bluuebunny/crossref_metadata_2025 huggingface dataset:
ANCA-assozierte Vaskulitis
Authors: Stegert Mihaela , Neumann Thomas , Daikeler Thomas
Published: May 2022

Zusammenfassung. Die nach ihrem immunserologischen Marker (anti-neutrophile zytoplasmatische Antikörper – ANCA) benannten ANCA-assoziierten Vaskulitiden (AAV) werden entsprechend der Chapel-Hill-Nomenklatur (2012) von anderen systemischen Kleingefässvaskulitiden abgegrenzt. Die mikroskopische Polyangiitis (MPA), die Granulomatose mit Polyangiitis (GPA) und die Eosinophile Granulomatose mit Polyangiitis (EGPA) werden nach klinischen, histologischen und bildgebenden Befunden diagnostiziert und klassifiziert. GPA und EGPA unterscheiden sich hauptsächlich durch das Vorhandensein von granulomatösen Entzündungen im Bereich der Atemwege von der MPA. Epidemiologisch betrachtet sind alle drei Entitäten seltene Autoimmunerkrankungen, wobei die Prävalenzen geographische Unterschiede zeigen. Trotz ihrer Seltenheit ist ein Erkennen der typischen Klinik prognostisch sehr wichtig. Entscheidend ist eine rechtzeitige Diagnosestellung, da unbehandelt die Prognose bezüglich der Erhaltung von Organfunktion sowie bezüglich des Überlebens schlecht ist. Neue, nebenwirkungsärmere Therapien sind in den letzten Jahren für diese Indikation geprüft worden. Eine wichtige Rolle spielt das Rituximab, das das Cyclophosphamid weitestgehend ersetzt hat. Ziel der neuen Therapieansätze ist die Reduktion der Exposition der Patienten gegenüber Steroiden. Therapie- und insbesondere Steroidnebenwirkungen sind neben der Erkrankung selbst Hauptursache der AAV-Morbidität.
Cardiac Disease, Depression, and Suicide Risk by Age
Authors: Cui Ruifeng , Shalaby Alaa , Rotondi Armando , Albright Amy , Callan Judith
Published: May 2022

Abstract. Cardiovascular disease is associated with depression and suicide risk, although there is only limited research available on whether these associations differ by age. This short report examined age differences in associations between cardiovascular disease, depression, and suicide risk. The sample consisted of 301 younger adults (aged 18–40 years) and 432 older adults (aged 60+ years) recruited through Amazon’s Mechanical Turk. The results show that older adults had more cardiovascular diagnoses, whereas younger adults with cardiovascular diagnoses had more depression symptomatology and suicide risk. Associations between cardiovascular disease (one or more diagnoses vs. no diagnoses) and mental health were moderated by age ( p < .05 for Age × Cardiovascular interaction predicting depression and predicting suicide risk). The findings highlight the importance of assessing and addressing mental-health concerns among cardiovascular patients, especially in younger demographics.
Incorporating interventions for unhealthy exercise into eating disorders treatment
Authors: Nahman Carolyn , Holland Josephine
Published: May 2022

Abstract. Introduction: There is little consensus on the treatment of unhealthy exercise in eating disorders. Many treatment programmes do not offer any interventions at all. This study explored the attitudes of those with lived experience towards incorporating treatments for unhealthy exercise in eating disorders. Methods: An online survey was created using onlinesurveys.ac.uk and distributed through social media. Analyses included calculation of descriptive statistics and inductive thematic analysis of free text responses. Results: One hundred and forty-six respondents completed the survey, over 50% identified as having lived experience of an eating disorder. Thematic analysis of free text responses from those with lived experience identified themes around the benefits of incorporating exercise into the treatment of eating disorders including the benefits of exercise on mental and physical health and the opportunity to develop a healthier relationship with exercise. The themes around the risks of incorporating exercise included slowing or limiting recovery and physical risks of exercising at low weight. The themes around the risks of not addressing exercise included leaving part of the disorder untreated and how this could affect recovery. Conclusion: Those with lived experience of eating disorders feel unhealthy exercise is an important part of the disorder to treat. There is recognition of the risks of doing so, but also benefits in helping people to learn a new healthy relationship with exercise.
Atmospheric Triggers of the Brunt Ice Shelf Calving in February 2021
Authors: Francis Diana , Fonseca Ricardo , Mattingly Kyle S. , Marsh Oliver J. , Lhermitte Stef , Cherif Charfeddine
Published: May 2022

The calving of Antarctic ice shelves remains unpredictable to date due to a lack of understanding of the role of the different climatic components in such events. In this study, the role of atmospheric forcing in the calving of the Brunt Ice Shelf (BIS) in February 2021 is investigated using a combination of observational and reanalysis data. The occurrence of a series of extreme cyclones around the time of the calving induced an oceanward sea‐surface slope of >0.08° leading to the calving along a pre‐existing rift. The severe storms were sustained by the development of a pressure dipole on both sides of the BIS associated with a La Niña event and the positive phase of the Southern Annular Mode. Poleward advection of warm and moist low‐latitude air over the BIS area just before the calving was also observed in association with atmospheric rivers accompanying the cyclones. Immediately after the calving, strong offshore winds continued and promoted the drift of the iceberg A‐74 in the Weddell Sea at a speed up to 700 m day−1. This study highlights the contribution of local atmospheric conditions to ice‐shelf dynamics. The link to the larger scale circulation patterns indicates that both need to be accounted for in the projections of Antarctic ice shelf evolution.
The Impact of Wettability on Dynamic Fluid Connectivity and Flow Transport Kinetics in Porous Media
Authors: Nhunduru Rumbidzai A. E. , Jahanbakhsh Amir , Shahrokhi Omid , Wlodarczyk Krystian L. , Garcia Susana , Maroto‐Valer M. Mercedes
Published: May 2022

