bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of MaWRKY40 and MaDLO1 as Effective Marker Genes for Tracking the Salicylic Acid-Mediated Immune Response in Bananas
Authors: Tzean Yuh , Hou Bo-Han , Tsao Shu-Ming , Chen Ho-Ming , Cheng An-Po , Chen Elena Gamboa , Chou Wei-Yi , Chao Chih-Ping , Shen Wei-Chiang , Chen Chyi-Chuann , Lee Ming-Chi , Ashraf Iqra , Yeh Hsin-Hung
Published: March 2021

Bananas are among the world’s most important cash and staple crops but are threatened by various devastating pathogens. The phytohormone salicylic acid (SA) plays a key role in the regulation of plant immune response. Tracking the expression of SA-responsive marker genes under pathogen infection is important in pathogenesis elucidation. However, the common SA-responsive marker genes are not consistently induced in different banana cultivars or different organs. Here, we conducted transcriptome analysis for SA response of a banana cultivar, ‘Pei-Chiao’ (Cavendish, AAA genome), and identified three genes, MaWRKY40, MaWRKY70, and Downy Mildew Resistant 6 (DMR6)-Like Oxygenase 1 (MaDLO1) that are robustly induced upon SA treatment in both the leaves and roots. Consistent induction of these three genes by SA treatment was also detected in both the leaves and roots of bananas belonging to different genome types such as ‘Tai-Chiao No. 7’ (Cavendish, AAA genome), ‘Pisang Awak’ (ABB genome), and ‘Lady Finger’ (AA genome). Furthermore, the biotrophic pathogen cucumber mosaic virus elicited the expression of MaWRKY40 and MaDLO1 in infected leaves of susceptible cultivars. The hemibiotrophic fungal pathogen Fusarium oxysporum f. sp. cubense tropical race 4 (TR4) also consistently induced the expression of MaWRKY40 and MaDLO1 in the infected roots of the F. oxysporum f. sp. cubense TR4-resistant cultivar. These results indicate that MaWRKY40 and MaDLO1 can be used as reliable SA-responsive marker genes for the study of plant immunity in banana. Revealing SA-responsive marker genes provides a stepping stone for further studies in banana resistance to pathogens.
Association of Breastfeeding and Child IQ Score at Age 5 Years
Authors: Plunkett Beth A. , Mele Lisa , Casey Brian M. , Varner Michael W. , Sorokin Yoram , Reddy Uma M. , Wapner Ronald J. , Thorp John M. , Saade George R. , Tita Alan T.N. , Rouse Dwight J. , Sibai Baha , Mercer Brian M. , Tolosa Jorge E. , Caritis Steve N. ,   for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network
Published: March 2021

OBJECTIVE:

To evaluate whether breastfeeding and its duration are associated with a reduced risk of low IQ scores or other neurodevelopmental problems.

METHODS:

We conducted a secondary analysis of two parallel multicenter, double-blinded randomized controlled trials in which participants with a singleton pregnancy and either subclinical hypothyroidism or hypothyroxinemia were treated with thyroxine or placebo. Our primary outcome was a low IQ score (less than 85 on the WPPSI-III [Wechsler Preschool and Primary Scale of Intelligence III] at age 5 years). Secondary outcomes included performance measures on other validated neurodevelopmental tests. Univariable and multivariable analyses were performed to evaluate the association between breastfeeding and neurodevelopmental outcomes. Stepwise backward proceeding linear and logistic regression models were used to develop the final adjusted models.

RESULTS:

Of the 772 participants studied, 614 (80%) reported breastfeeding. Of these, 31% reported breastfeeding for less than 4 months, 19% for 4–6 months, 11% for 7–9 months, 15% for 10–12 months and 23% for more than 12 months. IQ scores were available for 756 children; mean age-5 scores were higher with any breastfeeding (96.7±15.1) than without (91.2±15.0, mean difference 5.5, 95% CI 2.8–8.2), and low IQ scores were less frequent with any breastfeeding (21.5%) than with no breastfeeding (36.2%, odds ratio 0.48, 95% CI 0.33–0.71). In adjusted analyses, breastfeeding remained associated with reduced odds of low IQ score (adjusted odds ratio [aOR] 0.62, 95% CI 0.41–0.93), and each additional month of breastfeeding was associated with lower odds of a low IQ scores (aOR 0.97, 95% CI 0.939–0.996). No significant associations between breastfeeding and other neurodevelopmental outcomes were identified in adjusted analyses.

