bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Evaluation of a Nomogram to Predict the Eventual Severity of the First Episode of Acute Pancreatitis
Authors: Zhong Rui , Xu Jin , Luo Xujuan , Shi Xiaomin , Peng Yan , Xu Huan , Jiang Xin , Yan Yongfeng , Fu Xiangsheng , Tang Xiaowei
Published: July 2022

Objective

The aim of this research was to establish a nomogram for early prediction of the severity of acute pancreatitis (AP).

Methods

A total of 1860 AP patients from 2013 to 2020 were included in this study. According to the 2012 revised Atlanta classification, patients were divided into nonsevere AP group and severe AP (SAP) group. The baseline characteristics and first laboratory indicators after admission between the 2 groups were analyzed using univariate and multivariate logistic regression analysis in training set. R language was used for establishing a predictive nomogram and further verified in validation set.

Results

Univariate and multivariate logistic regression analysis in the training set showed red blood cell distribution width, d-dimer, apolipoprotein A1, and albumin were independent factors for SAP. A predictive nomogram was accordingly established based on the 4 indicators. Validation on this predictive nomogram showed high internal validation concordance index of 0.940 (95% confidence interval, 0.922–0.958) and high external validation concordance index of 0.943 (95% confidence interval, 0.920–0.966). The calibration curve, receiver operating characteristic curve, and decision curve analysis all showed that the nomogram had good predictive ability.

Conclusions

This nomogram may be an effective clinical tool for predicting the first episode of SAP.
In Patients With Melanoma Brain Metastases, Is Combination Immune Checkpoint Inhibition a Safe and Effective First-Line Treatment? A Critically Appraised Topic
Authors: Gritsch David , Mrugala Maciej M. , Marks Lisa A. , Wingerchuk Dean M. , O’Carroll Cumara B.
Published: July 2022

Background:

Combined PD-1/PD-L1 and CTLA-4 immune checkpoint inhibition for the has been shown to produce superior results in the treatment of malignant melanoma when compared to monotherapy. However, patients with intracranial disease were excluded from these studies given their poor prognosis.

Objective:

The objective of this study was to critically assess current evidence supporting the co-administration of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of melanoma brain metastases.

Methods:

The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology.

Results:

A recent, open-label, non-comparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and safety of nivolumab alone or in combination with ipilimumab in 79 adult patients with untreated, asymptomatic melanoma brain metastases. The rates of the primary outcome (intracranial response at ≥12 wk) in the primary endpoint cohort were 46% for cohort A (combination therapy) and 20% for cohort B (nivolumab monotherapy). No treatment related deaths were observed in the study. Grade 4 adverse events occurred in 9% of patients in cohort A and none in cohort B.

Conclusions:

Co-administration of ipilimumab and nivolumab as first-line therapy is effective in the treatment of asymptomatic melanoma brain metastases, with an acceptable safety profile.
Morules But Not Squamous Differentiation are a Reliable Indicator of CTNNB1 (β-catenin) Mutations in Endometrial Carcinoma and Precancers
Authors: Niu Shuang , Lucas Elena , Molberg Kyle , Strickland Amanda , Wang Yan , Carrick Kelley , Rivera-Colon Glorimar , Gwin Katja , SoRelle Jeffrey A. , Castrillon Diego H. , Zheng Wenxin , Chen Hao
Published: July 2022

Although collectively regarded as “squamous differentiation (SD)” in endometrial endometrioid carcinoma (EEC) and atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN), morules (often referred to as “squamous morules”) and true SD may represent two distinct phenomena. Here, we explored the distinction between morules versus SD and investigated the association of morules and SD with CTNNB1 mutations. A total of 270 cases of EEC and AH/EIN were studied, including EEC with (n=36) or without (n=36) morules and AH/EIN with (n=80) or without (n=118) morules. Cases were analyzed by immunohistochemistry and selected cases (n=20) by targeted next-generation sequencing panel. Near-perfect agreement was found between morules and glandular β-catenin nuclear staining in AH/EIN and EEC. A strong positive association was found between morules and glandular β-catenin nuclear staining (P<0.0001, Φ=0.59 in AH/EIN; P<0.0001, Φ=0.85 in EEC). There was no association between (1) morules and glandular PAX2 or PTEN aberrant expression or (2) SD and aberrant expression of β-catenin, PAX2 or PTEN (Φ=0.09, β-catenin; Φ=0.16, PAX2; Φ=0.13, PTEN). CTNNB1 mutations were identified in all 20 selected morule-containing cases (100%). Next-generation sequencing was performed on 2 (preprogestin and postprogestin treatment) biopsies from 1 patient, revealing identical mutational profile in morules and glands. In conclusion, (1) SD and morules are distinct biological phenomena; (2) the presence of morules, but not SD, is a reliable indicator of CTNNB1 mutations in EEC and AH/EIN. Our findings demonstrate that SD and morules are distinct biological phenomena. Since morules but not SD are associated with β-catenin mutations, the distinction is clinically relevant and should be included in diagnostic reports.
A community-based adapted exercise program to increase quality of life and self-efficacy among adults with physical disabilities: A mixed-method study
Authors: Oh Juntack , Davis Ronald
Published: July 2022

Background:

Self-efficacy is one of the key constructs that directly influence physical activity, community participation, and mental health while acting as a strong influence on the quality of life (QOL) for adults with physical disabilities (AWPDs). There are relatively few studies focusing on a community-based exercise program in this population.