Usually, models describing flow and transport for sub‐surface engineering processes at the Darcy‐scale do not take into consideration the effects of pore‐scale flow regimes and fluid connectivity on average flow functions. In this article, we investigate the impact of wettability on pore‐scale flow regimes. We show that fluid connectivity at the pore scale has a significant impact on average flow kinetics and therefore its contribution should not be ignored. Immiscible two‐phase flow simulations were performed in a two‐dimensional model of a Berea sandstone rock for wettability conditions ranging from moderately water‐wet to strongly oil‐wet. The simulation results show that wettability has a strong impact on invading fluid phase connectivity, which subsequently influences flow transport resistance. The effect of invading‐phase connectivity and ganglion dynamics (GD) on two‐phase displacement kinetics was also investigated. It was found that invading phase connectivity decreases away from the neutrally wet (intermediate wet) state. This study provides evidence that GD accelerate fluid flow transport kinetics during immiscible displacement processes. Lastly, the impact of wettability on fluid displacement efficiency and residual saturations was investigated. Maximum displacement efficiency occurred at the neutrally wet state.
Development of a New Pedotransfer Function Addressing Limitations in Soil Hydraulic Models and Observations
Authors: Wang Yunquan , Zhou Jieliang , Ma Rui , Zhu Gaofeng , Zhang Yongyong
Published: May 2022

The most applied pedotransfer functions (PTFs) often suffer from two main limitations: (a) the soil hydraulic models (SHMs) only account for capillary forces and/or the models show an unrealistic decrease near saturation for fine‐textured soils; (b) the observations of soil hydraulic properties (SHPs) used to generate the PTF generally do not cover very dry conditions. In this paper, we first present a simple method for predicting SHPs in the dry range from soil texture information. Together with measurements that cover only a relatively high matric potential range, the method yielded a good prediction of the complete SHPs from saturation to oven dryness. With this method, we extended a public dataset to cover dry conditions, and then applied it to develop a new PTF for a SHM that accounts for both capillary and adsorption forces and overcomes the unrealistic decrease near saturation for fine‐textured soils. A comparison with other PTF that was developed for the capillary‐based soil hydraulic model showed that the new PTF provided the most accurate predictions of SHPs. It reduced the root‐mean‐square‐error value from 0.055 to 0.045 cm3 cm−3 in predicting water content and from 0.84 to 0.66 log10 (cm d−1) in predicting hydraulic conductivity. We further applied this method to extend an existing capillary‐based PTF to dry conditions. The results showed an improved performance, with reported RMSE reduced from 0.058 (original) to 0.056 (extended) cm3 cm−3 and from 1.43 (original) to 1.20 (extended) log10 (cm d−1) for prediction of water content and hydraulic conductivity, respectively.
Apoptotic priming is defined by the dynamic exchange of Bcl-2 proteins between mitochondria and cytosol
Authors: King Louise E. , Rodriguez-Enriquez Ricardo , Pedley Robert , Mellor Charlotte E. L. , Wang Pengbo , Zindy Egor , White Michael R. H. , Brennan Keith , Gilmore Andrew P.
Published: May 2022

Apoptosis is regulated by interactions between the BH3-only and multi-domain Bcl-2 family proteins. These interactions are integrated on the outer mitochondrial membrane (OMM) where they set the threshold for apoptosis, known as mitochondrial priming. However, how mitochondrial priming is controlled at the level of single cells remains unclear. Retrotranslocation of Bcl-XL has been proposed as one mechanism, removing pro-apoptotic Bcl-2 proteins from the OMM, thus reducing priming. Contrary to this view, we now show that Bcl-XL retrotranslocation is inhibited by binding to its BH3-only partners, resulting in accumulation of these protein complexes on mitochondria. We find that Bcl-XL retrotranslocation dynamics are tightly coupled to mitochondrial priming. Quantifying these dynamics indicates the heterogeneity in priming between cells within a population and predicts how they subsequently respond to a pro-apoptotic signal.
Synovial mesenchymal progenitor derived aggrecan regulates cartilage homeostasis and endogenous repair capacity
Authors: Krawetz Roman J. , Wu Yiru Elizabeth , Bertram Karri L. , Shonak Anchita , Masson Anand O. , Ren Guomin , Leonard Catherine , Kapoor Mohit , Matyas John R. , Salo Paul T.
Published: May 2022

