bluuebunny/crossref_metadata_2025 huggingface dataset:
The OmegaWhite survey for short-period variable stars – VII. High amplitude short-period blue variables
Authors: Ramsay Gavin , Woudt Patrick A , Kupfer Thomas , van Roestel Jan , Paterson Kerry , Warner Brian , Buckley David A H , Groot Paul J , Heber Ulrich , Irrgang Andreas , Jeffery C Simon , Motsoaledi Mokhine , Schwartz Martinus J , Wevers Thomas
Published: April 2022

Blue Large-Amplitude Pulsators (BLAPs) are a relatively new class of blue variable stars showing periodic variations in their light curves with periods shorter than a few tens of minutes and amplitudes of more than 10 per cent. We report nine blue variable stars identified in the OmegaWhite survey conducted using ESO’s VST, which shows a periodic modulation in the range 7–37 min and an amplitude in the range 0.11–0.28 mag. We have obtained a series of followup photometric and spectroscopic observations made primarily using SALT and telescopes at SAAO. We find four stars which we identify as BLAPs, one of which was previously known. One star, OW  J0820–3301, appears to be a member of the V361 Hya class of pulsating stars and is spatially close to an extended nebula. One further star, OW J1819–2729, has characteristics similar to the sdAV pulsators. In contrast, OW J0815–3421 is a binary star containing an sdB and a white dwarf with an orbital period of 73.7 min, making it only one of six white dwarf-sdB binaries with an orbital period shorter than 80 min. Finally, high cadence photometry of four of the candidate BLAPs show features that we compare with notch-like features seen in the much longer period Cepheid pulsators.
Polarimetric analysis of STEREO observations of sungrazing kreutz comet C/2010 E6 (STEREO)
Authors: Nežič Rok , Bagnulo Stefano , Jones Geraint H , Knight Matthew M , Borisov Galin
Published: April 2022

Twin STEREO spacecraft pre-perihelion photometric and polarimetric observations of the sungrazing Kreutz comet C/2010 E6 (STEREO) in March 2010 at heliocentric distances 3−28 R⊙ were investigated using a newly created set of analysis routines. The comet fully disintegrated during its perihelion passage. Prior to that, a broadening and an increase of the intensity peak with decreasing heliocentric distance was accompanied by a drop to zero polarization at high phase angles (∼105°–135°, STEREO-B) and the emergence of negative polarization at low phase angles (∼25°–35°, STEREO-A). Outside the near-comet region, the tail exhibited a steep slope of increasing polarization with increasing cometocentric distance, with the slope becoming less prominent as the comet approached the Sun. The steep slope may be attributed to sublimation of refractory organic matrix and the processing of dust grains, or to presence of amorphous carbon. The change in slope with proximity to the Sun is likely caused by the gradual sublimation of all refractory material. The polarization signatures observed at both sets of phase angles closer to the comet photocentre as the comet approached the Sun are best explained by fragmentation of the nucleus, exposing fresh Mg-rich silicate particles, followed by their gradual sublimation. The need for further studies of such comets, both observational and theoretical, is highlighted, as well as the benefit of the analysis routines created for this work.
A 13-yr-long broad-band view of BL Lac
Authors: Sahakyan N , Giommi P
Published: April 2022

We present the results of an extensive analysis of the optical, ultraviolet, X-ray, and γ-ray data collected from the observations of the BL Lac objects prototype BL Lacertae carried out over a period of nearly 13 yr, between 2008 August and 2021 March. The source is characterized by strongly variable emission at all frequencies, often accompanied by spectral changes. In the γ-ray band several prominent flares have been detected, the largest one reaching the flux of Fγ(> 196.7 MeV) = (4.39 ± 1.01) × 10−6 photon cm−2 s−1. The X-ray spectral variability of the source during the brightest flare on MJD 59128.18 (2020 October 6) was characterized by a softer-when-brighter trend due to a shift of the synchrotron peak to ∼1016 Hz, well into the HBL domain. The widely changing multiwavelength emission of BL Lacertae was systematically investigated by fitting leptonic models that include synchrotron self-Compton and external Compton components to 511 high-quality and quasi-simultaneous broad-band spectral energy distributions (SEDs). The majority of selected SEDs can be adequately fitted within a one-zone model with reasonable parameters. Only 46 SEDs with soft and bright X-ray spectra and when the source was observed in very high energy γ-ray bands can be explained in a two-zone leptonic scenario. The HBL behaviour observed during the brightest X-ray flare is interpreted as due to the emergence of synchrotron emission from freshly accelerated particles in a second emission zone located beyond the broad-line region.
TedSim: temporal dynamics simulation of single-cell RNA sequencing data and cell division history
Authors: Pan Xinhai , Li Hechen , Zhang Xiuwei
Published: April 2022

