bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal analysis of SARS-CoV-2 vaccine breakthrough infections reveal limited infectious virus shedding and restricted tissue distribution
Authors: Ke Ruian , Martinez Pamela P. , Smith Rebecca L. , Gibson Laura L. , Achenbach Chad J. , McFall Sally , Qi Chao , Jacob Joshua , Dembele Etienne , Bundy Camille , Simons Lacy M. , Ozer Egon A. , Hultquist Judd F. , Lorenzo-Redondo Ramon , Opdycke Anita K. , Hawkins Claudia , Murphy Robert L. , Mirza Agha , Conte Madison , Gallagher Nicholas , Luo Chun Huai , Jarrett Junko , Conte Abigail , Zhou Ruifeng , Farjo Mireille , Rendon Gloria , Fields Christopher J. , Wang Leyi , Fredrickson Richard , Baughman Melinda E. , Chiu Karen K. , Choi Hannah , Scardina Kevin R. , Owens Alyssa N. , Broach John , Barton Bruce , Lazar Peter , Robinson Matthew L. , Mostafa Heba H. , Manabe Yukari C. , Pekosz Andrew , McManus David D. , Brooke Christopher B.
Published: September 2021

The global effort to vaccinate people against SARS-CoV-2 in the midst of an ongoing pandemic has raised questions about the nature of vaccine breakthrough infections and the potential for vaccinated individuals to transmit the virus. These questions have become even more urgent as new variants of concern with enhanced transmissibility, such as Delta, continue to emerge. To shed light on how vaccine breakthrough infections compare with infections in immunologically naive individuals, we examined viral dynamics and infectious virus shedding through daily longitudinal sampling in a small cohort of adults infected with SARS-CoV-2 at varying stages of vaccination. The durations of both infectious virus shedding and symptoms were significantly reduced in vaccinated individuals compared with unvaccinated individuals. We also observed that breakthrough infections are associated with strong tissue compartmentalization and are only detectable in saliva in some cases. These data indicate that vaccination shortens the duration of time of high transmission potential, minimizes symptom duration, and may restrict tissue dissemination.
Prostate cancer risk stratification via non-destructive 3D pathology with annotation-free gland segmentation and analysis
Authors: Xie W. , Reder N.P. , Koyuncu C. , Leo P. , Hawley S. , Huang H. , Mao C. , Postupna N. , Kang S. , Serafin R. , Gao G. , Han Q. , Bishop K.W. , Barner L.A. , Fu P. , Wright J.L. , Keene C.D. , Vaughan J.C. , Janowczyk A. , Glaser A.K. , Madabhushi A. , True L.D. , Liu J.T.C.
Published: September 2021

Prostate cancer treatment planning is largely dependent upon examination of core-needle biopsies. In current clinical practice, the microscopic architecture of the prostate glands is what forms the basis for prognostic grading by pathologists. Interpretation of these convoluted 3D glandular structures via visual inspection of a limited number of 2D histology sections is often unreliable, which contributes to the under- and over-treatment of patients. To improve risk assessment and treatment decisions, we have developed a workflow for non-destructive 3D pathology and computational analysis of whole prostate biopsies labeled with a rapid and inexpensive fluorescent analog of standard H&E staining. Our analysis is based on interpretable glandular features, and is facilitated by the development of image-translation-assisted segmentation in 3D (ITAS3D). ITAS3D is a generalizable deep-learning-based strategy that enables tissue microstructures to be volumetrically segmented in an annotation-free and objective (biomarker-based) manner without requiring real immunolabeling. To provide evidence of the translational value of a computational 3D pathology approach, we analyzed ex vivo biopsies (n = 300) extracted from archived radical-prostatectomy specimens (N = 50), and found that 3D glandular features are superior to corresponding 2D features for risk stratification of low-to intermediate-risk PCa patients based on their clinical biochemical recurrence (BCR) outcomes.

Significance

We present an end-to-end pipeline for computational 3D pathology of whole prostate biopsies, showing that non-destructive pathology has the potential to enable superior prognostic stratification for guiding critical oncology decisions.
Unique plasma metabolite signature for adolescents with Klinefelter syndrome reveals altered fatty acid metabolism
Authors: Davis Shanlee M , Urban Rhianna , D’Alessandro Angelo , Haines Julie , Chan Christine , Kelsey Megan , Howell Susan , Tartaglia Nicole , Zeitler Philip , Baker Peter
Published: September 2021