CONCLUSION:

Breastfeeding and its duration are associated with lower odds of low IQ score at age 5 years.
Clinical Epidemiology and Management of Hidradenitis Suppurativa
Authors: Sayed Christopher J. , Hsiao Jennifer L. , Okun Martin M. ,   for the Hidradenitis Suppurativa Foundation Women's Health Subcommittee
Published: March 2021

Hidradenitis suppurativa is a chronic immune-mediated inflammatory skin disease with a prevalence of 0.1–1%, characterized by nodules and abscesses in the axillae, groin, and inframammary areas, sometimes developing into tunnels (or fistulas) and scars. Because hidradenitis suppurativa is more common in women and in those aged 18–40 years, obstetrician–gynecologists (ob-gyns) have the opportunity to diagnose, educate, initiate treatment, and coordinate care with ancillary health care professionals. The recently published North American treatment guidelines, along with management information for patients with hidradenitis suppurativa who are pregnant or breastfeeding, are summarized. By diagnosing and optimizing hidradenitis suppurativa treatment early in the disease course, ob-gyns can reduce morbidity, with the potential to favorably alter disease trajectory.
Gastric Mucosa Fistula Secondary to Magnet Ingestion
Authors: Lorenze Alyssa , Downey Syndey , Costello Lisa M. , Menchini Cortney Ballengee
Published: March 2021

A 15-month-old female was incidentally found to have foreign bodies in the left upper quadrant on chest and abdominal imaging. She had no witnessed ingestion or gastrointestinal symptoms. Subsequent esophagogastroduodenoscopy showed 11 magnets, which formed a gastric mucosa fistula making endoscopic removal difficult. This case highlights the dangers of high-powered magnets and the unique challenges they can pose to endoscopists.
Reciprocal interactions between osteoclasts and nociceptive sensory neurons in bone cancer pain
Authors: Andriessen Amanda S. , Donnelly Christopher R. , Ji Ru-Rong
Published: March 2021

Many common cancers such as breast, prostate, and lung cancer metastasize to bones at advanced stages, producing severe pain and functional impairment. At present, the current pharmacotherapies available for bone cancer pain are insufficient to provide safe and efficacious pain relief. In this narrative review, we discuss the mechanisms used by cancer cells within the bone tumor microenvironment (TME) to drive bone cancer pain. In particular, we highlight the reciprocal interactions between tumor cells, bone-resorbing osteoclasts, and pain-sensing sensory neurons (nociceptors), which drive bone cancer pain. We discuss how tumor cells present within the bone TME accelerate osteoclast differentiation (osteoclastogenesis) and alter osteoclast activity and function. Furthermore, we highlight how this perturbed state of osteoclast overactivation contributes to bone cancer pain through (1) direct mechanisms, through their production of pronociceptive factors that act directly on sensory afferents; and (2) by indirect mechanisms, wherein osteoclasts drive bone resorption that weakens tumor-bearing bones and predisposes them to skeletal-related events, thereby driving bone cancer pain and functional impairment. Finally, we discuss some potential therapeutic agents, such as denosumab, bisphosphonates, and nivolumab, and discuss their respective effects on bone cancer pain, osteoclast overactivation, and tumor growth within the bone TME.
Sensory neuron–associated macrophages as novel modulators of neuropathic pain
Authors: Silva Conceição Elidianne Aníbal , Guimarães Rafaela Mano , Cunha Thiago Mattar
Published: March 2021

The peripheral nervous system comprises an infinity of neural networks that act in the communication between the central nervous system and the most diverse tissues of the body. Along with the extension of the primary sensory neurons (axons and cell bodies), a population of resident macrophages has been described. These newly called sensory neuron–associated macrophages (sNAMs) seem to play an essential role in physiological and pathophysiological processes, including infection, autoimmunity, nerve degeneration/regeneration, and chronic neuropathic pain. After different types of peripheral nerve injury, there is an increase in the number and activation of sNAMs in the sciatic nerve and sensory ganglia. The activation of sNAMs and their participation in neuropathic pain development depends on the stimulation of pattern recognition receptors such as Toll-like receptors and Nod-like receptors, chemokines/cytokines, and microRNAs. On activation, sNAMs trigger the production of critical inflammatory mediators such as proinflammatory cytokines (eg, TNF and IL-1β) and reactive oxygen species that can act in the amplification of primary sensory neurons sensitization. On the other hand, there is evidence that sNAMs can produce antinociceptive mediators (eg, IL-10) that counteract neuropathic pain development. This review will present the cellular and molecular mechanisms behind the participation of sNAMs in peripheral nerve injury–induced neuropathic pain development. Understanding how sNAMs are activated and responding to nerve injury can help set novel targets for the control of neuropathic pain.
Introduction for special issue on neuroimmune interactions in chronic pain
Authors: Malcangio Marzia
Published: March 2021

The growing awareness of the critical role played by the innate and adaptive immune systems in the mechanisms underlying chronic pain has prompted further research examining the modalities by which immune cells communicate with neurones, the aim being to identify new players involved in inflammatory and neuropathic pain signalling. This collection of research includes 9 articles on neuroimmune interactions as the underlying mechanisms for neuropathic pain including peripheral neuropathies, pain in rheumatoid arthritis and osteoarthritis, and bone cancer pain. The immune cells under scrutiny include macrophages, microglia, osteoclasts, and B cells, and their interactions with neurones in locations such as the dorsal root ganglia, blood–spinal cord barrier, spinal cord, and brain. Our hope is that this body of work may serve to furnish existing interest while also constituting a springboard of sorts for indispensable further investigation on neuroimmune interactions in chronic pain.
From the low-density lipoprotein receptor–related protein 1 to neuropathic pain: a potentially novel target
Authors: García-Fernández Patricia , Üçeyler Nurcan , Sommer Claudia
Published: March 2021