Recently, lineage tracing technology using CRISPR/Cas9 genome editing has enabled simultaneous readouts of gene expressions and lineage barcodes, which allows for the reconstruction of the cell division tree and makes it possible to reconstruct ancestral cell types and trace the origin of each cell type. Meanwhile, trajectory inference methods are widely used to infer cell trajectories and pseudotime in a dynamic process using gene expression data of present-day cells. Here, we present TedSim (single-cell temporal dynamics simulator), which simulates the cell division events from the root cell to present-day cells, simultaneously generating two data modalities for each single cell: the lineage barcode and gene expression data. TedSim is a framework that connects the two problems: lineage tracing and trajectory inference. Using TedSim, we conducted analysis to show that (i) TedSim generates realistic gene expression and barcode data, as well as realistic relationships between these two data modalities; (ii) trajectory inference methods can recover the underlying cell state transition mechanism with balanced cell type compositions; and (iii) integrating gene expression and barcode data can provide more insights into the temporal dynamics in cell differentiation compared to using only one type of data, but better integration methods need to be developed.
Blockchain-based application at a governmental level: disruption or illusion? The case of Estonia
Authors: Semenzin Silvia , Rozas David , Hassan Samer
Published: April 2022

Blockchain technology enables new kinds of decentralized systems. Thus, it has often been advocated as a “disruptive” technology that could have the potentiality of reshaping political, economic, and social relations, “solving” problems like corruption, power centralization, and distrust toward political institutions. Blockchain has been gradually gaining attention beyond finance and is thus applied by a range of different actors. This includes local, regional, and national governments interested in the potentiality of experimenting with blockchain-supported governance. This article contributes to identifying blockchain as a contested socio-political object prone to contradictory political imaginaries regarding its potentialities, particularly when applied to policy. The article explores some of the most praised of blockchain’s affordances (e.g., decentralization and transparency) in the context of Estonia, one of the most cited examples of blockchain governmental applications. Estonia has received international attention as the alleged first national infrastructure integrating blockchain. However, so far, few have asked: what kind of blockchain-based tools have been built by the Estonian government in practice and why? And to what extent do blockchain-based governmental applications reflect the original promises of disruption of the crypto-community? This article draws on a qualitative approach to explore several blockchain-based socio-technical objects to identify the narratives that have emerged in Estonia. The research shows clear contrasting views between stakeholders and technical experts from inside and outside the institutional sphere. The conflict revolves around two different social imaginaries associated with permissioned vs. public blockchains. The paper concludes with an analysis of the profound political implications of each vision.
Diplocarpon mespilicola sp. nov. Associated with Entomosporium Leaf Spot on Hawthorn in China
Authors: Chen Hao , White James F. , Malik Kamran , Qi Fang , Li Chunjie
Published: April 2022

Entomosporium leaf spot (ELS) is a serious hawthorn disease that mainly causes premature leaf senescence in various hawthorn growing areas worldwide. Diplocarpon mespili is the most commonly reported pathogen causing hawthorn ELS. From 2016 to 2018, hawthorn ELS disease surveys and samplings were carried out in five regions in three provinces of China. The disease incidence was about 20 to 95%. A total of 186 single-spored Diplocarpon isolates were obtained and identified using morphological and molecular phylogenetic analysis. The results showed that all isolates clustered, suggesting a distinct species that is here proposed as D. mespilicola sp. nov. This is the first report of the pathogen causing ELS on hawthorn in China, and it is similar to the species D. mespili. To explore the influence of temperature on the epidemiology of D. mespilicola, we studied the continuous influence of temperature and time on the germination of conidia by using nine time points and eight temperature gradient observations. This study indicated that the optimum temperature for conidial germination was 20.4°C, and the minimum germination time was 4.9 h. Using this information to develop a predictive model may provide a basis for disease management in hawthorn production in the future.
Diaporthe Diversity and Pathogenicity Revealed from a Broad Survey of Soybean Stem Blight in China
Authors: Zhao Xiaolin , Li Kainan , Zheng Sujiao , Yang Jin , Chen Changjun , Zheng Xiaobo , Wang Yuanchao , Ye Wenwu
Published: April 2022

Many species in the fungal Diaporthe (anamorph Phomopsis) genus have become a group of the most important pathogens that cause seed decay, stem and pot blight, and stem canker in soybean production worldwide, resulting in significant yield loss. Due to increased disease prevalence but a lack of research, we performed an extensive field survey to isolate and identify the Diaporthe species associated with soybean stem blight in six provinces of China between 2019 and 2020. A total of 92 Diaporthe isolates were identified based on morphological and multilocus phylogenetic analysis and classified into six species: D. longicolla, D. unshiuensis, D. sojae, D. caulivora, D. tectonigena, and an unknown Diaporthe sp. The most frequently identified species was D. longicolla with 57 isolates. High genetic diversity was observed for the D. longicolla isolates, and haplotype network analysis revealed a mixed structure among the population in the six provinces. In comparative pathogenicity assays, different virulence levels were observed among the 92 Diaporthe isolates. The results of this study provide new insights into the Diaporthe spp. associated with soybean stem blight in China and can help in the development of effective management strategies.
The Effect of Surgeon Experience on Short- to Medium-Term Complication Rate Following Operative Fixation of Acetabular Fractures
Authors: Butler Bennet A. , Hannan Zachary D. , Ghulam Qasim M. , DeLeon Genaro A. , O'Hara Nathan , Nascone Jason W. , Sciadini Marcus F. , O'Toole Robert V.
Published: April 2022

Objectives:

Operative management of acetabular fractures is technically challenging, but there is little data regarding how surgeon experience affects outcomes. Previous efforts have focused only on reduction quality in a single surgeon series. We hypothesized that increasing surgeon experience would be associated with improved acetabular surgical outcomes in general.

