bluuebunny/crossref_metadata_2025 huggingface dataset:
Mcm2 hypomorph leads to acute leukemia or hematopoietic stem cell failure, dependent on genetic context
Authors: Matsukawa Toshihiro , Yin Mianmian , Baslan Timour , Chung Yang Jo , Cao Dengchao , Bertoli Ryan , Zhu Yuelin J. , Walker Robert L. , Freeland Amy , Knudsen Erik , Lowe Scott W. , Meltzer Paul S. , Aplan Peter D.
Published: August 2022

Minichromosome maintenance proteins (Mcm2‐7) form a hexameric complex that unwinds DNA ahead of a replicative fork. The deficiency of Mcm proteins leads to replicative stress and consequent genomic instability. Mice with a germline insertion of a Cre cassette into the 3′UTR of the Mcm2 gene (designated Mcm2Cre) have decreased Mcm2 expression and invariably develop precursor T‐cell lymphoblastic leukemia/lymphoma (pre‐T LBL), due to 100–1000 kb deletions involving important tumor suppressor genes. To determine whether mice that were protected from pre‐T LBL would develop non‐T‐cell malignancies, we used two approaches. Mice engrafted with Mcm2Cre/Cre Lin−Sca‐1+Kit+ hematopoietic stem/progenitor cells did not develop hematologic malignancy; however, these mice died of hematopoietic stem cell failure by 6 months of age. Placing the Mcm2Cre allele onto an athymic nu/nu background completely prevented pre‐T LBL and extended survival of these mice three‐fold (median 296.5 vs. 80.5 days). Ultimately, most Mcm2Cre/Cre;nu/nu mice developed B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). We identified recurrent deletions of 100–1000 kb that involved genes known or suspected to be involved in BCP‐ALL, including Pax5, Nf1, Ikzf3, and Bcor. Moreover, whole‐exome sequencing identified recurrent mutations of genes known to be involved in BCP‐ALL progression, such as Jak1/Jak3, Ptpn11, and Kras. These findings demonstrate that an Mcm2Cre/Cre hypomorph can induce hematopoietic dysfunction via hematopoietic stem cell failure as well as a “deletor” phenotype affecting known or suspected tumor suppressor genes.
Artificial intelligence using deep neural network learning for automatic location of the interscalene brachial plexus in ultrasound images
Authors: Yang Xiao-Yu , Wang Le-Tian , Li Gen-Di , Yu Ze-Kuan , Li Dong-Li , Guan Qing-Lai , Zhang Qing-Rong , Guo Ting , Wang Hai-Lian , Wang Ying-Wei
Published: August 2022

BACKGROUND

Identifying the interscalene brachial plexus can be challenging during ultrasound-guided interscalene block.

OBJECTIVE

We hypothesised that an algorithm based on deep learning could locate the interscalene brachial plexus in ultrasound images better than a nonexpert anaesthesiologist, thus possessing the potential to aid anaesthesiologists.

DESIGN

Observational study.

SETTING

A tertiary hospital in Shanghai, China.

PATIENTS

Patients undergoing elective surgery.

INTERVENTIONS

Ultrasound images at the interscalene level were collected from patients. Two independent image datasets were prepared to train and evaluate the deep learning model. Three senior anaesthesiologists who were experts in regional anaesthesia annotated the images. A deep convolutional neural network was developed, trained and optimised to locate the interscalene brachial plexus in the ultrasound images. Expert annotations on the datasets were regarded as an accurate baseline (ground truth). The test dataset was also annotated by five nonexpert anaesthesiologists.

MAIN OUTCOME MEASURES

The primary outcome of the research was the distance between the lateral midpoints of the nerve sheath contours of the model predictions and ground truth.

RESULTS

The data set was obtained from 1126 patients. The training dataset comprised 11 392 images from 1076 patients. The test dataset constituted 100 images from 50 patients. In the test dataset, the median [IQR] distance between the lateral midpoints of the nerve sheath contours of the model predictions and ground truth was 0.8 [0.4 to 2.9] mm: this was significantly shorter than that between nonexpert predictions and ground truth (3.4 mm [2.1 to 4.5] mm; P < 0.001).

CONCLUSION

The proposed model was able to locate the interscalene brachial plexus in ultrasound images more accurately than nonexperts.

TRIAL REGISTRATION

ClinicalTrials.gov (https://clinicaltrials.gov) identifier: NCT04183972.
Trajectories of adolescent life satisfaction
Authors: Orben Amy , Lucas Richard E. , Fuhrmann Delia , Kievit Rogier A.
Published: August 2022

Increasing global policy interest in measuring and improving population wellbeing has prompted academic investigations into the dynamics of lifespan life satisfaction. Yet little research has assessed the complete adolescent age range, although it harbours developmental changes that could affect wellbeing far into adulthood. This study investigates how life satisfaction develops throughout the whole of adolescence, and compares this development to that in adulthood, by applying exploratory and confirmatory latent growth curve modelling to UK and German data, respectively (37 076 participants, 10–24 years). We find a near universal decrease in life satisfaction during adolescence. This decrease is steeper than at any other point across adulthood. Further, our findings suggest that adolescent girls' life satisfaction is lower than boys’, but that this difference does not extend into adulthood. The study highlights the importance of studying adolescent subjective wellbeing trajectories to inform research, policy and practice.
Weak self-supervised learning for seizure forecasting: a feasibility study
Authors: Yang Yikai , Truong Nhan Duy , Eshraghian Jason K. , Nikpour Armin , Kavehei Omid
Published: August 2022