Conditions related to cardiometabolic disease, including metabolic syndrome and type 2 diabetes, are common among men with Klinefelter syndrome (KS).The molecular mechanisms underlying this aberrant metabolism in KS are largely unknown, although there is an assumption that chronic testosterone deficiency plays a role. This cross-sectional study compared plasma metabolites in 31 pubertal adolescent males with KS to 32 controls of similar age (14 ± 2 yrs), pubertal stage, and body mass index z-score (0.1 ± 1.2), and then between testosterone treated (n=16) and untreated males with KS. The plasma metabolome in males with KS was distinctly different from controls, with 22% of measured metabolites having a differential abundance and seven metabolites nearly completely separating KS from controls (AUC>0.9, p<0.0001). Multiple saturated free fatty acids were higher in KS while mono- and polyunsaturated fatty acids were lower, and the top significantly enriched pathway was mitochondrial ß-oxidation of long-chain saturated fatty acids (enrichment ratio 16, p<0.0001). In contrast, there were no observed differences in metabolite concentrations between testosterone-treated and untreated individuals with KS. In conclusion, the plasma metabolome profile in adolescent males with KS is distinctly different from males without KS independent of age, obesity, pubertal development, or testosterone treatment status, and is suggestive of differences in mitochondrial ß-oxidation.
Fine analysis of lymphocyte subpopulations in SARS-CoV-2 infected patients: toward a differential profiling of patients with severe outcome
Authors: Clavarino Giovanna , Leroy Corentin , Epaulard Olivier , Raskovalova Tatiana , Vilotitch Antoine , Pernollet Martine , Dumestre-Pérard Chantal , Defendi Federica , Le Marechal Marion , Le Gouellec Audrey , Audoin Pierre , Bosson Jean-Luc , Poignard Pascal , Roustit Matthieu , Jacob Marie-Christine , Cesbron Jean-Yves
Published: September 2021

COVID-19 is caused by the human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in widespread morbidity and mortality. CD4+ T cells, CD8+ T cells and neutralizing antibodies all contribute to control SARS-CoV-2 infection. However, heterogeneity is a major factor in disease severity and in immune innate and adaptive responses to SARS-CoV-2. We performed a deep analysis by flow cytometry of lymphocyte populations of 125 hospitalized SARS-CoV-2 infected patients on the day of hospital admission. Five clusters of patients were identified using hierarchical classification on the basis of their immunophenotypic profile, with different mortality outcomes. Some characteristics were observed in all the clusters of patients, such as lymphopenia and an elevated level of effector CD8+CCR7- T cells. However, low levels of T cell activation are associated to a better disease outcome; on the other hand, profound CD8+ T-cell lymphopenia, a high level of CD4+ and CD8+ T-cell activation and a high level of CD8+ T-cell senescence are associated with a higher mortality outcome. Furthermore, a cluster of patient was characterized by high B-cell responses with an extremely high level of plasmablasts. Our study points out the prognostic value of lymphocyte parameters such as T-cell activation and senescence and strengthen the interest in treating the patients early in course of the disease with targeted immunomodulatory therapies based on the type of adaptive response of each patient.
How varying intervention, vaccination, mutation and ethnic conditions affect COVID-19 resurgence
Authors: Cao Longbing , Liu Qing
Published: September 2021

After a year of the unprecedented COVID-19 pandemic in 2020, the world has been overwhelmed by COVID-19 resurgences and virus mutations up to today. Here we develop a dynamic intervention, vaccination and mutation-driven epidemiological model with sequential interventions influencing epidemiological compartments and their state transition. We quantify epidemiological differences between waves under fatal viral mutations, the impacts of control or relaxation interventions and fatal virus mutations on resurgence under vaccinated or unvaccinated conditions, and estimate potential trends under varying interventions and mutations. Comprehensive analyses - between waves, with or without vaccinations, across representative countries with distinct ethnic and cultural backgrounds, what-if scenario simulations on second waves, and future 30-day trend - in two COVID-19 waves in Germany, France, Italy, Israel and Japan over 2020 and 2021 obtain quantitative empirical indication of the influence of strong vs. weak interventions, various combinations of control vs. relaxation strategies, and different transmissibility levels of coronavirus mutants on the behaviors and patterns of different waves and resurgences and future infection trends. The analyses quantify that (1) virus mutations, intervention fatigue, early relaxations, and lagging interventions, etc. may be common reasons for the resurgences observed in many countries; (2) timely strong interventions such as full lockdown will contain resurgence; (3) some resurgences relating to fatal mutants could have been better contained by either carrying forward the effective interventions from their early waves or implementing better controls and timing; (4) insufficient evidence is found on distinguishing the infection between unvaccinated and vaccinated countries while substantial vaccinations ensure much low mortality rate and high recovery rate; (5) resurgences with substantial vaccination have a much lower mortality rate and a higher recovery rate than those without vaccination; and (6) in the absence of sufficient vaccination, herd immunity and effective antiviral pharmaceutical treatments and with more infectious mutations, the widespread early or fast relaxation of interventions including public activity restrictions likely result in a COVID-19 resurgence. We also find the severity, number and timing of control and relaxation interventions determines a protection-deconfinement tradeoff, which can be used to evaluate the containment effect and the opportunity of resurgence and reopening under vaccination and fatal mutations.
Consensus molecular subtype differences linking colon adenocarcinoma and obesity revealed by a cohort transcriptomic analysis
Authors: Greene Michael W. , Abraham Peter T. , Kuhlers Peyton C. , Lipke Elizabeth A. , Heslin Martin J. , Wijaya Stanley T. , Odeniyi Ifeoluwa
Published: September 2021

Background

Colorectal cancer (CRC) is the third-leading cause of cancer-related deaths in the United States and worldwide. Obesity - a worldwide public health concern - is a known risk factor for cancer including CRC. However, the mechanisms underlying the link between CRC and obesity have yet to be fully elucidated in part because of the molecular heterogeneity of CRC. We hypothesized that obesity modulates CRC in a consensus molecular subtype (CMS)-dependent manner.

