bluuebunny/crossref_metadata_2025 huggingface dataset:
Great prognosis of concurrent anti-GBM disease and IgA nephropathy in a young woman: A case report
Authors: Shaojie Fu , Sensen Su , Jingda Huang , Luyu Wang , Fei Zhang , Jinyu Yu , Zhonggao Xu , Hao Wu
Published: September 2022

Rationale:

The causal relationship between anti-glomerular basement membrane (anti-GBM) disease and immunoglobulin A (IgA) nephropathy is still unclear and cases of concurrent anti-GBM disease and IgA nephropathy are very rare, especially with a good prognosis and long-term follow-up. Here, we report a case of concurrent anti-GBM disease and IgA nephropathy. By using corticosteroids and cyclophosphamide in combination with plasmapheresis, the patient achieved a very good prognosis with complete normalization of renal function and complete disappearance of hematuria and proteinuria at the subsequent follow-up. To our knowledge, no previous case with such a long follow-up and such a good prognosis have been reported.

Patient concerns:

This case report describes a 26-year-old Chinese woman who presented with fever as the initial symptom, followed by dysmorphic hematuria, overt proteinuria and rapidly worsening renal function. Before admission, the patient received symptomatic supportive treatment such as intravenous albumin infusion, improvement of circulation, but the symptoms were not significantly improved.

Diagnosis:

Per the results of kidney biopsy, the patient was diagnosed with crescentic glomerulonephritis and anti-GBM disease with IgA nephropathy.

Interventions:

The key to obtain a good prognosis was the early application of corticosteroids and cyclophosphamide in combination with plasmapheresis to make the anti-GBM antibody turn negative quickly.

Outcomes:

After 2 weeks of therapy, the patients’ anti-GBM antibody turned negative and serum creatinine improved to a normal range. After 10 months, the patient’s proteinuria level reached complete remission. After 12 months, the patient’s hematuria had disappeared completely.

Lessons:

This case provides experience in the treatment of concurrent anti-GBM disease and IgA nephropathy and highlights the importance of early application of plasmapheresis and immunosuppressive therapy to obtain a good prognosis.
Danshen decoction in the treatment of heart failure: A systematic review and meta-analysis protocol of randomized controlled trials
Authors: Liu Mengnan , Wang Raoqiong , Li Ziyi , Mazhar Maryam , Luo Gang , Yang Sijin
Published: September 2022

Background:

Heart failure (HF) is considered the clinical endpoint of all cardiovascular diseases (CVDs). Although a large number of HF drugs and therapies have been developed, it is still need to find therapies with better clinical efficacy and fewer side effects. The purpose of this systematic evaluation is to assess the efficacy and safety of Danshen decoction on HF and the improvement of cardiac function (CF).

Methods:

Four databases will be searched to identify any eligible studies, and this protocol does not require ethics committee review as the research is based on published articles. There are no restrictions set for the language, publication date, or status of the study. The clinical effective rate (CER) of HF treatment is considered to be the main result. CF, various serum inflammatory factors, and adverse events were defined as secondary outcomes. When more than 1 article is used to study the changes and results of the same index, we will conduct a meta-analysis. If the heterogeneity is not statistically significant (P > .10 or I
2 < 50%), a fixed-effect model will be established to estimate the overall intervention effect. Otherwise, random effect models will be used to provide more conservative results.

Results:

The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.

Conclusion:

This study will provide reliable evidence-based basis for the clinical application of Danshen decoction in the treatment of HF.
Global trends of researches on radioactive enteritis: A bibliometric and visualization study
Authors: Chen Daman , Zhao Kaibo , Guo Yongqi , Dong Mingxin , Cai Jiaxi , Zhou Yingjia , Wen Weibo , Shen Hongmei
Published: September 2022

Background:

Radiation enteritis (RE) caused by radiation therapy, can seriously affect human health. Recently, studies on RE have been growing rapidly, but there are no bibliometric studies on RE. This study aims to explore the development trends and research hotspots of RE.

Methods:

Academic papers on the Web of Science were retrieved on the topic of “radioactive enteritis” from the establishment of the database to December 2020. Countries, institutions, and subjects selected in this field were visualized using Citespace, HistCite, and Vosviewer. The annual trends in publications, distribution, co-authorship status, and research hotspots were analyzed.

Results:

The authors ranked first in terms of publication amount were Delaney, Francois, Milliat, and Vozenin-Brotons. The United States had the highest number of posts, followed by China, France, the United Kingdom, and Spain.