This paper proposes an artificial intelligence system that continuously improves over time at event prediction using initially unlabelled data by using self-supervised learning. Time-series data are inherently autocorrelated. By using a detection model to generate weak labels on the fly, which are concurrently used as targets to train a prediction model on a time-shifted input data stream, this autocorrelation can effectively be harnessed to reduce the burden of manual labelling. This is critical in medical patient monitoring, as it enables the development of personalized forecasting models without demanding the annotation of long sequences of physiological signal recordings. We perform a feasibility study on seizure prediction, which is identified as an ideal test case, as pre-ictal brainwaves are patient-specific, and tailoring models to individual patients is known to improve forecasting performance significantly. Our self-supervised approach is used to train individualized forecasting models for 10 patients, showing an average relative improvement in sensitivity by 14.30% and a reduction in false alarms by 19.61% in early seizure forecasting. This proof-of-concept on the feasibility of using a continuous stream of time-series neurophysiological data paves the way towards a low-power neuromorphic neuromodulation system.
Seasonal but not sex-biased gene expression of the carotenoid ketolase,CYP2J19, in the sexually dichromatic southern red bishop (Euplectes orix)
Authors: Lindsay Willow R. , Mendonça Rute , Slight Mathilda Waleij , Prager Maria , Andersson Mats X. , Mundy Nicholas I. , Andersson Staffan
Published: August 2022

Intense red colours in birds are often owing to ketocarotenoids (KCs). In many land birds, KCs are oxidized from dietary yellow precursors, presumably by the avian carotenoid ketolase CYP2J19, the regulation and constraints of which have important implications for condition-dependence and honest signalling of carotenoid colour displays. We investigated hepaticCYP2J19gene expression in the seasonally and sexually dichromatic southern red bishop (Euplectes orix) in relation to season, sex, progression of the prenuptial moult, testis size, body condition, redness and circulating sex steroids. A coloration function of CYP2J19 is supported by a seasonal upregulation prior to and during the carotenoid-depositing stage of the male prenuptial moult. However,CYP2J19expression was similarly high in females (which do not moult prenuptially), and remained high in males after moult, suggesting additional or alternative roles of hepatic CYP2J19 or its products, such as detoxification or antioxidant functions. In males, theCYP2J19upregulation preceded and was unrelated to the rise in plasma testosterone, but was correlated with androstenedione, probably of adrenal origin and compatible with luteinizing hormone-induced and (in females) oestrogen-suppressed moult. Finally, contrary to ideas that carotenoid ketolation rate mediates honest signalling of male quality,CYP2J19expression was not related to plumage redness or male body condition.
Variations in oral microbiome and its predictive functions between tumorous and healthy individuals
Authors: Yang Jing , He Peng , Zhou Mou , Li Sheng , Zhang Jing , Tao Xia , Wang Anna , Wu Xinwei
Published: August 2022

Introduction. The oral cavity is one of the largest reservoirs of microorganisms and many pathogenic bacteria have been shown to be associated with the aetiology of oral cancers.

Gap Statement. Owing to the complexity of oral microbial communities and their unclear relationship with oral cancer, identification of specific bacteria which contribute to oral cancer is a key imperative.

Aim. To compare and investigate the variations in the composition of the bacterial microbiome and its functions between patients with oral tumorous lesions and healthy subjects.

Methodology. Twenty-seven samples from individuals with oral tumours (five oral benign tumours and 22 oral squamous cell carcinomas) and 15 samples from healthy subjects were collected. Genomic DNA was extracted and the V3–V5 region of the 16S rRNA gene was sequenced. Subsequently, bioinformatic assessment was conducted using QIIME2, PICRUSt and linear discriminant analysis effect size analyses (LEfSe).

Results. The oral microbiota was composed mainly of the phyla

Proteobacteria

(31.76 %, 35.00 %),

Bacteroidetes

(30.13 %, 25.13 %) and

Firmicutes

(23.92 %, 17.07 %) in tumorous and healthy individuals, respectively.

Neisseria

,

Prevotella

,

Fusobacterium

,

Streptococcus

,

Capnocytophaga

,

Veillonella

,

Haemophilus

,

Prevotella

,

Porphyromonas

and

Leptotrichia

were the most abundant genera. Alpha diversity in the tumour group was significantly greater than that in the healthy group (P<0.05). Differential analysis of microbes between groups demonstrated a significantly higher number of

Neisseria

,

Veillonella

,

Streptococcus

,

Leptotrichia

,

Lautropia

,

Sphingopyxis

,

Sphingobium

,

Tannerella

,

Actinomyces

and

Rothia

in healthy controls compared with the tumour group. However, the genera

Treponema

,

Micrococcus

,

Pseudomonas

,

Janthinobacterium

, Parvimos,

Loktanella

,

Staphylococcus

,

Acinetobacter

,

Catonella

,

Aggregatibacter

and

Propionibacterium

were significantly higher in the tumour group. Pathways related to cancers, cell motility, environmental adaptation, metabolism and signal transduction were enhanced in the tumour group, while functions associated with immune system diseases, replication, repair and translation were significantly enhanced in the healthy group.