Methods

RNA-seq data and associated tumor and patient characteristics including body weight and height data for 232 patients were obtained from The Cancer Genomic Atlas – Colon Adenocarcinoma (TCGA-COAD) database. Tumor samples were classified into the four CMSs with the CMScaller R package; Body mass index (BMI) was calculated and categorized as normal, overweight, and obese.

Results

We observed a significant difference in CMS categorization between BMI categories. Differentially expressed genes (DEGs) between obese and overweight samples and normal samples differed across the CMSs, and associated prognostic analyses indicated that the DEGs had differing effects on survival. Using Gene Set Enrichment Analysis, we found differences in Hallmark gene set enrichment between obese and overweight samples and normal samples across the CMSs. We constructed Protein-Protein Interaction networks and observed differences in obesity-regulated hub genes for each CMS. Finally, we analyzed and found differences in predicted drug sensitivity between obese and overweight samples and normal samples across the CMSs.

Conclusions

Thus, we conclude that obesity has CMS-specific effects on the CRC tumor transcriptome.
Estimation of Vaccine Efficacy for Variants that Emerge After the Placebo Group Is Vaccinated
Authors: Follmann Dean , Fay Michael , Magaret Craig , Gilbert Peter
Published: September 2021

SARS-CoV-2 continues to evolve and the vaccine efficacy against variants is challenging to estimate. It is now common in phase III vaccine trials to provide vaccine to those randomized to placebo once efficacy has been demonstrated, precluding a direct assessment of placebo controlled vaccine efficacy after placebo vaccination. In this work we extend methods developed for estimating vaccine efficacy post placebo vaccination to allow variant specific time varying vaccine efficacy, where time is measured since vaccination. The key idea is to infer counterfactual strain specific placebo case counts by using surveillance data that provide the proportions of the different strains. This blending of clinical trial and observational data allows estimation of strain-specific time varying vaccine efficacy, or sieve effects, including for strains that emergent after placebo vaccination. The key requirements are that surveillance strain distribution accurately reflect the strain distribution for a placebo group, throughout follow-up after placebo group vaccination and that at least one strain is present before and after placebo vaccination. For illustration, we develop a Poisson approach for an idealized design under a rare disease assumption and then use a proportional hazards modeling to better reflect the complexities of field trials with staggered entry, crossover, and smoothly varying strain specific vaccine efficacy We evaluate these by theoretical work and simulations, and demonstrate that useful estimation of the efficacy profile is possible for strains that emerge after vaccination of the placebo group. An important principle is to incorporate sensitivity analyses to guard against mis-specfication of the strain distribution. We also provide an approach for use when genotyping of the infecting strains of the trial participants has not been done.
The association between influenza vaccination, all-cause mortality and cardiovascular mortality: a protocol for a living systematic review and prospective meta-analysis
Authors: Liu Rong , Patel Anushka , Du Xin , Liu Hueiming , Liu Bette , Wang Chi , Di Tanna Gian Luca
Published: September 2021

Introduction

Influenza virus infection is known to increase the risk of cardiovascular events, especially in populations with pre-existing cardiovascular disease. Considering that influenza is vaccine preventable, international guidelines recommend high-risk populations with CVD receive an influenza vaccine every year, but there are various classifications of recommendations and levels of evidence. Previous systematic reviews concluded uncertain evidence on influenza vaccine efficacy for preventing cardiovascular events in the general population or in populations with pre-existing CVD. Limited safety data of influenza vaccines were reported for populations with pre-existing CVD. Randomized control trials with larger sample sizes relative to previous studies are emerging, the findings of these trials are likely to be highly influential on summary efficacy estimates.

Methods and analysis

We aim to perform a living systematic review and a prospective meta-analysis to evaluate the efficacy and safety of influenza vaccines compared to no vaccines or placebo for preventing mortality or cardiovascular disease events in the general population and in populations with pre-existing CVD.

Ethics and dissemination

Formal ethical review is not required as this study does not need primary data collection. We will publish results of the living systematic review and prospective meta-analysis in a peer-reviewed journal. Findings will also be presented at relevant meetings.

PROSPERO registration number

CRD42021222519.

Strengths and limitations of this study

The living systematic review will continually incorporate the latest research findings and keep the synthesized information updated. A prospective meta-analysis will better address this evolving evidence.

Safety of influenza vaccines in populations with pre-existing cardiovascular diseases will be studied in particular to complete the current evidence base.

Observational studies may affect the overall quality of the study results. We will stratify the analysis by study design and present both randomized and non-randomized results.
Variant abundance estimation for SARS-CoV-2 in wastewater using RNA-Seq quantification
Authors: Baaijens Jasmijn A. , Zulli Alessandro , Ott Isabel M. , Petrone Mary E. , Alpert Tara , Fauver Joseph R. , Kalinich Chaney C. , Vogels Chantal B.F. , Breban Mallery I. , Duvallet Claire , McElroy Kyle , Ghaeli Newsha , Imakaev Maxim , Mckenzie-Bennett Malaika , Robison Keith , Plocik Alex , Schilling Rebecca , Pierson Martha , Littlefield Rebecca , Spencer Michelle , Simen Birgitte B. ,   Yale SARS-CoV-2 Genomic Surveillance Initiative, Hanage William P. , Grubaugh Nathan D. , Peccia Jordan , Baym Michael
Published: September 2021