Objective:

This study aims to quantitatively examine a community-based adapted exercise program on the QOL and self-efficacy of AWPDs. In addition, we explored AWPD's perceived benefits of community-based exercise programming and any factors that may influence those perceived benefits.

Method:

Adults with physical disabilities (N = 50) participated in a 9-week community-based adapted exercise program (90-minute session, twice per week). QOL (WHOQOL-BREF) and self-efficacy were measured at baseline and at the conclusion of the program. A follow-up focus group (n = 22) was conducted at the postprogram. Quantitative data were analyzed by paired t test (α = 0.05). Qualitative data were analyzed by thematic coding and content analysis.

Result:

Significant improvement with moderate effect size was found across all variables. Two main themes emerged from the qualitative analysis: 1) perceived benefit of exercise program and 2) factors of an exercise program for AWPD.

Conclusion:

A community-based exercise program and self-efficacy play a large role in the exercise behaviors and QOL of AWPDs. The benefits of exercise and factors identified as promoting exercise may be carefully considered to improve QOL for this population. The finding of this study offers practical recommendations to community-based exercise specialists, which would assist in establishing an appropriate exercise program for AWPDs.
Azygos Vein Enlargement Secondary to Superior Vena Cava Syndrome on 18F-FDG PET/CT
Authors: Filizoglu Nuh , Ozguven Salih , Ones Tunc , Turoglu Halil Turgut , Erdil Tanju Yusuf
Published: July 2022

Obstruction of the blood flow from the superior vena cava (SVC) to the right atrium causes the SVC syndrome. The azygos system is the most important way to overcome SVC obstruction. Azygos vein enlargement can be seen secondary to the SVC syndrome. Although a few cases showing 18F-FDG uptake along the SVC in SVC syndrome were reported before, 18F-FDG PET/CT findings of azygos vein enlargement have not been documented yet. Herein, we presented an intriguing case of azygos vein enlargement secondary to SVC syndrome on 18F-FDG PET/CT.
Preoperative Radiotherapy in Patients With Primary Retroperitoneal Sarcoma
Authors: Callegaro Dario , Raut Chandrajit P. , Ajayi Taiwo , Strauss Dirk , Bonvalot Sylvie , Ng Deanna , Stoeckle Eberhard , Fairweather Mark , Rutkowski Piotr , van Houdt Winan J. , Gelderblom Hans , Sangalli Claudia , Hayes Andrew , Honoré Charles , Gladdy Rebecca A. , Fau Magali , Haas Rick , Tzanis Dimitri , Miah Aisha B. , Chung Peter , Baldini Elizabeth H. , Marreaud Sandrine , Litiere Saskia , Swallow Carol J. , Gronchi Alessandro
Published: July 2022

Objective:

The aim of the present study was to compare the effect of radiotherapy (RT) on abdominal recurrence-free survival (ARFS) in patients with primary retroperitoneal sarcoma treated in the EORTC-STBSG-62092 (STRASS) phase 3 randomized controlled trial (STRASS cohort) and off-trial (STREXIT cohort) and to pool STRASS and STREXIT data to test the hypothesis that RT improves ARFS in patients with liposarcoma.

Background:

The STRASS trial did not show any difference in ARFS between patients treated with preoperative radiotherapy+surgery (RT+S) versus surgery alone (S).

Methods:

All consecutive adult patients not enrolled in STRASS and underwent curative-intent surgery for a primary retroperitoneal sarcoma with or without preoperative RT between 2012 and 2017 (STRASS recruiting period) among ten STRASS-recruiting centres formed the STREXIT cohort. The effect of RT in STREXIT was explored with a propensity score (PS)-matching analysis. Primary endpoint was ARFS defined as macroscopically incomplete resection or abdominal recurrence or death of any cause, whichever occurred first.

Results:

STRASS included 266 patients, STREXIT included 831 patients (727 after excluding patients who received preoperative chemotherapy, 202 after 1:1 PS-matching). The effect of RT on ARFS in STRASS and 1:1 PS-matched STREXIT cohorts, overall and in patients with liposarcoma, was similar. In the pooled cohort analysis, RT administration was associated with better ARFS in patients with liposarcoma [N=321, hazard ratio (HR), 0.61; 95% confidence interval (CI), 0.42–0.89]. In particular, patients with well-differentiated liposarcoma and G1-2 dedifferentiated liposarcoma (G1-2 DDLPS, n=266) treated with RT+S had better ARFS (HR, 0.63; 95% CI, 0.40–0.97) while patients with G3 DDLPS and leiomyosarcoma had not. At the current follow-up, there was no association between RT and overall survival or distant metastases-free survival.