Conclusion. Variations in the oral microbiota and its functions showed a correlation with oral tumours. The tumour group showed an increased abundance of some multi-drug-resistant and periodontitis-related pathogens. The significantly altered microbiotas may serve as potential biomarkers or inform combination therapy for oral tumours.
Streptococcus agalactiae imports spermidine by a member of the amino acid/polyamine antiporter family to endure citric acid stress at the vaginal pH
Authors: Khazaal Sarah , Al Safadi Rim , Osman Dani , Hiron Aurélia , Gilot Philippe
Published: August 2022

Polyamines bind to various cellular components, such as nucleic acids, phospholipids, proteins and nucleotides. They are involved in the virulence and protection against physiological stresses of several bacterial species.

Streptococcus agalactiae

is able to colonize the vaginal tract of asymptomatic pregnant women and to resist, by an as yet poorly characterized mechanism, pH 4.0, the low physiological pH of this environment. We identified a transporter of the amino acid/polyamine antiporter family (SAK_1604 in strain A909) that shares 39.8 % similar amino acids with CadB and 34.7 % with PotE, two transporters implicated in acid resistance in

Escherichia coli

. We found that sak_1604 is overexpressed in the presence of spermidine and during citric acid stress at the vaginal pH, but not during lactic acid or HCl stresses at the same pH or during a sodium citrate stress at pH 7.4. Dihydrogen citrate is the predominant form of citric acid at pH 4.0. Using a deletion mutant, we proved that SAK_1604 is involved in the survival of

S. agalactiae

during citric acid stress at pH 4.0 in the presence of spermidine, and we showed by TLC analysis that it is involved in spermidine transport in these conditions. Our data open new perspectives on the comprehension of the molecular mechanisms allowing

S. agalactiae

to survive at the physiological pH of the vagina and on the unsuspected role of an ionic form of citric acid.
Direct visualization of sequence-specific DNA binding by gonococcal type IV pili
Authors: Hughes-Games Alex , Davis Sean A. , Hill Darryl J.
Published: August 2022

Neisseria gonorrhoeae

, the causative agent of gonorrhoea, is a major burden on global healthcare systems, with an estimated ~80–90 million new global cases annually. This burden is exacerbated by increasing levels of antimicrobial resistance, which has greatly limited viable antimicrobial therapies. Decreasing gonococcal drug susceptibility has been driven largely by accumulation of chromosomal resistance determinants, which can be acquired through natural transformation, whereby DNA in the extracellular milieu is imported into cells and incorporated into the genome by homologous recombination.

N. gonorrhoeae

possesses a specialized system for DNA uptake, which strongly biases transformation in favour of DNA from closely related bacteria by recognizing a 10–12 bp DNA uptake sequence (DUS) motif, which is highly overrepresented in their chromosomal DNA. This process relies on numerous proteins, including the DUS-specific receptor ComP, which assemble retractile protein filaments termed type IV pili (T4P) extending from the cell surface, and one model for neisserial DNA uptake proposes that these filaments bind DNA in a DUS-dependent manner before retracting to transport DNA into the periplasm. However, conflicting evidence indicates that elongated pilus filaments may not have such a direct role in DNA binding uptake as this model suggests. Here, we quantitatively measured DNA binding to gonococcal T4P fibres by directly visualizing binding complexes with confocal fluorescence microscopy in order to confirm the sequence-specific, comP-dependent DNA binding capacity of elongated T4P fibres. This supports the idea that pilus filaments could be responsible for initially capturing DNA in the first step of sequence-specific DNA uptake.
How competition for funding impacts scientific practice
Authors: Meirmans Stephanie
Published: August 2022

In the research integrity literature, funding enters in two different ways: as elevating questionable research practices due to perverse incentives, and as being a potential player to incentivize researchers to behave well. Other recent studies have emphasized the importance of the latter, asking funding experts. Here, I explored how the impact of competitive research funding on science is being perceived by active researchers. More specifically, I have conducted a series of group sessions with researchers in two different countries with a different degree of competition for funding, in three disciplinary fields (medical sciences, natural sciences and the humanities), and with researchers in two different career stages (permanent versus temporary employment). Researchers across all groups experienced that competition for funding shapes science, with many unintended questionable side effects. Intriguingly, these questionable effects had little to do with the type of questionable research practices (QRP’s) typically being presented in the research integrity literature. While the notion of QRP’s focuses on publications and assumes that there would essentially be a correct way to do the science, researchers worried about the shaping of science via funding. According to my session participants, rather than ending up as really being wrong, this shaping could result in predictable, fashionable, short-sighted, and overpromising science. And still, this was seen as highly problematic: scientists experienced that the ‘projectification’ of science makes it more and more difficult to do any science of real importance: plunging into the unknown or addressing big issues that would need a long-term horizon to mature.
Activity in developing prefrontal cortex is shaped by sleep and sensory experience
Authors: Gómez Lex J. , Dooley James C. , Blumberg Mark S.
Published: August 2022

In developing rats, behavioral state exerts a profound modulatory influence on neural activity throughout the sensorimotor system, including primary motor cortex (M1). We hypothesized that similar state-dependent modulation occurs in higher-order cortical areas with which M1 forms functional connections. Here, using 8- and 12-day-old rats cycling freely between sleep and wake, we record neural activity in M1, secondary motor cortex (M2), and medial prefrontal cortex (mPFC). At both ages in all three areas, neural activity increased during active sleep (AS) compared with wake. Regardless of behavioral state, neural activity in M2 and mPFC increased during periods when limbs were moving. This movement-related activity in M2 and mPFC, like that in M1, is driven by sensory feedback. Our results, which diverge from those of previous studies using anesthetized pups, demonstrate that AS-dependent modulation and sensory responsivity extend to prefrontal cortex. These findings expand the range of factors shaping the activity-dependent development of higher-order cortical areas.
Activating mutations in FGFR3 are associated with clonal expansion events and high de novo rates in the male germline
Authors: Moura Sofia , Hartl Ingrid , Yasari Atena , Brumovska Veronika , Striedner Yasmin , Bishara Marina , Mair Theresa , Ebner Thomas , Schütz Gerhard J. , Sevcsik Eva , Tiemann-Boege Irene
Published: August 2022