Design:

Retrospective cohort study.

Setting:

Urban academic level-I trauma center.

Patients/Participants:

Seven hundred ninety-five patients who underwent an open reduction internal fixation for an acetabular fracture.

Results:

There was a significant association between surgeon experience and certain outcomes, specifically reoperation rate (16.9% overall), readmission rate (13.9% overall), and reduction quality. Deep infection rate (9.7% overall) and secondary displacement rate (3.7% overall) were not found to have a significant association with surgeon experience. For reoperation rate, the time until 50% peak performance was 2.4 years in practice.

Conclusion:

Surgeon experience had a significant association with reoperation rate, quality of reduction, and readmission rate after open reduction internal fixation of acetabular fractures. Other patient outcomes were not found to be associated with surgeon experience.

Level of Evidence:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Nonvascularized fibular harvest in children: impact on donor limbs
Authors: Agarwal Anil
Published: April 2022

Nonvascularized fibular graft is commonly used in children. We investigated periosteal intactness, proportion of harvested fibula and the distal remnant for their association to regeneration and development of ankle valgus in 25 donor limbs (n = 18 patients). The fibulae were harvested from healthy legs with all possible care to preserve periosteum. Intraoperatively, periosteal breach and length of graft obtained were recorded. Follow-up radiographs at 6 months documented lateral distal tibial angle, fibular station, and longitudinal continuous regeneration of fibula in the donor limb. Limbs with and without regeneration/ankle valgus were matched for proportion of harvested length and distal remnant, respectively. Odds ratios for periosteum breach versus nonregeneration and nonregeneration versus ankle valgus were additionally calculated. The average harvest length and distal remnant were 15.1 and 4.5 cm, respectively. The periosteum intactness was maintained in 18 (72%) limbs. At 6 months follow-up, regeneration of fibula was present in 15 (60%) limbs. The postharvest-acquired ankle valgus was present in five limbs (24%). There was almost 2.5 times increased likelihood of nonregeneration, if periosteum was breached. The odds ratio for nonregeneration versus regeneration to the development of ankle valgus stood at 12 (P = 0.0483). Periosteal breach increased the odds of nonregeneration of harvested fibula. The length of harvested segment did not appear to have significant influence on regeneration nor did distal segment on ankle valgus. The nonregeneration of fibula, however, made the limb prone to ankle valgus.
Effects of an Inpatient Physical Rehabilitation Program Designed for Persons with Amputations of Traumatic or Vascular Etiologies
Authors: Utiyama Daniela Mitiyo Odagiri , Alfieri Fábio Marcon , dos Santos Artur César Aquino , Ribeiro Carla Paschoal Corsi , Sales Viviane Caroline , Battistella Linamara Rizzo
Published: April 2022

Introduction

Rehabilitation after amputation is essential, and descriptions of inpatient rehabilitation programs for individuals with amputation are scarce. Therefore, the objective of this study was to describe the effects of an inpatient physical rehabilitation program on mobility, balance, function, and gait of individuals with unilateral lower-limb amputations.

Materials and Methods

This was a retrospective before-after study. Data were extracted from medical records of individuals with lower-limb amputation admitted for inpatient intensive rehabilitation programs. Data on etiology, functional mobility (by timed up and go [TUG]), balance and functionality (amputee mobility predictor [AMP]), and gait (2-minute walk test [2MWT]) were collected before and after prosthetic fitting phase of an inpatient rehabilitation program. Patient information was stratified as traumatic and vascular etiologies, and after descriptive analysis, general outcomes and intragroup results were compared with t-test and followed by linear regressions analysis for a better understanding of the demographic and clinical roles on treatment evolution.

Results

Group comparison evidenced differences of age between traumatic and vascular groups, as traumatic amputations had greater incidence among younger individuals, regardless of the prosthesis phase. Before the prosthesis fitting and regardless of the groups, there were significant improvements on AMP, 2MWT, and TUG, and the differences between both groups were influenced by their baseline conditions. After prosthesis fitting, significant improvements were identified, regardless of the etiology.

Conclusions

This study provides evidence that individuals with amputation who are admitted to an intensive hospitalized physical rehabilitation program experience benefits in mobility, balance, functionality, and gait capacity irrespective of causality or if the prosthesis was provided. Gains evidenced in the preprosthetic phase were continued in the postprosthetic phase.

Clinical Relevance

Inpatient rehabilitation programs for individuals with amputation are beneficial for improving the functionality of these individuals. This type of multidisciplinary rehabilitation provides functional improvements to the patient from the preprosthetic to the prosthetic phases, favoring global rehabilitation in a short period, which can reduce treatment time and provide better living conditions for the patient.
Superior Dialytic Removal of Bilirubin and Bile Acids by Free Fatty Acid Displacement and Its Synergy With Albumin-Based Dialysis
Authors: Shi Yuanyuan , Wang Yifeng , Shen Yue , Zhu Qiuyu , Ding Feng
Published: April 2022