Conclusions:

In this study, preoperative RT was associated with better ARFS in patients with primary well-differentiated liposarcoma and G1-2 DDLPS.
Does slow release oral morphine have impact on craving and impulsivity in heroin dependent individuals?
Authors: Giustiniani Julie , Rothen Stéphane , Penzenstadler Louise , Colombo Laura , Calzada Gérard , Thorens Gabriel , Zullino Daniele
Published: July 2022

Craving and impulsivity are addiction components which explain why heroin-dependant individuals (HDI), continue using heroin despite not wanting to do so. Opioid maintenance treatment (OMT), such as slow-release oral morphine (SROM), is the most effective treatment for opioid dependence. However, the impact of SROM on craving and impulsivity remains unclear. In this observational study, 23 HDI receiving SROM, their usual OMT, took part in the experiment. Each of the participants filled in the perceived level of craving with a visual analog scale. Their impulsivity was assessed via three laboratory tasks, the stop-signal reaction time, the Balloon Analogue Risk Task and delay discounting. Each evaluation was performed before and after SROM administration. Craving was significantly reduced after administration of SROM (difference 2.83; P = 0.0010), whereas there were no significant differences in performance in the three laboratory tasks. In the long term, we observed an improvement on delay discounting correlated with the duration and dosage of SROM. The acute impact of SROM appears to significantly reduce craving, without impacting impulsivity. Observation of the correlation between delay discounting and the duration and dosage of OMT is of great interest and should be studied further.
Bacillus rhizoplanae sp. nov. from maize roots
Authors: Kämpfer Peter , Lipski André , McInroy John A. , Clermont Dominique , Criscuolo Alexis , Glaeser Stefanie P.
Published: July 2022

A Gram-stain-positive, aerobic and endospore-forming bacterial strain, isolated from the root surface of maize (Zea mays) was taxonomically studied. It could be clearly shown that, based on 16S rRNA gene sequence similarity comparisons, strain JJ-63T is a member of the genus

Bacillus

, most closely related to the type strain of

Bacillus pseudomycoides

(98.61%), followed by

Bacillus cereus

(98.47 %). Detailed phylogenetic analysis based on the 16S rRNA gene and the 87 proteins conserved within the phylum

Firmicutes

placed the strain into the Cereus clade. The average nucleotide identity, average amino acid identity and digital DNA–DNA hybridization values against the type strain of

B. pseudomycoides

were 80.97, 81.45 and 26.30 %, respectively. The quinone system of strain JJ-63T consisted exclusively of menaquinone MK-7. The polar lipid profile consisted of the major components diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and an unidentified glycolipid. Major fatty acids were iso- and anteiso-branched with the major compounds iso-C15 : 0 and iso-C17 : 0. Also, the characteristic compounds C13 : 0 iso and C16 : 1
cis10 were found. Physiological and biochemical characteristics allowed a further phenotypic differentiation of strain JJ-63T from the most closely related species. For this reason, JJ-63T represents a novel species of the genus

Bacillus

, for which the name Bacillus rhizoplanae sp. nov. is proposed, with JJ-63T (=LMG 32091T=CCM 9090T=DSM 111827T= CIP 111899T) as the type strain.
Generating dynamic carbon-dioxide from the respiratory-volume time series: A feasibility study using neural networks
Authors: Agrawal V. , Zhong Xiaole Z. , Chen J. J.
Published: July 2022

In the context of fMRI, carbon dioxide (CO2) is a well-known vasodilator that has been widely used to monitor and interrogate vascular physiology. Moreover, spontaneous fluctuations in end-tidal carbon dioxide (PETCO2) reflects changes in arterial CO2 and has been demonstrated as the largest physiological noise source in the low-frequency range of the resting-state fMRI (rs-fMRI) signal. Increasing appreciation for the role of CO2 in fMRI has given rise to methods that use it for physiological denoising or estimating cerebrovascular reactivity. However, the majority of rs-fMRI studies do not involve CO2 recordings, and most often only heart rate and respiration are recorded. While the intrinsic link between these latter metrics and CO2 led to suggested possible analytical models, they have not been widely applied. In this proof-of-concept study, we propose a deep learning approach to reconstruct CO2 and PETCO2 data from respiration waveforms in the resting state. We demonstrate that the one-to-one mapping between respiration and CO2 recordings can be well predicted using fully convolutional networks (FCNs), achieving a Pearson correlation coefficient (r) of 0.946 ± 0.056 with the ground truth CO2. Moreover, dynamic PETCO2 can be successfully derived from the predicted CO2, achieving r of 0.512 ± 0.269 with the ground truth. Importantly, the FCN-based methods outperform previously proposed analytical methods. In addition, we provide guidelines for quality assurance of respiration recordings for the purposes of CO2 prediction. Our results demonstrate that dynamic CO2 can be obtained from respiration-volume using neural networks, complementing the still few reports in deep-learning of physiological fMRI signals, and paving the way for further research in deep-learning based bio-signal processing.
REM sleep has minute-scale rhythms in mice and humans: A non-binary continuum between phasic and tonic microstates
Authors: Bueno-Junior Lezio S. , Ruckstuhl Maxwell S. , Lim Miranda M. , Watson Brendon O.
Published: July 2022