Conclusion:

Future research in the field of RE will focus on double-blind clinical trials of RE, and the related mechanisms, such as oxidative stress and apoptosis.
Analysis of rotational deformity correction by lateral lumbar interbody fusion with two-staged anterior-posterior combined corrective fusion surgery for adult degenerative kyphoscoliosis
Authors: Abe Tetsutaro , Miyazaki Masashi , Kanezaki Shozo , Hirakawa Masashi , Iwasaki Tatsuya , Tsumura Hiroshi
Published: September 2022

The present study is retrospective analysis of consecutively collected data. Lateral lumber interbody fusion (LLIF) is widely used in cases of adult spinal deformities. However, the corrective effects of LLIF cage insertion on the vertebral rotation deformity in the axial plane and the individual effects of LLIF and direct vertebral rotation (DVR) on rotational correction are unclear. To individually examine the corrective effects of LLIF and posterior corrective fusion surgery with direct DVR on vertebral rotation deformities in adult degenerative kyphoscoliosis. We analyzed 21 patients (5 males and 16 females) who underwent two-staged anterior-posterior combined corrective fusion surgery for adult degenerative kyphoscoliosis. Surgical time, blood loss, facet joint osteoarthritis (OA) grade, disc degeneration, cage height, vertebral rotational angle, and various X-ray parameters were investigated as evaluation items. The X-ray parameters showed significant postoperative improvements. The mean vertebral rotation angle was 6.4° ± 5.2° preoperatively, 3.5° ± 3.3° after LLIF (P = .014, vs preoperative), and 1.6° ± 1.7° after posterior corrective fusion surgery with DVR (P = .011, vs preoperative). Correlation analysis between the vertebral rotation angle and various measured values revealed that the vertebral rotation angle after LLIF was correlated with the cage height (r = −0.46, P = .032). The vertebral rotation angle after DVR was correlated with the facet joint OA grade (r = −0.49, P = .018) and the wedge angle after posterior corrective fusion surgery with DVR (R = 0.57, P = .006). We conclude that the effects of rotational deformity correction with LLIF cage insertion and additional posterior corrective fixation with DVR can be useful for correcting vertebral rotation deformities.
Comparing the diagnostic accuracy of PET and CMR for the measurement of left ventricular volumes and ejection fraction: a system review and meta-analysis
Authors: Ye Yong , Yang Ying , Gong Jie , Shao Wen-wen , Yu Cheng-xin
Published: September 2022

Background

Cardiac magnetic resonance (CMR) has been recognized as the gold standard for the evaluation of left ventricular (LV) function. Cardiac gated PET allows the simultaneous assessment of LV function with the evaluation of myocardial perfusion and metabolism. But the correlations between PET and CMR remain controversial.

Methods

We conducted a systematic electronic search of PubMed, Embase and the Cochrane Library. Forest plot, spearman correlation analysis and Bland-Altman analysis were used to evaluate the correlations between PET and CMR.

Results

Pooled analysis of 13 studies showed that PET underestimated left ventricular end-diastolic volumes (LVEDV) [mean difference (MD), −15.30; 95% confidence interval (CI), −23.10 to −7.50; P < 0.001] and left ventricular end-systolic volumes (LVESV) (MD, −6.20; 95% CI, −12.58 to 0.17; P = 0.06) but not left ventricular ejection fraction (LVEF) (MD, −0.35; 95% CI, −1.75 to 1.06; P = 0.63). Overall, there were very good correlations between PET and CMR measurements for LVEDV (r, 0.897), LVESV (r, 0.924) and LVEF (r, 0.898). Subgroup analysis indicated that LVEDV ≥180 ml and LVEF <40% reduced the accuracy of PET, especially the measurement of LVEF (r, LVEDV ≥180 vs. r, LVEDV<180: 0.821 vs. 0.944; r, LVEF<40% vs. r, LVEF ≥40%: 0.784 vs. 0.901).

Conclusions

Correlations between PET and CMR measurements of LVEDV, LVESV and LVEF were excellent, but these two methods could not be used interchangeably for accurate measurements of LV volume and LVEF in patients with significantly increased LV volume and decreased LVEF.
Technical Outcomes in Pediatric Endoscopic Retrograde Cholangiopancreatography: Data from an International Collaborative
Authors: Troendle David M. , Ruan Wenly , Fishman Douglas S. , Barth Bradley A. , Liu Quin Y. , Giefer Matthew , Kim Kyung Mo , Martinez Mercedes , Dall’oglio Luigi , Torroni Filippo , De Angelis Paola , Faraci Simona , Bitton Sam , Wilsey Michael , Khalaf Racha , Werlin Steven , Dua Kulwinder , Gugig Roberto , Huang Clifton , Mamula Petar , Quiros J. Antonio , Zheng Yuhua , Grover Amit , Fox Victor L.
Published: September 2022

Objectives:

Endoscopic retrograde cholangiopancreatography (ERCP) in adults has been extensively studied through multicenter prospective studies. Similar pediatric studies are lacking. The Pediatric ERCP Database Initiative (PEDI) is a multicenter collaborative aiming to evaluate the indications and technical outcomes in pediatric ERCPs.

Methods:

In this prospective cohort study, data were recorded for pediatric ERCPs performed across 15 centers. A pre-procedure, procedure, 2-week post-procedure follow-up, and adverse event form were completed for each ERCP performed. Univariate and stepwise linear regression was performed to identify factors associated with technically successful procedures and adverse events.