Aggrecan is a critical component of the extracellular matrix of all cartilages. One of the early hallmarks of osteoarthritis (OA) is the loss of aggrecan from articular cartilage followed by degeneration of the tissue. Mesenchymal progenitor cell (MPC) populations in joints, including those in the synovium, have been hypothesized to play a role in the maintenance and/or repair of cartilage, however, the mechanism by which this may occur is unknown. In the current study, we have uncovered that aggrecan is secreted by synovial MPCs from healthy joints yet accumulates inside synovial MPCs within OA joints. Using human synovial biopsies and a rat model of OA, we established that this observation in aggrecan metabolism also occurs in vivo. Moreover, the loss of the “anti-proteinase” molecule alpha-2 macroglobulin (A2M) inhibits aggrecan secretion in OA synovial MPCs, whereas overexpressing A2M rescues the normal secretion of aggrecan. Using mice models of OA and cartilage repair, we have demonstrated that intra-articular injection of aggrecan into OA joints inhibits cartilage degeneration and stimulates cartilage repair respectively. Furthermore, when synovial MPCs overexpressing aggrecan were transplanted into injured joints, increased cartilage regeneration was observed vs. wild-type MPCs or MPCs with diminished aggrecan expression. Overall, these results suggest that aggrecan secreted from joint-associated MPCs may play a role in tissue homeostasis and repair of synovial joints.
Extended intergenic DNA contributes to neuron-specific expression of neighboring genes in the mammalian nervous system
Authors: Jaura Ravneet , Yeh Ssu-Yu , Montanera Kaitlin N. , Ialongo Alyssa , Anwar Zobia , Lu Yiming , Puwakdandawa Kavindu , Rhee Ho Sung
Published: May 2022

Mammalian genomes comprise largely intergenic noncoding DNA with numerous cis-regulatory elements. Whether and how the size of intergenic DNA affects gene expression in a tissue-specific manner remain unknown. Here we show that genes with extended intergenic regions are preferentially expressed in neural tissues but repressed in other tissues in mice and humans. Extended intergenic regions contain twice as many active enhancers in neural tissues compared to other tissues. Neural genes with extended intergenic regions are globally co-expressed with neighboring neural genes controlled by distinct enhancers in the shared intergenic regions. Moreover, generic neural genes expressed in multiple tissues have significantly longer intergenic regions than neural genes expressed in fewer tissues. The intergenic regions of the generic neural genes have many tissue-specific active enhancers containing distinct transcription factor binding sites specific to each neural tissue. We also show that genes with extended intergenic regions are enriched for neural genes only in vertebrates. The expansion of intergenic regions may reflect the regulatory complexity of tissue-type-specific gene expression in the nervous system.
Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers
Authors: Shukla N. , Levine M. F. , Gundem G. , Domenico D. , Spitzer B. , Bouvier N. , Arango-Ossa J. E. , Glodzik D. , Medina-Martínez J. S. , Bhanot U. , Gutiérrez-Abril J. , Zhou Y. , Fiala E. , Stockfisch E. , Li S. , Rodriguez-Sanchez M. I. , O’Donohue T. , Cobbs C. , Roehrl M. H. A. , Benhamida J. , Iglesias Cardenas F. , Ortiz M. , Kinnaman M. , Roberts S. , Ladanyi M. , Modak S. , Farouk-Sait S. , Slotkin E. , Karajannis M. A. , Dela Cruz F. , Glade Bender J. , Zehir A. , Viale A. , Walsh M. F. , Kung A. L. , Papaemmanuil E.
Published: May 2022

The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.
HDLBP binds ER-targeted mRNAs by multivalent interactions to promote protein synthesis of transmembrane and secreted proteins
Authors: Zinnall Ulrike , Milek Miha , Minia Igor , Vieira-Vieira Carlos H. , Müller Simon , Mastrobuoni Guido , Hazapis Orsalia-Georgia , Del Giudice Simone , Schwefel David , Bley Nadine , Voigt Franka , Chao Jeffrey A. , Kempa Stefan , Hüttelmaier Stefan , Selbach Matthias , Landthaler Markus
Published: May 2022

The biological role of RNA-binding proteins in the secretory pathway is not well established. Here, we describe that human HDLBP/Vigilin directly interacts with more than 80% of ER-localized mRNAs. PAR-CLIP analysis reveals that these transcripts represent high affinity HDLBP substrates and are specifically bound in their coding sequences (CDS), in contrast to CDS/3’UTR-bound cytosolic mRNAs. HDLBP crosslinks strongly to long CU-rich motifs, which frequently reside in CDS of ER-localized mRNAs and result in high affinity multivalent interactions. In addition to HDLBP-ncRNA interactome, quantification of HDLBP-proximal proteome confirms association with components of the translational apparatus and the signal recognition particle. Absence of HDLBP results in decreased translation efficiency of HDLBP target mRNAs, impaired protein synthesis and secretion in model cell lines, as well as decreased tumor growth in a lung cancer mouse model. These results highlight a general function for HDLBP in the translation of ER-localized mRNAs and its relevance for tumor progression.
Steering the reaction pathway of syngas-to-light olefins with coordination unsaturated sites of ZnGaOx spinel
Authors: Li Na , Zhu Yifeng , Jiao Feng , Pan Xiulian , Jiang Qike , Cai Jun , Li Yifan , Tong Wei , Xu Changqi , Qu Shengcheng , Bai Bing , Miao Dengyun , Liu Zhi , Bao Xinhe
Published: May 2022

Significant progress has been demonstrated in the development of bifunctional oxide-zeolite catalyst concept to tackle the selectivity challenge in syngas chemistry. Despite general recognition on the importance of defect sites of metal oxides for CO/H2 activation, the actual structure and catalytic roles are far from being well understood. We demonstrate here that syngas conversion can be steered along a highly active and selective pathway towards light olefins via ketene-acetate (acetyl) intermediates by the surface with coordination unsaturated metal species, oxygen vacancies and zinc vacancies over ZnGaOx spinel−SAPO-34 composites. It gives 75.6% light-olefins selectivity and 49.5% CO conversion. By contrast, spinel−SAPO-34 containing only a small amount of oxygen vacancies and zinc vacancies gives only 14.9% light olefins selectivity at 6.6% CO conversion under the same condition. These findings reveal the importance to tailor the structure of metal oxides with coordination unsaturated metal sites/oxygen vacancies in selectivity control within the oxide-zeolite framework for syngas conversion and being anticipated also for CO2 hydrogenation.
Structural basis for inhibition of the Cation-chloride cotransporter NKCC1 by the diuretic drug bumetanide
Authors: Zhao Yongxiang , Roy Kasturi , Vidossich Pietro , Cancedda Laura , De Vivo Marco , Forbush Biff , Cao Erhu
Published: May 2022