Rapid eye movement sleep (REM) is believed to have a binary temporal structure with “phasic” and “tonic” microstates, defined by motoric activity versus quiescence, respectively. However, we observed in mice that the frequency of theta activity (a marker of rodent REM) fluctuates in a non-binary fashion, with the extremes of that fluctuation correlating with phasic-type and tonic-type facial motricity. This demonstrates that phasic and tonic REM rather represent ends of a continuum. These cycles of brain physiology and facial movement occurred at 0.01-0.06 Hz, or infraslow frequencies, and affected cross-frequency coupling and neuronal assembly activity in the neocortex, suggesting network functional impact. We then confirmed that humans also demonstrate non-binary phasic/tonic microstates, with continuous 0.01-0.04 Hz respiratory rate cycles matching the incidence of eye movements. Thus, we discovered a fundamental property of REM, which can yield new insights into our understanding of sleep health.
MINE is a method for detecting spatial density of regulatory chromatin interactions based on a MultI-modal NEtwork
Authors: Gong Haiyan , Li Minghong , Ji Mengdie , Zhang Xiaotong , Yuan Zan , Zhang Sichen , Yang Yi , Li Chun , Chen Yang
Published: July 2022

Chromatin interactions play essential roles in chromatin conformation and gene expression. However, few tools exist to analyze the spatial density of regulatory chromatin interactions. Here, we present the MultI-modal NEtwork (MINE) toolkit, including MINE-Loop, MINE-Density, and MINE-Viewer. MINE-Loop network modeling integrates Hi-C, ATAC-seq, and histone ChIP-seq data to enhance the detection of regulatory chromatin interactions (RCIs, i.e., chromatin interactions that are anchoring regulatory elements to chromatin); MINE-Density quantifies the spatial density of regulatory chromatin interactions identified by MINE-Loop within different chromatin conformations; and MINE-Viewer facilitates 3D visualization of the density of chromatin interactions and participating regulatory factors, such as transcription factors. We applied MINE to investigate the relationship between the spatial density of regulatory chromatin interactions (SD-RCI) and chromatin volume change in HeLa cells before and after liquid-liquid phase separation. Changes in SD-RCI before and after treating the HeLa cells with 1,6-hexanediol showed that the change in chromatin volume was related to the degree of activation or repression of genes in chromatin interactions. The MINE toolkit provides a new method for quantitative study of chromatin conformation.

Graphical Abstract

In Brief

Gong et al. provide a toolkit MINE to explore the relationship between spatial density of regulatory chromatin interactions, gene expression and chromatin structure change.

Highlights

MINE toolkit was provided to detect more regulatory chromatin interactions (RCI), count the spatial density of regulatory chromatin interactions and visualize the density of chromatin interactions with transcription factors in three-dimension.

Chromatin regions were divided into developed active hub, developing active hub, developed repressive hub, and developing repressive hub according to the density of active or repressive regulatory chromatin interactions.

The change of chromatin structure before and after liquid-liquid phase separation is quantitively described by using the MINE toolkit.
Correction of susceptibility distortion in EPI: a semi-supervised approach with deep learning
Authors: Legouhy Antoine , Graham Mark , Guerreri Michele , Stee Whitney , Villemonteix Thomas , Peigneux Philippe , Zhang Hui
Published: July 2022

Echo planar imaging (EPI) is the most common approach for acquiring diffusion and functional MRI data due to its high temporal resolution. However, this comes at the cost of higher sensitivity to susceptibility-induced B0 field inhomogeneities around air/tissue inter-faces. This leads to severe geometric distortions along the phase encoding direction (PED). To correct this distortion, the standard approach involves an analogous acquisition using an opposite PED leading to images with inverted distortions and then non-linear image registration, with a transformation model constrained along the PED, to estimate the voxelwise shift that undistorts the image pair and generates a distortion-free image. With conventional image registration approaches, this type of processing is computationally intensive. Recent advances in unsupervised deep learning-based approaches to image registration have been proposed to drastically reduce the computational cost of this task. However, they rely on maximizing an intensity-based similarity measure, known to be suboptimal surrogate measures of image alignment. To address this limitation, we propose a semi-supervised deep learning algorithm that directly leverages ground truth spatial transformations during training. Simulated and real data experiments demonstrate improvement to distortion field recovery compared to the unsupervised approach, improvement image similarity compared to supervised approach and precision similar to TOPUP but with much faster processing.
Evolutionary stability of social commitment
Authors: Shirokawa Yuka , Shimada Masakazu , Shimada Nao , Sawai Satoshi
Published: July 2022

Conflict resolution between individual cells and a group is essential for multicellularity. The social amoebaDictyostelium discoideumswitches between solitary growth and social fruitification depending on nutrient availability. Under starvation, cells form fruiting bodies consisting of spores and non-viable altruistic stalk cells. Once cells socially committed, they complete fruitification even with a renewed source of nutrients. This social commitment is puzzling because it deprives individual cells of benefits of quickly resuming solitary growth. One idea posits that traits that facilitate premature de-commitment are somehow hindered from being selected. We studied outcomes of premature de-commitment by forced refeeding. We show that when refed cells resume sociality together with non-refed cells, besides some becoming solitary outside of fruiting bodies, a large fraction was redirected to a sub-region of altruistic stalk regardless of their original fate. The refed cells exhibited reduced cohesivity and were sorted out to the altruistic positions in morphogenesis. Furthermore, a theoretical model considering evolution of cell-cell association revealed a valley in the fitness landscape that prevents invasion of de-committing mutants. Our results provide a general scheme that naturally penalizes withdrawal from a society by evolving a specific division of labor that less cohesive individuals become altruists.