Effectively monitoring the spread of SARS-CoV-2 variants is essential to efforts to counter the ongoing pandemic. Wastewater monitoring of SARS-CoV-2 RNA has proven an effective and efficient technique to approximate COVID-19 case rates in the population. Predicting variant abundances from wastewater, however, is technically challenging. Here we show that by sequencing SARS-CoV-2 RNA in wastewater and applying computational techniques initially used for RNA-Seq quantification, we can estimate the abundance of variants in wastewater samples. We show by sequencing samples from wastewater and clinical isolates in Connecticut U.S.A. between January and April 2021 that the temporal dynamics of variant strains broadly correspond. We further show that this technique can be used with other wastewater sequencing techniques by expanding to samples taken across the United States in a similar timeframe. We find high variability in signal among individual samples, and limited ability to detect the presence of variants with clinical frequencies <10%; nevertheless, the overall trends match what we observed from sequencing clinical samples. Thus, while clinical sequencing remains a more sensitive technique for population surveillance, wastewater sequencing can be used to monitor trends in variant prevalence in situations where clinical sequencing is unavailable or impractical.
Interfered Chromosome Pairing Promotes Meiosis Instability of Autotetraploid Arabidopsis by High Temperatures
Authors: Fu Huiqi , Zhao Jiayi , Ren Ziming , Yang Ke , Wang Chong , Zhang Xiaohong , Elesawi Ibrahim Eid , Zhang Xianhua , Xia Jing , Chen Chunli , Lu Ping , Chen Yongxing , Liu Hong , Yu Guanghui , Liu Bing
Published: September 2021

Alterations of environmental temperature affect multiple meiosis processes in flowering plants. Polyploid plants derived from whole genome duplication (WGD) have enhanced genetic plasticity and tolerance to environmental stress, but meanwhile face a challenge for organization and segregation of doubled chromosome sets. In this study, we investigated the impact of increased environmental temperature on male meiosis in autotetraploid Arabidopsis thaliana. Under low to mildly-increased temperatures (5-28°C), irregular chromosome segregation universally takes place in synthesized autotetraploid Columbia-0 (Col-0). Similar meiosis lesions occur in autotetraploid rice (Oryza sativa L.) and allotetraploid canola (Brassica napus cv. Westar), but not in evolutionary-derived hexaploid wheat (Triticum aestivum). As temperature increases to extremely high, chromosome separation and tetrad formation are severely disordered due to univalent formation caused by suppressed crossing-over. We found a strong correlation between tetravalent formation and successful chromosome pairing, both of which are negatively correlated with temperature elevation, suggesting that increased temperature interferes with crossing-over prominently by impacting homolog pairing. Besides, we showed that loading irregularities of axis proteins ASY1 and ASY4 co-localize on the chromosomes of syn1 mutant, and the heat-stressed diploid and autotetraploid Col-0, revealing that heat stress affects lateral region of synaptonemal complex (SC) by impacting stability of axis. Moreover, we showed that chromosome axis and SC in autotetraploid Col-0 are more sensitive to increased temperature than that of diploid Arabidopsis. Taken together, our study provide evidence suggesting that WGD without evolutionary and/or natural adaption negatively affects stability and thermal tolerance of meiotic recombination in Arabidopsis thaliana.
Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats
Authors: Kucharska Iga , Hossain Lamia , Ivanochko Danton , Yang Qiren , Rubinstein John L , Pomès Régis , Julien Jean-Philippe
Published: September 2021

Malaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region of CSP can prevent parasite infection. Although much has been uncovered about the molecular basis of antibody recognition of the PfCSP repeats, data remains scarce for PvCSP. Here, we performed molecular dynamics simulations for peptides comprising the PvCSP repeats from strains VK210 and VK247 to reveal how the PvCSP central repeats are highly disordered, with minor propensities to adopt turn conformations. Next, we solved eight crystal structures to unveil the interactions of two inhibitory monoclonal antibodies (mAbs), 2F2 and 2E10.E9, with PvCSP repeats. Both antibodies can accommodate subtle sequence variances in the repeat motifs and recognize largely coiled peptide conformations that also contain isolated turns. Our structural studies uncover various degrees of Fab-Fab homotypic interactions upon recognition of the PvCSP central repeats by these two inhibitory mAbs, similar to potent mAbs against PfCSP. These findings augment our understanding of host-Plasmodium interactions, and contribute molecular details of Pv inhibition by mAbs to unlock structure-based engineering of PvCSP-based vaccines.
Vascular risk is not associated with PET measures of Alzheimer’s disease neuropathology among cognitively normal older adults
Authors: Bilgel Murat , Bannerjee Alisa , Shafer Andrea , An Yang , Resnick Susan M.
Published: September 2021

Cardiovascular disease (CVD) is associated with a higher risk of developing dementia. Studies have found that vascular risk factors are associated with greater amyloid-β (Aβ) and tau burden, which are hallmark neuropathologies of Alzheimer’s disease (AD). Evidence for these associations during the preclinical stages of AD, when Aβ and tau pathologies first become detectable, is mixed. Quantifying the effect of vascular risk among cognitively normal individuals can help focus the efforts to develop therapeutic approaches aimed at modifying the course of preclinical AD.