Cation-chloride cotransporters (CCCs) NKCC1 and NKCC2 catalyze electroneutral symport of 1 Na+, 1 K+, and 2 Cl−across cell membranes. NKCC1 mediates trans-epithelial Cl−secretion and regulates excitability of some neurons and NKCC2 is critical to renal salt reabsorption. Both transporters are inhibited by the so-called loop diuretics including bumetanide, and these drugs are a mainstay for treating edema and hypertension. Here, our single-particle electron cryo-microscopy structures supported by functional studies reveal an outward-facing conformation of NKCC1, showing bumetanide wedged into a pocket in the extracellular ion translocation pathway. Based on these and the previously published inward-facing structures, we define the translocation pathway and the conformational changes necessary for ion translocation. We also identify an NKCC1 dimer with separated transmembrane domains and extensive transmembrane and C-terminal domain interactions. We further define an N-terminal phosphoregulatory domain that interacts with the C-terminal domain, suggesting a mechanism whereby (de)phosphorylation regulates NKCC1 by tuning the strength of this domain association.
Autophagy regulation by RNA alternative splicing and implications in human diseases
Authors: González-Rodríguez Patricia , Klionsky Daniel J. , Joseph Bertrand
Published: May 2022

Autophagy and RNA alternative splicing are two evolutionarily conserved processes involved in overlapping physiological and pathological processes. However, the extent of functional connection is not well defined. Here, we consider the role for alternative splicing and generation of autophagy-related gene isoforms in the regulation of autophagy in recent work. The impact of changes to the RNA alternative splicing machinery and production of alternative spliced isoforms on autophagy are reviewed with particular focus on disease relevance. The use of drugs targeting both alternative splicing and autophagy as well as the selective regulation of single autophagy-related protein isoforms, are considered as therapeutic strategies.
Ultra-compact snapshot spectral light-field imaging
Authors: Hua Xia , Wang Yujie , Wang Shuming , Zou Xiujuan , Zhou You , Li Lin , Yan Feng , Cao Xun , Xiao Shumin , Tsai Din Ping , Han Jiecai , Wang Zhenlin , Zhu Shining
Published: May 2022

Ideal imaging, which is constantly pursued, requires the collection of all kinds of optical information of the objects in view, such as three-dimensional spatial information (3D) including the planar distribution and depth, and the colors, i.e., spectral information (1D). Although three-dimensional spatial imaging and spectral imaging have individually evolved rapidly, their straightforward combination is a cumbersome system, severely hindering the practical applications of four-dimensional (4D) imaging. Here, we demonstrate the ultra-compact spectral light-field imaging (SLIM) by using a transversely dispersive metalens array and a monochrome imaging sensor. With only one snapshot, the SLIM presents advanced imaging with a 4 nm spectral resolution and near-diffraction-limit spatial resolution. Consequently, visually indistinguishable objects and materials can be discriminated through SLIM, which promotes significant progress towards ideal plenoptic imaging.
Towards a microwave single-photon counter for searching axions
Authors: Pankratov A. L. , Revin L. S. , Gordeeva A. V. , Yablokov A. A. , Kuzmin L. S. , Il’ichev E.
Published: May 2022

The major task of detecting axions or axion-like particles has two challenges. On the one hand, the ultimate sensitivity is required, down to the energy of a single microwave photon of the yoctojoule range. On the other hand, since the detected events are supposed to be rare, the dark count rate of the detector must be extremely low. We show that this trade-off can be approached due to the peculiar switching dynamics of an underdamped Josephson junction in the phase diffusion regime. The detection of a few photons’ energy at 10 GHz with dark count time above 10 s and the efficiency close to unity was demonstrated. Further enhancements require a detailed investigation of the junction switching dynamics.
Safety and immunogenicity of four-segmented Rift Valley fever virus in the common marmoset
Authors: Wichgers Schreur Paul J. , Mooij Petra , Koopman Gerrit , Verstrepen Babs E. , Fagrouch Zahra , Mortier Daniella , van Driel Nikki , Kant Jet , van de Water Sandra , Bogers Willy M. , Punt Carine , van Keulen Lucien , Verschoor Ernst J. , Kortekaas Jeroen
Published: May 2022

