bluuebunny/crossref_metadata_2025 huggingface dataset:
Making friends with uncertainty: experiences of developing a transdiagnostic group intervention targeting intolerance of uncertainty in IAPT. Feasibility, acceptability and implications
Authors: Mofrad Layla , Tiplady Ashley , Payne Danielle , Freeston Mark
Published: October 2020

Co-morbid mental health diagnoses present challenges for services structured to provide disorder-specific models of treatment, such as those structured around Improving Access to Psychological Therapies (IAPT). Intolerance of uncertainty (IU) has been identified as both disorder specific and transdiagnostic, although little research explores transdiagnostic approaches to treatment of IU alone. A cognitive behavioural therapy treatment targeting IU previously established for individual therapy was adapted for a group within an IAPT primary care service: the ‘Making Friends with Uncertainty’ (MFWU) group. Twenty patients presenting with symptoms of a range of disorders including generalised anxiety disorder, obsessive compulsive disorder and depression completed the intervention in three groups. Measures of IU, anxiety and depression administered in the first and final sessions of the group have been analysed as well as examining common themes in participant feedback and facilitators’ own reflections. The results showed that nine participants (45%) showed reliable change in IU following the group and 16 (80%) showed reliable change on a measure of depression or anxiety. A thematic analysis identified universality, tolerance and acceptance and the manifestation of IU in the group process as key. The results suggest that the MFWU group provides an effective and feasible option for individuals presenting to IAPT services, including those reporting co-morbid difficulties. Implications for future practice are discussed as iteration and evaluation of the framework and content will continue.

Key learning aims

(1)

To gain an overview of a transdiagnostic model of IU.

(2)

To develop understanding of a group intervention for building tolerance to uncertainty.

(3)

To describe some group processes observed and learn from the delivery of a transdiagnostic group intervention.

(4)

To consider applications of transdiagnostic treatment in a group setting in IAPT.

(5)

To understand how to structure a group treatment for IU, and which factors to consider.
Erfolgreiche Supervision in der Psychotherapieausbildung
Authors: Maiwald Lisa Marie , Kühne Franziska , Junga Yvonne Marie , Rudolph Daniela , Witthöft Michael , Lüthke Lisa , Heid Evelyn , Weck Florian
Published: October 2020

Zusammenfassung. Theoretischer Hintergrund: Supervision fand als Forschungsgegenstand in der Kognitiven Verhaltenstherapie vergleichsweise wenig Beachtung. Fragestellung: Ziel der explorativen Studie war es, Voraussetzungen und Auswirkungen erfolgreicher Supervision zu erheben. Methode: Elf Supervisor_innen und zehn Supervisand_innen des Weiterbildungsstudiengangs Psychologische Psychotherapie (Verhaltenstherapie) wurden mittels halbstrukturierter Leitfadeninterviews befragt. Die Auswertung erfolgte anhand der qualitativen Inhaltsanalyse nach Mayring. Ergebnisse: Es wurden Personenmerkmale (z. B. Kritikfähigkeit, Offenheit, Strukturiertheit), eine tragfähige Supervisionsbeziehung (z. B. vertrauensvolle Atmosphäre) sowie Methoden (z. B. Videoanalyse) als Voraussetzungen für erfolgreiche Supervision beschrieben. Diese dienen vor allem der Förderung psychotherapeutischer Kompetenzen. Schlussfolgerung: Erfolgreiche Supervision ist strukturiert und interpersonell effektiv gestaltet. Vermutlich spielen Merkmale der Supervisand_innen (z. B. Kritikfähigkeit) eine bedeutsamere Rolle als bisher angenommen. Theoretische Annahmen stützend wurden die Auswirkungen vorwiegend in der Förderung psychotherapeutischer Kompetenzen gesehen.
Constraining Uncertainty in Projected Gross Primary Production With Machine Learning
Authors: Schlund Manuel , Eyring Veronika , Camps‐Valls Gustau , Friedlingstein Pierre , Gentine Pierre , Reichstein Markus
Published: October 2020

