bluuebunny/crossref_metadata_2025 huggingface dataset:
IL-25 participates in keratinocyte-driven dermal matrix turnover and is reduced in systemic sclerosis epidermis
Authors: Russo Barbara , Borowczyk Julia , Cacialli Pietro , Moguelet Philippe , Truchetet Marie-Elise , Modarressi Ali , Brembilla Nicolò C , Bertrand Julien , Boehncke Wolf-Henning , Chizzolini Carlo
Published: February 2022

Objectives

Evidence shows that dysfunctional SSc keratinocytes contribute to fibrosis by altering dermal homeostasis. Whether IL-25, an IL-17 family member regulating many epidermal functions, takes part in skin fibrosis is unknown. Here we address the role of IL-25 in skin fibrosis.

Methods

The expression of IL-25 was evaluated by immunofluorescence and in situ hybridization in 10 SSc and seven healthy donor (HD) skin biopsies. Epidermal equivalents (EE) reconstituted by primary HD keratinocytes were used as a model to study transcriptomic changes induced by IL-25 in the epidermis. RNA expression profile in EEs was characterized by RNAseq. The conditioned medium (CM) from primary SSc and HD keratinocytes primed with IL-25 was used to stimulate fibroblasts. IL-6, IL-8, MMP-1, type-I collagen (Col-I), and fibronectin production by fibroblasts was assessed by ELISA.

Results

SSc epidermis expressed lower levels of IL-25 compared with HDs. In EEs, IL-25 regulated several molecular pathways related to wound healing and extracellular matrix remodelling. Compared with control CM, the CM from IL-25-primed keratinocytes enhanced the fibroblast production of MMP-1, IL-6 and IL-8, but not of Col-I nor fibronectin. However, IL-25 significantly reduced the production of Col-I when applied directly to fibroblasts. The activation of keratinocytes by IL-25 was receptor-dependent and evident after a very short incubation time (10 min), largely mediated by IL-1, suggesting enhanced and specific release of preformed mediators.

Conclusions

These results show that IL-25 participates in skin homeostasis, and its decreased expression in SSc may contribute to skin fibrosis by favouring extracellular matrix deposition over degradation.
Dioxin Disrupts Thyroid Hormone and Glucocorticoid Induction of klf9, a Master Regulator of Frog Metamorphosis
Authors: Han David T , Zhao Weichen , Powell Wade H
Published: February 2022

Frog metamorphosis, the development of an air-breathing froglet from an aquatic tadpole, is controlled by thyroid hormone (TH) and glucocorticoids (GC). Metamorphosis is susceptible to disruption by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AHR) agonist. Krüppel-like factor 9 (klf9), an immediate early gene in the endocrine-controlled cascade of expression changes governing metamorphosis, can be synergistically induced by both hormones. This process is mediated by an upstream enhancer cluster, the klf9 synergy module (KSM). klf9 is also an AHR target. We measured klf9 mRNA following exposures to triiodothyronine (T3), corticosterone (CORT), and TCDD in the Xenopus laevis cell line XLK-WG. klf9 was induced 6-fold by 50 nM T3, 4-fold by 100 nM CORT, and 3-fold by 175 nM TCDD. Cotreatments of CORT and TCDD or T3 and TCDD induced klf9 7- and 11-fold, respectively, whereas treatment with all 3 agents induced a 15-fold increase. Transactivation assays examined enhancers from the Xenopus tropicalis klf9 upstream region. KSM-containing segments mediated a strong T3 response and a larger T3/CORT response, whereas induction by TCDD was mediated by a region ∼1 kb farther upstream containing 5 AHR response elements (AHREs). This region also supported a CORT response in the absence of readily identifiable GC responsive elements, suggesting mediation by protein-protein interactions. A functional AHRE cluster is positionally conserved in the human genome, and klf9 was induced by TCDD and TH in HepG2 cells. These results indicate that AHR binding to upstream AHREs represents an early key event in TCDD’s disruption of endocrine-regulated klf9 expression and metamorphosis.
Genetic Diversity of Phymatotrichopsis omnivora Based on Mating Type and Microsatellite Markers Reveals Heterothallic Mating System
Authors: Mattupalli Chakradhar , Cuenca Fernanda Proaño , Shiller Jason B. , Watkins Tara , Hansen Karen , Garzon Carla D. , Marek Stephen M. , Young Carolyn A.
Published: February 2022

Phymatotrichopsis omnivora is a member of Pezizomycetes and causes root rot disease on a broad range of dicotyledonous plants. Using recently generated draft genome sequence data from four P. omnivora isolates, we developed simple sequence repeat (SSR) markers and identified both mating type genes (MAT1-1-1 and MAT1-2-1) in this fungus. To understand the genetic diversity of P. omnivora isolates (n = 43) and spore mats (n = 29) collected from four locations (Oklahoma, Texas, Arizona, and Mexico) and four host crops (cotton, alfalfa, peach, and soybean), we applied 24 SSR markers and showed that of the 72 P. omnivora isolates and spore mats tested, 41 were distinct genotypes. Furthermore, the developed SSR markers did not show cross-transferability to other close relatives of P. omnivora in the class Pezizomycetes. A multiplex PCR detecting both mating type idiomorphs and a reference gene (TUB2) was developed to screen P. omnivora isolates. Based on the dataset we tested, P. omnivora is a heterothallic fungus with both mating types present in the United States in a ratio close to 1:1. We tested P. omnivora spore mats obtained from spatially distinct disease rings that developed in a center-pivot alfalfa field and showed that both mating types can be present not only in the same field but also within a single spore mat. This study shows that P. omnivora has the genetic toolkit for generating sexually diverse progeny, providing impetus for future studies that focus on identifying sexual morphs in nature.
Hip Pain in Patients With Spinal Muscular Atrophy: Prevalence, Intensity, Interference, and Factors Associated With Moderate to Severe Pain
Authors: Xu Amy L. , Crawford Thomas O. , Sponseller Paul D.
Published: February 2022