Rift Valley fever virus (RVFV) is an emerging mosquito-borne bunyavirus that is highly pathogenic to wild and domesticated ruminants, camelids, and humans. While animals are exclusively infected via mosquito bites, humans can also be infected via contact with contaminated tissues or blood. No human vaccine is available and commercialized veterinary vaccines do not optimally combine efficacy with safety. We previously reported the development of two novel live-attenuated RVF vaccines, created by splitting the M genome segment and deleting the major virulence determinant NSs. The vaccine candidates, referred to as the veterinary vaccine vRVFV-4s and the human vaccine hRVFV-4s, were shown to induce protective immunity in multiple species after a single vaccination. Anticipating accidental exposure of humans to the veterinary vaccine and the application of hRVFV-4s to humans, the safety of each vaccine was evaluated in the most susceptible nonhuman primate model, the common marmoset (Callithrix jacchus). Marmosets were inoculated with high doses of each vaccine and were monitored for clinical signs as well as for vaccine virus dissemination, shedding, and spreading to the environment. To accurately assess the attenuation of both vaccine viruses, separate groups of marmosets were inoculated with the parent wild-type RVFV strains. Both wild-type strains induced high viremia and disseminated to primary target organs, associated with mild-to-severe morbidity. In contrast, both vaccines were well tolerated with no evidence of dissemination and shedding while inducing potent neutralizing antibody responses. The results of the studies support the unprecedented safety profile of both vaccines for animals and humans.
Therapeutic efficacy of an Ad26/MVA vaccine with SIV gp140 protein and vesatolimod in ART-suppressed rhesus macaques
Authors: Ventura John D. , Nkolola Joseph P. , Chandrashekar Abishek , Borducchi Erica N. , Liu Jinyan , Mercado Noe B. , Hope David L. , Giffin Victoria M. , McMahan Katherine , Geleziunas Romas , Murry Jeffrey P. , Yang Yunling , Lewis Mark G. , Pau Maria G. , Wegmann Frank , Schuitemaker Hanneke , Fray Emily J. , Kumar Mithra R. , Siliciano Janet D. , Siliciano Robert F. , Robb Merlin L. , Michael Nelson L. , Barouch Dan H.
Published: May 2022

Developing an intervention that results in virologic control following discontinuation of antiretroviral therapy (ART) is a major objective of HIV-1 cure research. In this study, we investigated the therapeutic efficacy of a vaccine consisting of adenovirus serotype 26 (Ad26) and modified vaccinia Ankara (MVA) with or without an SIV Envelope (Env) gp140 protein with alum adjuvant in combination with the TLR7 agonist vesatolimod (GS-9620) in 36 ART-suppressed, SIVmac251-infected rhesus macaques. Ad26/MVA therapeutic vaccination led to robust humoral and cellular immune responses, and the Env protein boost increased antibody responses. Following discontinuation of ART, virologic control was observed in 5/12 animals in each vaccine group, compared with 0/12 animals in the sham control group. These data demonstrate therapeutic efficacy of Ad26/MVA vaccination with vesatolimod but no clear additional benefit of adding an Env protein boost. SIV-specific cellular immune responses correlated with virologic control. Our findings show partial efficacy of therapeutic vaccination following ART discontinuation in SIV-infected rhesus macaques.
MCM complexes are barriers that restrict cohesin-mediated loop extrusion
Authors: Dequeker Bart J. H. , Scherr Matthias J. , Brandão Hugo B. , Gassler Johanna , Powell Sean , Gaspar Imre , Flyamer Ilya M. , Lalic Aleksandar , Tang Wen , Stocsits Roman , Davidson Iain F. , Peters Jan-Michael , Duderstadt Karl E. , Mirny Leonid A. , Tachibana Kikuë
Published: May 2022

Eukaryotic genomes are compacted into loops and topologically associating domains (TADs)1–3, which contribute to transcription, recombination and genomic stability4,5. Cohesin extrudes DNA into loops that are thought to lengthen until CTCF boundaries are encountered6–12. Little is known about whether loop extrusion is impeded by DNA-bound machines. Here we show that the minichromosome maintenance (MCM) complex is a barrier that restricts loop extrusion in G1 phase. Single-nucleus Hi-C (high-resolution chromosome conformation capture) of mouse zygotes reveals that MCM loading reduces CTCF-anchored loops and decreases TAD boundary insulation, which suggests that loop extrusion is impeded before reaching CTCF. This effect extends to HCT116 cells, in which MCMs affect the number of CTCF-anchored loops and gene expression. Simulations suggest that MCMs are abundant, randomly positioned and partially permeable barriers. Single-molecule imaging shows that MCMs are physical barriers that frequently constrain cohesin translocation in vitro. Notably, chimeric yeast MCMs that contain a cohesin-interaction motif from human MCM3 induce cohesin pausing, indicating that MCMs are ‘active’ barriers with binding sites. These findings raise the possibility that cohesin can arrive by loop extrusion at MCMs, which determine the genomic sites at which sister chromatid cohesion is established. On the basis of in vivo, in silico and in vitro data, we conclude that distinct loop extrusion barriers shape the three-dimensional genome.
Limited cross-variant immunity from SARS-CoV-2 Omicron without vaccination
Authors: Suryawanshi Rahul K. , Chen Irene P. , Ma Tongcui , Syed Abdullah M. , Brazer Noah , Saldhi Prachi , Simoneau Camille R. , Ciling Alison , Khalid Mir M. , Sreekumar Bharath , Chen Pei-Yi , Kumar G. Renuka , Montano Mauricio , Gascon Ronne , Tsou Chia-Lin , Garcia-Knight Miguel A. , Sotomayor-Gonzalez Alicia , Servellita Venice , Gliwa Amelia , Nguyen Jenny , Silva Ines , Milbes Bilal , Kojima Noah , Hess Victoria , Shacreaw Maria , Lopez Lauren , Brobeck Matthew , Turner Fred , Soveg Frank W. , George Ashley F. , Fang Xiaohui , Maishan Mazharul , Matthay Michael , Morris Mary Kate , Wadford Debra , Hanson Carl , Greene Warner C. , Andino Raul , Spraggon Lee , Roan Nadia R. , Chiu Charles Y. , Doudna Jennifer A. , Ott Melanie
Published: May 2022