Using Bayesian analysis, we examined the relationship of Aβ and tau pathology with concurrent vascular risk among 87 cognitively normal individuals (median age 77, interquartile range 70– 83) in the Baltimore Longitudinal Study of Aging. We quantified vascular risk as the probability of developing CVD within 10 years using published equations from the Framingham Heart Study. Aβ and tau pathologies were measured using positron emission tomography.

As expected, Aβ positive participants had greater tau in the entorhinal cortex (EC) and inferior temporal gyrus (ITG) (difference in means = 0.09, p < 0.05 for each region), and 10-year CVD risk was positively correlated with white matter lesion burden (r = 0.24, p = 0.03). However, we did not find any associations between CVD risk and Aβ or tau. The data provided over two- and four-fold evidence towards the lack of a correlation between CVD risk and tau in the EC (Bayes factor BF = 2.4) and ITG (BF = 4.0), respectively. We found over three-fold evidence towards the lack of a difference in mean CVD risk by Aβ group (BF = 3.4). These null findings were replicated using a data-driven vascular risk score in the BLSA based on a principal component analysis of eight indicators of vascular health.

Our data provide moderate evidence towards the lack of an association between vascular risk and concurrent AD neuropathology among cognitively normal older adults. This finding suggests that vascular risk and AD neuropathology may constitute independent pathways in the development of cognitive impairment and dementia.

Highlights

Vascular risk is associated with white matter lesion load, but not amyloid-β or tau

Moderate evidence for lack of association between vascular risk & early AD pathology

Vascular risk and Alzheimer’s neuropathology may constitute independent pathways
Engineering genetically-encoded synthetic biomarkers for breath-based cancer detection
Authors: Vermesh Ophir , D’Souza Aloma L. , Alam Israt S. , Wardak Mirwais , McLaughlin Theresa , El Rami Fadi , Sathirachinda Ataya , Bell John C. , James Michelle L. , Hori Sharon S. , Gross Eric R. , Gambhir Sanjiv Sam
Published: September 2021

Breath analysis holds great promise for rapid, noninvasive early cancer detection; however, clinical implementation is impeded by limited signal from nascent tumors and high background expression by non-malignant tissues. To address this issue, we developed a novel breath-based reporter system for early cancer detection using D-limonene, a volatile organic compound (VOC) from citrus fruit that is not produced in humans, in order to minimize background signal and maximize sensitivity and specificity for cancer detection. We metabolically engineered HeLa human cervical cancer cells to express limonene at levels detectable by mass spectrometry by introducing a single plant gene encoding limonene synthase. To improve limonene production and detection sensitivity twofold, we genetically co-expressed a modified form of a key enzyme in the cholesterol biosynthesis pathway. In a HeLa xenograft tumor mouse model, limonene is a sensitive and specific volatile reporter of tumor presence and growth, permitting detection of tumors as small as 5 mm. Moreover, tumor detection in mice improves proportionally with breath sampling time. By continuously collecting VOCs for 10 hours, we improve sensitivity for cancer detection 100-fold over static headspace sampling methods. Whole-body physiologically-based pharmacokinetic (PBPK) modeling and simulation of tumor-derived limonene predicts detection of tumors as small as 7 mm in humans, equivalent to the detection limit of clinical imaging modalities, such as PET, yet far more economical.

Significance Statement

We developed a breath-based reporter system using the plant terpene, D-limonene – a volatile secondary metabolite that gives citrus fruit its characteristic scent but is not produced in human tissues – as a biomarker for early cancer detection. Results from this study could pave the way for in vivo gene delivery and tumor-specific expression of exogenous volatile cancer reporters with broad applicability to the early diagnosis of a wide variety of cancers.
Functional connectivity gradients as a common neural architecture for predictive processing in the human brain
Authors: Katsumi Yuta , Kamona Nada , Zhang Jiahe , Bunce Jamie G. , Hutchinson J. Benjamin , Yarossi Mathew , Tunik Eugene , Quigley Karen S. , Dickerson Bradford C. , Barrett Lisa Feldman
Published: September 2021

Predictive processing is emerging as a common computational hypothesis to account for diverse psychological functions subserved by a brain, providing a systems-level framework for characterizing structure-function relationships of its distinct substructures. Here, we contribute to this framework by examining gradients of functional connectivity as a low dimensional spatial representation of functional variation in the brain and demonstrating their computational implications for predictive processing. Specifically, we investigated functional connectivity gradients in the cerebral cortex, the cerebellum, and the hippocampus using resting-state functional MRI data collected from large samples of healthy young adults. We then evaluated the degree to which these structures share common principles of functional organization by assessing the correspondence of their gradients. We show that the organizing principles of these structures primarily follow two functional gradients consistent with the existing hierarchical accounts of predictive processing: A model-error gradient that describes the flow of prediction and prediction error signals, and a model-precision gradient that differentiates regions involved in the representation and attentional modulation of such signals in the cerebral cortex. Using these gradients, we also demonstrated triangulation of functional connectivity involving distinct subregions of the three structures, which allows characterization of distinct ways in which these structures functionally interact with each other, possibly subserving unique and complementary aspects of predictive processing. These findings support the viability of computational hypotheses about the functional relationships between the cerebral cortex, the cerebellum, and the hippocampus that may be instrumental for understanding the brain’s dynamics within its large-scale predictive architecture.
Artificial introns for effective expression of transgenes in mammalian cells
Authors: Naberezhnov D.S. , Lesovaya E.A. , Kirsanov K.I. , Yakubovskaya M.G.
Published: September 2021