Background:

A subset of patients with spinal muscular atrophy (SMA) develop hip pain. We analyzed (1) the characteristics of hip pain in patients with SMA (prevalence, intensity, interference with activities, and responsiveness to treatment) and (2) factors (patient, clinical, and radiographic) associated with moderate to severe pain.

Methods:

We performed a retrospective record review and telephone survey of 104 patients with SMA (77% response rate; 44% female; mean age, 22±13 y) who presented for treatment between 2010 and 2020. Patient, clinical, and radiographic characteristics (when available) were recorded. Patients with current or past hip pain were asked about pain characteristics. Pain intensity and interference were assessed with the Brief Pain Inventory, modified for SMA (scale, 0 to 10 with 0 indicating no pain/interference). We used univariate analysis and ordered logistic regression to determine associations between patient factors and hip pain (α=0.05).

Results:

Hip pain occurred in 60/104 patients (58%), with 15 (14%) indicating moderate to severe pain. Compared with patients with normal body mass index values, patients who were obese had 5.4 times the odds [95% confidence interval (CI), 1.3-23] of moderate to severe pain. Hip contractures [adjusted odds ratio (aOR), 3.2; 95% CI, 1.2-8.8] and dislocations (aOR, 2.9; 95% CI, 1.1-7.9) were associated with greater odds of pain compared with hips without these presentations. Surgical correction for scoliosis (aOR, 2.6; 95% CI, 1.1-6.5) was also associated with greater odds of moderate to severe pain. Femoral head migration percentage was the only radiographic parameter associated with pain. Mean modified Brief Pain Inventory pain intensity was 2.1±2.3. Prolonged sitting, sleep, and transfers (eg, bed to wheelchair) were the activities most affected by pain.

Conclusions:

Hip pain was moderate to severe in 14% of patients with SMA. Obesity, hip contractures, surgical correction of scoliosis, and hip dislocations were independently associated with pain. Although mean pain intensity was low, hip pain interfered with daily activities, including prolonged sitting, sleep, and transfers.

Level of Evidence:

Level III.
Evaluation of the impact of changes in the autopsy rate on mortality trend of pulmonary embolism, Finland, 1996–2017
Authors: Sane Markus , Sund Reijo , Mustonen Pirjo
Published: February 2022

Pulmonary embolism is listed as a cause of death in fewer and fewer cases in the twenty-first century. Autopsies reveal undiagnosed pulmonary embolism at a significant rate, but fewer and fewer autopsies are being performed. It could be that deaths from pulmonary embolism are not decreasing, but are increasingly missed because of decreasing autopsy rate. Population-based registry data of all individuals with pulmonary embolism related death from the Finnish death certificate archive from 1996 to 2017 were collected. The pulmonary embolism mortality trend was analysed with linear regression and the association of pulmonary embolism mortality with the number of autopsies was also assessed. Deaths with pulmonary embolism as immediate, underlying and contributory cause of death were not only included, but also analysed separately. In addition, the estimated pulmonary embolism mortality when presumptively missed pulmonary embolisms are taken into account is presented. During 1996–2017, the pulmonary embolism related mortality rate decreased 28% from 25: 100 000 to 18: 100 000, if all pulmonary embolism deaths were analysed, and 51% from 21: 100 000 to 11: 100 000 if contributory pulmonary embolism deaths were excluded. From 1996 to 2009, autopsy rate in the population remained unchanged, but declined thereafter. In 1996, autopsy rate was 31.1% (15 319/49167) and in 2017 20.1% (10830/53 923). Our results suggest that there has been real improvement in the prevention of death from pulmonary embolism in Finland in the twenty-first century. However, due to the decreasing autopsy rate, the pulmonary embolism mortality trend after 2010 should be interpreted more carefully.
Reversal of factor Xa inhibitors associated intracranial haemorrhage at a tertiary medical centre
Authors: Milioglou loannis , Liao Katherine , Traeger Jessica , McKenzie Christy , Burrelli Correy , Khunayfir Abdalmalik Khalid Bin , Makii Jason , Hoffer Alan
Published: February 2022