The terrestrial biosphere is currently slowing down global warming by absorbing about 30% of human emissions of carbon dioxide (CO2). The largest flux of the terrestrial carbon uptake is gross primary production (GPP) defined as the production of carbohydrates by photosynthesis. Elevated atmospheric CO2concentration is expected to increase GPP (“CO2fertilization effect”). However, Earth system models (ESMs) exhibit a large range in simulated GPP projections. In this study, we combine an existing emergent constraint on CO2fertilization with a machine learning approach to constrain the spatial variations of multimodel GPP projections. In a first step, we use observed changes in the CO2seasonal cycle at Cape Kumukahi to constrain the global mean GPP at the end of the 21st century (2091–2100) in Representative Concentration Pathway 8.5 simulations with ESMs participating in the Coupled Model Intercomparison Project Phase 5 (CMIP5) to 171 ± 12 Gt C yr−1, compared to the unconstrained model range of 156–247 Gt C yr−1. In a second step, we use a machine learning model to constrain gridded future absolute GPP and gridded fractional GPP change in two independent approaches. For this, observational data are fed into the machine learning algorithm that has been trained on CMIP5 data to learn relationships between present‐day physically relevant diagnostics and the target variable. In a leave‐one‐model‐out cross‐validation approach, the machine learning model shows superior performance to the CMIP5 ensemble mean. Our approach predicts an increased GPP change in northern high latitudes compared to regions closer to the equator.
Quantification of Chaotic Intrinsic Variability of Sea‐Air CO2 Fluxes at Interannual Timescales
Authors: Gehlen M. , Berthet S. , Séférian R. , Ethé Ch. , Penduff T.
Published: October 2020

Chaotic intrinsic variability (CIV) emerges spontaneously from nonlinear ocean dynamics even without any atmospheric variability. Eddy‐permitting numerical simulations suggest that CIV is a significant contributor to the interannual to decadal variability of physical properties. Here we show from an ensemble of global ocean eddy‐permitting simulations that large‐scale interannual CIV propagates from physical properties to sea‐air CO2 fluxes in areas of high mesoscale eddy activity (e.g., Southern Ocean and western boundary currents). In these regions and at scales larger than 500 km (~5°), CIV contributes significantly to the interannual variability of sea‐air CO2 fluxes. Between 35°S and 45°S (midlatitude Southern Ocean), CIV amounts to 23.76 TgC yr−1 or one half of the atmospherically forced variability. Locally, its contribution to the total interannual variance of sea‐air CO2 fluxes exceeds 76%. Outside eddy‐active regions its contribution to total interannual variability is below 16%.
Late 20th Century Indian Ocean Heat Content Gain Masked by Wind Forcing
Authors: Ummenhofer Caroline C. , Ryan Svenja , England Matthew H. , Scheinert Markus , Wagner Patrick , Biastoch Arne , Böning Claus W.
Published: October 2020

Rapid increases in upper 700‐m Indian Ocean heat content (IOHC) since the 2000s have focused attention on its role during the recent global surface warming hiatus. Here, we use ocean model simulations to assess distinct multidecadal IOHC variations since the 1960s and explore the relative contributions from wind stress and buoyancy forcing regionally and with depth. Multidecadal wind forcing counteracted IOHC increases due to buoyancy forcing from the 1960s to the 1990s. Wind and buoyancy forcing contribute positively since the mid‐2000s, accounting for the drastic IOHC change. Distinct timing and structure of upper ocean temperature changes in the eastern and western Indian Ocean are linked to the pathway how multidecadal wind forcing associated with the Interdecadal Pacific Oscillation is transmitted and affects IOHC through local and remote winds. Progressive shoaling of the equatorial thermocline—of importance for low‐frequency variations in Indian Ocean Dipole occurrence—appears to be dominated by multidecadal variations in wind forcing.
Common Mechanism for Interannual and Decadal Variability in the East African Long Rains
Authors: Walker Dean P. , Marsham John H. , Birch Cathryn E. , Scaife Adam A. , Finney Declan L.
Published: October 2020

The East African long rains constitute the main crop‐growing season in the region. Interannual predictability of this season is low in comparison to the short rains, and recent decadal drying contrasts with climate projections of a wetter future (the “East African climate paradox”). Here, we show that long rains rainfall totals are strongly correlated with 700 hPa zonal winds across the Congo basin and Gulf of Guinea (
). Westerly anomalies align with more rainfall, with the same mechanism controlling covariability on interannual and decadal time scales. On both time scales wind anomalies are linked to geopotential anomalies over the Sahel and Sahara, and warming there. Rainfall and wind are significantly correlated with the Madden‐Julian Oscillation (MJO) amplitude, and around 18% of the decadal drying can be explained by MJO amplitude variability. This work shows that predictions of East African rainfall across time scales require robust prediction of both zonal winds and MJO activity.
Turbulent Wavefield Morphology and Ion Scattering in the Magnetosheath
Authors: Chaston C. C. , Travnicek P. , Russell C. T.
Published: October 2020