Introns are widely used in the assembly of genetic constructions expressing transgenic proteins in eukaryotic cells for the enhancement of this expression. However, the choice of introns that can be applied for such purposes is limited by the excessively large size of the majority of natural introns (several thousand nucleotides) and therefore they cannot be cloned in a genetic construction. With the help of site-directed mutagenesis we have generated a library of short (99 nucleotides long) introns. The efficiency of these introns in the enhancement of gene expression was analyzed. As a result, a set of 12 introns was selected. The generated intros can be used for genetic constructions with high expression level of recombinant proteins.
Spatial organization of nuclear pores in Xenopus laevis oocytes
Authors: Ravazzano Linda , Bonfanti Silvia , Guerra Roberto , Montel Fabien , La Porta Caterina A. M. , Zapperi Stefano
Published: September 2021

Nuclear pores are protein assemblies inserted in the nuclear envelope of eukaryotic cells, acting as main gates for communication between nucleus and cytoplasm. So far, nuclear pores have been extensively studied to determine their structure and composition, yet their spatial organization and geometric arrangement on the nuclear surface are still poorly understood. Here, we analyze super-resolution images of the surface of Xenopus laevis oocyte nuclei during development, and characterize the arrangement of nuclear pores using tools commonly employed to study the atomic structural and topological features of soft matter. To interpret the experimental results, we hypothesize an effective interaction among nuclear pores and implemented it in extensive numerical simulations of octagonal clusters mimicking typical pore shapes. Thanks to our simple model, we find simulated spatial distributions of nuclear pores that are in excellent agreement with experiments, suggesting that an effective interaction among nuclear pores exists and could explain their geometrical arrangement. Furthermore, our results show that the statistical features of the geometric arrangement of nuclear pores do not depend on the type of pore-pore interaction, attractive or repulsive, but are mainly determined by the octagonal symmetry of each single pore. These results pave the way to further studies needed to determine the biological nature of pore-pore interactions.
Domestication Reshaped the Genetic Basis of Inbreeding Depression in a Maize Landrace Compared to its Wild Relative, Teosinte
Authors: Samayoa L.F. , Olukolu B.A. , Yang C.J. , Chen Q. , Stetter Markus G. , York Alessandra M. , Sanchez-Gonzalez Jose de Jesus , Glaubitz Jeffrey C. , Bradbury Peter J. , Romay Maria Cinta , Sun Qi , Yang Jinliang , Ross-Ibarra Jeffrey , Buckler Edward S. , Doebley J.F. , Holland J.B.
Published: September 2021

Inbreeding depression is the reduction in fitness and vigor resulting from mating of close relatives observed in many plant and animal species. The extent to which the genetic load of mutations contributing to inbreeding depression is due to rare large-effect variation versus potentially more common variants with very small individual effects is unknown and may be affected by population history. We compared the effects of outcrossing and self-fertilization on 18 traits in a landrace population of maize, which underwent a population bottleneck during domestication, and a neighboring population of its wild relative teosinte. Inbreeding depression was greater in maize than teosinte for 15 of 18 traits, congruent with the greater segregating genetic load predicted from sequence data in the maize population. For many traits - and more commonly in maize - genetic variation among selffertilized families was less than expected based on additive and dominance variance estimated in outcrossed families, suggesting that a negative covariance between additive and homozygous dominance effects limits the variation available to selection under partial inbreeding. We identified quantitative trait loci (QTL) representing large-effect rare variants carried by only a single parent, which were more important in teosinte than maize. Teosinte also carried more putative juvenile-acting lethal variants identified by segregation distortion. These results suggest a mixture of mostly polygenic, smalleffect recessive variation underlying inbreeding depression, with an additional contribution from rare larger-effect variants that was more important in teosinte but depleted in maize following to the domestication bottleneck. Purging associated with the maize domestication bottleneck may have selected against large effect variants, but polygenic load is harder to purge and segregating mutational burden increased in maize compared to teosinte.
Update on the mosquito fauna (Diptera: Culicidae) distribution in Cabo Verde: occurrence of the species complexes Anopheles gambiae and Culex pipiens (pipiens, quinquefasciatus and their hybrids)
Authors: Da Veiga Leal Silvânia , Fernandes Varela Isaias Baptista , Sousa Monteiro Davidson Daniel , Ramos de Sousa Celivianne Marisia , Mendonça Maria da Luz Lima , De Pina Adilson José , Lopes Gonçalves Aderitow Augusto , Osório Hugo Costa
Published: September 2021