Prior to the approval of andexanet, there were no FDA-approved reversal agents indicated for the treatment of factor Xa inhibitor (FXaI) associated major bleed. Four-factor prothrombin complex concentrate (4F-PCC) has been widely used off-label for FXaI-associated bleeding. The purpose of this study was to compare the effectiveness and safety of andexanet and 4F-PCC for the reversal of FXaI-associated intracranial haemorrhage. The primary end point is in-hospital mortality; secondary endpoints include haemostatic efficacy and safety. This study is a singlecentre, retrospective chart review, including patients admitted between 1 January 2016 and 15 August 2019, who received 4F-PCC or andexanet for the management of FXaI-associated intracranial haemorrhage. Of the 45 patients included in this study, 23 patients were in the andexanet group and 22 were in the 4F-PCC group. At index admission, mean age was 76 years and the majority of patients (64%) were on apixaban with 33% presented with Glasgow Coma Scale 24 (GCS) score less than 12. At hospital discharge, 47% of patients in the andexanet group had died or discharged to hospice compared with 45% in the 4F-PCC group. No thromboembolic events were observed in either group within 5 days after administration of the reversal agent. The results of this study suggest that haemostasis and mortality at discharge during the index hospitalization appears to be similar between groups. Prospective randomized control trials comparing safety and efficacy of andexanet and 4F-PCC are needed.
Three-Dimensional Biomechanics of the Trunk and Upper Extremity During Overhead Throwing in Wheelchair Lacrosse Athletes With Spinal Cord Injury
Authors: Hanks Matthew M. , Schnorenberg Alyssa J. , Lee Kenneth K. , Slavens Brooke A.
Published: February 2022

Objective

Quantify differences in overhead throwing kinematics between wheelchair lacrosse athletes with spinal cord injury and able-bodied lacrosse athletes.

Design

This is a cross-sectional, prospective study. Motion analysis captured overhead throwing motions of five wheelchair lacrosse athletes with spinal cord injury and six able-bodied lacrosse athletes seated in a wheelchair and standing. Three-dimensional thorax and dominant arm sternoclavicular, acromioclavicular, glenohumeral, elbow, and wrist joint angles, ranges of motion, as well as angular velocities were computed using an inverse kinematics model. Nonparametric tests assessed group differences (P < 0.05).

Results

Participants with spinal cord injury exhibited less peak thorax axial rotation, ranges of motion, and angular velocity, as well as greater wrist flexion than able-bodied participants seated. Participants with spinal cord injury exhibited less peak thorax axial rotation and lateral bending, ranges of motion, and three-dimensional angular velocities; less peak two-dimensional sternoclavicular joint motion, ranges of motion, and peak angular velocities; less peak acromioclavicular joint protraction angular velocity; less glenohumeral joint adduction-abduction and internal-external rotation motion, ranges of motion, and angular velocities; and greater wrist flexion than able-bodied participants standing.

Conclusions

Kinematic differences were observed between groups, with athletes with spinal cord injury exhibiting less thorax and upper extremity joint motion and slower joint angular velocities than able-bodied athletes. This knowledge may provide insights for movement patterns and potential injury risk in wheelchair lacrosse.
Psychopharmacology of agitation in acute psychotic and manic episodes
Authors: Stetson Sean R. , Osser David N.
Published: February 2022

Purpose of review

To provide updated guidance for the medication treatment of acute agitation in the setting of psychosis or mania on inpatient psychiatric units.

Recent findings

This topic presented challenges: studies are sparse, tend to be under-powered, and are difficult to compare. Though there have been few recent studies, there have been several recent meta-analyses, Cochrane reviews, and published guidelines that sift through the primarily older evidence as well as more recent trials. The reviewers often do not agree on what seems to have the best evidence for efficacy and safety.

We conclude that the best approach is to summarize in some detail the evidence for each possible treatment and the interpretations published recently on each of those treatments, and then present recommendations for medication management in tiered rankings, based on the authors’ qualitative review of the data and opinions. For oral treatment, the first-tier options are (alphabetically) haloperidol with lorazepam, lorazepam alone, and olanzapine. The second tier includes haloperidol with promethazine, loxapine inhaler, and risperidone alone. Tier 3 includes asenapine and quetiapine. For intramuscular treatment, the first-tier includes haloperidol plus promethazine, and olanzapine alone, and the second-tier includes haloperidol with lorazepam, and lorazepam alone.
Interpretable Deep Learning Model Reveals Subsequences of Various Functions for Long Non-coding RNA Identification
Authors: Lin Rattaphon , Wichadakul Duangdao
Published: February 2022

Long non-coding RNAs (lncRNAs) play crucial roles in many biological processes and are implicated in several diseases. With the next-generation sequencing technologies, substantial un-annotated transcripts have been discovered. Classifying unannotated transcripts using biological experiments is more time-consuming and expensive than computational approaches. Several tools for identifying long non-coding RNAs are available. These tools, however, did not explain which features in their tools contributed to the prediction results. Here, we present Xlnc1DCNN, a tool for distinguishing long non-coding RNAs (lncRNAs) from protein-coding transcripts (PCTs) using a one-dimensional convolutional neural network with prediction explanations. The evaluation results of the human test set showed that Xlnc1DCNN outperformed other state-of-the-art tools in terms of accuracy and F1-score. The explanation results revealed that lncRNA transcripts were mainly identified as sequences with no conserved regions or with a region of transmembrane helix while protein-coding transcripts were mostly classified by conserved protein domains or families. The explanation results also conveyed the probably inconsistent annotations among the public databases, lncRNA transcripts which contain protein domains or families, as well as protein-coding transcripts which are nonsense-mediated decay or processed transcripts. Xlnc1DCNN is freely available at https://github.com/cucpbioinfo/Xlnc1DCNN.
Multidimensional single-cell analysis identifies a role of CD2-CD58 interactions for clinical antitumor T cell responses
Authors: Romain Gabrielle , Strati Paolo , Rezvan Ali , Fathi Mohsen , Bandey Irfan N , Adolacion Jay R T , Heeke Darren , Liadi Ivan , Marques-Piubelli Mario L , Solis Luisa M. , Mahendra Ankit , Vega Francisco , Cooper Laurence J.N. , Singh Harjeet , Mattie Mike , Bot Adrian , Neelapu Sattva , Varadarajan Navin
Published: February 2022