Significance Statement

Evolution of unicellular to multicellular organisms must resolve conflicts of reproductive interests between individual cells and the group. In the social amoebaDictyostelium, a transition from a solitary to multicellular group occurs under starvation. Once cells commit themselves to multicellular organization, the process continues even when shifting to an environment that favors solitary growth. Our study revealed that cells forced to partially revert to a de-committed state take an altruistic role through interaction with socially committed cells. The de-committed cells exhibited reduced cohesivity and were sorted out to altruistic positions in morphogenesis. This inevitably penalizes ‘selfish’ cells that revert to solitary growth too quickly. Our results explain group-level behavior that is apparently difficult to understand from an individual-level fitness.
AlphaViz: Visualization and validation of critical proteomics data directly at the raw data level
Authors: Voytik Eugenia , Skowronek Patricia , Zeng Wen-Feng , Tanzer Maria C. , Brunner Andreas-David , Thielert Marvin , Strauss Maximilian T. , Willems Sander , Mann Matthias
Published: July 2022

Although current mass spectrometry (MS)-based proteomics identifies and quantifies thousands of proteins and (modified) peptides, only a minority of them are subjected to in-depth downstream analysis. With the advent of automated processing workflows, biologically or clinically important results within a study are rarely validated by visualization of the underlying raw information. Current tools are often not integrated into the overall analysis nor readily extendable with new approaches. To remedy this, we developed AlphaViz, an open-source Python package to superimpose output from common analysis workflows on the raw data for easy visualization and validation of protein and peptide identifications. AlphaViz takes advantage of recent breakthroughs in the deep learning-assisted prediction of experimental peptide properties to allow manual assessment of the expected versus measured peptide result. We focused on the visualization of the 4-dimensional data cuboid provided by Bruker TimsTOF instruments, where the ion mobility dimension, besides intensity and retention time, can be predicted and used for verification. We illustrate how AlphaViz can quickly validate or invalidate peptide identifications regardless of the score given to them by automated workflows. Furthermore, we provide a ‘predict mode’ that can locate peptides present in the raw data but not reported by the search engine. This is illustrated the recovery of missing values from experimental replicates. Applied to phosphoproteomics, we show how key signaling nodes can be validated to enhance confidence for downstream interpretation or follow-up experiments. AlphaViz follows standards for open-source software development and features an easy-to-install graphical user interface for end-users and a modular Python package for bioinformaticians. Validation of critical proteomics results should now become a standard feature in MS-based proteomics.
A Comparative Study of Epithelial Transport in the Rat and Mouse Kidneys: Modelling and Analysis
Authors: Layton Anita T.
Published: July 2022

The goal of the present study was to investigate the functional implications of sex and species differences in the pattern of transporters along nephrons in the rat and mouse kidney, as reported by Veiras et al. (J Am Soc Nephrol28: 3504–3517, 2017). To do so, we developed the first sex-specific computational models of epithelial water and solute transport along the nephrons from male and female mouse kidneys, and conducted simulations along with our published rat models. These models account for the sex differences in the abundance of apical and basolateral transporters, glomerular filtration rate, and tubular dimensions. Model simulations predict that 73% and 57% of filtered Na+is reabsorbed by the proximal tubules of male and female rat kidneys, respectively. Due to their smaller transport area and lower NHE3 activity, the proximal tubules in the mouse kidney reabsorb a significantly smaller fraction of the filtered Na+, at 53% in male and only 34% in female. The lower proximal fractional Na+reabsorption in female kidneys of both rat and mouse is due primarily to their smaller transport area, lower Na+/H+exchanger activity, and lower claudin-2 abundance, culminating in significantly larger fractional delivery of water and Na+to the downstream nephron segments in female kidneys. Conversely, the female distal nephron exhibits a higher abundance of key Na+transporters, including Na+-Cl−cotransporters in both species, epithelial Na+channels for the female rat, and Na+-K+-Cl−cotransporters for the female mouse. The higher abundance of transporters accounts for the enhanced water and Na+transport along the female rat and mouse distal nephrons, relative to the respective male, resulting in similar urine excretion between the sexes. Model simulations indicate that the sex and species differences in renal transporter patterns may partially explain the experimental observation that, in response to a saline load, the diuretic and natriuretic responses were more rapid in female rats than males, but no significant sex difference was found in mice. These computational models can serve as a valuable tool for analyzing findings from experimental studies conducted in rats and mice, especially those involving genetic modifications.
A pH-dependent cluster of charges in a conserved cryptic pocket on flaviviral envelopes
Authors: Zuzic Lorena , Marzinek Jan K. , Anand Ganesh S. , Warwicker Jim , Bond Peter J.
Published: July 2022