Delayed fatherhood results in a higher risk to inherit a new germline mutation that might result in a congenital disorder in the offspring. In particular, some FGFR3 mutations increase in frequency with age, but there are still a large number of uncharacterized FGFR3 mutations that could be expanding in the male germline with potentially early or late-onset effects in the offspring. Here, we investigated the mutation frequency in the DNA of human testis and sperm and the activation state of the expressed mutant protein of eight different FGFR3 variants categorized by ClinVar as deleterious, benign, or not reported. Overall, the ligand-independent activation of the mutant protein resulted in a increased number of mutant sperm; although, strong activating mutations did not necessarily result in the highest frequencies. Moreover, only two mutants c.952G>A and c.1620C>A showed an increase with the donor’s age; the latter also forming larger clonal expansions in the testis. We also showed that the prediction of deleteriousness of a mutation is not always accurate, and similar in silico scores can reflect either a gain-of-function or loss-of-function. Our approach led to the discovery of two novel variants c.1261G>A and c.952G>A to have promiscuous FGFR3 activation and increased mutation frequencies in the male germline. The large fraction of donors with mutations suggests a high de novo rate potentially explained by a selective advantage before the maturation of the male germline. This sequence-function study provides important data for the evaluation and interpretation of variants with relevant clinical implications.
Analysis of multiple causes of death: a review of methods and practices
Authors: Bishop Karen , Balogun Saliu , Eynstone-Hinkins James , Moran Lauren , Martin Melonie , Banks Emily , Rao Chalapati , Joshy Grace
Published: August 2022

Background

Research and reporting of mortality indicators typically focus on a single underlying cause of death selected from multiple causes recorded on a death certificate. The need to incorporate the multiple causes in mortality statistics - reflecting increasing multimorbidity and complex causation patterns - is recognised internationally. This review aims to identify and appraise relevant multiple cause analytical methods and practices.

Methods

We searched Medline, PubMed, Scopus and Web of Science from inception to December 2020 without language restrictions, supplemented by consultation with international experts. Eligible articles included those analysing multiple causes of death from death certificates. The process identified 4,080 articles; after screening, 434 full texts were reviewed.

Results

Most reviewed articles (77%, n=332) were published since 2001. The majority examined mortality by “any-mention” of a cause of death (87%, n=377) and assessed pairwise combinations of causes (56%, n=245). Recently emerging (since 2001) were applications of methods to group deaths based on common cause patterns using, for example, cluster analysis (2%, n=9), and the application of multiple cause weights to re-evaluate mortality burden (1%, n=5). Multiple cause methods applied to specific research objectives are described for recently emerging approaches.

Conclusion

This review confirms rapidly increasing international interest in the analysis of multiple causes of death and provides the most comprehensive overview of methods and practices to date. Available multiple cause methods are diverse but suit a range of research objectives, that with greater data availability and technology could be further developed and applied across a range of settings.
The transcriptomic landscape of normal and ineffective erythropoiesis at single cell resolution
Authors: Doty Raymond T. , Lausted Christopher G. , Munday Adam D. , Yang Zhantao , Yan Xiaowei , Meng Changting , Tian Qiang , Abkowitz Janis L.
Published: August 2022

Ineffective erythropoiesis, the death of maturing erythroid cells, is a common cause of anemia. To better understand why this occurs, we studied the fates and adaptations of single erythroid marrow cells from individuals with Diamond Blackfan anemia (DBA), del(5q) myelodysplastic syndrome (del(5q) MDS), and normal controls, and defined an unhealthy (vs. healthy) differentiation trajectory, using velocity pseudotime and cell surface protein assessment. The pseudotime trajectories diverge immediately after the cells upregulate transferrin receptor (CD71), import iron, and initiate heme synthesis, although cell death occurs much later. Cells destined to die highly express heme responsive genes, including ribosomal protein and globin genes. In contrast, surviving cells downregulate heme synthesis, while upregulating DNA damage response, hypoxia and HIF1 pathways. Surprisingly, 24±12% of cells from controls follow the unhealthy trajectory, implying that heme also regulates cell fate decisions during normal red cell production. Del(5q) MDS (unlike DBA) results from somatic mutations, so many normal (unmutated) erythroid cells persist. By independently tracking their trajectory, we gained insight into why they cannot expand to prevent anemia. In addition, we show that intron retention is especially prominent during red cell differentiation. The additional information provided by messages with retained introns also allowed us to align data from multiple independent experiments and thus accurately query the transcriptomic changes that occur as single erythroid cells mature.
The potential health impact of prospective Strep A vaccines: a modeling study
Authors: Giannini Fiona , Cannon Jeffrey W. , Cadarette Daniel , Bloom David E. , Moore Hannah C , Carapetis Jonathan , Abbas Kaja
Published: August 2022