The in vivo persistence of adoptively transferred T cells is predictive of anti-tumor response. Identifying functional properties of infused T cells that lead to in vivo persistence and tumor eradication has remained elusive. We profiled CD19-specific CAR T cells that comprise the infusion products used to treat large B cell lymphomas using high-throughput single-cell technologies based on Timelapse Imaging Microscopy In Nanowell Grids (TIMING) that integrates killing, cytokine secretion, and transcriptional profiling. Our results show that the directional migration of CD19-specific CAR T cells is correlated with polyfunctionality. We identified that CD2 on T cells is associated with directional migration and that the interaction between CD2 on T cells and CD58 on lymphoma cells accelerates killing and serial killing. Consistent with this, we observed elevated CD58 expression on pre-treatment tumor samples in patients with relapsed or refractory large B cell lymphomas treated with CD19-specific CAR T cell therapy was associated with complete clinical response and survival. These results highlight the importance of studying dynamic T-cell tumor cell interactions in identifying optimal antitumor responses.

KEY POINTS

- Profiling patient infusion products revealed that polyfunctional CAR T cells show directional migration, which is associated with higher CD2 expression

- The ligand for CD2, CD58 is expressed at higher levels in the tumors of lymphoma patients who respond better to CAR T cell treatment
Expansion and differentiation ofex vivocultured erythroblasts in scalable stirred bioreactors
Authors: Gallego-Murillo Joan Sebastián , Iacono Giulia , van der Wielen Luuk A.M. , van den Akker Emile , von Lindern Marieke , Wahl Sebastian Aljoscha
Published: February 2022

Transfusion of donor-derived red blood cells (RBCs) is the most common form of cell therapy. Production of transfusion-ready cultured RBCs (cRBCs) is a promising replacement for the current fully donor-dependent therapy. However, very large number of cells are required for transfusion. Here we scale-up cRBC production from static cultures to 0.5 L stirred tank bioreactors, and identify the effect of operating conditions on the efficiency of the process. Oxygen requirement of proliferating erythroblasts (0.55-2.01 pg/cell/h) required sparging of air to maintain the dissolved oxygen concentration at the tested setpoint (2.88 mg O2/L). Erythroblasts could be cultured at dissolved oxygen concentrations as low as 0.7 O2mg/mL without negative impact on proliferation, viability or differentiation dynamics. Stirring speeds of up to 600 rpm supported erythroblast proliferation, while 1800 rpm led to a transient halt in growth and accelerated differentiation followed by a recovery after 5 days of culture. Erythroblasts could also be differentiated in bioreactors, with final enucleation levels and hemoglobin content similar to parallel cultures under static conditions. After defining optimal mixing and aeration strategies, erythroblast proliferation cultures were successfully scaled up to 3 L bioreactors.
Examining clustered somatic mutations with SigProfilerClusters
Authors: Bergstrom Erik N. , Kundu Mousumy , Tbeileh Noura , Alexandrov Ludmil B.
Published: February 2022

Clustered mutations are found in the human germline as well as in the genomes of cancer and normal somatic cells. Clustered events can be imprinted by a multitude of mutational processes, and they have been implicated in both cancer evolution and development disorders. Existing tools for identifying clustered mutations have been optimized for a particular subtype of clustered event and, in most cases, relied on a predefined inter-mutational distance (IMD) cutoff combined with a piecewise linear regression analysis. Here we present SigProfilerClusters, an automated tool for detecting all types of clustered mutations by calculating a sample-dependent IMD threshold using a simulated background model that takes into account extended sequence context, transcriptional strand asymmetries, and regional mutation densities. SigProfilerClusters disentangles all types of clustered events from non-clustered mutations and annotates each clustered event into an established subclass, including the widely used classes of doublet-base substitutions, multi-base substitutions, omikli, and kataegis. SigProfilerClusters outputs non-clustered mutations and clustered events using standard data formats as well as provides multiple visualizations for exploring the distributions and patterns of clustered mutations across the genome.

Availability

SigProfilerClusters is freely available at https://github.com/AlexandrovLab/SigProfilerClusters with support across most operating systems and extensive documentation at https://osf.io/qpmzw/wiki/home/.