One of the cardinal features of any liver replacement therapy is the ability to remove accumulated metabolites. However, an unsolved problem is the low dialyzability of lipophilic toxins. This study aimed to explore whether bilirubin and bile acids removal can be increased by free fatty acid (FFA) displacement and its synergy with albumin dialysis. First, we found that the protein binding of both bilirubin and bile acids decreased significantly with increasing FFA concentrations when co-incubated directly. Then, in vitro dialysis showed that fatty acid mixtures infusion prefilter effectively increased the fractional removals of bilirubin and bile acids, showing higher efficiency compared with albumin-based hemodialysis (HD); in vivo dialysis in liver failure rats showed that lipid emulsion administration resulted in higher reduction ratios and more total solute removals for bilirubin and bile acids after 4 h HD compared with control, which were also superior to albumin-based HD. Finally, the highest dialysis efficacy was always observed by their synergy whether in vitro or in vivo. These findings highlight that FFA displacement-based HD could efficiently improve the dialytic removal of bilirubin and bile acids, which might even be more efficient than albumin-based HD. Their synergy may represent a promising strategy to maximize the removal of circulating bilirubin and bile acids accumulated in liver failure.
Patient-reported continuous clinical response to golimumab in adults with moderately to severely active ulcerative colitis: results from GO OBSERVE, a real-world European observational study
Authors: Ferrante Marc , Schirbel Anja , Pierik Marieke J. , Haas Thomas , Flamant Mathurin , Khalifa Ahmed , Philip George , Cornillie Freddy , Meehan Alan G. , Govoni Marinella
Published: April 2022

Background

In PURSUIT, golimumab (GLM) was efficacious in patients with moderate-to-severe ulcerative colitis (UC). We assessed whether remote monitoring of combined patient-reported Mayo stool frequency and rectal bleeding scores is an effective real-world outcome measure for assessing maintenance of GLM-induced clinical response.

Methods

This was a 54-week prospective, observational cohort study conducted at 43 European outpatient clinics in adults with moderate-to-severe UC who were biologic naïve or had received a maximum of one other biological therapy. Patients were treated according to European GLM UC label/local practice. Clinical response (based on partial or full Mayo score) was assessed at week 6, 10, or 14 of induction, depending on local practice. Investigators remotely monitored scores every 4 weeks. The primary endpoint was the proportion of induction responders in patient-reported continuous clinical response (pCCR) at week 54, defined as absence of UC flare based on combined patient-reported Mayo stool frequency and rectal bleeding scores every 4 weeks and full or partial Mayo score. A key secondary endpoint was the proportion of induction responders in clinical remission at week 54.

Results

Among 109 patients, 37 (34.0%) received at least two GLM induction doses and completed induction in clinical response (induction responders). At week 54, 15/37 (40.5%) induction responders were in pCCR, and 21/37 (56.8%) were in clinical remission.

Conclusion

In daily clinical practice, regular remote monitoring of combined patient-reported Mayo stool frequency and rectal bleeding scores appears to be a meaningful real-world outcome measure for monitoring maintenance of GLM-induced clinical response in UC.
The Safety Showdown
Authors: Daniels Darami A. , Caruso Stephanie , Morrell Briyana , Eukel Heidi N.
Published: April 2022

Educational escape rooms actively engage learners and foster teamwork. It is unclear if they result in nursing practice change. Three hundred ninety-eight nursing and ancillary caregivers participated in an escape room involving patient safety and fall prevention concepts. An average rating of 4.3 out of 5 on the escape room perception scale was obtained via a postsurvey, showing positive perceptions of the event. In a delayed postsurvey, participants discussed resultant patient safety practice changes.
Morphologic Differences in Sagittal Synostosis with Age before Surgery
Authors: Massenburg Benjamin B. , Shepard Elizabeth , Mercan Ezgi , Nassar Amer , Birgfeld Craig B. , Lee Amy , Ellenbogen Richard G. , Hopper Richard A.
Published: April 2022

Background:

It is important to determine whether sagittal synostosis–associated scaphocephaly is static in the presurgical period, or whether there are morphologic differences with time to include in surgical decision-making. The authors’ purpose was to perform cross-sectional analysis of cranial morphology before any surgical intervention in children with sagittal synostosis younger than 9 months compared to matched controls.

Methods:

The authors performed morphometric analysis on computed tomographic scans from 111 untreated isolated sagittal synostosis patients younger than 9 months and 37 age-matched normal controls. The authors divided the patients into three age groups and performed statistical comparison between sagittal synostosis and controls for each group.

Results:

Sagittal synostosis cephalic indices were stable and lower in patients than in controls across groups. Total cranial volume was equivalent, but sagittal synostosis patients had a greater posterior volume than controls at all ages and a smaller middle fossa volume at older ages. Pterional width was greater in sagittal synostosis patients than in controls for each age group. Frontal bossing vectors were most severe in the youngest age groups and least in the older group. Occipital protuberance was consistent across the age groups.