The World Health Organization published the preferred product characteristics for a Group AStreptococcus(Strep A) vaccine in 2018. Based on these parameters for the age of vaccination, vaccine efficacy, duration of protection from vaccine-derived immunity, and vaccination coverage, we developed a static cohort model to estimate the projected health impact of Strep A vaccination at the global, regional, and national levels and by country-income category. We used the model to analyse six strategic scenarios. Based on Strep A vaccine introduction between 2022 and 2034 for the primary scenario, we estimated vaccination at birth for 30 vaccinated cohorts could avert 2.5 billion episodes of pharyngitis, 345 million episodes of impetigo, 1.3 million episodes of invasive disease, 24 million episodes of cellulitis, and 6 million cases of rheumatic heart disease globally. Vaccination impact in terms of burden averted per fully vaccinated individual is highest in North America for cellulitis and in Sub-Saharan Africa for rheumatic heart disease.
Psychological frailty in older adults: a systematic scoping review
Authors: Zhao Jinlong , Liu Justina , Tyrovolas Stefanos , Mutz Julian
Published: August 2022

Background

Psychological frailty, along with physical and cognitive frailty, is linked to an increased risk of negative health outcomes among older adults. However, the definition of psychological frailty has received limited attention. A thorough comprehension of the concept of psychological frailty is therefore required.

Objectives

To review existing definitions of psychological frailty and to provide a comprehensive overview of the concept of psychological frailty and associated measurements.

Methods

This review followed the PRISMA guidelines for scoping reviews and the JBI Manual for Evidence Synthesis. Eligibility criteria were developed based on the Participants-Concept-Context (PCC) framework. We searched CINAHL, Scopus, PubMed, Web of Science, and PsycINFO databases and other sources for relevant studies published between January 2003 to March 2022.

Results

The final scoping review included 58 studies. 40 (69%) of these studies provided a definition of psychological frailty and 7 studies provided a novel definition. The other 11 studies focused on components of defining psychological frailty. To better characterize psychological frailty, we propose four groups of components, including mood, cognitive, mental health, and fatigue-associated problems. We identified 28 measuring tools across studies and the Tilburg frailty indicator was the most frequently used (46.6% of studies).

Conclusions

Psychological frailty is a complex concept that lacks a consensus definition. It should include both psychological features and physical frailty. Depression and other psychological problems are commonly used to define psychological frailty. This scoping review outlines future research directions to refine the concept of psychological frailty.
The Effects of CdSe/ZnS Quantum Dots on the Photosynthesis Rate of the Chlorella Vulgaris Beads
Authors: Dissanayake Wimeth , Hailstone Richard , Bao Mengdi , Wang Ruo-Qian , Yong Xin , Du Ke
Published: August 2022

Photosynthesizing microalgae produce more than 50% of oxygen in the atmosphere and are crucial for the survival of many living systems such as coral reefs. To address the declining of coral reefs, artificial reefs have been introduced to encapsulate the aglae cells in a polymer matrix but the effects of nanoscale pollutants on these engineered systems have not been fully understood. In this work, quantum dots with a size smaller than 10 nm are being used to elucidate the photosynthesis performance of the sodium alginate beads encapsulated with Chlorella vulgaris (C. vulgaris). The fluorescent quantum dots can move into the alginate matrix and the fluorescence intensity in the algae beads is correlated with the quantum dot concentration. We further show that the photosynthesis of the algae beads are sensitive to the quantum dot concentration and are also time sensitive. In the first 48 min of quantum dot exposure, both carbon dioxide absorption and oxygen production are low, suggesting limited photosynthesis. After the initial incubation, the photosynthesis rate quickly increases even though more inhibition is still observed with higher concentration of the quantum dots.
Neuronal dynamics of the default mode network and anterior insular cortex: Intrinsic properties and modulation by salient stimuli
Authors: Chao Tzu-Hao Harry , Lee Byeongwook , Hsu Li-Ming , Cerri Domenic Hayden , Zhang Wei-Ting , Wang Tzu-Wen Winnie , Ryali Srikanth , Menon Vinod , Shih Yen-Yu Ian
Published: August 2022

The default mode network (DMN) is closely associated with self-referential mental functions and its dysfunction is implicated in many neuropsychiatric disorders. However, the neurophysiological properties and task-based functional organization of the rodent DMN are poorly understood, limiting its translational utility. Here, we combine fiber-photometry with fMRI and computational modeling to characterize dynamics of putative rodent DMN nodes and their interactions with the anterior insular cortex (AI) of the salience network. We reveal neuronal activity changes in AI and DMN nodes prior to fMRI-derived DMN activations and uncover cyclical transition patterns between spatiotemporal neuronal activity states. Finally, we demonstrate that salient oddball stimuli suppress the DMN and enhance AI neuronal activity, and that the AI causally inhibits the retrosplenial cortex, a prominent DMN node. These findings elucidate previously unknown properties regarding the neurobiological foundations of the rodent DMN and its modulation by salient stimuli, paving the way for future translational studies.