Contact

ebergstr@eng.ucsd.edu or L2alexandrov@health.ucsd.edu
Residual force enhancement within the human quadriceps is greatest during submaximal stretch-hold contractions at a very long muscle length
Authors: Bakenecker Patrick , Weingarten Tobias , Hahn Daniel , Raiteri Brent
Published: February 2022

Little is known about how muscle length affects residual force enhancement (rFE) in humans. We therefore investigated rFE at short, long, and very long muscle lengths within the human quadriceps and patellar tendon (PT) using conventional dynamometry with motion capture (rFETQ) and a new, non-invasive shear-wave tensiometry technique (rFEWS). Eleven healthy male participants performed submaximal (50% max.) EMG-matched fixed-end reference and stretch-hold contractions across these muscle lengths while muscle fascicle length changes of the vastus lateralis (VL) were captured using B-mode ultrasound. We found significant rFETQ at long (7±5%) and very long (12±8%) but not short (2±5%) muscle lengths, whereas rFEWS was only significant at the very long (38±27%), but not short (8±12%) or long (6±10%) muscle lengths. We also found significant relationships between VL fascicle length and rFETQ (r=0.63, p=.001) and rFEWS (r=0.52, p=.017), but relationships were not significant between VL fascicle stretch amplitude and rFETQ (r=0.33, p=.126) or rFEWS (r=0.29, p=.201). PT shear-wave speed-angle relationships did not agree with estimated quadriceps muscle force-angle relationships, which indicates that estimating PT loads from shear-wave tensiometry might be inaccurate. We conclude that increasing muscle length rather than stretch amplitude contributes more to rFE during submaximal voluntary contractions of the human quadriceps.
Environmental contributions to the evolution of trait differences inGeum triflorum: implications for restoration
Authors: Volk Kate , Braasch Joseph , Ahlering Marissa , Hamilton Jill A.
Published: February 2022

Premise of the Study

Understanding how environment influences the distribution of trait variation across a species’ range has important implications for seed transfer during restoration. Heritable genetic differences associated with environment could impact fitness when transferred into new environments. Here, we test the degree to which the environment shapes the evolution and distribution of genetic effects for traits important to adaptation.

Methods

In a common garden experiment, we quantified trait differentiation for populations ofGeum triflorumsourced from three distinct ecoregions and evaluated the ability of climate to predict trait variation. Populations were sourced from alvar ecoregions which experience predictable extremes in seasonal water availability and the prairie ecoregion which exhibits unpredictable changes in water availability.

Key Results

Plants sourced from alvar ecoregions exhibited smaller but more numerous stomata and greater intrinsic water use efficiency relative to prairie plant populations supporting the evolution of ecotypic differences. Estimates of standing genetic variance and heritable genetic variation for quantitative traits suggest alvar populations have greater adaptive potential. However, reduced evolvability suggest all populations ofG. triflorummay have limited capacity to evolve in response to environmental change.

Conclusions

These results point towards the importance of understanding the role of environment in shaping the distribution and evolution of genetic differences across seed populations and how these data may inform recommendations for seed transfer across novel environments and our expectations of populations’ adaptive potential.
Joint structural annotation of small molecules using liquid chromatography retention order and tandem mass spectrometry data
Authors: Bach Eric , Schymanski Emma L. , Rousu Juho
Published: February 2022

We present LC-MS2Struct, a machine learning framework for structural annotation of small molecule data arising from liquid chromatography-tandem mass spectrometry (LC-MS2) measurements. LC-MS2Struct jointly predicts the annotations for a set of mass spectrometry features in a sample, using a novel structured prediction model trained to optimally combine the output of state-of-the-art MS2scorers and observed retention orders. We evaluate our method on a dataset covering all publicly available reversed phase LC-MS2data in the MassBank reference database, including 4327 molecules measured using 18 different LC conditions from 16 contributors, greatly expanding the chemical analytical space covered in previous multi-MS2scorer evaluations. LC-MS2Struct obtains significantly higher annotation accuracy than earlier methods and improves the annotation accuracy of state-of-the-art MS2scorers by up to 106%. The use of stereochemistry-aware molecular fingerprints improves prediction performance, which highlights limitations in existing approaches and has strong implications for future computational LC-MS2developments.
Stress-induced phase separation of ERES components into Sec bodies precedes ER exit inhibition in mammalian cells
Authors: van Leeuwen Wessel , Nguyen Dan T.M. , Grond Rianne , Veenendaal Tineke , Farías Ginny G. , Rabouille Catherine
Published: February 2022

Phase separation of ER-exit-sites (ERES) components into membraneless compartments, the Sec bodies, occurs in Drosophila cells upon specific cellular stressors, i.e., salt stress and amino acid starvation, and their formation is linked to the inhibition of the early secretory pathway. Here, we show Sec bodies also form in secretory mammalian INS-1 cells upon the same stress. These reversible and membraneless structures are positive for ERES components, including both isoforms of Sec16 (A and B) and COPII subunits. We find that Sec16A, but not Sec16B, is a driver for Sec body formation. We show that the coalescence of ERES components into Sec bodies occurs by fusion, in line with their liquid-droplet properties. Lastly, we demonstrate that stress-induced ER-exit inhibition is a consequence of the significant coalescence of Sec16A into Sec bodies, leading to its depletion from ERES that become non-functional. Stress relief causes an immediate dissolution of Sec bodies and the concomitant restoration of protein exit from the ER. We propose a model in which dynamic conversion between ERES and Sec body assembly, driven by Sec16A, regulates protein exit from the ER during stress and upon stress relief in mammalian cells, thus providing a conserved pro-survival mechanism in response to stress.
The global exposure of species ranges and protected areas to forest management
Authors: Jung Martin , Lewis Matt , Lesiv Myroslava , Arnell Andy , Fritz Steffen , Visconti Piero
Published: February 2022