SARS-CoV-2 Delta and Omicron are globally relevant variants of concern. Although individuals infected with Delta are at risk of developing severe lung disease, infection with Omicron often causes milder symptoms, especially in vaccinated individuals1,2. The question arises of whether widespread Omicron infections could lead to future cross-variant protection, accelerating the end of the pandemic. Here we show that without vaccination, infection with Omicron induces a limited humoral immune response in mice and humans. Sera from mice overexpressing the human ACE2 receptor and infected with Omicron neutralize only Omicron, but not other variants of concern, whereas broader cross-variant neutralization was observed after WA1 and Delta infections. Unlike WA1 and Delta, Omicron replicates to low levels in the lungs and brains of infected animals, leading to mild disease with reduced expression of pro-inflammatory cytokines and diminished activation of lung-resident T cells. Sera from individuals who were unvaccinated and infected with Omicron show the same limited neutralization of only Omicron itself. By contrast, Omicron breakthrough infections induce overall higher neutralization titres against all variants of concern. Our results demonstrate that Omicron infection enhances pre-existing immunity elicited by vaccines but, on its own, may not confer broad protection against non-Omicron variants in unvaccinated individuals.
A compilation of fecal microbiome shotgun metagenomics from hematopoietic cell transplantation patients
Authors: Yan Jinyuan , Liao Chen , Taylor Bradford P. , Fontana Emily , Amoretti Luigi A. , Wright Roberta J. , Littmann Eric R. , Dai Anqi , Waters Nicholas , Peled Jonathan U. , Taur Ying , Perales Miguel-Angel , Siranosian Benjamin A. , Bhatt Ami S. , van den Brink Marcel R. M. , Pamer Eric G. , Schluter Jonas , Xavier Joao B.
Published: May 2022

Hospitalized patients receiving hematopoietic cell transplants provide a unique opportunity to study the human gut microbiome. We previously compiled a large-scale longitudinal dataset of fecal microbiota and associated metadata, but we had limited that analysis to taxonomic composition of bacteria from 16S rRNA gene sequencing. Here we augment those data with shotgun metagenomics. The compilation amounts to a nested subset of 395 samples compiled from different studies at Memorial Sloan Kettering. Shotgun metagenomics describes the microbiome at the functional level, particularly in antimicrobial resistances and virulence factors. We provide accession numbers that link each sample to the paired-end sequencing files deposited in a public repository, which can be directly accessed by the online services of PATRIC to be analyzed without the users having to download or transfer the files. Then, we show how shotgun sequencing enables the assembly of genomes from metagenomic data. The new data, combined with the metadata published previously, enables new functional studies of the microbiomes of patients with cancer receiving bone marrow transplantation.
Work schedule and seasonal influences on sleep and fatigue in helicopter and fixed-wing aircraft operations in extreme environments
Authors: Fletcher Adam , Stewart Simon , Heathcote Karen , Page Peter , Dorrian Jillian
Published: May 2022

Sleep and fatigue were investigated in aviation search and rescue, firefighting, emergency medical services and offshore transfer operations in 210 participants, for 21 days each, across 17 datasets in seven countries. Sleep data were collected using wrist-worn actigraphs and sleep diaries. Sustained attention was assessed using a 5-min Psychomotor Vigilance Task (PVT). Duty information was provided from corporate IT systems. Despite the number of 24 h operations, most work occurred during daytime hours, and most sleep occurred at night. There were seasonal changes in work and sleep patterns, with naps used to augment total sleep time. The proportion of sleep occurring during duty varied from zero to 30%. Differences in PVT response times were trivial to small. Legislation that defines flight, duty time and minimum rest limits assume that sleep is not obtained during duty periods, apart from some napping under Fatigue Risk Management Systems (FRMS). However, especially in cases where the aviation service requires waiting for tasks (e.g. search and rescue, emergency medical response), this assumption may not always hold. FRMS should accommodate different modes of working that safely facilitate sleep during duty time where appropriate.
Impact of Bayesian penalized likelihood reconstruction on quantitative and qualitative aspects for pulmonary nodule detection in digital 2-[18F]FDG-PET/CT
Authors: Lohaus Niklas , Enderlin Florian , Skawran Stephan , Maurer Alexander , Abukwaik Ahmad M. A. , Franzen Daniel , Huellner Martin W. , Messerli Michael
Published: May 2022

To evaluate the impact of block sequential regularized expectation maximization (BSREM) reconstruction on quantitative and qualitative aspects of 2-[18F]FDG-avid pulmonary nodules compared to conventional ordered subset expectation maximization (OSEM) reconstruction method. Ninety-one patients with 144 2-[18F]FDG-avid pulmonary nodules (all ≤ 20 mm) undergoing PET/CT for oncological (re-)staging were retrospectively included. Quantitative parameters in BSREM and OSEM (including point spread function modelling) were measured, including maximum standardized uptake value (SUVmax). Nodule conspicuity in BSREM and OSEM images was evaluated by two readers. Wilcoxon matched pairs signed-rank test was used to compare quantitative and qualitative parameters in BSREM and OSEM. Pulmonary nodule SUVmax was significantly higher in BSREM images compared to OSEM images [BSREM 5.4 (1.2–20.7), OSEM 3.6 (0.7–17.4); p = 0.0001]. In a size-based analysis, the relative increase in SUVmax was more pronounced in smaller nodules (≤ 7 mm) as compared to larger nodules (8–10 mm, or > 10 mm). Lesion conspicuity was higher in BSREM than in OSEM (p < 0.0001). BSREM reconstruction results in a significant increase in SUVmax and a significantly improved conspicuity of small 2-[18F]FDG-avid pulmonary nodules compared to OSEM reconstruction. Digital 2-[18F]FDG-PET/CT reading may be enhanced with BSREM as small lesion conspicuity is improved.
Understanding how socioeconomic inequalities drive inequalities in COVID-19 infections
Authors: Laajaj Rachid , Webb Duncan , Aristizabal Danilo , Behrentz Eduardo , Bernal Raquel , Buitrago Giancarlo , Cucunubá Zulma , de la Hoz Fernando , Gaviria Alejandro , Hernández Luis Jorge , De Los Rios Camilo , Ramírez Varela Andrea , Restrepo Silvia , Schady Norbert , Vives Martha
Published: May 2022