Highlights

Concurrent measurement of neuronal (GCaMP) and fMRI signals in retrosplenial, cingulate, prelimbic, and anterior insula cortices

GCaMP signals reveal neuronal antagonism between AI and fMRI-derived DMN activation and deactivation

GCaMP signals reveal salient oddball stimuli-induced suppression of prelimbic, cingulate and retrosplenial cortices, and activation of anterior insular cortex

Anterior insular cortex causally inhibits retrosplenial cortex during processing of salient oddball stimuli

Findings delineate neurofunctional organization of the rodent DMN and provide a more informed model for translational studies
A comprehensive single-cell breast tumor atlas defines cancer epithelial and immune cell heterogeneity and interactions predicting anti-PD-1 therapy response
Authors: Xu Lily , Saunders Kaitlyn , Knutsdottir Hildur , Chen Kenian , Maués Julia , Hodgdon Christine , Roussos Torres Evanthia T. , Reddy Sangeetha M. , Xu Lin , Chan Isaac S.
Published: August 2022

We present an integrated single-cell RNA-seq resource of the breast tumor microenvironment consisting of 236,363 cells from 119 biopsy samples across 8 publicly available datasets. In this computational study, we first leverage this novel resource to define cancer epithelial cell heterogeneity based on two clinically relevant markers and identify six new and distinct subsets of natural killer cells. We then illustrate how cancer epithelial cell heterogeneity impacts immune cell interactions. We develop T cell InteractPrint, which considers how cancer epithelial cell heterogeneity shifts the predicted strength of T cell interactions. We use InteractPrint to predict response to immune checkpoint inhibition (ICI) in two clinical trials testing immunotherapy in patients with breast cancer. T cell InteractPrint was predictive in both trials (AUC = 0.81 and 0.84), versus PD-L1 expression (AUC = 0.54 and 0.72). This result provides an alternative predictive biomarker to PD-L1 to select patients who should receive ICI.

STATEMENT OF SIGNIFICANCE

We developed a novel integrated single-cell atlas of the breast tumor microenvironment to interrogate breast tumor cell heterogeneity and define how heterogenous cancer epithelial cell and immune cell interactions predict response to anti-PD-1 therapy.
3D-Beacons: Decreasing the gap between protein sequences and structures through a federated network of protein structure data resources
Authors: Varadi Mihaly , Nair Sreenath , Sillitoe Ian , Tauriello Gerardo , Anyango Stephen , Bienert Stefan , Borges Clemente , Deshpande Mandar , Green Tim , Hassabis Demis , Hatos Andras , Hegedus Tamas , Hekkelman Maarten L , Joosten Robbie , Jumper John , Laydon Agata , Molodenskiy Dmitry , Piovesan Damiano , Salladini Edoardo , Salzberg Steven L. , Sommer Markus J , Steinegger Martin , Suhajda Erzsebet , Svergun Dmitri , Tenorio-Ku Luiggi , Tosatto Silvio , Tunyasuvunakool Kathryn , Waterhouse Andrew Mark , Žídek Augustin , Schwede Torsten , Orengo Christine , Velankar Sameer
Published: August 2022

While scientists can often infer the biological function of proteins from their 3-dimensional quaternary structures, the gap between the number of known protein sequences and their experimentally determined structures keeps increasing. A potential solution to this problem is presented by ever more sophisticated computational protein modelling approaches. While often powerful on their own, most methods have strengths and weaknesses. Therefore, it benefits researchers to examine models from various model providers and perform comparative analysis to identify what models can best address their specific use cases. To make data from a large array of model providers more easily accessible to the broader scientific community, we established 3D-Beacons, a collaborative initiative to create a federated network with unified data access mechanisms. The 3D-Beacons Network allows researchers to collate coordinate files and metadata for experimentally determined and theoretical protein models from state-of-the-art and specialist model providers and also from the Protein Data Bank.
A tumour-promoting senescent secretome triggered by platinum chemotherapy exploits a targetable TGFβR1/Akt-mTOR axis in lung cancer
Authors: González-Gualda Estela , Macias David , Morsli Samir , Martín José Ezequiel , Ou Hui-Ling , Denholm Mary , Olan Ioana , Hoffmann Reuben , Dane Mark , Veroutis Dimitris , Medrano Guillermo , Mulero Francisca , Martins Carla P. , Barbacid Mariano , Gorgoulis Vassilis , Korkola James E. , Rassl Doris M. , Doherty Gary J. , Rintoul Robert C. , Narita Masashi , Muñoz-Espín Daniel
Published: August 2022

Platinum-based chemotherapy is commonly used for non-small cell lung cancer (NSCLC) treatment, yet clinical outcomes remain poor. Cellular senescence and its associated secretory phenotype (SASP) can have multiple tumour-promoting activities, although these are largely unexplored in lung cancer. Here we show that cisplatin-derived SASP enhances the malignant phenotype of lung cancer cells. Using xenograft, orthotopic and KrasG12V-driven murine NSCLC models, we demonstrate that cisplatin-induced senescent cells strongly promote tumour progression. Mechanistically, we find that a TGF-β-enriched SASP drives pro-proliferative effects through TGFβR1 and Akt/mTOR pathway activation. We validate the translational relevance of chemotherapy-induced SASP using clinical NSCLC samples from patients who received neoadjuvant platinum-based chemotherapy. Importantly, TGFβR1 inhibition with galunisertib or senolytic treatment significantly reduces tumour promotion driven by cisplatin-induced senescence. Finally, we demonstrate, using distinct murine NSCLC models, that addition of TGFBR1 inhibitors to platinum-based chemotherapy reduces tumour burden and improves survival, providing pre-clinical proof-of-concept for future trial designs.
Cell size scaling laws: a unified theory
Authors: Rollin Romain , Joanny Jean-François , Sens Pierre
Published: August 2022