This review describes the roles of the low-density lipoprotein receptor–related protein 1 (LRP-1) in inflammatory pathways, nerve nerve degeneration and -regeneration and in neuropathic pain. Induction of LRP-1 is able to reduce the activation of the proinflammatory NFκB-mediated pathway and the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase and p38 signaling pathways, in turn decreasing the production of inflammatory mediators. Low-density lipoprotein receptor-related protein 1 activation also decreases reactive astrogliosis and polarizes microglial cells and macrophages from a proinflammatory phenotype (M1) to an anti-inflammatory phenotype (M2), attenuating the neuroinflammatory environment. Low-density lipoprotein receptor-related protein 1 can also modulate the permeability of the blood–brain barrier and the blood–nerve barrier, thus regulating the infiltration of systemic insults and cells into the central and the peripheral nervous system, respectively. Furthermore, LRP-1 is involved in the maturation of oligodendrocytes and in the activation, migration, and repair phenotype of Schwann cells, therefore suggesting a major role in restoring the myelin sheaths upon injury. Low-density lipoprotein receptor-related protein 1 activation can indirectly decrease neurodegeneration and neuropathic pain by attenuation of the inflammatory environment. Moreover, LRP-1 agonists can directly promote neural cell survival and neurite sprouting, decrease cell death, and attenuate pain and neurological disorders by the inhibition of MAPK c-Jun N-terminal kinase and p38-pathway and activation of MAPK extracellular signal–regulated kinase pathway. In addition, activation of LRP-1 resulted in better outcomes for neuropathies such as Alzheimer disease, nerve injury, or diabetic peripheral neuropathy, attenuating neuropathic pain and improving cognitive functions. To summarize, LRP-1 plays an important role in the development of different experimental diseases of the nervous system, and it is emerging as a very interesting therapeutic target.
Pain matters for central sensitization: sensory and psychological parameters in patients with fibromyalgia syndrome
Authors: Rehm Stefanie , Sachau Juliane , Hellriegel Jana , Forstenpointner Julia , Børsting Jacobsen Henrik , Harten Pontus , Gierthmühlen Janne , Baron Ralf
Published: March 2021

Introduction:

Patients suffering from fibromyalgia syndrome (FMS) are heterogenous. They often present with sensory abnormalities and comorbidities.

Objectives:

We aimed to answer the following questions: (1) Is there a specific somatosensory profile in our patient cohort? (2) Can we detect subgroups characterized by a specific combination of sensory and psychological features? and (3) Do psychological parameters influence sensory signs?

Methods:

In 87 patients with FMS quantitative sensory testing was performed on the hand and evaluated in combination with questionnaire results regarding pain, psychological comorbidities, sleep, and functionality.

Results:

Patients presented different somatosensory patterns, but no specific subgroups regarding sensory signs and psychological features were detected. Hypersensitivity for noxious mechanical and thermal stimuli and hyposensitivity for nonnoxious mechanical stimuli were the most prominent features. Thirty-one percent of patients showed signs of central sensitization as indicated by abnormally increased pinprick hyperalgesia or dynamic mechanical allodynia. Central sensitization was associated with higher pain intensities (P < 0.001). Only a small influence of psychiatric comorbidities on mechanical pain sensitivity (P = 0.044) and vibration detection (P = 0.028) was found, which was partly associated with high pain intensities. A small subgroup of patients (11.4%) demonstrated thermal hyposensitivity (loss of small-fiber function).

Conclusion:

Patients with FMS showed various somatosensory abnormalities. These were not significantly influenced by psychological comorbidities. Signs for central sensitization were detected in about one-third of patients and associated with higher pain intensities. This supports the notion of central sensitization being a major pathophysiological mechanism in FMS, whereas small-fiber loss may be less important.
Factors associated with maternal tetanus vaccination in Myanmar: An analysis of Demographic and Health Survey data
Authors: Tun Zaw Myo , Ring Zau , Tam Clarence C
Published: March 2021

Background

Tetanus toxoid vaccination is a life-saving maternal and child health intervention. Understanding gaps in maternal vaccination coverage is key to informing progress towards universal health coverage. We assessed maternal tetanus vaccination coverage in Myanmar and investigated factors associated with being unvaccinated.

Method

We analysed 2015-16 Demographic and Health Survey data including women aged 15-49 years with at least one childbirth in the last five years. The outcome was self-reported receipt of tetanus vaccine at least once during the last pregnancy. We used logistic regression models to assess factors associated with being unvaccinated.

Results

Overall maternal tetanus vaccination coverage was 85.7%. Sub-national coverage was lowest in the predominantly ethnic minority states of Shan, Kayin, and Chin at 69.6%, 77.4%, and 79.9%, respectively. Factors associated with a lack of vaccination were: not receiving antenatal care (odds ratio (OR): 18.99, 95% confidence interval (CI): 14.21, 25.39); receiving antenatal care at home (OR: 2.05, 95% CI: 1.46, 2.88), private and non-governmental organization clinics (OR: 2.88, 95% CI: 1.81, 4.58, compared to public facilities); and not wanting to go to a health facility alone (OR: 1.53, 95% CI: 1.14, 2.06). Higher educational attainment was associated with lower odds of being unvaccinated (OR: 0.48, 95% CI: 0.32, 0.70 for secondary relative to no education).