Results:

A total of 1124 ERCPs were performed on 857 patients from May 1, 2014 to May 1, 2018. The median age was 13.5 years [interquartile range (IQR) 9.0–15.7]. Procedures were technically successful in the majority of cases (90.5%) with success more commonly encountered for procedures with biliary indications [odds ratio (OR) 4.2] and less commonly encountered for native papilla anatomy (OR 0.4) and in children <3 years (OR 0.3). Cannulation was more often successful with biliary cannulation (95.9%) compared to pancreatic cannulation via the major papilla (89.6%, P < 0.0001) or minor papilla (71.2%, P < 0.0005). The most commonly identified adverse events included post-ERCP pancreatitis (5%), pain not related to post-ERCP pancreatitis (1.8%), and bleeding (1.2%). Risk factors for the development of each were identified.

Conclusions:

This large prospective study demonstrates that ERCP is reliable and safe in the pediatric population. It highlights the utility of PEDI in evaluating the technical outcomes of pediatric ERCPs and demonstrates the potential of PEDI for future studies in pediatric ERCPs.
Application of Prospect Theory in Obstetrics by Evaluating Mode of Delivery and Outcomes in Neonates Born Small or Appropriate for Gestational Age
Authors: Michaeli Jennia , Michaeli Ofir , Rozitzky Ariel , Grisaru-Granovsky Sorina , Feldman Naomi , Srebnik Naama
Published: September 2022

(Abstracted from JAMA Network Open 2022;5(3):e222177)

The antenatal diagnosis of fetal weight is a challenge that relies on sonographic estimations and the clinical assessment of fetal and maternal status. Meanwhile, the rate of detection of fetal growth restriction (FGR) is <40%.
Risk of Pregnancy Complications in Living Kidney Donors: A Systematic Review and Meta-analysis
Authors: Bellos Ioannis , Pergialiotis Vasilios
Published: September 2022

(Abstracted from Eur J Obstet Gynecol Reprod Biol 2022;270:35–41)

The criterion standard for management of end-stage kidney disease is kidney donation. However, kidney donation remains a complicated medical issue for the donor, as mid- and long-range complications are possible as a result of the procedure.
Neurofibromin 1 mediates sleep depth in Drosophila
Authors: Brown Elizabeth B. , Zhang Jiwei , Lloyd Evan , Lanzon Elizabeth , Botero Valentina , Tomchik Seth , Keene Alex C.
Published: September 2022

Neural regulation of sleep and metabolic homeostasis are critical in many aspects of human health. Despite extensive epidemiological evidence linking sleep dysregulation with obesity, diabetes, and metabolic syndrome, little is known about the neural and molecular basis for the integration of sleep and metabolic function. The RAS GTPase-activating gene Neurofibromin (Nf1) has been implicated in the regulation of sleep and metabolic rate, raising the possibility that it serves to integrate these processes, but the effects on sleep consolidation and physiology remain poorly understood. A key hallmark of sleep depth in mammals and flies is a reduction in metabolic rate during sleep. Here, we use indirect calorimetry to define the role of Nf1 on sleep-dependent changes in metabolic rate. Flies lacking Nf1 fail to suppress metabolic rate during sleep, raising the possibility that loss of Nf1 prevents flies from integrating sleep and metabolic state. Sleep of Nf1 mutant flies is fragmented with a reduced arousal threshold in Nf1 mutants, suggesting Nf1 flies fail to enter deep sleep. The effects of Nf1 on sleep can be localized to a subset of neurons expressing the GABA receptor Rdl. Selective knockdown of Nf1 in Rdl-expressing neurons increases gut permeability and reactive oxygen species (ROS) in the gut, suggesting a critical role for deep sleep in gut homeostasis. Together, these findings suggest Nf1 acts in GABA-sensitive neurons to modulate sleep depth in Drosophila.
Electrochemical disruption of extracellular electron transfer inhibits Pseudomonas aeruginosa cell survival within biofilms and is synergistic with antibiotic treatment
Authors: Otero Fernanda Jiménez , Newman Dianne K. , Tender Leonard M.
Published: September 2022

Survival of cells within oxygen-limited regions in Pseudomonas aeruginosa biofilms is enabled by using small redox active molecules as electron shuttles to access distal oxidants. This respiratory versatility makes P. aeruginosa biofilms common in chronic wound infections and recalcitrant to treatment. Here, we show that electrochemically controlling the redox state of these electron shuttles, specifically pyocyanin, can impact cell survival within anaerobic P. aeruginosa biofilms and can act synergistically with antibiotic treatment. We inhibited pyocyanin redox cycling under anoxic conditions by blocking its ability to be re-oxidized and thus serve as an electron shuttle via poising an electrode at a reductive potential that cannot regenerate oxidized pyocyanin (i.e. −400mV vs Ag/AgCl). This resulted in a decrease in CFUs within the biofilm of 100x compared to samples exposed to an electrode poised at an oxidizing potential that permits pyocyanin re-oxidation (i.e. +100mV vs Ag/AgCl). Phenazine-deficient Δphz* biofilms were not affected by the redox potential of the electrode, but were re-sensitized by adding pyocyanin. The effect of EET disruption was exacerbated when biofilms were treated with sub-MICs of a range of antibiotics. Most notably, 4 μg/ml of the aminoglycoside gentamicin in a reductive environment almost completely eradicated wild type biofilms but had no effect on the survival of Δphz* biofilms, suggesting reduced phenazines are toxic, and combined with antibiotic treatment can lead to extensive killing.