Flaviviruses are enveloped viruses which include numerous human pathogens of escalating global health concern that are predominantly transmitted by mosquitoes and ticks. Some, such as dengue virus, exhibit the phenomenon of antibody-dependent enhancement (ADE) of disease, making traditional vaccine-based routes of fighting viral infections problematic. The pH-dependent conformational change of the envelope (E) protein required for fusion between the viral and endosomal membranes is an attractive point of inhibition by antivirals as it also has the potential to diminish the effects of ADE. Here, we systematically examined six flaviviruses by employing large-scale molecular dynamics (MD) simulations of a ∼400,000 atom raft system that represents a substantial portion of the curved flaviviral envelope. We utilised a benzene-mapping approach over a total of 14 μs of sampling time, leading to discovery of shared hotspots and elucidation of the dynamic behaviour of conserved cryptic sites. A cryptic pocket previously shown to bind a detergent molecule exhibited significant strain-specific characteristics. An alternative conserved cryptic site located at the E protein domain interfaces showed a more consistent dynamic behaviour across flaviviruses and contains a buried, conserved cluster of ionisable residues that includes His144, previously implicated in the pH-dependent conformational switch required for fusion. The dynamics of the cluster were further explored in extensive constant-pH simulations and revealed cluster and domain-interface disruption under low pH conditions. Based on this, we propose a cluster-dependent mechanism that addresses inconsistencies in the histidine-switch hypothesis and highlights the role of cluster protonation in orchestrating the domain dissociation pivotal for the formation of the fusogenic trimer.

GRAPHICAL ABSTRACT
Shared and host-specific transcriptomic response of Pseudomonas donghuensis P482 to the exudates of tomato (Dicot) and maize (Monocot) shed light on the host-adaptive traits in the promiscuous root colonizing bacteria
Authors: Krzyżanowska Dorota M. , Jabłońska Magdalena , Kaczyński Zbigniew , Czerwicka-Pach Małgorzata , Macur Katarzyna , Jafra Sylwia
Published: July 2022

Plants of different genotypes and physiological states recruit different populations of root microbiota. The selection is driven by the immune response of the plant and the composition of root exudates. Some bacteria, including Pseudomonas spp., are promiscuous root colonizers. It is yet unclear what particular changes in lifestyle enable them to thrive in the company of different plant hosts. In this study, we used RNAseq to identify genes of the differential (host-specific) and shared (host-independent) transcriptomic responses of a biocontrol strain Pseudomonas donghuensis P482 to the root exudates of two phylogenetically distinct plant species, tomato (Dicot) and maize (Monocot), both of which can be colonized by the bacterium. The host-independent response of P482 to exudates involved upregulated expression of arsenic resistance genes and bacterioferritin synthesis. Contrary, we observed downregulation of pathways related to sulfur assimilation, sensing of ferric citrate and/or other iron carriers, the acquisition of heme, the assembly of the type VI secretion system, and amino acid transport. Pathways upregulated in P482 specifically by tomato exudates included nitric oxide detoxification, repair of iron-sulfur clusters, respiration through the cyanide-insensitive cytochrome bd, and catabolism of amino acids and/or fatty acids. The maize-specific response included upregulation of genes associated with motility, the activity of MexE and two other RND efflux pumps, and copper tolerance. To provide more context to the study, we determined the chemical composition of exudates by GC-MS, NMR, and LC-SRM. Our results bring new insight into the host-driven metabolic adaptations of promiscuous root colonizing bacteria.

Significance statement

Understanding factors determining the composition and the activity of plant-associated microbiota is crucial to harnessing their potential to benefit plant health. Traits that enable microorganisms to colonize plants have long been the subject of study, with many important factors identified for particular host-microbe systems. However, studies involving more than a single plant host are rare. This results in many unanswered questions on the host-specific and universal aspects of metabolism that enable more promiscuous root colonizers to interact with different plant hosts. The presented study begins to fill this knowledge gap by providing data on the metabolic pathways involved in the differential and shared response of Pseudomonas donghuensis strain P482 to the exudates of phylogenetically distant plant species: tomato and maize.
Comparing the accuracy and efficiency of third generation DNA barcode sequencing: Oxford Nanopore Technologies versus Pacific Biosciences
Authors: Cuber Piotr , Chooneea Darren , Geeves Clementine , Salatino Silvia , Creedy Thomas J. , Griffin Claire , Sivess Laura , Barnes Ian , Price Ben , Misra Raju
Published: July 2022

At times of drastic decrease in biodiversity and loss of species, sometimes referred to as the “sixth mass extinction” or “Holocene extinction”, there is a high demand on the development of effective tools for studying and monitoring biodiversity. In the past decade, new promising technologies, such as third generation sequencing (TGS), enabled massive, rapid, and cost-effective data analysis of non-model organisms, accelerating taxonomic identification studies and contributing to conservation applications. Here, we focus on the comparison of the two main TGS providers, Pacific Biosciences (PacBio), and Oxford Nanopore Technologies (ONT), for the purpose of DNA barcoding. For ONT, we also tested selected combinations of different types of flow cells and ligation sequencing kits. Out of five tested combinations (PacBio, ONT Flongle flow cell & SQK-LSK110 kit, R9 flow cell & SQK-LSK109 kit, R9 & SQK-LSK100 kit, and R10 flow cell & Q20+ chemistry kit), ONT’s Flongle turned out to be most variable in returning the results, but at the same time the most cost efficient. The highest numbers of successfully sequenced samples were achieved with the ONT’s R10 & Q20+ chemistry combination. In terms of library preparation time, ONT protocols are the quickest, whereas regarding cost effectiveness - using Sanger pricing per sample as a cut-off - various technologies become affordable depending on the number of samples used. Although both tested platforms are suitable for DNA barcoding, we further discuss their limitations and applicability to different studies, with a special focus on the price and the number of samples. The pipeline we developed, from whole specimens to final DNA barcode consensuses, can aid planning and budgeting biodiversity studies, maximising the number of specimens sequenced in one run and speeding up the sample processing time.
Structural and functional landscape of α-synuclein fibril conformations amplified from cerebrospinal fluid
Authors: Sokratian Arpine , Zhou Ye , Xu Enquan , Viverette Elizabeth , Dillard Lucas , Yuan Yuan , Li Joshua Y. , Matarangas Ariana , Bouvette Jonathan , Borgnia Mario , Bartesaghi Alberto , West Andrew
Published: July 2022