We analyze multipoint measurements in magnetosheath plasmas, just upstream of the Earth's magnetopause, to investigate the morphology of the turbulent fields and coincident 3‐D ion distributions observed. Using interferometric and generalized wave polarization analyses, we show how the fields comprise a multiscale spectrum of Alfvénic structures composed of flow shears and vortices, and current sheets and filaments advected over the spacecraft with the magnetosheath flow. It is shown how these features are correlated with intervals of enhanced ion energy, temperature anisotropy, and impulsive variations in the agyrotropy of ion velocity space distributions. It is demonstrated that the observed variation in ion properties is inconsistent with an adiabatic response but is instead correlated with the spectral energy density of nonplanar structures at ion gyroradii scales. The capacity of these field structures to scatter ions is considered.
Holocene Monsoon Change and Abrupt Events on the Western Chinese Loess Plateau as Revealed by Accurately Dated Stalagmites
Authors: Tan Liangcheng , Li Yanzhen , Wang Xiqian , Cai Yanjun , Lin Fangyuan , Cheng Hai , Ma Le , Sinha Ashish , Edwards R. Lawrence
Published: October 2020

Here we present, to date, the highest‐resolved (~5 years) and most precisely dated Holocene monsoon climate reconstruction for the western Chinese Loess Plateau based on five replicated stalagmite δ18O records from Wuya Cave, eastern Gansu, China. Our record suggests the wettest period occurred between 10,500 and 6,600 a BP in this region. After this period, the amplitude of Asian summer monsoon decadal‐scale variability progressively increased likely in response to increasing ENSO frequency since the middle Holocene. Our study reveals similar asymmetric centennial‐scale double‐plunging structures of the 8.2, 5.5, and 2.8 ka events in the western Chinese Loess Plateau, suggesting a possible role of solar activity whose impact was amplified around 8.2 ka BP by the meltwater flood. In contrast, the 4.2 ka event exhibit gradually declining monsoon rainfall with centennial‐ to decadal‐scale fluctuations.
Recent Increase in Tropical Cyclone Weakening Rates Over the Western North Pacific
Authors: Song Jinjie , Klotzbach Philip J. , Duan Yihong , Guo Hongtao
Published: October 2020

This study investigates annual mean changes in 24‐h weakening rates of western North Pacific tropical cyclones (TCs) and annual number of rapid weakening (RW) events from 1982 to 2019. There is a significant increasing trend in the mean weakening rate, which correlates with a significant increase in RW number. Because stronger TCs are more likely to experience greater weakening rates and thus undergo RW, the increase in the ratio of intense TCs to all TCs can cause an increase in the weakening rate and RW frequency. Furthermore, the weakening rate and the RW number significantly increase over the region of 25°N–35°N, 120°E–150°E from 1982–2000 to 2001–2019. Over this region, there are stronger sea surface temperature gradients in more recent years, likely contributing to a higher probability of TCs undergoing RW. Other environmental variables do not exhibit significant changes. Our study highlights inhomogeneous Pacific warming that may favor RW of TCs.
Rapid Reconfiguration of the Greenland Ice Sheet Coastal Margin
Authors: Moon Twila A. , Gardner Alex S. , Csatho Beata , Parmuzin Ivan , Fahnestock Mark A.
Published: October 2020

The Greenland Ice Sheet has lost mass at an accelerating rate over the last two decades, but limits of early remote sensing restricted examination of localized change at an ice‐sheet‐wide scale. We use satellite‐derived ice sheet surface velocities, glacier terminus advance/retreat, and surface elevation change data spanning ~1985–2015 to explore local characteristics of what is now a rapid reconfiguration of the ice sheet coastal margin. Widespread glacier terminus retreat is a more consistent climate response indicator than surface velocities, though local velocity patterns provide indicators of ice flow reconfiguration, including narrowing zones of fast‐flow, ice flow rerouting, and outlet abandonment. The implications of this observed rapid reconfiguration are wide ranging and likely include alteration of subglacial hydrology, iceberg discharge, liquid freshwater flux, potential nutrient and sediment flux, and mass flux. Without detailed observations of earlier deglaciations and with present limits on ice sheet model capabilities, these observational records provide an important analogue for past deglaciation and for projecting future ice loss.
Evaluation of an angiotensin Type 1 receptor blocker on the reconsolidation of fear memory
Authors: Swiercz Adam P. , Iyer Laxmi , Yu Zhe , Edwards Allison , Prashant N. M. , Nguyen Bryan N. , Horvath Anelia , Marvar Paul J.
Published: October 2020