Conclusions:

Upper parietal narrowing and occipital protuberance were the consistent deformities across age groups, with the most parietal constriction seen in older patients. Frontal bossing was not consistent and was more severe in the younger patients. The authors did not detect significant pterional constriction, and the appearance of constriction is relative to adjacent morphology and not absolute.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, II.
A Neurodynamic Model of Inter-Brain Coupling in the Gamma Band
Authors: Quentin Moreau , Lena Adel , Caitriona Douglas , Ghazaleh Ranjbaran , Guillaume Dumas
Published: April 2022

The use of EEG to simultaneously record multiple brains (i.e., hyperscanning) during social interactions has led to the discovery of inter-brain coupling (IBC). IBC is defined as the neural synchronization between people and is considered to be a marker of social interaction. IBC has previously been observed across different frequency bands, including Theta [4-7 Hz]. Given the proximity of this frequency range with behavioral rhythms, models have been able to combine IBC in Theta with sensorimotor coordination patterns. Interestingly, empirical EEG-hyperscanning results also report the emergence of IBC in the Gamma range [>30 Hz]. Gamma oscillations’ fast and transient nature makes a direct link between Gamma-IBC and other (much slower) interpersonal dynamics difficult, leaving Gamma-IBC without a plausible model. However, at the intra-brain level, Gamma activity is coupled with the dynamics of lower frequencies through cross-frequency coupling (CFC). This paper provides a biophysical explanation for the emergence of Gamma inter-brain coupling using a Kuramoto model of four oscillators divided into two separate (brain) units. By modulating both the degree of inter-brain coupling in the Theta band (i.e., between-units coupling) and CFC (i.e., intra-unit Theta-Gamma coupling), we provide a theoretical explanation of the observed Gamma-IBC phenomenon in the EEG-hyperscanning literature.
Privacy-Preserving Statistical Analysis of Genomic Data using Compressive Mechanism with Haar Wavelet Transform*
Authors: Yamamoto Akito , Shibuya Tetsuo
Published: April 2022

To promote the use of personal genome information in medicine, it is important to analyze the relationship between diseases and the human genomes. Therefore, statistical analysis using genomic data is often conducted, but there is a privacy concern with respect to releasing the statistics as they are. Existing methods to address this problem using the concept of differential privacy cannot provide accurate outputs under strong privacy guarantees, making them less practical. In this study, for the first time we investigate the application of a compressive mechanism to genomic statistical data and propose two approaches. The first is to apply the normal compressive mechanism to the statistics vector along with an algorithm to determine the number of nonzero entries in a sparse representation. The second is to alter the mechanism based on the data, aiming to release significant SNPs with a high probability. In this algorithm, we apply the compressive mechanism with the input as a sparse vector for significant data and the Laplace mechanism for non-significant data. Using the Haar transform for the wavelet matrix in the compressive mechanism is advantageous to determine the number of nonzero elements and the amount of noise. In addition, we theoretically prove that our proposed method achieves ϵ-differential privacy. We evaluated our methods in terms of accuracy, rank error, and run time compared to the Laplace and exponential mechanisms. The results show that our second method in particular can guarantee both high privacy assurance as well as utility. The Python implementation of our experiments is available at https://github.com/ay0408/CompLaplace.
Hypervoxels: a multidimensional framework for the representation and analysis of neuroimaging data
Authors: Luque Laguna Pedro A. , Beyh Ahmad , de S. Requejo Francisco , Stones Richard , Jones Derek K. , Goldstein Laura. H. , Catani Marco , Williams Steve C.R. , Dell’Acqua Flavio
Published: April 2022

Most neuroimaging modalities use regular grids of voxels to represent the three-dimensional space occupied by the brain. However, a regular 3D voxel grid does not reflect the anatomical and topological complexity represented by the brain’s white matter connections. In contrast, tractography reconstructions based on diffusion MRI provide a closer characterisation of the white matter pathways followed by the neuronal fibres interconnecting different brain regions. In this work, we introduce hypervoxels as a new methodological framework that combines the spatial encoding capabilities of multidimensional voxels with the anatomical and topological information found in tractography data. We provide a detailed description of the framework and evaluate the benefits of using hypervoxels by carrying out comparative voxel and hypervoxel cluster inference analyses on diffusion MRI data from a neuroimaging study on amyotrophic lateral sclerosis (ALS). Compared to the voxel analyses, the use of hypervoxels improved the detection of effects of interest in the data in terms of statistical significance levels and spatial distribution across white matter regions known to be affected in ALS. In these regions, the hypervoxel results also identified specific white matter pathways that resolve the anatomical ambiguity otherwise observed in the results from the voxel analyses. The observed increase in sensitivity and specificity can be explained by the superior ability of hypervoxel-based methods to represent and disentangle the anatomical overlap of white matter connections. Based on this premise, we expect that the use of hypervoxels should improve the analysis of neuroimaging data when the effects of interest under investigation are expected to be aligned along distinct but potentially overlapping white matter pathways.
Core and accessory effectors of type VI secretion systems contribute differently to the intraspecific diversity of Pseudomonas aeruginosa
Authors: Habich Antonia , Galeev Alibek , Vargas Verónica Chaves , Vogler Olga , Ghoul Melanie , Andersen Sandra B. , Johansen Helle Krogh , Molin Søren , Griffin Ashleigh S. , Unterweger Daniel
Published: April 2022