Interpretation

We identified regional, structural, and individual differences in maternal tetanus vaccination coverage. Achieving universal coverage of maternal tetanus vaccination will largely depend on the ability to provide accessible antenatal care to most women who do not currently receive it.
OsbZIP62/OsFD7, a functional ortholog of Flowering Locus D (FD), regulates floral transition and panicle development in rice
Authors: Kaur Amarjot , Nijhawan Aashima , Yadav Mahesh , Khurana Jitendra P.
Published: March 2021

We have characterized a rice bZIP protein coding geneOsbZIP62/OsFD7that expresses preferentially in SAM and during early panicle developmental stages in comparison to other OsFDs characterised till date. Surprisingly, unlike OsFD1, OsFD7 interacts directly and more efficiently with OsFTLs; the interaction is strongest with OsFTL1 followed by Hd3a and RFT1, as confirmed by FLIM-FRET analysis. Also, OsFD7 is phosphorylated at its C-terminal end by OsCDPK41 and OsCDPK49in vitroand this phosphorylated moiety is recognized by OsGF14 proteins.OsFD7RNAi transgenics were late flowering; the transcript levels of some floral meristem identity genes (e.g.OsMADS14,OsMADS15andOsMADS18) were also down-regulated. It was quite interesting to note that these RNAi lines exhibited dense panicle morphology with increase in the number of primary and secondary branches resulting in longer panicles and more seeds probably due to downregulation ofSepallata(SEP) family genes. In comparison to other FD-like proteins characterized thus far from rice, it appears that OsFD7 may have undergone diversification during evolution resulting in the acquisition of newer functions and thus playing dual role in floral transition and panicle development in rice.

Highlight

OsbZIP62/OsFD7 interacts with major flowering regulators participating in the processes of floral transition as well as panicle and floral organ development.
Sex, age, tissue, and disease patterns of matrisome expression in GTEx transcriptome data
Authors: Nieuwenhuis Tim O. , Rosenberg Avi Z. , McCall Matthew N. , Halushka Marc K.
Published: March 2021

The extracellular matrix (ECM) has historically been explored through proteomic methods. Whether or not global transcriptomics can yield meaningful information on the human matrisome is unknown. Gene expression data from 17,382 samples across 52 tissues, were obtained from the Genotype-Tissue Expression (GTEx) project. Additional datasets were obtained from The Cancer Genome Atlas (TCGA) program and the Gene Expression Omnibus for comparisons. Gene expression levels generally recapitulated proteome-derived matrisome expression patterns. Further, matrisome gene expression properly clustered tissue types, with some matrisome genes including SERPIN family members having tissue-restricted expression patterns. Deeper analyses revealed 388 genes varied by age and 222 varied by sex in at least one tissue, with expression correlating with digitally imaged histologic tissue features. A comparison of TCGA tumor, TCGA adjacent normal and GTEx normal tissues demonstrated robustness of the GTEx samples as a generalized control, while also determining a common primary tumor matrisome. Additionally, GTEx tissues served as a useful non-diseased control in a separate study of idiopathic pulmonary fibrosis matrix changes. Altogether, these findings indicate that the transcriptome, in general, and GTEx in particular, has value in understanding the state of organ ECM.
Hierarchical semantic composition of biosimulation models using bond graphs
Authors: Shahidi Niloofar , Pan Michael , Safaei Soroush , Tran Kenneth , Crampin Edmund J. , Nickerson David P.
Published: March 2021

Simulating complex biological and physiological systems and predicting their behaviours under different conditions remains challenging. Breaking systems into smaller and more manageable modules can address this challenge, assisting both model development and simulation. Nevertheless, existing computational models in biology and physiology are often not modular and therefore difficult to assemble into larger models. Even when this is possible, the resulting model may not be useful due to inconsistencies either with the laws of physics or the physiological behaviour of the system. Here, we propose a general methodology for composing models, combining the energy-based bond graph approach with semantics-based annotations. This approach improves model composition and ensures that a composite model is physically plausible. As an example, we demonstrate this approach to automated model composition using a model of human arterial circulation. The major benefit is that modellers can spend more time on understanding the behaviour of complex biological and physiological systems and less time wrangling with model composition.

Author summary

Biological and physiological systems usually involve multiple underlying processes, mechanisms, structures, and phenomena, referred to here as sub-systems. Modelling the whole system every time from scratch requires a huge amount of effort. An alternative is to model each sub-system in a modular fashion,i.e., containing meaningful interfaces for connecting to other modules. Such modules are readily combined to produce a whole-system model. For the combined model to be consistent, modules must be described using the same modelling scheme. One way to achieve this is to use energy-based models that are consistent with the conservation laws of physics. Here, we present an approach that achieves this using bond graphs, which allows modules to be combined faster and more efficiently. First, physically plausible modules are generated using a small number of template modules. Then a meaningful interface is added to each module to automate connection. This approach is illustrated by applying this method to an existing model of the circulatory system and verifying the results against the reference model.
Capturing scientific knowledge in computable form
Authors: Wong Jeffrey V. , Franz Max , Siper Metin Can , Fong Dylan , Durupinar Funda , Dallago Christian , Luna Augustin , Giorgi John , Rodchenkov Igor , Babur Özgün , Bachman John A. , Gyori Benjamin M. , Demir Emek , Bader Gary D. , Sander Chris
Published: March 2021