Importance

Biofilms provide a protective environment but they also present challenges to the cells living within them, such as overcoming diffusion limitation of nutrients and oxygen. Pseudomonas aeruginosa overcomes oxygen limitation by secreting soluble redox active molecules as electron shuttles to access distal oxygen. Here, we show that electrochemically blocking the redox cycling of one of these electron shuttles, pyocyanin, decreases cell survival within biofilms and acts synergistically with gentamicin to kill cells. Our results highlight the importance of the role that the redox cycling of electron shuttles fulfills within P. aeruginosa biofilms.
The Psychosis Human Connectome Project: Design and rationale for studies of visual neurophysiology
Authors: Schallmo Michael-Paul , Weldon Kimberly B. , Kamath Rohit S. , Moser Hannah R. , Montoya Samantha A. , Killebrew Kyle W. , Demro Caroline , Grant Andrea N. , Marjańska Małgorzata , Sponheim Scott R. , Olman Cheryl A.
Published: September 2022

Visual perception is abnormal in psychotic disorders such as schizophrenia. In addition to hallucinations, laboratory tests show differences in fundamental visual processes including contrast sensitivity, center-surround interactions, and perceptual organization. A number of hypotheses have been proposed to explain visual dysfunction in psychotic disorders, including an imbalance between excitation and inhibition. However, the precise neural basis of abnormal visual perception in people with psychotic psychopathology (PwPP) remains unknown. Here, we describe the behavioral and 7 tesla MRI methods we used to interrogate visual neurophysiology in PwPP as part of the Psychosis Human Connectome Project (HCP). In addition to PwPP (n = 66) and healthy controls (n = 43), we also recruited first-degree biological relatives (n = 44) in order to examine the role of genetic liability for psychosis in visual perception. Our visual tasks were designed to assess fundamental visual processes in PwPP, whereas MR spectroscopy enabled us to examine neurochemistry, including excitatory and inhibitory markers. We show that it is feasible to collect high-quality data across multiple psychophysical, functional MRI, and MR spectroscopy experiments with a sizable number of participants at a single research site. These data, in addition to those from our previously described 3 tesla experiments, will be made publicly available in order to facilitate further investigations by other research groups. By combining visual neuroscience techniques and HCP brain imaging methods, our experiments offer new opportunities to investigate the neural basis of abnormal visual perception in PwPP.
Ancient multiplicity in cyclic nucleotide-gated (CNG) cation channel repertoire was reduced in the ancestor of Olfactores before re-expansion by whole genome duplications in vertebrates
Authors: Lagman David , Haines Helen J. , Abalo Xesús M. , Larhammar Dan
Published: September 2022

Cyclic nucleotide-gated (CNG) cation channels are important heterotetrameric proteins in the retina, with different subunit composition in cone and rod photoreceptor cells: three CNGA3 and one CNGB3 in cones and three CNGA1 and one CNGB1 in rods. CNGA and CNGB subunits form separate subfamilies. We have analyzed the evolution of the CNG gene family in metazoans, with special focus on vertebrates by using sequence-based phylogeny and conservation of chromosomal synteny to deduce paralogons resulting from the early vertebrate whole genome duplications (WGDs). Our analyses show, unexpectedly, that the CNGA subfamily had four sister subfamilies in the ancestor of bilaterians and cnidarians that we named CNGC, CNGD, CNGE and CNGF. Of these, CNGC, CNGE and CNGF were lost in the ancestor of Olfactores while CNGD was lost in the vertebrate ancestor. The remaining CNGA and CNGB genes were expanded by a local duplication of CNGA and the subsequent chromosome duplications in the basal vertebrate WGD events. Upon some losses, this resulted in the gnathostome ancestor having three members in the visual CNGA subfamily (CNGA1-3), a single CNGA4 gene, and two members in the CNGB subfamily (CNGB1 and CNGB3). The nature of chromosomal rearrangements in the vertebrate CNGA paralogon was resolved by including the genomes of a non-teleost actinopterygian and an elasmobranch. After the teleost-specific WGD, additional duplicates were generated and retained for CNGA1, CNGA2, CNGA3 and CNGB1. Furthermore, teleosts retain a local duplicate of CNGB3. The retention of duplicated CNG genes is explained by their subfunctionalisation and photoreceptor-specific expression. In conclusion, this study provides evidence for four previously unknown CNG subfamilies in invertebrates and further evidence that the early vertebrate WGD events were instrumental in the evolution of the vertebrate visual and central nervous systems.
Mental fatigue impairs physical performance but not the neural drive to the muscle
Authors: Alix-Fages Carlos , Jiménez-Martínez Pablo , de Oliveira Daniela Souza , Möck Sebastian , Balsalobre-Fernández Carlos , Del Vecchio Alessandro
Published: September 2022