Across the world, the COVID-19 pandemic has disproportionately affected economically disadvantaged groups. This differential impact has numerous possible explanations, each with significantly different policy implications. We examine, for the first time in a low- or middle-income country, which mechanisms best explain the disproportionate impact of the virus on the poor. Combining an epidemiological model with rich data from Bogotá, Colombia, we show that total infections and inequalities in infections are largely driven by inequalities in the ability to work remotely and in within-home secondary attack rates. Inequalities in isolation behavior are less important but non-negligible, while access to testing and contract-tracing plays practically no role because it is too slow to contain the virus. Interventions that mitigate transmission are often more effective when targeted on socioeconomically disadvantaged groups.
Investigating meteorological/groundwater droughts by copula to study anthropogenic impacts
Authors: Sadeghfam Sina , Mirahmadi Rasa , Khatibi Rahman , Mirabbasi Rasoul , Nadiri Ata Allah
Published: May 2022

A critical understanding of the water crisis of Lake Urmia is the driver in this paper for a basin-wide investigation of its Meteorological (Met) droughts and Groundwater (GW) droughts. The challenge is to formulate a data-driven modelling strategy capable of discerning anthropogenic impacts and resilience patterns through using 21-years of monthly data records. The strategy includes: (i) transforming recorded timeseries into Met/GW indices; (ii) extracting their drought duration and severity; and (iii) deriving return periods of the maximum drought event through the copula method. The novelty of our strategy emerges from deriving return periods for Met and GW droughts and discerning anthropogenic impacts on GW droughts. The results comprise return periods for Met/GW droughts and their basin-wide spatial distributions, which are delineated into four zones. The information content of the results is statistically significant; and our interpretations hint at the basin resilience is already undermined, as evidenced by (i) subsidence problems and (ii) altering aquifers' interconnectivity with watercourses. These underpin the need for a planning system yet to emerge for mitigating impacts and rectifying their undue damages. The results discern that aquifer depletions stem from mismanagement but not from Met droughts. Already, migration from the basin area is detectable.
Antimicrobial potential and osteoblastic cell growth on electrochemically modified titanium surfaces with nanotubes and selenium or silver incorporation
Authors: Staats Kevin , Pilz Magdalena , Sun Jie , Boiadjieva-Scherzer Tzvetanka , Kronberger Hermann , Tobudic Selma , Windhager Reinhard , Holinka Johannes
Published: May 2022

Titanium nanotube surfaces containing silver, zinc, and copper have shown antimicrobial effects without decreasing osteoblastic cell growth. In this in-vitro study we present first results on the biological evaluation of surface modifications by incorporating selenium and silver compounds into titanium-dioxide (TiO2) nanotubes by electrochemical deposition. TiO2-nanotubes (TNT) and Phosphate-doped TNT (pTNT) were grown on the surface of Ti6Al4V discs by anodization. Hydroxyapatite (HA), selenium (Se) and silver (Ag) compounds were incorporated by electrochemical deposition. Colony forming units ofStaphylococcus epidermidis (DSM 3269)were significantly decreased in SepTNT (0.97 ± 0.18 × 106 CFU/mL), SepTNT-HA (1.2 ± 0.39 × 106 CFU/mL), AgpTNT (1.36 ± 0.42 × 106 CFU/mL) and Ag2SepTNT (0.999 ± 0.12 × 106 CFU/mL) compared to the non-modified control (2.2 ± 0.21 × 106 CFU/mL). Bacterial adhesion was calculated by measuring the covered area after fluorescence staining. Adhesion was lower in SepTNT (37.93 ± 12%;P = 0.004), pTNT (47.3 ± 6.3%,P = 0.04), AgpTNT (24.9 ± 1.8%;P < 0.001) and Ag2SepTNT (14.9 ± 4.9%;P < 0.001) compared to the non-modified control (73.7 ± 11%). Biofilm formation and the growth of osteoblastic cells (MG-63) was observed by using Crystal Violet staining. Biofilm formation was reduced in SepTNT (22 ± 3%,P = 0.02) and Ag2SepTNT discs (23 ± 11%,P = 0.02) compared to the non-modified control (54 ± 8%). In comparison with the non-modified control the modified SepTNT-HA and pTNT surfaces showed a significant higher covered area with osteoblastic MG-63-cells. Scanning electron microscope (SEM) images confirmed findings regarding bacterial and osteoblastic cell growth. These findings show a potential synergistic effect by combining selenium and silver with titanium nanotubes.
Generalisation effects of predictive uncertainty estimation in deep learning for digital pathology
Authors: Pocevičiūtė Milda , Eilertsen Gabriel , Jarkman Sofia , Lundström Claes
Published: May 2022