Technological advances in computing provide major opportunities to accelerate scientific discovery. The wide availability of structured knowledge would allow us to take full advantage of these by enabling efficient human-computer interaction. Traditionally, biological knowledge is captured in publications and knowledge bases, however, the information in articles is not directly accessible to computers, and knowledge bases are constrained by finite resources available for manual curation. To accelerate knowledge capture and communication and to keep pace with the rapid growth of scientific reports, we developed the Biofactoid (biofactoid.org) software suite, which crowdsources structured knowledge in articles from authors. Biofactoid is a web-based system that lets scientists draw a network of interactions between genes, their products, and chemical compounds and employs smart-automation to translate user input into a structured language using the expressive power of a formal ontology. The resulting data is shared via public information resources, enabling author-curated knowledge to be appreciated in the context of all existing computable knowledge. Authors of recently published papers across a range of journals have already contributed their pathway information, much of which is novel and extends existing pathway databases into new biological areas. We envision the adoption of Biofactoid for crowdsourced curation by scientists and publishers as part of an ecosystem of tools that accelerate scientific communication and discovery.

Availability

Biofactoid server athttps://biofactoid.org
Sampling of Structure and Sequence Space of Small Protein Folds
Authors: Linsky T , Noble K , Tobin A , Crow R , Carter Lauren , Urbauer J , Baker D , Strauch EM
Published: March 2021

Nature only samples a small fraction in sequence space, yet many more amino acid combinations can fold into stable proteins. Furthermore, small structural variations in a single fold, which may only be a few amino acids different from the next homolog, define their molecular function. Hence, to design proteins with novel molecular functionalities, such as molecular recognition, methods to control and sample shape diversity are necessary. To explore this space, we developed and experimentally validated a computational platform that can design a wide variety of small protein folds while sampling high shape diversity. We designed and evaluated about 30,000 de novo protein designs of 7 different folds. Among these designs, about 6,200 stable proteins were identified, with predicted structures having first-of-its-kind minimalized thioredoxin. Obtained data revealed more protein folding rules, such as helix connecting loops, which were in nature. Beyond providing a resource database for protein engineering, our data presents a large training data set for machine learning. We developed a high-accuracy classifier to predict the stability of our designed proteins. The methods and the wide range of new protein shapes provide a basis for the design of new protein function without compromising stability.
Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics
Authors: Zhang Anni M.Y. , de Winter Twan J.J. , Wang Su , Flibotte Stephane , Zhao Yiwei Bernie , Hu Xiaoke , Li Hong , Schaeffer David F. , Johnson James D. , Kopp Janel L.
Published: March 2021

Hyperinsulinemia is independently associated with increased risk and mortality of pancreatic cancer. We recently reported that a ∼50% reduction in pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice could be achieved with reduced insulin production. However, only female mice remained normoglycemic and only the gene dosage of rodent-specificIns1alleles was tested in our previous model. Moreover, we did not delve into the molecular and cellular mechanisms associated with modulating hyperinsulinemia. Here, we studied PanIN lesion development in both male and femalePtf1aCreER;KrasLSL-G12Dmice lacking the rodent specificIns1gene, and possessing one or two alleles of the wild-typeIns2gene to modulate insulin production. High-fat diet induced hyperinsulinemia was transiently and modestly reduced, without affecting glucose tolerance, in male and female mice with only one allele ofIns2. Genetic reduction of insulin production resulted in mice with a tendency for less PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia affected multiple cell types in the pancreas, with the most statistically significant effects on local immune cell populations, which were highly represented in our analysis. Specifically, hyperinsulinemia modulated pathways associated with protein translation, MAPK-ERK signaling, and PI3K-AKT signaling, which were changed in epithelial cells and subsets of immune cells. These data suggest a role for the immune microenvironment in hyperinsulinemia-driven PanIN development. Together with our previous work, we propose that mild suppression of insulin levels may be useful in preventing pancreatic cancer by acting on multiple cell types.
Distinct generation of subjective vividness and confidence during naturalistic memory retrieval in angular gyrus
Authors: Zou Futing , Kwok Sze Chai
Published: March 2021

Our subjective experience of remembering guides and monitors the reconstruction of past and simulation of the future, which enables us to identify mistakes and adjust our behavior accordingly. However, it remains incompletely understood what underlies the process of subjective mnemonic experience. Here, we combined behavior, repetitive transcranial magnetic stimulation (rTMS), and functional neuroimaging to probe whether vividness and confidence are generated differently during retrieval. We found that preretrieval rTMS targeting the left angular gyrus (AnG) selectively attenuated the vividness efficiency compared to control stimulation while keeping metacognitive efficiency and objective memory accuracy unaffected. Using trial-wise data, we showed that AnG stimulation altered the mediating role of vividness in confidence in the accuracy of memory judgment. Moreover, resting-state functional connectivity of hippocampus and AnG was specifically associated with vividness efficiency, but not metacognitive efficiency across individuals. Together, these results identify the causal involvement of AnG in gauging the vividness, but not the confidence, of memory, thereby suggesting a differentiation account of conscious assessment of memory by functionally and anatomically dissociating the monitoring of vividness from confidence.
Genomic heterogeneity affects the response to Daylight Saving Time
Authors: Tyler Jonathan , Fang Yu , Goldstein Cathy , Forger Daniel , Sen Srijan , Burmeister Margit
Published: March 2021