Bacteria use type VI secretion systems (T6SSs) to deliver effector proteins into other cells or the extracellular space. Those effectors kill microbes1, manipulate eukaryotic cells2, and sequester nutrients3. Which T6SS-mediated functions are generalisable across bacteria of a species or are specific to particular strains is little known. Here, we use genomics to test for the intraspecific diversity of T6SS effectors in the opportunistic pathogen Pseudomonas aeruginosa. We found effectors that are omnipresent and conserved across strains acting as ‘core effectors’, while additional ‘accessory effectors’ vary. In vitro and in vivo experiments demonstrate different roles of the two types of effectors in bacterial killing and virulence. Further, effectors compose various effector combinations. Within one local population of clinical isolates, we observed 36 combinations among 52 bacterial lineages. These findings show the distinct contribution of T6SS effectors to strain-level variation of a bacterial pathogen and might reveal conserved targets for novel antibiotics.
Expansion of Ventral Foregut Primes the Enhancer Landscape for Organ Specific Differentiation
Authors: Wong Yan Fung , Kumar Yatendra , Proks Martin , Herrera Jose Alejandro Romero , Rothová Michaela Mrugala , Monteiro Rita S. , Pozzi Sara , Jennings Rachel E. , Hanley Neil A. , Bickmore Wendy A. , Brickman Joshua M.
Published: April 2022

Cell proliferation is fundamental for almost all stages of development and differentiation that require an increase cell number. Although cell cycle phase has been associated with differentiation, the actual process of proliferation is not seen as having a specific role. Here we exploit human embryonic stem cell derived endodermal progenitors that we find are an in vitro model for the ventral foregut. These cells exhibit expansion dependent increases in differentiation efficiency to pancreatic progenitors that are linked to organ-specific enhancer priming at the level of chromatin accessibility and the decommissioning of lineage inappropriate enhancers. Our findings suggest that cell proliferation in embryonic development is about more than tissue expansion, it is required to ensure equilibration of gene regulatory networks allowing cells to become primed for future differentiation. The use of expansion of lineage specific intermediates may therefore be an important step in high fidelity in vitro differentiation.
Exploring the mobilome and resistome of Enterococcus faecium in a One Health context across two continents
Authors: Sanderson Haley , Gray Kristen L. , Manuele Alexander , Maguire Finlay , Khan Amjad , Liu Chaoyue , Rudrappa Chandana N. , Nash John H. E. , Robertson James , Bessonov Kyrylo , Oloni Martins , Alcock Brian P. , Raphenya Amogelang R. , McAllister Tim A. , Peacock Sharon J. , Raven Kathy E. , Gouliouris Theodore , McArthur Andrew G. , Brinkman Fiona S. L. , Fink Ryan C. , Zaheer Rahat , Beiko Robert G.
Published: April 2022

Enterococcus faecium is a ubiquitous opportunistic pathogen that is exhibiting increasing levels of antimicrobial resistance (AMR). Many of the genes that confer resistance and pathogenic functions are localized on mobile genetic elements (MGEs), which facilitate their transfer between lineages. Here, features including resistance determinants, virulence factors, and MGEs were profiled in a set of 1273 E. faecium genomes from two disparate geographic locations (in the UK and Canada) from a range of agricultural, clinical, and associated habitats. Neither lineages of E. faecium nor MGEs are constrained by geographic proximity, but our results show evidence of a strong association of many profiled genes and MGEs with habitat. Many features were associated with a group of clinical and municipal wastewater genomes that are likely forming a new human-associated ecotype. The evolutionary dynamics of E. faecium make it a highly versatile emerging pathogen, and its ability to acquire, transmit, and lose features presents a high risk for the emergence of new pathogenic variants and novel resistance combinations. This study provides a workflow for MGE-centric surveillance of AMR in Enterococcus that can be adapted to other pathogens.
Positive fitness effects help explain the broad range ofWolbachiaprevalences in natural populations
Authors: Karisto Petteri , Duplouy Anne , de Vries Charlotte , Kokko Hanna
Published: April 2022

The bacterial endosymbiontWolbachiais best known for its ability to modify its host’s reproduction by inducing cytoplasmic incompatibility (CI) to facilitate its own spread. Classical models predict either near-fixation of costlyWolbachiaonce the symbiont has overcome a threshold frequency (invasion barrier), orWolbachiaextinction if the barrier is not overcome. However, natural populations do not all follow this pattern:Wolbachiacan also be found at low frequencies (below one half) that appear stable over time.Wolbachiais known to have pleiotropic fitness effects (beyond CI) on its hosts. Existing models typically focus on the possibility that these are negative. Here we consider the possibility that the symbiont provides direct benefits to infected females (e.g. resistance to pathogens) in addition to CI. We discuss an underappreciated feature ofWolbachiadynamics: that CI with additional fitness benefits can produce low-frequency (<1/2) stable equilibria. Additionally, without a direct positive fitness effect, any stable equilibrium close to one half will be sensitive to perturbations, which make such equilibria unlikely to sustain in nature. The results hold for both diplodiploid and different haplodiploid versions of CI. We suggest that insect populations showing low-frequencyWolbachiainfection might host CI-inducing symbiotic strains providing additional (hidden or known) benefits to their hosts, especially when classical explanations (ongoing invasion, source-sink dynamics) have been ruled out.
Novel frontier in wildlife monitoring: identification of small rodent species from faecal pellets using Near-Infrared Reflectance Spectroscopy (NIRS)
Authors: Tuomi Maria W. , Murguzur Francisco J.A. , Hoset Katrine S. , Soininen Eeva M. , Vesterinen Eero , Utsi Tove Aa. , Kaino Sissel , Bråthen Kari Anne
Published: April 2022

Small rodents are prevalent and functionally important across world’s biomes, making their monitoring salient for ecosystem management, conservation, forestry and agriculture. Yet, there is a dearth of cost-effective and non-invasive methods for large-scale, intensive sampling. As one such method, fecal pellet counts readily provide relative abundance indices. Given available analytical methods, feces could also allow for determination of multiple ecological and physiological variables, including community composition. We developed calibration models for rodent taxonomic determination using fecal near-infrared reflectance spectroscopy (fNIRS).