The majority of vertebrate species globally are dependent on forests, most of which require active protection to safeguard global biodiversity. Forests, however, are increasingly either being disturbed, planted or managed in the form of timber or food plantations. Because of a lack of spatial data, forest management has commonly been ignored in previous conservation assessments. Here we show – using a new global map of forest management - that disturbed and human managed forests cover the distributional ranges of most forest-associated species. Even more worrying, protected areas are increasingly being established in areas dominated by disturbed forests. Our results imply that species extinction risk and habitat assessments might have been overly optimistic with forest management practices being ignored. With forest restoration being in the centre of climate and conservation policies in this decade, we caution that policy makers should explicitly consider forest management.
Neurodevelopmental Patterns of Early Postnatal White Matter Maturation Represent Distinct Underlying Microstructure and Histology
Authors: Nazeri Arash , Krsnik Željka , Kostović Ivica , Ha Sung Min , Kopić Janja , Alexopoulos Dimitrios , Kaplan Sydney , Meyer Dominique , Luby Joan L. , Warner Barbara B. , Rogers Cynthia E. , Barch Deanna M. , Shimony Joshua S. , McKinstry Robert C. , Neil Jeffrey J. , Smyser Christopher D. , Sotiras Aristeidis
Published: February 2022

During the early postnatal period, cerebral white matter undergoes rapid maturation through a complex series of interrelated cellular and histogenetic processes. Accurately quantifying these processes is important for improving understanding of early brain development, developmental abnormalities related to prematurity, and neurodevelopmental diseases. Past efforts have used magnetic resonance imaging (MRI) to track these developmental processes in vivo. However, most previous studies have relied on single imaging modality data and have often been limited by small samples and analytics that do not evaluate complex multivariate imaging patterns. Here, we applied an advanced unsupervised multivariate pattern analysis technique, non-negative matrix factorization (NMF), to T2w/T1w signal ratio maps from a large cohort of newborns (Developing Human Connectome Project [dHCP], n=342), revealing patterns of synchronous white matter maturation. These patterns showed divergent age-related maturational trajectories and differential susceptibility to premature birth, which were replicated in an independent large sample of newborns (Early Life Adversity, Biological Embedding, and Risk for Developmental Precursors of Mental Disorders [eLABE], n=239). Furthermore, we showed that T2w/T1w signal variations in white matter maturational patterns are explained by differential contributions of white matter microstructure indices (i.e., free water content and neurite density index) derived from neurite orientation dispersion and density imaging (NODDI) modeling of diffusion-weighted MRI. Finally, we demonstrated how white matter maturation patterns relate to distinct histological features by comparing our findings with postmortem late fetal/early postnatal brain tissue staining. Together, these results delineate a novel MRI representation of white matter microstructural and histological reorganization during the early postnatal development.
A methodology for selection and quality control of the radiological computer vision deployment at the megalopolis scale
Authors: Andreychenko Anna E. , Logunova Tatiana A. , Gombolevskiy Victor A. , Nikolaev Aleksandr E. , Vladzymyrskyy Anton V. , Sinitsyn Valentin E. , Morozov Sergey P.
Published: February 2022

In recent years, there has been tremendous interest in the use of artificial intelligence (AI) in radiology in order to automate the interpretation. However, uncontrolled and widespread use of AI solutions may have negative consequences. Therefore, before implementing such technologies in healthcare, thorough training of personnel, adaptation of information systems, and standardized datasets for an external validation are required. All this necessitates a formation of a unique unified methodology. The best practices of AI introduction in diagnostic radiology are still subject to debate and require new results of a scientific-practical research with the assessment of implementation conditions.

This work discusses expected issues and potential solutions for the introduction of computer vision-based technologies for automatic analysis of radiological examinations with an emphasis on the real-life experience gained during simultaneous AI implementation into practice of more than a hundred state radiology departments in 2020-2021 in Moscow, Russia (an experiment). The experiment used end-user software testing approaches, quality assurance of AI-based radiological solutions, and accuracy assessment of the AI-empowered diagnostic tools on local data. The methods were adapted and optimized to ensure a successful real-life radiological AI deployment on the extraordinary large scale. The experiment involved in total around thousand diagnostic devices and thousand radiologists. AI deployment was associated with additional options in a routine radiologist’s workflow: triage; additional series formed by AI with indication of pathological findings and their classification; report template prepared by AI in accordance with the target clinical task, user feedback on AI performance.

A multi-stage methodology for implementing AI into radiological practice that was developed and advanced during the experiment is described in this report.

Essentials

A methodology for the AI deployment for non-academic radiological sites excluded more than half of the offered AI solutions that do not fulfill the diagnostic and functional requirements

Quality control of AI should be supported by not only data scientists, IT specialists or engineers, but also by radiologists at all stages of selection and testing.