Circadian rhythms drive the timing of many physiological events in the 24-hour day. When individuals undergo an abrupt external shift (e.g., change in work schedule or travel across multiple time zones), circadian rhythms become misaligned with the new time and may take several days to adjust. Chronic circadian misalignment, e.g., as a result of shift work, has been shown to lead to several physical and mental health problems. Despite the serious health implications of circadian misalignment, relatively little is known about how genetic variation affects an individual’s ability to shift to abrupt external changes. Accordingly, we use the one-hour advance from the onset of daylight saving time (DST) as a natural experiment to comprehensively study how individual heterogeneity affects the shift of sleep-wake rhythms in response to an abrupt external time change. We find that individuals genetically predisposed to a morning tendency adjust to the advance in a few days, while genetically predisposed evening-inclined individuals have not shifted. Observing differential effects by genetic disposition after a one-hour advance underscores the importance of heterogeneity in adaptation to external schedule shifts, and these genetic differences may affect how individuals adjust to jet lag or shift work as well.
A Comparative Analysis of Novel Deep Learning and Ensemble Learning Models to Predict the Allergenicity of Food Proteins
Authors: Wang Liyang , Niu Dantong , Zhao Xinjie , Wang Xiaoya , Hao Mengzhen , Che Huilian
Published: March 2021

Traditional food allergen identification mainly relies on in vivo and in vitro experiments, which often needs a long period and high cost. The artificial intelligence (AI)-driven rapid food allergen identification method has solved the above mentioned two drawbacks and is becoming an efficient auxiliary tool. Aiming to overcome the limitations of lower accuracy of traditional machine learning models in predicting the allergenicity of food proteins, this work proposed to introduce deep learning model - transformer with self-attention mechanism, ensemble learning models (representative as Light Gradient Boosting Machine (LightGBM) eXtreme Gradient Boosting (XGBoost)) to solve the problem. In order to highlight the superiority of the proposed novel method, the study also selected various commonly used machine learning models as the baseline classifiers. The results of 5-fold cross-validation showed that the AUC of the deep model was the highest (0.9578), which was better than the ensemble learning and baseline algorithms. But the deep model need to be pre-trained, and the training cost is the highest. By comparing the characteristics of the transformer model and boosting models, it can be analyzed that, each model has its own advantage, which provides novel clues and inspiration for the rapid prediction of food allergens in the future.
Whole-genome analysis of multiple wood ant population pairs supports similar speciation histories, but different degrees of gene flow, across their European range
Authors: Portinha Beatriz , Avril Amaury , Bernasconi Christian , Helanterä Heikki , Monaghan Josie , Seifert Bernhard , Sousa Vitor C. , Kulmuni Jonna , Nouhaud Pierre
Published: March 2021

The application of demographic history modeling and inference to the study of divergence between species is becoming a cornerstone of speciation genomics. The demographic history is usually reconstructed by analysing a single population from each species, assuming that the divergence history inferred between these populations represents the actual speciation history. However, this assumption is rarely explicitly tested, and it may not be met when species diverge with gene flow. For instance, secondary contact between two species after a range expansion may be confined into a specific geographic region. In this study, we tested to what extent the divergence history inferred from two heterospecific populations would vary depending on their geographic locations, using mound-building red wood ants. The wood ant speciesFormica polyctenaandF. aquiloniahave contrasting distributions in Europe and naturally hybridize in Finland. We first performed whole-genome resequencing of 20 individuals sampled in multiple populations across both species ranges. We then reconstructed the divergence histories of distinct heterospecific population pairs using a coalescent-based approach. We found that the analysis of these different population pairs always supported a scenario of divergence with gene flow, suggesting that species divergence started in the Pleistocene (ca. 500 kya) and occurred with continuous asymmetrical gene flow fromF. aquiloniatoF. polyctenauntil a recent time, when migration stopped (2-19 kya, depending on the population pair considered). However, we found support for contemporary gene flow in the sympatric population pair from Finland, where hybrids have been described. Overall, our results suggest that divergence histories reconstructed from a few individuals may be reliable and applicable at the species level. Nonetheless, the geographical context of populations chosen to represent their species should be taken into account, as it may affect estimates of migration rates between species when gene flow is heterogeneous across their geographical ranges.
Metapopulation Structure of Diatom-associated Marine Bacteria
Authors: Qu Liping , Feng Xiaoyuan , Chen Yuerong , Li Lingyu , Wang Xiaojun , Hu Zhong , Wang Hui , Luo Haiwei
Published: March 2021