The dimensions and compositions of cells are tightly regulated by active processes. This exquisite control is embodied in the robust scaling laws relating cell size, dry mass, and nuclear size. Despite accumulating experimental evidence, a unified theoretical framework is still lacking. Here, we show that these laws and their breakdown can be explained quantitatively by three simple, yet generic, physical constraints defining altogether the Pump and Leak model (PLM). Based on estimations, we clearly map the PLM coarse-grained parameters with the dominant cellular events they stem from. We propose that dry mass density homeostasis arises from the scaling between proteins and small osmolytes, mainly amino-acids and ions. Our theory predicts this scaling to naturally fail, both at senescence when DNA and RNAs are saturated by RNA polymerases and ribosomes respectively, and at mitotic entry due to the counterion release following histone tail modifications. We further show that nuclear scaling result from osmotic balance at the nuclear envelope (NE) and a large pool of metabolites, which dilutes chromatin counterions that do not scale during growth.
Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol
Authors: Tang Vi T. , McCormick Joseph , Xu Bolin , Wang Yawei , Fang Huan , Wang Xiao , Siemieniak David , Khoriaty Rami , Emmer Brian T. , Chen Xiao-Wei , Ginsburg David
Published: August 2022

PCSK9 negatively regulates low-density lipoprotein receptor (LDLR) abundance on the cell surface, leading to decreased hepatic clearance of LDL particles and increased levels of plasma cholesterol. We previously identified SURF4 as a cargo receptor that facilitates PCSK9 secretion in HEK293T cells (Emmer et al., 2018). Here, we generated hepatic SURF4-deficient mice (Surf4fl/flAlb-Cre+) to investigate the physiologic role of SURF4 in vivo. Surf4fl/flAlb-Cre+ mice exhibited normal viability, gross development, and fertility. Plasma PCSK9 levels were reduced by ∽60% in Surf4fl/flAlb-Cre+ mice, with a corresponding ∽50% increase in steady state LDLR protein abundance in the liver, consistent with SURF4 functioning as a cargo receptor for PCSK9. Surprisingly, these mice exhibited a marked reduction in plasma cholesterol and triglyceride levels out of proportion to the partial increase in hepatic LDLR abundance. Detailed characterization of lipoprotein metabolism in these mice instead revealed a severe defect in hepatic lipoprotein secretion, consistent with prior reports of SURF4 also promoting the secretion of apolipoprotein B. Despite a small increase in liver mass and lipid content, histologic evaluation revealed no evidence of steatohepatitis or fibrosis in Surf4fl/flAlb-Cre+ mice. Acute depletion of hepatic SURF4 by CRISPR/Cas9 or liver-targeted siRNA in adult mice confirms these findings. Together, these data support the physiologic significance of SURF4 in the hepatic secretion of PCSK9 and APOB-containing lipoproteins and its potential as a therapeutic target in atherosclerotic cardiovascular diseases.
Tumor necrosis factor is a necroptosis-associated alarmin
Authors: Pinci Francesca , Gaidt Moritz M. , Jung Christophe , Nagl Dennis , Kuut Gunnar , Hornung Veit
Published: August 2022

Necroptosis is a form of regulated cell death that can occur downstream of several immune pathways. While previous studies have shown that dysregulated necroptosis leads to strong inflammatory responses, little is known about the identity of the endogenous molecules that trigger necroptosis-mediated inflammatory responses. Using a reductionist in vitro model, we found that soluble TNF is strongly released in the context of necroptosis. On the one hand, necroptosis promotes TNF translation by inhibiting negative regulatory mechanisms acting at the post-transcriptional level. On the other hand, necroptosis markedly enhances TNF release by activating ADAM proteases. In studying TNF release at single-cell resolution, we found that TNF release triggered by necroptosis is activated in a switch-like manner and exceeds steady-state TNF processing in magnitude and speed. Although this shedding response precedes massive membrane damage, it is closely associated with lytic cell death. In fact, we found that lytic cell death induction using a pore-forming toxin also triggers TNF shedding, indicating that the activation of ADAM proteases is not strictly related to the necroptotic pathway but associated with biophysical changes of the cell membrane upon lytic cell death. These results demonstrate that lytic cell death, particularly necroptosis, is a critical trigger for TNF release and thus qualify TNF as a necroptosis-associated alarmin.
Spatial neglect after stroke is reduced when lying inside a 3T MRI scanner
Authors: Karnath Hans-Otto , Rosenzopf Hannah , Stammler Britta , Smaczny Stefan , Lindner Axel
Published: August 2022

Recently, it was discovered that the static magnetic field of an MRI scanner not only causes horizontal vestibular nystagmus in healthy individuals but, in addition, leads to a horizontal bias of spatial orienting and exploration that closely resembles the one observed in stroke patients with spatial neglect (a disorder of spatial attention and exploration). The present study asked whether the behavioral effects of this magnetic vestibular stimulation (MVS) can be inverted and thus be used to reduce the pathological bias of stroke patients with spatial neglect. Indeed, when patients with left-sided spatial neglect entered the scanner with their feet first, i.e., with the magnetic field vector pointing from head to toes, MVS inside the scanner reduced the ipsilesionally biased distribution of overt attention and the corresponding neglect of the left parts of the search-space. Thus, an intervention as simple as lying in a 3T MRI scanner bears the potential to become an integral part of a future strategy for treating spatial neglect.
CTRR-ncRNA: A Translation-oriented Knowledgebase for Cancer Resistance and Recurrence Associated Non-coding RNAs
Authors: Tang Tong , Liu Xingyun , Wu Rongrong , Shen Li , Ren Shumin , Shen Bairong
Published: August 2022