Lewy body dementias are pathologically defined by the deposition of α-synuclein fibrils into inclusions throughout the brain. Cerebrospinal fluid(CSF) in disease harbors circulating α-synuclein-fibril seeds, and parental α-synuclein fibrils can template core structure into amplified fibrils. Using cryo-electron microscopy, we identify six novel α-synuclein fibril assemblies amplified from ten CSF samples (3.8Å to 2.9Å nominal resolutions). Fibrils are classified based on two types of filament interaction, two types of β-sheet stacking, and two types of hydrophobic pocket. CSF-amplified fibril products have one, two, or three distinct assemblies each. Six of ten samples share a common fibril assembly. Within this classification, the fibrils have distinct profiles in amyloid dye binding, and dramatically different potencies in both seeding new inclusions in neurons and evoked microglial pro-inflammatory responses. However, no single structural feature predicts functional phenotypes. Our results highlight CSF as a valuable resource to identify novel α-synuclein assemblies potentially important in disease.
Genetic and geometric heredity interact to drive polarized flow in the Drosophila embryo
Authors: Gehrels Emily , Chakrabortty Bandan , Merkel Matthias , Lecuit Thomas
Published: July 2022

Tissue flow during morphogenesis is commonly driven by local constriction of cell cortices, which is caused by activation of actomyosin contractility. This can lead to long-range flows due to tissue viscosity. However, in the absence of cell-intrinsic polarized forces or polarity in forces external to the tissue, these flows must be symmetric and centered around the region of contraction. Polarized tissue flows have been previously demonstrated to arise from the coupling of such contractile flows to points of increased friction or adhesion to external structures. However, we show with experiments and modeling that the onset of polarized tissue flow in early Drosophila morphogenesis occurs independent of adhesion and is instead driven by a geometric coupling of apical actomyosin contractility to tissue curvature. Particularly, the onset of polarized flow is driven by a mismatch between the position of apical myosin activation and the position of peak curvature at the posterior pole of the embryo. Our work demonstrates how genetic and geometric information inherited from the mother interact to create polarized flow during embryo morphogenesis.
A core UPS molecular complement implicates unique endocytic compartments at the parasite-host interface in Giardia lamblia
Authors: Balmer Erina A. , Wirdnam Corina D. , Faso Carmen
Published: July 2022

Unconventional protein secretion (UPS) plays important roles in processes for the survival of the cell and whole organisms. In contrast to canonical secretory routes, UPS does not generally require secretory signal sequences and often bypasses secretory compartments such as the ER and the Golgi apparatus.

Giardia lamblia is a protozoan parasite of global medical importance and reduced subcellular complexity known to release several proteins, some of them virulence factors, without canonical secretory signals, thus implicating UPS at the parasite-host interface. No dedicated machinery nor mechanism(s) for UPS in Giardia are currently known, although speculations on unique endocytic Giardia compartments called PV/PECs have been put forth.

To begin to address the question of whether PV/PECs are implicated in virulence-associated UPS and to define the composition of molecular machinery involved in release of confirmed and putative virulence factors, in this study we employed affinity purification and mass spectrometry coupled to microscopy-based subcellular localization and signal correlation quantification techniques to investigate protein complexes of eleven reported unconventionally-secreted putative and confirmed virulence factors, all predicted to be cytosolic. A subset of selected putative and confirmed virulence factors, along with their interaction partners, unequivocally associate to the surface of PV/PECs. Extended and validated interactomes point to a core PV/PECs-associated UPS machinery, which includes uncharacterized and Giardia-specific coiled-coil proteins and NEK kinases. Finally, a specific subset of the alpha-giardin protein family was invariably found enriched in all PV/PECs-associated protein interactomes, highlighting a previously unappreciated role for these proteins at PV/PECs and in UPS.