Mental fatigue (MF) does not only affect cognitive but also physical performance. This study aimed to explore the effects of MF on muscle endurance, rate of perceived exertion (RPE), and motor units’ activity. Ten healthy males participated in a randomised crossover study. The subjects attended two identical experimental sessions separated by three days with the only difference of a cognitive task (incongruent Stroop task [ST]) and a control condition (watching a documentary). Perceived MF and motivation were measured for each session at baseline and after each cognitive task. Four contractions at 20% of maximal voluntary contraction (MVIC) were performed at baseline, after each cognitive and after muscle endurance task while measuring motor units by high-density surface electromyography. Muscle endurance until failure at 50% of MVIC was measured after each cognitive task and the RPE was measured right after failure. ST significantly increased MF (p = 0.001) reduced the motivation (p = 0.008) for the subsequent physical task and also impaired physical performance (p = 0.044). However, estimates of common synaptic inputs and motor unit discharge rates as well as RPE were not affected by MF (p> 0.11). In conclusion, MF impairs muscle endurance and motivation for the physical task but not the neural drive to the muscle at any frequency bands. Although it is physiologically possible for mentally fatigued subjects to generate an optimal neuromuscular function, the altered perception and motivation seems to limit physical performance. Our results suggest that the corticospinal pathways are not affected by MF.
How do age, available support, gender and attitudes affect the quality of data collected by young citizen scientists in an ecological research project?
Authors: Aivelo Tuomas
Published: September 2022

1: Citizen science is increasingly used to collect ecological data. Specifically, participation of school students in authentic research has been suggested as having a multitude of benefits from data collection to science education. Nevertheless, the overall quality and quantity of data concerns ecologists who are using data for further analysis.

2: I coordinate a citizen science project, the Helsinki Urban Rat Project where lower and upper secondary school students collect data on urban rat occurrence through the use of track plates that record rat footprints. Within the project, both the success and accuracy of participating young citizen scientists can be assessed by comparing their results by professional researchers’ results and due to the use of an additional questionnaire relate this to the background variables (i.e., age, gender, available support, attitudes and sensitivity to disgust).

3: I found out that, in contrast to results from previous studies, age was not a significant variable, but rather available support and voluntary participation with rewards increased data quality. Additionally, higher liking of biology as a school subject was associated with the lower accuracy, whereas a higher interest in environment with higher accuracy.

4: The young citizen scientists provided reliable data with the exception of overrepresented false positive observations. My results suggest that the quality and quantity of citizen-generated data are not straightforwardly dependent on the selected target groups. Citizen science activities should be planned by careful consideration of the context, for example the school strongly shapes the participatory activities.
PICKLES v3: the updated database of pooled in vitro CRISPR knockout library essentiality screens
Authors: Novak Lance C , Chou Juihsuan , Colic Medina , Bristow Christopher A. , Hart Traver
Published: September 2022

PICKLES (https://pickles.hart-lab.org) is an updated web interface to a freely available database of genome-scale CRISPR knockout fitness screens in human cell lines. Using a completely rewritten interface, researchers can explore gene knockout fitness phenotypes across cell lines and tissue types and compare fitness profiles with fitness, expression, or mutation profiles of other genes. The database has been updated to include data from three CRISPR libraries (Avana, Score, and TKOv3), and includes information from 1,162 whole-genome screens probing the knockout fitness phenotype of 18,959 genes. Source code for the interface and the integrated database are available for download.
FrameRate: learning the coding potential of unassembled metagenomic reads
Authors: Liu-Wei Wang , Aubrey Wayne , Clare Amanda , Hoehndorf Robert , Creevey Christopher J. , Dimonaco Nicholas J.
Published: September 2022

Motivation

Metagenomic assembly is a slow and computationally intensive process and despite needing iterative rounds for improvement and completeness the resulting assembly often fails to incorporate many of the input sequencing reads. This is further complicated when there is reduced read-depth and/or artefacts which result in chimeric assemblies both of which are especially prominent in the assembly of metagenomic datasets. Many of these limitations could potentially be overcome by exploiting the information content stored in the reads directly and thus eliminating the need for assembly in a number of situations.

Results

We explored the prediction of coding potential of DNA reads by training a machine learning model on existing protein sequences. Named ‘FrameRate’, this model can predict the coding frame(s) from unassembled DNA sequencing reads directly, thus greatly reducing the computational resources required for genome assembly and similarity-based inference to pre-computed databases. Using the eggNOG-mapper function annotation tool, the predicted coding frames from FrameRate were functionally verified by comparing to the results from full-length protein sequences reconstructed with an established metagenome assembly and gene prediction pipeline from the same metagenomic sample. FrameRate captured equivalent functional profiles from the coding frames while reducing the required storage and time resources significantly. FrameRate was also able to annotate reads that were not represented in the assembly, capturing this ‘missing’ information. As an ultra-fast read-level assembly-free coding profiler, FrameRate enables rapid characterisation of almost every sequencing read directly, whether it can be assembled or not, and thus circumvent many of the problems caused by contemporary assembly workflows.