Cancer therapy resistance and recurrence (CTRR) are the dominant causes of death in cancer patients. Recent studies have indicated that non-coding RNAs (ncRNAs) can not only reverse the resistance to cancer therapy but also are crucial biomarkers for the evaluation and prediction of CTRR. Herein, we developed CTRR-ncRNA, a knowledgebase of CTRR-associated ncRNAs, aiming to provide an accurate and comprehensive resource for research involving association between CTRR and ncRNAs. Compared to most of the existing cancer databases, CTRR-ncRNA is focused on the clinical characterization of cancers, including cancer subtypes, as well as survival outcomes and response to personalized therapy of cancer patients. Information pertaining to biomarker ncRNAs has also been documented for the development of personalized CTRR prediction. A user-friendly interface and several functional modules have been incorporated into the database. Based on the preliminary analysis of genotype–phenotype relationships, universal ncRNAs have been found to be potential biomarkers for CTRR. The CTRR-ncRNA is a translation-oriented knowledgebase and it provides a valuable resource for mechanistic investigations and explainable artificial intelligence-based modelling. CTRR-ncRNA is freely available to the public at http://ctrr.bioinf.org.cn/.
Reduced fibrous capsule elastic fibers from biologic ECM-enveloped CIEDs in minipigs, supported with a novel compression mechanics model
Authors: de Guzman Roche C. , Meer Allison S. , Mathews Aidan A. , Israel Atara R. , Moses Michael T. , Sams Clarence M. , Deegan Daniel B.
Published: August 2022

BACKGROUND

Fibrous capsules (Fb) in response to cardiovascular implantable electronic devices (CIEDs), including a pacemaker (P) system, can produce patient discomfort and difficulties in revision surgery due partially to their increased compressive strength, previously linked to elevated tissue fibers.

OBJECTIVE

To quantify structural proteins, determine if biologic extracellular matrix-enveloped CIEDs (PECM) caused differential Fb properties, and to implement a realistic mechanical model.

METHODS

Retrieved Fb (-P and -PECM) from minipigs were subjected to biomechanical (shear oscillation and uniaxial compression) and histological (collagen I and elastin) analyses.

RESULTS

Fb-PECM showed significant decreases compared to Fb-P in: low strain-loss modulus (390 vs. 541 Pa) across angular frequencies, high strain-compressive elastic modulus (1043 vs. 2042 kPa), and elastic fiber content (1.92 vs. 3.15 μg/mg tissue). Decreases in elastin were particularly noted closer to the implant’s surface (Fb-PECM = 71% vs. Fb-P = 143% relative to dermal elastin at mid-tangential sections) and verified with a solid mechanics hyperelasticity with direction-dependent fiber viscoelasticity compression simulation (r2 ≥ 98.9%).

CONCLUSIONS

The biologic envelope composed of decellularized porcine small intestine submucosa ECM for CIEDs promoted fibrous tissues with less elastic fibers. Novel compression modeling analyses directly correlated this singular reduction to more desirable subcutaneous tissue mechanics.
Integration of external biomass reactions into existing metabolic models
Authors: García María Moscardó , Pacheco Maria , Sauter Thomas
Published: August 2022

Currently, seven biomass objective functions have been defined in human metabolic reconstructions. The integration of published biomass reactions into alternative models can contribute to the prediction power of the model. Thus, in this work, we present a workflow to integrate reactions and biomass functions originating from several genome-scale reconstructions into models other than their home models. Additionally, a benchmark to identify the biomass that confers the highest prediction accuracy in terms of gene essentiality and growth predictions is provided.

For complete details on the use and execution of this protocol, please refer to Moscardó García et al. (2021).
Whole genome assembly and annotation of the lucerne weevilSitona discoideus
Authors: Katuwal Mandira , Bhattarai Upendra R. , Phillips Craig B. , Gemmell Neil J. , Dowle Eddy
Published: August 2022

Weevils are a diverse insect group that includes many economically important invasive pest species. Despite their importance and diversity, only nine weevil genomes have been sequenced, representing a tiny fraction of this heterogeneous taxon. The genusSitonaconsists of over 100 species, includingSitona discoideus(Coleoptera: Curculionidae: Entiminae), commonly known as lucerne (or alfalfa root) weevil.Sitona discoideusis an important pest of forage crops, particularlyMedicagospecies. Using a dual sequencing approach with Oxford Nanopore MinION long-reads and 10x Genomics linked-read sequencing, we generated a high-quality hybrid genome assembly ofS. discoideus. Benchmarks derived from evolutionarily informed expectations of gene content for near-universal single-copy orthologs comparison (BUSCO) scores are above 96% for single-copy orthologs derived from eukaryotes, arthropods, and insects. With ade novorepeat library, Repeatmasker annotated 81.45% of the genome as various repeat elements, of which 22.1% were unclassified. Using the MAKER2 pipeline, we annotated 10,008 protein-coding genes and 13,611 mRNAs. Furthermore, 68.84% of total predicted mRNAs and 67.90% of predicted proteins were functionally annotated to one or more of InterPro, gene ontology, and Pfam databases. This high-quality genome assembly and annotation will enable the development of critical novel genetic pest control technologies and act as an essential reference genome for broader population genetics and weevil comparative genetic studies.