Deep learning (DL) has shown great potential in digital pathology applications. The robustness of a diagnostic DL-based solution is essential for safe clinical deployment. In this work we evaluate if adding uncertainty estimates for DL predictions in digital pathology could result in increased value for the clinical applications, by boosting the general predictive performance or by detecting mispredictions. We compare the effectiveness of model-integrated methods (MC dropout and Deep ensembles) with a model-agnostic approach (Test time augmentation, TTA). Moreover, four uncertainty metrics are compared. Our experiments focus on two domain shift scenarios: a shift to a different medical center and to an underrepresented subtype of cancer. Our results show that uncertainty estimates increase reliability by reducing a model’s sensitivity to classification threshold selection as well as by detecting between 70 and 90% of the mispredictions done by the model. Overall, the deep ensembles method achieved the best performance closely followed by TTA.
Association between health literacy and purpose in life and life satisfaction among health management specialists: a cross-sectional study
Authors: Hirooka Nobutaka , Kusano Takeru , Kinoshita Shunsuke , Aoyagi Ryutaro , Saito Kohei , Nakamoto Hidetomo
Published: May 2022

Purpose in life is anchored as a goal in national health promotion plans in several countries. Health literacy is the ability to find, understand, use, and evaluate health-related information; this ability has been investigated in terms of its effect on health outcomes and is said to play a critical role in health promotion. In the context of national health promotion, the effect of health literacy on purpose in life and life satisfaction remains unclear; therefore, this study aims to determine the effect of health literacy. A cross-sectional study was conducted on Japanese health management specialists (N = 1920). Health literacy was measured using the Communicative and Critical Health Literacy scale. Purpose in life and life satisfaction were measured using the Ikigai-9 scale and a Likert scale, respectively. We analyzed the associations between health literacy and purpose in life and life satisfaction with regression analyses. Age, sex, income, education, marital status, psychological stress, and diseases as present illness were adjusted in the statistical models. Our multiple linear regressions indicated that health literacy was significantly associated with purpose in life (β = 0.199, p < 0.001), after adjusting for covariates (age, sex, income, education, marital status, psychological factor, and disease status). Life satisfaction was also significantly associated with health literacy (β = 0.126, p < 0.001). Health literacy is associated with purpose in life and life satisfaction among specialists in health management. Health literacy plays a critical role in lifestyle-related disease prevention and health promotion. Interventions to improve health literacy may be warranted in the context of national health promotion.
Intelligent career planning via stochastic subsampling reinforcement learning
Authors: Guo Pengzhan , Xiao Keli , Ye Zeyang , Zhu Hengshu , Zhu Wei
Published: May 2022

Career planning consists of a series of decisions that will significantly impact one’s life. However, current recommendation systems have serious limitations, including the lack of effective artificial intelligence algorithms for long-term career planning, and the lack of efficient reinforcement learning (RL) methods for dynamic systems. To improve the long-term recommendation, this work proposes an intelligent sequential career planning system featuring a career path rating mechanism and a new RL method coined as the stochastic subsampling reinforcement learning (SSRL) framework. After proving the effectiveness of this new recommendation system theoretically, we evaluate it computationally by gauging it against several benchmarks under different scenarios representing different user preferences in career planning. Numerical results have demonstrated that our system is superior to other benchmarks in locating promising optimal career paths for users in long-term planning. Case studies have further revealed that our SSRL career path recommendation system would encourage people to gradually improve their career paths to maximize long-term benefits. Moreover, we have shown that the initial state (i.e., the first job) can have a significant impact, positively or negatively, on one’s career, while in the long-term view, a carefully planned career path following our recommendation system may mitigate the negative impact of a lackluster beginning in one’s career life.
10-Hz tACS over the prefrontal cortex improves phonemic fluency in healthy individuals
Authors: Sun Ya , Huang Lihui , Hua Qiaoling , Liu Qiang
Published: May 2022

Verbal fluency is an important indicator of human verbal ability. Methods to improve fluency is an interesting issue necessitating investigation. To do this, the current study required participants to randomly receive transcranial alternating current stimulation (tACS) at 10 Hz, 40 Hz (control frequency), and sham stimulation over the prefrontal cortex before a phonemic fluency task. It was found that 10-Hz tACS significantly improved phonemic fluency relative to sham stimulation. This result demonstrates the modulatory effect of 10-Hz tACS on language ability.
Inhibitory control hinders habit change
Authors: Horváth Kata , Nemeth Dezso , Janacsek Karolina
Published: May 2022

Our habits constantly influence the environment, often in negative ways that amplify global environmental and health risks. Hence, change is urgent. To facilitate habit change, inhibiting unwanted behaviors appears to be a natural human reaction. Here, we use a novel experimental design to test how inhibitory control affects two key components of changing (rewiring) habit-like behaviors in healthy humans: the acquisition of new habit-like behavior and the simultaneous unlearning of an old one. We found that, while the new behavior was acquired, the old behavior persisted and coexisted with the new. Critically, inhibition hindered both overcoming the old behavior and establishing the new one. Our findings highlight that suppressing unwanted behaviors is not only ineffective but may even further strengthen them. Meanwhile, actively engaging in a preferred behavior appears indispensable for its successful acquisition. Our design could be used to uncover how new approaches affect the cognitive basis of changing habit-like behaviors.