Radiologists need to understand the capabilities, limitations of AI by getting an additional training.
Improved Metagenomic Binning with Transformers
Authors: Shenker-Tauris Nina , Gehrig Jeanette
Published: February 2022

Abstract

Traditional metagenome binning methods cluster contiguous DNA sequences (contigs) based on uncontextualized features of the sequences which ignores both the semantic relationship between genes and the positional embedding of k-mers. This paper presents a novel binning method that addresses these concerns. Firstly, taken from natural language processing literature, a sequence representation model - Bidirectional Encoder Representations from Transformers (BERT) - is utilized to generate semantic and positional contig embeddings. Secondly, two workflows are presented; one which applies a hierarchical density-based clustering algorithm to find metagenomic bins and the other which incorporates contig embedding into a state-of-the-art binner. Experimental results on a publicly available metagenomic dataset show superior clustering for shorter contigs compared to traditionally used tetranucleotide frequency (TNF), reconstruction of up to 17% more high-precision genomes, and improved semantic understanding of contigs.
Optimisation-based modelling for drug discovery in malaria
Authors: Li Yutong , Cardoso-Silva Jonathan , Papageorgiou Lazaros G. , Tsoka Sophia
Published: February 2022

The discovery of new antimalarial medicines with novel mechanisms of action is important, given the ability of parasites to develop resistance to current treatments. Through the Open Source Malaria project that aims to discover new medications for malaria, several series of compounds have been obtained and tested. Analysis of the effective fragments in these compounds is important in order to derive means of optimal drug design and improve the relevant pharmaceutical application. We have previously reported a novel optimisation-based method for quantitative structure-activity relationship modelling, modSAR, that provides explainable modelling of ligand activity through a mathematical programming formulation. Briefly, modSAR clusters small molecules according to chemical similarity, determines the optimal split of each cluster into appropriate regions, and derives piecewise linear regression equations to predict the inhibitory effect of small molecules. Here, we report application of modSAR in the analysis of OSM anti-malarial compounds and illustrate how rules generated by the model can provide interpretable results for the contribution of individual ECFP fingerprints in predicting ligand activity, and contribute to the search for effective drug treatments.
Single Cell Proteomics Using a Trapped Ion Mobility Time-of-Flight Mass Spectrometer Provides Insight into the Post-translational Modification Landscape of Individual Human Cells
Authors: Orsburn Benjamin C. , Yuan Yuting , Bumpus Namandjé N.
Published: February 2022

Single cell proteomics is a powerful tool with potential for markedly enhancing understanding of cellular processes. Previously reported single cell proteomics innovations employ Orbitrap mass spectrometers. In this study we describe the development, optimization, and application of multiplexed single cell proteomics to the analysis of human-derived cells using trapped ion mobility time-of-flight mass spectrometry. This method, denoted as pasefRiQ is an advance as it allows accurate peptide quantification at picogram peptide concentrations. When employing a peptide carrier channel to boost protein sequence coverage, we obtain over 40,000 tandem mass spectra in 30 minutes, while achieving higher sequence coverage of each identified protein than described for SCOPE2. Using NCI-H-358 cells, which are a human bronchioalveolar carcinoma and KRASG12C model cell line, we demonstrate that the level of coverage achieved using this method enables the quantification of up to 1,255 proteins per cell and the detection of multiple classes of post-translational modifications in single cells. Further, when cells were treated with sotorasib, a KRASG12C covalent inhibitor, pasefRiQ revealed cell-to-cell variability in the impact of the drug on the NCI-H-358 cells, providing insight missed by traditional analyses. We provide multiple resources necessary for the application of single cell proteomics to drug treatment studies including tools to reduce cell cycle linked proteomic effects from masking pharmacological phenotypes.

Significance Statement

This work describes the establishment of a single cell proteomics method using a time-of-flight mass spectrometer. Through this approach, we demonstrate the confident identification of post- translational modifications in single human-derived cells. Additionally, using a KRASG12C covalent inhibitor as a model compound we show that this method can be used to understand pharmacological responses of single human-derived cultured cells.
Relevance study of vector competence and insecticide resistance in Aedes aegypti laboratory lines
Authors: Wang Lanjiao , Fontaine Albin , Gaborit Pascal , Guidez Amandine , Issaly Jean , Girod Romain , Kazanji Mirdad , Rousset Dominique , Vignuzzi Marco , Epelboin Yanouk , Dusfour Isabelle
Published: February 2022

The urban mosquito species Aedes aegypti is the main vector of arboviruses worldwide. Mosquito control with insecticides is the most prevalent method for preventing transmission in the absence of effective vaccines and available treatments; however, the extensive use of insecticides has led to the development of resistance in mosquito populations throughout the world, and the number of epidemics caused by arboviruses has increased.

Three mosquito lines with different resistance profiles to deltamethrin were isolated in French Guiana, including one with the I1016 knock-down resistant allele. Significant differences were observed in the cumulative proportion of mosquitoes with a disseminated chikungunya virus infection over time. In addition, certain genes (CYP6BB2, CYP6N12, GST2, trypsin) were variably overexpressed in the midgut at 7 days after an infectious blood meal in these three lines. Therefore, detoxification enzymes and kdr mutations may contribute to an enhanced midgut barrier and reduced dissemination rate.

Our work shows that vector competence for chikungunya virus varied between Ae. aegypti laboratory lines with different deltamethrin-resistance profiles. More accurate verification of the functional association between insecticide resistance and vector competence remains to be demonstrated.