Availability

https://github.com/NickJD/FrameRate

Contact

liuwei.wang@fu-berlin.deandnicholas@dimonaco.co.uk
Robust eIF4B levels undermine invasive growth and immune evasion mechanisms in murine triple negative breast cancer models
Authors: Smith Randall , Diba Leila Zabihi , Srinivasan Aravind , Zollo Robert , Ossevoort Thomas , He Qian , Colligan Sean H. , Dolan Melissa , Vedire Yeshwanth , Sultana Tomina , Venkatesh Meera , Arora Aayush P. , Gawlak Sarah , Washington Deschana , Brackett Craig M. , Yao Song , Ebos John M.L. , Abrams Scott I. , Barbi Joseph , Walker Sarah E.
Published: September 2022

Dysregulated protein synthesis is seen in many aggressive cancers, including metastatic breast cancer. However, the specific contributions of certain translation initiation factors to in vivo disease remain undefined. This is particularly true of eIF4B, an RNA-binding protein and cofactor of the RNA helicase eIF4A and associated eIF4F cap-binding complex. While eIF4A, eIF4G, and eIF4E are well-known to contribute to the progression of many cancer types including metastatic breast cancers, the role played by eIF4B in breast cancer remains relatively unclear. We therefore explored how naturally divergent and experimentally modulated eIF4B levels impact tumor growth and progression in well-characterized murine triple negative breast cancer (TNBC) models. Surprisingly, we found that higher eIF4B levels in mouse and human breast cancers were associated with less aggressive phenotypes. shRNA-mediated eIF4B knockdown in TNBC lines failed to markedly alter proliferation and global translation in the cells in vitro and only modestly hindered their growth as primary mammary tumors growth in mice. However, eIF4B knockdown significantly enhanced invasive growth in vitro and exacerbated both tumor burden and mortality relative to nontargeting shRNA controls in a model of metastatic disease. Analysis of eIF4B levels and breast cancer patient survival reinforced a link to better outcomes. Interestingly, low eIF4B expression was also associated with more formidable immune evasion in vitro and in vivo, implicating a novel immunomodulatory role for this factor in the malignant setting that suggests a mode of action beyond its historical role as a co-activator of eIF4A/F.

Significance Statement

Metastasis is the leading cause of cancer-related mortality. Despite many advances in our understanding of this complex process and the molecular and cellular events involved, mechanisms that allow secondary tumors to arise and persist remain incompletely understood. Uncharacterized metastatic determinants active at the level of translational control may be exploitable as novel therapy targets or biomarkers predicting a tumor’s potential for spread and recurrence. Here we describe previously unrecognized consequences of dysregulated eIF4B levels in murine breast cancer that shed light on how this translation initiation factor contributes to disease outcomes. Our findings suggest that eIF4B levels direct metastatic risk and immune evasion, and further study should establish its value in personalized treatment decisions and development of future therapies.
Prefrontal neuronal dynamics in the absence of task execution
Authors: Pu Shusen , Dang Wenhao , Qi Xue-Lian , Constantinidis Christos
Published: September 2022

Prefrontal cortical activity represents stimuli in working memory tasks in a low-dimensional manifold that transforms over the course of a trial. Such transformations reflect specific cognitive operations, so that, for example, the rotation of stimulus representations is thought to reduce interference by distractor stimuli. Here we show that rotations occur in the low-dimensional activity space of prefrontal neurons in naïve monkeys, while passively viewing familiar stimuli. Moreover, some aspects of these rotations remain remarkably unchanged after training to perform working memory tasks. Significant training effects are still present in population dynamics, which further distinguish correct and error trials during task execution. Our results reveal automatic functions of prefrontal neural circuits, allow transformations that may aid cognitive flexibility.
Single-cell Pairwise Relationships Untangled by Composite Embedding model
Authors: Subedi Sishir , Park Yongjin P.
Published: September 2022

In multi-cellular organisms, cell identity and functions are primed and refined through interactions with other surrounding cells. Here, we propose a scalable machine learning method, termed SPRUCE, which is designed to systematically ascertain common cell-cell communication patterns embedded in single-cell RNA-seq data. We applied our approach to investigate tumour microenvironments consolidating multiple breast cancer data sets and found seven frequently-observed interaction signatures and underlying gene-gene interaction networks. Our results implicate that a part of tumour heterogeneity, especially within the same subtype, is better understood by differential interaction patterns rather than the static expression of known marker genes.
Genetic, Clinical Underpinnings of Brain Change Along Two Neuroanatomical Dimensions of Clinically-defined Alzheimer’s Disease
Authors: Wen Junhao , Yang Zhijian , Nasrallah Ilya M. , Cui Yuhan , Erus Guray , Srinivasan Dhivya , Abdulkadir Ahmed , Mamourian Elizabeth , Skampardoni Ioanna , Hwang Gyujoon , Singh Ashish , Bergman Mark , Bao Jingxuan , Varol Erdem , Zhou Zhen , Boquet-Pujadas Aleix , Chen Jiong , Toga Arthur W. , Saykin Andrew J. , Hohman Timothy J. , Thompson Paul M. , Villeneuve Sylvia , Gollub Randy , Sotiras Aristeidis , Wittfeld Katharina , Grabe Hans J. , Tosun Duygu , Bilgel Murat , An Yang , Marcus Daniel S. , LaMontagne Pamela , Benzinger Tammie L. , Heckbert Susan R. , Austin Thomas R. , Launer Lenore J. , Espeland Mark , Masters Colin L , Maruff Paul , Fripp Jurgen , Johnson Sterling C. , Morris John C. , Albert Marilyn S. , Bryan R. Nick , Resnick Susan M. , Ferrucci Luigi , Fan Yong , Habes Mohamad , Wolk David , Shen Li , Shou Haochang , Davatzikos Christos ,   iSTAGING, the AI4AD, and the ADSP phenotypic harmonization consortia, the BLSA, the PREVENT-AD, and the ADNI studies
Published: September 2022