Marine bacteria-phytoplankton interaction ultimately shapes ecosystem productivity. The biochemical mechanisms underlying their interactions become increasingly known, yet how these ubiquitous interactions drive bacterial evolution has not been illustrated. Here, we sequenced genomes of 294 bacterial isolates associated with 19 coexisting diatom cells. These bacteria constitute eight genetically monomorphic populations of the globally abundant Roseobacter group. Six of these populations are members ofSulfitobacter, arguably the most prevalent bacteria associated with marine diatoms. A key finding is that populations varying at the intra-specific level have been differentiated and each are either associated with a single diatom host or with multiple hosts not overlapping with those of other populations. These closely related populations further show functional differentiation; they differ in motility phenotype and they harbor distinct types of secretion systems with implication for mediating organismal interactions. This interesting host-dependent population structure is even evident for demes within a genetically monomorphic population but each associated with a distinct diatom cell, as shown by a greater similarity in genome content between isolates from the same host compared to those from different hosts. Importantly, the intra- and inter-population differentiation pattern remains when the analyses are restricted to isolates from intra-specific diatom hosts, ruling out distinct selective pressures and instead suggesting coexisting microalgal cells as physical barriers of bacterial gene flow. Taken together, microalgae-associated bacteria display a unique microscale metapopulation structure, which consists of numerous small populations whose evolution is driven by random genetic drift.
CRISPR enriches for cells with mutations in a p53-related interactome, and this can be inhibited
Authors: Jiang Long , Ingelshed Katrine , Shen Yunbing , Boddul Sanjaykumar V. , Iyer Vaishnavi Srinivasan , Kasza Zsolt , Sedimbi Saikiran , Lane David P. , Wermeling Fredrik
Published: March 2021

CRISPR/Cas9 can be used to inactivate or modify genes by inducing double-stranded DNA breaks1–3. As a protective cellular response, DNA breaks result in p53-mediated cell cycle arrest and activation of cell death programs4,5. Inactivatingp53mutations are the most commonly found genetic alterations in cancer, highlighting the important role of the gene6–8. Here, we show that cells deficient in p53, as well as in genes of a core CRISPR-p53 tumor suppressor interactome, are enriched in a cell population when CRISPR is applied. Such enrichment could pose a challenge for clinical CRISPR use. Importantly, we identify that transient p53 inhibition suppresses the enrichment of cells with these mutations. Furthermore, in a data set of >800 human cancer cell lines, we identify parameters influencing the enrichment ofp53mutated cells, including strong baselineCDKN1Aexpression as a predictor for an active CRISPR-p53 axis. Taken together, our data identify strategies enabling safe CRISPR use.
Aβ promotes amyloidogenic processing of APP through a Go/Gβγ signaling
Authors: Antonino Magdalena , Marmo Paula , Freites Carlos Leandro , Quassollo Gonzalo , Sanchez Maria Florencia , Lorenzo Alfredo , Anahí Bignante Elena
Published: March 2021

Alzheimer’s disease (AD) is characterized by a cognitive impairment associated to amyloid beta (Aβ) aggregation and deposition in the brain. Aβ is generated by sequential cleavage of the amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase complex. The mechanisms that underlie exacerbated production of Aβ, favoring its deposition in the brain, is largely unknown. In vitro studies have shown that Aβ aggregates trigger enhanced production of Aβ by a yet non described mechanism. Here, we show that in different cell types, including human neurons derived from induced pluripotent stem cells (iPSC), oligomers and fibrils of Aβ enhance the convergence and interaction of APP and BACE1 in endosomal compartments. We demonstrated a key role of Aβ-APP/Go/Gβγ signaling on the amyloidogenic processing of APP. We show that APP mutants with impaired capacity to bind Aβ or to activate Go protein, are unable to exacerbate APP and BACE1 colocalization in the presence of Aβ. Moreover, pharmacological inhibition of Gβγ subunits signaling with gallein, abrogate Aβ-dependent interaction of APP and BACE1 in endosomes preventing β-processing of APP. Collectively, these findings uncover a feed-forward mechanism of amyloidogenesis that might contribute to Aβ pathology in early stages of AD and suggest that gallein might have clinical relevance.
TCR signaling promotes the assembly of RanBP2/RanGAP1-SUMO1/Ubc9 nuclear pore subcomplex via PKC-θ-mediated phosphorylation of RanGAP1
Authors: He Yujiao , Yang Zhiguo , Zhao Chen-Si , Gong Yu , Xiao Zhihui , Li Yun-Yi , Chen Yiqi , Feng Dianying , Altman Amnon , Li Yingqiu
Published: March 2021