In this study, we aimed to update the mosquito species composition and distribution based on a national entomological survey in all municipalities of Cabo Verde. This includes the sibling species of the Culex pipiens complex, namely Cx. pipiens, Cx. quinquefasciatus and their hybrids, in locations where information is not available. The entomological survey took place from October 2017 to September 2018, in all municipalities of Cabo Verde. Mosquito larvae and pupae were collected in breeding sites and samples were sent to the Laboratory of Medical Entomology of the National Institute of Public Health for the morphological identification of the species. The mosquitoes morphologically identified in Anopheles gambiae and Culex pipiens complexes of species were further molecular analysed to species confirmation. A total of 814 breeding sites were surveyed and 10 mosquito species of five genera were identified. The greatest number of mosquito species was reported in the island of Santiago. The most widespread species in the country were Aedes aegypti and Culex quinquefasciatus. Anopheles arabiensis was the only species identified in the Gambiae complex of species. The results of this study will assist decision makers in important health policies to control mosquitoes and vector-borne diseases towards a strategic approach by timely detection of changes in species diversity.
Genome-wide association analysis of cotton salt stress response-related sites
Authors: Zheng Juyun , Zhang Zeliang , Gong Zhaolong , Liang Yajun , Sang Zhiwei , Xu YanChao , Li Xueyuan , Wang Jungduo
Published: September 2021

Soil salinization is the main abiotic stress factor affecting agricultural production worldwide, and salt stress has a significant impact on plant growth and development. Cotton is one of the most salt-tolerant crops. Its salt tolerance varies greatly depending on the variety, growth stage, organs, and soil salt types. Therefore, the selection and utilization of excellent salt-tolerant germplasm resources and the excavation of excellent salt-tolerant salt and salt resistance genes play important roles in improving cotton production in saline-alkali soils. In this study, we analysed the population structure and genetic diversity of 144 elite Gossypium hirsutum cultivar accessions collected from around the world, and especially from China. Illumina Cotton SNP 70K was used to obtain genome-wide single-nucleotide polymorphism (SNP) data for 149 experimental materials, and 18,432 highly consistent SNP loci were obtained by filtering. PCA (principal component analysis) indicated that 149 upland cotton materials could be divided into 2 subgroups, including subgroup 1 with 78 materials and subgroup 2 with 71 materials. Using the obtained SNP and other marker genotype test results, under salt stress, the salt tolerance traits 3d_Germination_potential, 3d_Bud_length_drop_rate, 7d_Germination_rate, 7d_Bud_length_drop_rate, 7d_Germination_weight, 3d_Bud_length, 7d_Bud_length, relative_germination_potential, Relative_germination_rate, 7d_Bud_weight_drop_rate, Salt tolerance index 3d_Germination_potential_index, 3d_Bud_length_index, 7d_Bud_length_index, 7d_Bud_weight_index, and 7d_Germination_rate_index were evaluated by genome association analysis. A total of 27 SNP markers closely related to salt tolerance traits and 15 SNP markers closely related to salt tolerance index were detected. At the SNP locus associated with the traits of the bud length decline rate at 7 days, alleles Gh_A01G0034 and Gh_D01G0028 related to plant salt tolerance were detected, and they are related to intracellular transport, membrane microtubule formation and actin network. This study provides a theoretical basis for the selection and breeding of salt-tolerant upland cotton varieties.
MAPK cascades mediating Trichoderma brevicrassum strain TC967 against phytopathogen Rhizoctonia solani
Authors: Zhang Yi , Zhuang Wen-Ying
Published: September 2021

Trichoderma brevicrassum strain TC967 is a novel biological control agent (BCA) against the plant pathogen Rhizoctonia solani and promotes plant growth. MAPK (mitogen-activated protein kinase) cascades were involved in biocontrol by Trichoderma, but functions of each MAPK in regulating biocontrol have not been characterized in one Trichoderma. In this study, we assembled and annotated the genome of strain TC967, and identified its three MAPK gene sequences. Functions of Fus3-, Slt2- and Hog1-MAPK in strain TC967 were dissected. The three MAPKs were all involved in hyphal growth. The Hog1-MAPK was essential for conidiation and tolerance to hyperosmotic stress. The Fus3- and Slt2-MAPK both mediated cell-wall integrity (CWI) and activities of chitinase and protease. The Fus3- and Hog1-MAPK mediated response to oxidative stress. Our biocontrol assays demonstrated that the Fus3- and Slt2-MAPK mutants were considerably more effective in disease control than the wild-type strain. RNA-seq analysis revealed that MAPK collectively played a major role in regulating biocontrol-related gene expressions, including of the genes in charge of secondary metabolism, fungal cell wall-degrading enzymes (FCWDEs) and small secreted cysteine-rich proteins (SSCPs).

Author summary

Soil-born fungal pathogens pose an emerging threat to crop production. Trichoderma brevicrassum strain TC967 has the ability to control the notorious phytopathogen Rhizoctonia solani and promote plant growth. In this study, we explored the functions of three-types of MAPK in mediating biocontrol process, and uncovered that Fus3-, Slt2- and Hog1-MAPK are involved in hyphal growth, conidiation, tolerance to hyperosmotic stress, cell-wall integrity, activities of chitinase and protease, and response to oxidative stress. Biocontrol ability of strain TC967 was accelerated after deletion of the Fus3- and Slt2-MAPK genes. MAPK collectively played a major role in regulating biocontrol-related gene expressions as revealed by RNA-seq analysis. To our knowledge, this is the first report of the functions of MAPKs in regulating biocontrol in one Trichoderma. Our results provide a reference for improvement of biocontrol ability of Trichoderma strains from the view of MAPK cascades.
A closed Candidatus Odinarchaeum genome exposes Asgard archaeal viruses
Authors: Tamarit Daniel , Caceres Eva F. , Krupovic Mart , Nijland Reindert , Eme Laura , Robinson Nicholas P. , Ettema Thijs J. G.
Published: September 2021