Alzheimer’s disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised clustering technique known as Surreal-GAN, through which we identified two dominant dimensions of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the “diffuse-AD” (R1) dimension shows widespread brain atrophy, and the “MTL-AD” (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g.,APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated toAPOEdifferentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were “druggable genes” for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed thatAPOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction – driven by genes different fromAPOE– which may collectively contribute to the early pathogenesis of AD.
Inhibitory andin silicomolecular docking ofXeroderris stuhlmannii(Taub.) Mendonca & E.P. Sousa phytochemical compounds on human α-glucosidases
Authors: Nyathi Brilliant , Bvunzawabaya Jonathan Tatenda , Mudawarima Chido Venissa P , Manzombe Emily , Tsotsoro Kudakwashe , Selemani Major Allen , Munyuki Gadzikano , Rwere Freeborn
Published: September 2022

Ethnopharmacological relevance

Herbal traditional medicine is used by millions of people in Africa for treatment of ailments such as diabetes mellitus, stomach disorders and respiratory diseases.Xeroderris stuhlmannii (Taub.) Mendonca & E.P. Sousa (X. stuhlmannii(Taub.)) is a medicinal plant used traditionally in Zimbabwe to treat type 2 diabetes mellitus (T2DM) and its complications. However, there is no scientific evidence to support its inhibitory effect against digestive enzymes (α-glucosidases) that are linked to high blood sugar in humans.

Aim of the study

: This work aims to investigate whether bioactive phytochemicals of crudeX. stuhlmannii(Taub.) can scavenge free radicals and inhibit α-glucosidases in order to reduce blood sugar in humans.

Materials and methods

Here we examined the free radical scavenging potential of crude aqueous, ethyl acetate and methanolic extracts ofX. stuhlmannii(Taub.) using the diphenyl-2-picrylhydrazyl assayin vitro. Furthermore, we carried outin vitroinhibition of α-glucosidases (α-amylase and α-glucosidase) by the crude extracts using chromogenic 3,5-dinitrosalicylic acid and p-nitrophenyl-α-D-glucopyranoside substrates. We also used molecular docking approaches (Autodock Vina) to screen for bioactive phytochemical compounds targeting the digestive enzymes.

Results

Our results showed that phytochemicals inX. stuhlmannii(Taub.) aqueous, ethyl acetate and methanolic extracts scavenged free radicals with IC50values ranging from 0.002-0.013 μg/mL. Furthermore, crude aqueous, ethyl acetate and methanolic extracts significantly inhibited α-amylase and α-glucosidase with IC50values of 10.5-29.5 μg/mL (versus 54.1±0.7 μg/mL for acarbose) and 8.8-49.5 μg/mL (versus 161.4±1.8 μg/mL for acarbose), respectively.In silicomolecular docking findings and pharmacokinetic predictions showed that myricetin is likely a novel plant-derived α-glucosidase inhibitor.

Conclusion

Collectively, our findings suggest pharmacological targeting of digestive enzymes byX. stuhlmannii(Taub.) crude extracts may reduce blood sugar in humans with T2DM via inhibition of α-glucosidases.
The energetic effect of hip flexion and retraction in walking at different speeds: a modeling study
Authors: Jin Jian , Kistemaker Dinant , van Dieën Jaap H. , Daffertshofer Andreas , Bruijn Sjoerd M.
Published: September 2022

In human walking, power for propulsion is generated primarily via ankle and hip muscles. The addition of a ‘passive’ hip spring to simple bipedal models appears more efficient than using only push-off impulse, at least, when hip spring associated energetic costs are not considered. Hip flexion and retraction torques, however, are not ‘free’, as they are produced by muscles demanding metabolic energy. Studies evaluating the inclusion of hip actuation costs, especially during the swing phase, and the hip actuation’s energetic benefits are few and far between. It is also unknown whether these possible benefits/effects may depend on speed. We simulated a planar flat-feet model walking stably over a range of speeds. We asked whether the addition of independent hip flexion and retraction remains energetically beneficial when considering work-based metabolic cost of transport (MCOT) with different efficiencies of doing positive and negative work. We found asymmetric hip actuation can reduce the estimated MCOT relative to ankle actuation by up to 6%, but only at medium speeds. The corresponding optimal strategy is zero hip flexion and some hip retraction actuation. The reason for this reduced MCOT is a reduction in collision loss being larger than the associated increase in hip negative work. Both terms require positive mechanical work to compensate, yielding a larger reduction in metabolic work per step than the reduction in step length. Our study shows how ankle actuation, hip flexion, and retraction actuation can be coordinated to reduce MCOT.
Graph construction method impacts variation representation and analyses in a bovine super-pangenome
Authors: Leonard Alexander S. , Crysnanto Danang , Mapel Xena M. , Bhati Meenu , Pausch Hubert
Published: September 2022