The nuclear pore complex (NPC) is the sole and selective gateway for nuclear transport and its dysfunction has been associated with many diseases. The NPC subcomplex RanBP2, which consists of RanBP2 (Nup358), RanGAP1-SUMO1 and Ubc9, regulates the assembly and function of the NPC. The roles of immune signaling in NPC assembly remain poorly understood. Here, we show that, following TCR stimulation, protein kinase C-θ (PKC-θ) directly phosphorylates RanGAP1 to facilitate RanBP2 subcomplex assembly and nuclear import and, thus, the nuclear translocation of AP-1 transcription factor. Mechanistically, TCR stimulation induces the translocation of activated PKC-θ to the NPC, where it interacts with and phosphorylates RanGAP1 on Ser504and Ser506. RanGAP1 phosphorylation increases its binding affinity for Ubc9, thereby promoting sumoylation of RanGAP1 and, finally, assembly of the RanBP2 subcomplex. Our findings reveal an unexpected role of PKC-θ as a direct regulator of nuclear import and uncover a phosphorylation-dependent sumoylation of RanGAP1, delineating a novel link between TCR signaling and assembly of the RanBP2 NPC subcomplex.
The Intervening Domain Is Required For DNA-binding and Functional Identity of Plant MADS Transcription Factors
Authors: Lai Xuelei , Vega-Leon Rosario , Hugouvieux Veronique , Blanc-Mathieu Romain , van der Wal Froukje , Lucas Jérémy , Silva Catarina S. , Jourdain Agnès , Muino Jose , Nanao Max H. , Immink Richard , Kaufmann Kerstin , Parcy François , Smaczniak Cezary , Zubieta Chloe
Published: March 2021

The MADS transcription factors (TF) are an ancient protein family with a high degree of sequence identity that bind almost identical DNA sequences across all eukaryotic kingdoms of life, yet fulfill dramatically different physiological roles. In plants, the family is divided into two main lineages, type I and II, based on sequence conservation of the DNA-binding MADS-box domain (M domain) with yeast and animal M domains. Here, we demonstrate that DNA binding in both lineages absolutely requires a short amino acid sequence C-terminal to the M domain called the Intervening domain (I domain) in type II MADS. Structural elucidation of the MI domains from the floral regulator, SEPALLATA3 (SEP3), shows a highly conserved MADS-box fold with the I domain forming an alpha helix and acting to stabilize the M domain. Based on secondary structure prediction, sequences fulfilling the same function as the SEP3 I domain can be found in both lineages of plant MADS TFs, suggesting the I domain is a conserved and required part of the DNA-binding domain. Using the floral organ identity MADS TFs, SEP3, APETALA1 (AP1) and AGAMOUS (AG), domain swapping demonstrate that the I domain alters DNA-binding specificity based on seq-DAP-seq experiments. Yeast 2-hybrid experiments further revealed the role of the I domain in dimerization specificity. Surprisingly, introducing AG carrying the I domain of AP1 in the Arabidopsisap1mutant, resulted in a high degree of complementation and restoration of first and second whorl organs. Taken together, these data demonstrate that the I domain acts both as an integral part of the DNA-binding domain and strongly contributes to the functional identity of the MADS TF.
A precise and adaptive neural mechanism for predictive temporal processing in the frontal cortex
Authors: Meirhaeghe Nicolas , Sohn Hansem , Jazayeri Mehrdad
Published: March 2021

The theory of predictive processing posits that the nervous system uses expectations to process information predictively. Direct empirical evidence in support of this theory however has been scarce and largely limited to sensory areas. Here, we report a precise and adaptive neural mechanism in the frontal cortex of non-human primates consistent with predictive processing of temporal events. We found that the speed at which neural states evolve over time is inversely proportional to the statistical mean of the temporal distribution of an expected stimulus. This lawful relationship was evident across multiple experiments and held true during learning: when temporal statistics underwent covert changes, neural responses underwent predictable changes that reflected the new mean. Together, these results highlight a precise mathematical relationship between temporal statistics in the environment and neural activity in the frontal cortex that could serve as a mechanistic foundation for predictive temporal processing.
Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation
Authors: Deganutti Giuseppe , Liang Yi-Lynn , Zhang Xin , Khoshouei Maryam , Clydesdale Lachlan , Belousoff Matthew J. , Venugopal Hari , Truong Tin T. , Glukhova Alisa , Keller Andrew N. , Gregory Karen J. , Leach Katie , Christopoulos Arthur , Danev Radostin , Reynolds Christopher A. , Zhao Peishen , Sexton Patrick M. , Wootten Denise
Published: March 2021

The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we have combined cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding by four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data revealed that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists.
Distinct profiles of spatio-temporal brain dynamics along symptoms dimensions in autism
Authors: Mullier Emeline , Kojovic Nada , Denervaud Solange , Vohryzek Jakub , Hagmann Patric , Schaer Marie
Published: March 2021

Autism Spectrum Disorders are accompanied by atypical brain activity and impairments in brain connectivity. In particular, dynamic functional connectivity approaches highlighted aberrant brain fluctuations at rest in individuals with autism compared to a group composed of typically developed individuals, matched in age and gender. However, the characterization of these variations remains unclear. Here, we quantified the spatio-temporal network dynamics using two novel dynamic group-based measures, namely system diversity and spatio-temporal diversity. Using the public database ABIDE 1, we explored the differences between individuals with autism and typically developed individuals. Our results show evidence that individuals with autism have atypical connectivity patterns over time characterized by a lower integration of heterogeneous cognitive processes and unstable functional activity, except for the default mode network presenting its own specific dynamic pattern. Within the autism group, we find this pattern of results to be stronger in more severely affected patients with a predominance of symptoms in the social affect domain. However, patients with prominently restricted and repetitive behaviours demonstrate a more conservative profile of brain dynamics characterized by a lower spatio-temporal diversity of the default mode network.