Our results demonstrate fNIRS as an accurate and robust method for predicting genus and species identity of five co-existing subarctic microtine rodent species. We show that sample exposure to weathering did not reduce accuracy, indicating suitability of the method for samples collected from the field. Diet was not a major determinant of species prediction accuracy in our samples, as diet exhibited large variation and overlap between species. While regional calibration models predicted poorly samples from another region, calibration models including samples from two regions provided a good prediction accuracy for both regions.

We propose fNIRS as a fast and cost-efficient high-throughoutput method for rodent taxonomic determination, and highlight its potential for cross-regional calibrations and use on field-collected samples. FNIRS can facilitate rodent population censuses at larger spatial extent than before deemed feasible, if combined with pellet-count based abundance indices. Given the versatility of fNIRS analytics, developing such monitoring schemes can support ecosystem- and interaction-based approaches to monitoring.
Peptidoglycan maturation controls spatiotemporal organisation of outer membrane proteins in Escherichia coli
Authors: Mamou Gideon , Corona Federico , Cohen-Khait Ruth , Sun Dawei , Sridhar Pooja , Knowles Timothy J. , Kleanthous Colin , Vollmer Waldemar
Published: April 2022

Linkages between the outer membrane of Gram-negative bacteria and the peptidoglycan layer are crucial to the maintenance of cellular integrity and enable survival in challenging environments1–5. The functionality of the outer membrane relies on outer membrane proteins (OMPs), which are inserted by the β-barrel assembly machine, BAM6, 7. Previous work has shown that growing Escherichia coli cells segregate old OMPs towards the poles by an unknown mechanism8. Here, we demonstrate that peptidoglycan underpins the spatiotemporal organisation of OMPs. Mature, tetrapeptide-rich peptidoglycan binds to BAM components and suppresses OMP foldase activity. Nascent peptidoglycan, which is enriched in pentapeptides and concentrated at septa9, associates with BAM poorly and has little impact on its activity, leading to preferential insertion of OMPs at division sites. Synchronising OMP biogenesis to cell wall growth enables bacteria to replenish their OMPs by binary partitioning. Our study reveals that Gram-negative bacteria coordinate the assembly of two major cell envelope layers by rendering OMP biogenesis responsive to peptidoglycan maturation. This coordination offers new possibilities for the design of antibiotics that disrupt cell envelope integrity.
An adaptive filtering framework for non-specific and inefficient reactions in multiplex digital PCR based on sigmoidal trends
Authors: Miglietta Luca , Xu Ke , Chhaya Priya , Kreitmann Louis , Hill-Cawthorne Kerri , Bolt Frances , Holmes Alison , Georgiou Pantelis , Rodriguez-Manzano Jesus
Published: April 2022

Real-time digital PCR (qdPCR) coupled with artificial intelligence has shown the potential of unlocking scientific breakthroughs, particularly in the field of molecular diagnostics for infectious diseases. One of the most promising applications is the use of machine learning (ML) methods to enable single fluorescent channel PCR multiplex by extracting target-specific kinetic and thermodynamic information contained in amplification curves. However, the robustness of such methods can be affected by the presence of undesired amplification events and nonideal reaction conditions. Therefore, here we proposed a novel framework to filter non-specific and low efficient reactions from qdPCR data using outlier detection algorithms purely based on sigmoidal trends of amplification curves. As a proof-of-concept, this framework is implemented to improve the classification performance of the recently reported ML-based Amplification Curve Analysis (ACA), using available data from a previous publication where the ACA method was used to screen carbapenemase-producing organisms in clinical isolates. Furthermore, we developed a novel strategy, named Adaptive Mapping Filter (AMF), to consider the variability of positive counts in digital PCR. Over 152,000 amplification events were analyzed. For the positive reactions, filtered and unfiltered amplification curves were evaluated by comparing against melting peak distribution, proving that abnormalities (filtered out data) are linked to shifted melting distribution or decreased PCR efficiency. The ACA was applied to compare classification accuracies before and after AMF, showing an improved sensitivity of 1.18% for inliers and 20% for outliers (p-value < 0.0001). This work explores the correlation between kinetics of amplification curves and thermodynamics of melting curves and it demonstrates that filtering out non-specific or low efficient reactions can significantly improve the classification accuracy for cutting edge multiplexing methodologies.
Rational design by structural biology of industrializable, long-acting antihyperglycemic GLP-1 receptor agonists
Authors: Sun Lei , Zheng Zhi-Ming , Shao Chang-Sheng , Li Ming-Wei , Wang Li , Wang Han , Zhao Gen-Hai , Wang Peng
Published: April 2022