Taken together, our results provide the first characterization of a virulence-associated UPS protein complex in Giardia lamblia at PVs/PECs, suggesting a novel link between these primarily endocytic and feeding organelles and UPS at the parasite-host interface.
Origins of smooth muscle and evolutionary specializations of the pulmonary mesenchyme in the vertebrate lung
Authors: Goodwin Katharine , Palmer Michael A. , Lemma Bezia , Nelson Celeste M.
Published: July 2022

Evolution has generated a beautiful diversity of epithelial architectures in the lungs of terrestrial vertebrates, from the tree-like lungs of mammals, to the sac-like lungs of reptiles, to the looped airways of birds. The physical mechanisms that generate pulmonary epithelia of such different shapes are just beginning to be uncovered. Pulmonary smooth muscle plays stage-dependent roles in shaping the epithelium during lung development in the mouse, anole, and chicken. We hypothesized that differences in the timing and spatial patterns of smooth muscle differentiation correspond to distinct patterns of gene expression in the pulmonary mesenchyme. To test this hypothesis and investigate differences in pulmonary smooth muscle patterning across terrestrial vertebrates, we generated scRNA-seq datasets from lungs of mouse, anole, and chicken embryos. These data revealed that smooth muscle regulators are expressed in similar patterns in mouse and anole lungs, in which epithelial branches are sculpted by smooth muscle, but diverge in chicken lungs, in which the epithelium branches in the absence of smooth muscle. Pulmonary smooth muscle differentiates from the lung mesenchyme in mouse and anole. Surprisingly, however, bioinformatic and experimental evidence suggest that pulmonary smooth muscle is derived from vascular smooth muscle in chicken. Furthermore, our data revealed differences in the timing and extent of smooth muscle innervation across species. These findings highlight how terrestrial vertebrates have evolutionarily repurposed similar morphogenetic motifs to build lungs that suit their energetic needs.
Cardiac contraction and relaxation are regulated by beta 1 adrenergic receptor-generated cAMP pools at distinct membrane locations
Authors: Lin Ting-Yu , Mai Quynh N. , Zhang Hao , Wilson Emily , Chien Huan-Chieh , Yee Sook Wah , Giacomini Kathleen M. , Olgin Jeffrey E. , Irannejad Roshanak
Published: July 2022

Cells interpret a variety of signals through G protein-coupled receptors (GPCRs) and stimulate the generation of second messengers such as cyclic adenosine monophosphate (cAMP). A long-standing puzzle is deciphering how GPCRs elicit different physiological responses despite generating similar levels of cAMP. We previously showed that some GPCRs generate cAMP from both the plasma membrane and the Golgi apparatus. Here, we demonstrate that cardiomyocytes distinguish between subcellular cAMP inputs to elicit different physiological outputs. We show that generating cAMP from the Golgi leads to regulation of a specific PKA target that increases the rate of cardiomyocyte relaxation. In contrast, cAMP generation from the plasma membrane activates a different PKA target that increases contractile force. We further validated the physiological consequences of these observations in intact zebrafish and mice. Thus, we demonstrate that the same GPCR acting through the same second messenger regulates cardiac contraction and relaxation dependent on its subcellular location.
High-performing neural network models of visual cortex benefit from high latent dimensionality
Authors: Elmoznino Eric , Bonner Michael F.
Published: July 2022

Geometric descriptions of deep neural networks (DNNs) have the potential to uncover core representational principles of computational models in neuroscience. Here we examined the geometry of DNN models of visual cortex by quantifying the latent dimensionality of their natural image representations. A popular view holds that optimal DNNs compress their representations onto low-dimensional subspaces to achieve invariance and robustness, which suggests that better models of visual cortex should have lower dimensional geometries. Surprisingly, we found a strong trend in the opposite direction—neural networks with high-dimensional image subspaces tended to have better generalization performance when predicting cortical responses to held-out stimuli in both monkey electrophysiology and human fMRI data. Moreover, we found that high dimensionality was associated with better performance when learning new categories of stimuli, suggesting that higher dimensional representations are better suited to generalize beyond their training domains. These findings suggest a general principle whereby high-dimensional geometry confers computational benefits to DNN models of visual cortex.
Morphological and sensorimotor phenotypes in a zebrafish CHARGE syndrome model are domain-dependent
Authors: Hodorovich Dana R. , Lindsley Patrick M. , Berry Austen A. , Burton Derek F. , Marsden Kurt C.
Published: July 2022

CHARGE syndrome is a rare disorder characterized by a spectrum of defects affecting multiple tissues and behavioral difficulties such as autism, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, anxiety, and sensory deficits. Most CHARGE cases arise fromde novo, loss-of-function mutations in a master transcriptional regulator, chromodomain-helicase-DNA-binding-protein-7 (CHD7). CHD7 regulates key neurodevelopmental factors and is required for neural processes including neuronal differentiation and neural crest cell migration, but how CHD7 affects neural circuit function to regulate behavior is unclear. To investigate the pathophysiology of behavioral symptoms in CHARGE, we established a mutantchd7zebrafish line using CRISPR/Cas9 that recapitulates multiple CHARGE phenotypes. Using a panel of behavioral assays, we find thatchd7mutants have specific auditory and visually driven behavioral deficits that are independent of defects in sensory structures, implicatingchd7in the regulation of underlying brain circuits. Furthermore, by analyzing multiplechd7alleles we show that the penetrance of morphological and behavioral phenotypes depends on the mutation location. These results provide novel insight into the heterogeneity of CHARGE syndrome and will inform future work to define mechanisms of CHD7-dependent neurobehavioral symptoms.

Summary statement

Mutation location withinchd7affects the expression of CHARGE Syndrome-related morphological and behavioral phenotypes in a larval zebrafish CHARGE model.