Asgard archaea have recently been identified as the closest archaeal relatives of eukaryotes. Their ecology remains enigmatic, and their virome, completely unknown. Here, we describe the closed genome of Ca. Odinarchaeum yellowstonii LCB_4, and, from this, obtain novel CRISPR arrays with spacer targets to several viral contigs. We find related viruses in sequence data from thermophilic environments and in the genomes of diverse prokaryotes, including other Asgard archaea. These novel viruses open research avenues into the ecology and evolution of Asgard archaea.
Sites of active gene regulation in the prenatal frontal cortex and their role in neuropsychiatric disorders
Authors: Kouakou Manuela R. , Cameron Darren , Hannon Eilis , Dempster Emma L. , Mill Jonathan , Hill Matthew J. , Bray Nicholas J.
Published: September 2021

Common genetic variation appears to largely influence risk for neuropsychiatric disorders through effects on gene regulation. It is therefore possible to shed light on the biology of these conditions by testing for enrichment of associated genetic variation within regulatory genomic regions operating in specific tissues or cell types. Here, we have used ATAC-Seq to map open chromatin (an index of active regulatory genomic regions) in bulk tissue, NeuN+ and NeuN− nuclei from the prenatal human frontal cortex, and tested enrichment of SNP heritability for 5 neuropsychiatric disorders (autism spectrum disorder, ADHD, bipolar disorder, major depressive disorder and schizophrenia) within these regions. We observed significant enrichment of SNP heritability for ADHD, major depressive disorder and schizophrenia within open chromatin regions mapped in bulk fetal frontal cortex, and for all 5 tested neuropsychiatric conditions when we restricted these sites to those overlapping histone modifications indicative of enhancers (H3K4me1) or promoters (H3K4me3) in fetal brain. SNP heritability for neuropsychiatric disorders was significantly enriched in open chromatin regions identified in fetal frontal cortex NeuN- as well as NeuN+ nuclei overlapping fetal brain H3K4me1 or H3K4me3 sites. We additionally demonstrate the utility of our mapped open chromatin regions for prioritizing potentially functional SNPs at genome-wide significant risk loci for neuropsychiatric disorders. Our data provide evidence for an early neurodevelopmental component to a range of neuropsychiatric conditions and highlight an important role for regulatory genomic regions active within both NeuN+ and NeuN− cells of the prenatal brain.
Mixed Origins: HIV gp120-specific memory develops from pre-existing memory and naïve B cells following vaccination in humans
Authors: Basu Madhubanti , Piepenbrink Michael S. , Fucile Christopher , Bunce Catherine A. , Man Li-Xing , Liesveld Jane , Rosenberg Alexander F. , Keefer Michael C. , Kobie James J.
Published: September 2021

The most potent and broad HIV envelope (Env)-specific antibodies often when reverted to their inferred germline versions representing the naïve B cell receptor, fail to bind Env suggesting that the initial responding B cell population is not exclusively comprised of a naïve population, but also a pre-existing cross-reactive antigen-experienced B cell pool that expands following Env exposure. Previously we isolated gp120-reactive monoclonal antibodies (mAbs) from participants in HVTN 105, an HIV vaccine trial. Using deep sequencing VH-lineage tracking we identified several of these mAb lineages in pre-immune peripheral blood. Several of these pre-immune lineages also persisted in the bone marrow, including CD138+ long-lived plasma cell compartment, ∼7 months after the final vaccination. The majority of the pre-immune lineage members included IgM, however IgG and IgA members were also prevalent and exhibited somatic hypermutation. These results suggest that vaccine-induced gp120-specific antibody lineages originate from both naïve and cross-reactive memory B cells.
Natural variation in Arabidopsis ISR1 affects iron localization and induced systemic resistance
Authors: Socha Amanda L. , Song Yi , Ross Brandon S. , Bush Jenifer , Ausubel Frederick M. , Guerinot Mary Lou , Haney Cara H.
Published: September 2021

Beneficial root-associated bacteria can induce systemic resistance (ISR) to foliar pathogens and there is known transcriptional and genetic overlap in the root response to iron deficiency and ISR. A previous study found that there is natural variation in ISR among Arabidopsis accessions. The Ws accession is deficient in ISR, and the responsible recessive genetic locus, named ISR1, was mapped to chromosome 3. To find candidate genes that may underlie ISR deficiency in Ws, we identified genes that are induced in response to the ISR-triggering bacterium Pseudomonas simiae WCS417 and to iron stress and that have non-synonymous mutations in the Ws genome with respect to the ISR-responsive Col-0. We identified a kelch-domain containing protein encoded by At3g07720 that has a genomic rearrangement in Ws. We found that overexpression of Col-0 At3g07720 restores ISR to Ws, indicating that At3g07720 encodes ISR1. Isr1 loss of function mutants do not affect plant growth under iron limiting conditions but have increased levels of apoplastic iron. We found that iron supplementation, P. simiae WCS417, or a loss of isr1 enhance ROS production in a non-additive manner, suggesting they work through the same mechanism to enhance resistance. Our findings show that ISR1 is required for iron localization, immunity, and ISR, and suggest that increased iron uptake induced by ISR-eliciting bacteria may directly contribute to immunity through increased reactive oxygen production.