Several models and algorithms have been proposed to build pangenomes from multiple input assemblies, but their impact on variant representation, and consequently downstream analyses, is largely unknown. We create multi-species “super-pangenomes” using pggb, cactus, and minigraph with theBos taurus taurusreference sequence and eleven haplotype-resolved assemblies from taurine and indicine cattle, bison, yak, and gaur. We recover 221k nonredundant structural variations (SVs) from the pangenomes, of which 135k (61%) are common to all three. SVs derived from assembly-based calling show high agreement with the consensus calls from the pangenomes (96%), but validate only a small proportion of variations private to each graph. Pggb and cactus, which also incorporate base-level variation, have approximately 95% exact matches with assembly-derived small variant calls, which significantly improves the edit rate when realigning assemblies compared to minigraph. We use the three pangenomes to investigate 9,566 variable number tandem repeats (VNTRs), finding 63% have identical predicted repeat counts in the three graphs, while minigraph can over or underestimate the count given its approximate coordinate system. We examine a highly variable VNTR locus and show that repeat unit copy number impacts expression of proximal genes and non-coding RNA. Our findings indicate good consensus between the three pangenome methods but also show their individual strengths and weaknesses that need to be considered when analysing different types of variants from multiple input assemblies.
Temporal asymmetries and interactions between dorsal and ventral visual pathways during object recognition
Authors: Ayzenberg Vladislav , Simmons Claire , Behrmann Marlene
Published: September 2022

Despite their anatomical and functional distinctions, there is growing evidence that the dorsal and ventral visual pathways interact to support object recognition. However, the exact nature of these interactions remains poorly understood. Is the presence of identity-relevant object information in the dorsal pathway simply a byproduct of ventral input? Or, might the dorsal pathway be a source of input to the ventral pathway for object recognition? In the current study, we used high-density EEG – a technique with high temporal precision and spatial resolution sufficient to distinguish parietal and temporal lobes – to characterize the dynamics of dorsal and ventral pathways during object viewing. Using multivariate analyses, we found that category decoding in the dorsal pathway preceded that in the ventral pathway. Importantly, the dorsal pathway predicted the multivariate responses of the ventral pathway in a time-dependent manner, rather than the other way around. Together, these findings suggest that the dorsal pathway is a critical source of input to the ventral pathway for object recognition.
Improved models for the relationship between age and the probability of trypanosome infection in female tsetse, Glossina pallidipes Austen
Authors: Hargrove J. W. , Van Sickle J.
Published: September 2022

Between 1990 and 1999, at Rekomitjie Research Station, Zambezi Valley, Zimbabwe, 29,360 female G. pallidipes were dissected to determine their ovarian category and trypanosome infection status. Overall prevalences were 3.45% and 2.66% for T. vivax and T. congolense, respectively, declining during each year as temperatures increased from July - December. Fits to age-prevalence data using Susceptible-Exposed-Infective (SEI) and SI compartmental models were statistically better than those obtained using a published catalytic model, which made the unrealistic assumption that no female tsetse survived more than seven ovulations. The improved models require knowledge of fly mortality, estimated separately from ovarian age distributions. Infection rates were not significantly higher for T. vivax than for T. congolense. For T. congolense in field-sampled female G. pallidipes, we found no statistical support for a model where the force of infection was higher at the first feed than subsequently. The long survival of adult female tsetse, combined with feeding at intervals ≤ 3 days, ensures that post-teneral feeds, rather than the first feed, play the dominant role in the epidemiology of T. congolense infections in G. pallidipes. This is supported by estimates that only about 3% of wild hosts at Rekomitjie were harbouring sufficient T. congolense to ensure that tsetse feeding off them take an infected meal, so that the probability of ingesting an infected meal is low at every meal.
Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers
Authors: Nussbaum Daniel P. , Martz Colin A. , Waters Andrew M. , Barrera Alejandro , Rutter Justine C. , Cerda-Smith Christian G. , Stewart Amy E. , Wu Chao , Cakir Merve , Levandowski Cecilia B. , Kantrowitz David E. , McCall Shannon J , Pierobon Mariaelena , Petricoin Emanuel F. , Smith J. Joshua , Reddy Timothy E. , Der Channing J. , Taatjes Dylan J. , Wood Kris C.
Published: September 2022

Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this novel class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and tumor-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved population-level process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, tumor-specific resistance programs.