellRegMap provides a principled approach to identify and characterize heterogeneity in allelic effects across cellular contexts of different granularity, including cell subtypes and continuous cell transitions. We validate CellRegMap using simulated data and apply it to two recent studies of differentiating iPSCs, where we uncover a previously underappreciated heterogeneity of genetic effects across cellular contexts. Finally, we identify fine-grained genetic regulation in neuronal subtypes for eQTL that are colocalized with human disease variants.
Nuclear Pore Complex Acetylation Regulates mRNA Export and Cell Cycle Commitment in Budding Yeast
Authors: Gomar-Alba Mercè , Pozharskaia Vasilisa , Schaal Celia , Kumar Arun , Jacquel Basile , Charvin Gilles , Igual J. Carlos , Mendoza Manuel
Published: September 2021

Nuclear pore complexes (NPCs) mediate communication between the nucleus and the cytoplasm and regulate gene expression by interacting with transcription and mRNA export factors. Lysine acetyl-transferases (KATs) promote transcription through acetylation of chromatin-associated proteins. We find that Esa1, the KAT subunit of the yeast NuA4 complex, also acetylates the nuclear pore basket component Nup60 to promote mRNA export. Acetylation of Nup60 recruits to the nuclear basket the mRNA export factor Sac3, the scaffolding subunit of the Transcription and Export 2 (TREX-2) complex. Esa1-dependent nuclear export of mRNAs promotes entry into S phase, and is inhibited by the Hos3 deacetylase in G1 daughter cells to restrain their premature commitment to a new cell division cycle. This mechanism also inhibits expression of the nutrient-regulated GAL1 gene specifically in daughter cells. These results reveal how acetylation contributes to the functional plasticity of NPCs in specific cell types, and demonstrate how the evolutionarily conserved NuA4 complex regulates gene expression dually at the level of transcription and mRNA export, by modifying the nucleoplasmic entrance to nuclear pores.
Visualizing Molecules of FunctionalHumanProfilin
Authors: Pimm Morgan L. , Liu Xinbei , Tuli Farzana , Heritz Jennifer , Lojko Ashley , Henty-Ridilla Jessica L.
Published: September 2021

Profilin-1 (PFN1) is a cytoskeletal protein that regulates the dynamics of actin and microtubule assembly. Thus, PFN1 is essential for the normal division, motility, and morphology of cells. Unfortunately, conventional fusion and direct labeling strategies compromise different facets of PFN1 function. As a consequence, the only methods used to determine known PFN1 functions have been indirect and often deduced in cell-free biochemical assays. We engineered and characterized two genetically encoded versions of tagged PFN1 that behave identical to each other and the tag-free protein. In biochemical assays purified proteins bind to PIP lipids, catalyze nucleotide exchange on actin monomers, stimulate formin-mediated actin filament assembly, and impact microtubule dynamics. Halo-PFN1 or mApple-PFN1 restored morphological and cytoskeletal functions in PFN1-deficient mammalian cells. In biochemical assays, mAp-PFN1 bound tubulin dimers (kD= 1.89 μM) and the sides of microtubules in vitro. Titrations of self-labeling Haloligands were used to visualize molecules of PFN1. This approach combined with specific function-disrupting point-mutants (Y6D and R88E) revealed PFN1 bound to microtubules in live cells. Cells expressing the ALS-associated G118V disease variant did not associate with actin filaments or microtubules. Thus, these tagged PFN1s are reliable tools for studying the dynamic interactions of PFN1 with actin or microtubules in vitro as well as in important cell processes or disease-states.