Importance

Three Ae. aegypti lines, isolated from the same collection site, underwent different insecticide selection pressures against deltamethrin under laboratory conditions. As a result, they developed different resistant profiles. In this study, when these lines were fed an artificial infectious blood meal containing chikungunya virus, all three lines including the reference strain showed a high infection rate. There was no statistical difference in infection rate found; however, the dissemination rate of the virus from midgut to head were significantly different. A higher resistance level detected by the WHO test was correlated with a lower viral dissemination rate for each strain. This study presented evidence that the insecticide selection pressure or the existence of insecticide resistance could lead to differences in viral dissemination or even transmission in mosquito populations. We hope that our study can give more insights into understanding the roles of mosquito insecticide resistance on viral transmission.
Comprehensive humoral and cellular immune responses to SARS-CoV-2 variants in diverse Chinese populations: A benefit perspective of national vaccination
Authors: Li Jiwei , Wu Jing , Long Qiuyue , Wu Yanan , Hu Xiaoyi , He Yukun , Jiang Mingzheng , Li Jia , Zhao Lili , Yang Shuoqi , chen Xiaoyong , Wang Minghui , Zheng Jianshi , Wu Fangfang , Wu Ruiliang , Ren Lihong , Bu Liang , Wang Houzhao , Li Ke , Fu Lijuan , Zhang Guojun , Zheng Yali , Gao Zhancheng
Published: February 2022

The emerging SARS-CoV-2 variants have made great challenges to current vaccine and pandemic control strategies. B.1.1.529 (Omicron), which was classified as a variant of concern (VOC) by the World Health Organization on November 26th, 2021, has quickly become the dominant circulating variant and causing waves of infections. It is urgent to understand the current immune status of the general population given that pre-existing immunity has been established by national vaccination or exposure to past variants. Using sera from 85 individuals (including 21 convalescents of natural infection, 15 cases suffered a breakthrough infection after vaccination, and 49 vaccinated participants without infection history), we showed that the cross-neutralizing activity against VOCs such as Omicron can be detected in 53 (62.4%) cases, although less potent than against the Wuhan-1 strain (WT), with a 3.9-fold reduction in geometric mean neutralizing titer (GMT) (130.7, 95% CI 88.4-193.3 vs 506, 355.8-719.7, respectively). Subgroup analysis revealed significantly enhanced neutralizing activity against WT and VOCs in Delta convalescent sera. The neutralizing antibodies against Omicron were detectable in 75% of convalescents and 44.9% of healthy donors (p = 0.006), with a GMT of 289.5, 180.9-463.3 and 42.6, 31.3-59, respectively. However, the protective effect against VOCs was weaker in young convalescents (aged < 18y), with a detectable rate of 50% and a GMT of 46.4 against Omicron, similar to vaccinees. The pan-sarbecovirus neutralizing activities were not observed in vaccinated SARS-CoV-1 survivors. A booster dose significantly increased the breadth and magnitude of neutralization against WT and VOCs to different degrees than full vaccination. In addition, we showed that COVID-19 inactivated vaccines can elicit Omicron-specific T cell responses. The positive rates of ELISpot reactions were 26.7% (4/15) and 43.8% (7/16) in the full vaccination group and the booster vaccination group, respectively. The neutralizing antibody titers declined while T-cell responses remain robust over 6 months. These findings will inform the optimization of public health vaccination and intervention strategies to protect diverse populations against SARS-CoV-2 variants.
Zoogeographic patterns on very small spatial scales in rock-dwellingPlectostomasnails from Borneo (Gastropoda: Caenogastropoda: Diplommatinidae)
Authors: Schilthuizen Menno , van Til Angelique
Published: February 2022

We mapped the fine-grained distribution patterns ofPlectostomamicrosnails on two small isolated limestone outcrops in Malaysian Borneo. On both hills, two species were present (P. simplexandP. concinnumon Tandu Batu;P. fraternumandP. concinnumon Tomanggong Besar), but the patterns we found were different. On Tomanggong Besar, the two species occupy different parts of the hill and meet along a narrow hybrid zone that is characterised by a significantly higher rate of predation byAtoposslugs. On Tandu Batu, the two species broadly overlap and do not form hybrids. The predation rate here is the same in both species, regardless of whether they occur in monospecific localities or in mixed localities. Our results show that even small limestone outcrops of a few hundred m in diameter cannot be considered to be uniformly populated by limestone dwelling snails, and a detailed analysis of intra-hill patterns may reveal information on species differences and maintenance.
Reversions to consensus are positively selected in HIV-1 and bias substitution rate estimates
Authors: Druelle Valentin , Neher Richard A.
Published: February 2022

HIV-1 is a rapidly evolving virus able to evade host immunity through rapid adaptation during chronic infection. The HIV-1 group M has diversified since its zoonosis into several subtypes at a rate of the order of 10−3 changes per site per year. This rate varies between different parts of the genome and its inference is sensitive to the time scale and diversity spanned by the sequence data used. Higher rates are estimated on short time scales and particularly for within-host evolution, while rate estimates spanning decades or the entire HIV-1 pandemic tend to be lower. The underlying causes of this difference are not well understood.

We investigate here the role of rapid reversions toward a preferred evolutionary sequence state on multiple time scales. We show that within-host reversion mutations are under positive selection and contribute substantially to sequence turnover, especially at conserved sites. We then use the rates of reversions and non-reversions estimated from longitudinal within-host data to parametrize a phylogenetic sequence evolution model. Sequence simulation of this model on HIV-1 phylogenies reproduces diversity and apparent evolutionary rates of HIV-1 in gag and pol, suggesting that a tendency to rapidly revert to a consensus-like state can explain much of the time dependence of evolutionary rate estimates in HIV-1.