Glucagon-like peptide-1 (GLP-1) is easily degraded by dipeptidyl peptidase-4 (DPP-4) in the human body, limiting its therapeutic effect on type II diabetes. Therefore, improving GLP-1 receptor agonist (GLP-1RA) stability is a major obstacle for drug development. We analyzed human GLP-1, DPP-4, and GLP-1 receptor structures and designed three GLP-1RAs, which were introduced into fusion protein fragments and changed in the overall conformation. This modification effectively prevented GLP-1RAs from entering DPP-4 active center without affecting GLP-1Ras ability to bind to GLP-1R, the new GLP-1RA hypoglycemic effect lasting for >24 h. Through molecular modeling, molecular dynamics calculation, and simulation, possible tertiary structure models of GLP-1RAs were obtained; molecular docking with DPP-4 and GLP-1R showed access to the fusion protein. The overall conformational change of GLP-1RAs prevented DPP-4 binding, without affecting GLP-1Ras affinity to GLP-1R. This study provides important drug design ideas for GLP-1RA development and a new example for application of structural biology-based protein design in drug development.
Strong and consistent associations of waterbird community composition with HPAI H5 occurrence in European wild birds
Authors: Huang Zheng Y.X. , Yin Shenglai , Zhang Yong , de Boer Willem F. , Mundkur Taej , Artois Jean , Velckers Francisca , Tian Huaiyu , Takekawa John Y. , Si Yali , Han Guan-Zhu , Zhang Huimin , Chen Yuyang , Chai Hongliang , Xu Chi
Published: April 2022

Since 2014, highly pathogenic avian influenza (HPAI) H5 viruses of clade 2.3.4.4 have been dominating the outbreaks across Europe, causing massive deaths among poultry and wild birds. However, the factors shaping its broad-scale outbreak patterns remain unclear. With extensive waterbird survey datasets of about 7,000 sites across Europe, we here demonstrated that H5N8 occurrence in wild birds in the 2016/17 and 2020/21 epidemics as well as H5N1 occurrence in 2005/06 epidemic were strongly associated with very similar waterbird community attributes, pointing to the possibility of similar interspecific transmission processes between different epidemics. A simple extrapolation of the model constructed from the 2016/17 epidemic can well predict the H5N8 pattern in wild birds in 2020/21 epidemic. We also found a dilution effect of phylogenetic diversity that was always negatively correlated with H5 occurrence in wild birds. In contrast, H5N8 occurrence in poultry was subject to different risk factors between the two epidemics. In general, waterbird community composition play a much more important role in determining the spatial pattern of H5N8 in wild birds than in poultry. Our work contributes to reveal the factors driving H5N8 patterns, and highlights the value of waterbird community factors in future HPAI surveillance and prediction.
Variation in subcortical anatomy: relating interspecies differences, heritability, and brain-behavior relationships
Authors: Blostein Nadia , Devenyi Gabriel A. , Patel Sejal , Patel Raihaan , Tullo Stephanie , Plitman Eric , Costantino Manuela , Markello Ross , Parent Olivier , Bedford Saashi A. , Sherwood Chet C. , Hopkins William D , Seidlitz Jakob , Raznahan Armin , Chakravarty M. Mallar
Published: April 2022

There has been an immense research focus on the topic of cortical reorganization in human evolution, but much less is known regarding the reorganization of subcortical circuits which are intimate working partners of the cortex. Here, by combining advanced image analysis techniques with comparative neuroimaging data, we systematically map organizational differences in striatal, pallidal and thalamic anatomy between humans and chimpanzees. We relate interspecies differences, a proxy for evolutionary changes, to genetics and behavioral correlates. We show that highly heritable morphological measures are significantly expanded across species, in contrast to previous findings in the cortex. The identified morphological-cognitive latent variables were associated with striatal expansion, and affective latent variables were associated with more evolutionarily-conserved areas in the thalamus and globus pallidus. These findings provide new insight into the architecture of these subcortical hubs and can provide greater information on the role of these structures in health and illness.
Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target
Authors: Wagner Matthias Paulus , Formaglio Pauline , Gorgette Olivier , Dziekan Jerzy Michal , Huon Christèle , Berneburg Isabell , Rahlfs Stefan , Barale Jean-Christophe , Feinstein Sheldon I. , Fisher Aron B. , Ménard Didier , Bozdech Zbynek , Amino Rogerio , Touqui Lhousseine , Chitnis Chetan E.
Published: April 2022

The uptake and digestion of host hemoglobin by malaria parasites during blood stage growth leads to significant oxidative damage of membrane lipids. Repair of lipid peroxidation damage is crucial for parasite survival. Here, we demonstrate that Plasmodium falciparum imports a host antioxidant enzyme, peroxiredoxin 6 (PRDX6), during hemoglobin uptake from the red blood cell cytosol. PRDX6 is a lipid peroxidation repair enzyme with phospholipase A2 (PLA2) activity. Inhibition of PRDX6 with a PLA2 inhibitor, Darapladib, increases lipid peroxidation damage in the parasite and disrupts transport of hemoglobin-containing vesicles to the food vacuole, causing parasite death. Furthermore, inhibition of PRDX6 synergistically reduces the survival of artemisinin-resistant parasites following co-treatment of parasite cultures with artemisinin and Darapladib. Thus, PRDX6 is a unique host-derived drug target for development of antimalarial drugs that could help overcome artemisinin resistance.

GRAPHICAL ABSTRACT