Inhibition of the angiotensin type 1 receptor (AT1R) has been shown to decrease fear responses in both humans and rodents. These effects are attributed to modulation of extinction learning, however the contribution of AT1R to alternative memory processes remains unclear. Using classic Pavlovian conditioning combined with radiotelemetry and whole-genome RNA sequencing, we evaluated the effects of the AT1R antagonist losartan on fear memory reconsolidation. Following the retrieval of conditioned auditory fear memory, animals were given a single intraperitoneal injection of losartan or saline. In response to the conditioned stimulus (CS), losartan-treated animals exhibited significantly less freezing at 24 h and 1 week; an effect that was dependent upon memory reactivation and independent of conditioned cardiovascular reactivity. Using an unbiased whole-genome RNA sequencing approach, transcriptomic analysis of the basolateral amygdala (BLA) identified losartan-dependent differences in gene expression during the reconsolidation phase. These findings demonstrate that post-retrieval losartan modifies behavioral and transcriptomic markers of conditioned fear memory, supporting an important regulatory role for this receptor in reconsolidation and as a potential pharmacotherapeutic target for maladaptive fear disorders such as PTSD.
Early expansion of myeloid-derived suppressor cells inhibits SARS-CoV-2 specific T-cell response and may predict fatal COVID-19 outcome
Authors: Sacchi Alessandra , Grassi Germana , Bordoni Veronica , Lorenzini Patrizia , Cimini Eleonora , Casetti Rita , Tartaglia Eleonora , Marchioni Luisa , Petrosillo Nicola , Palmieri Fabrizio , D’Offizi Gianpiero , Notari Stefania , Tempestilli Massimo , Capobianchi Maria Rosaria , Nicastri Emanuele , Maeurer Markus , Zumla Alimuddin , Locatelli Franco , Antinori Andrea , Ippolito Giuseppe , Agrati Chiara
Published: October 2020

The immunological mechanisms underlying the clinical presentation of SARS-CoV-2 infection and those influencing the disease outcome remain to be defined. Myeloid-derived suppressor cells (MDSC) have been described to be highly increased during COVID-19, however, their role remains elusive. We performed an in depth analysis of MDSC in 128 SARS-CoV-2 infected patients. Polymorphonuclear (PMN)-MDSC expanded during COVID-19, in particular in patients who required intensive care treatments, and correlated with IL-1β, IL-6, IL-8, and TNF-α plasma levels. PMN-MDSC inhibited T-cells IFN-γ production upon SARS-CoV-2 peptides stimulation, through TGF-β- and iNOS-mediated mechanisms, possibly contrasting virus elimination. Accordingly, a multivariate regression analysis found a strong association between PMN-MDSC percentage and fatal outcome of the disease. The PMN-MDSC frequency was higher in non-survivors than survivors at the admission time, followed by a decreasing trend. Interestingly, this trend was associated with IL-6 increase in non-survivors but not in survivors. In conclusion, this study indicates PMN-MDSC as a novel factor in the pathogenesis of SARS-CoV2 infection, and open up to new therapeutic options.
The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress
Authors: Coates James T. T. , Rodriguez-Berriguete Gonzalo , Puliyadi Rathi , Ashton Thomas , Prevo Remko , Wing Archie , Granata Giovanna , Pirovano Giacomo , McKenna Gillies W. , Higgins Geoff S.
Published: October 2020

Platinum chemotherapies are highly effective cytotoxic agents but often induce resistance when used as monotherapies. Combinatorial strategies limit this risk and provide effective treatment options for many cancers. Here, we repurpose atovaquone (ATQ), a well-tolerated & FDA-approved anti-malarial agent by demonstrating that it potentiates cancer cell death of a subset of platinums. We show that ATQ in combination with carboplatin or cisplatin induces striking and repeatable concentration- and time-dependent cell death sensitization in vitro across a variety of cancer cell lines. ATQ induces mitochondrial reactive oxygen species (mROS), depleting intracellular glutathione (GSH) pools in a concentration-dependent manner. The superoxide dismutase mimetic MnTBAP rescues ATQ-induced mROS production and pre-loading cells with the GSH prodrug N-acetyl cysteine (NAC) abrogates the sensitization. Together, these findings implicate ATQ-induced oxidative stress as key mediator of the sensitizing effect. At physiologically achievable concentrations, ATQ and carboplatin furthermore synergistically delay the growth of three-dimensional avascular spheroids. Clinically, ATQ is a safe and specific inhibitor of the electron transport chain (ETC) and is concurrently being repurposed as a candidate tumor hypoxia modifier. Together, these findings suggest that ATQ is deserving of further study as a candidate platinum sensitizing agent.
Trichohyalin-like 1 protein plays a crucial role in proliferation and anti-apoptosis of normal human keratinocytes and squamous cell carcinoma cells
Authors: Makino Teruhiko , Mizawa Megumi , Yoshihisa Yoko , Yamamoto Seiji , Tabuchi Yoshiaki , Miyai Masashi , Hibino Toshihiko , Sasahara Masakiyo , Shimizu Tadamichi
Published: October 2020

Epidermal differentiation is a complex process that requires the regulated and sequential expression of various genes. Most fused-type S100 proteins are expressed in the granular layer and it is hypothesized that these proteins may be associated with cornification and barrier formation. We previously identified a member of the fused-type S100 proteins, Trichohyalin-like 1 (TCHHL1) protein. TCHHL1 is distributed in the basal layer of the normal epidermis. Furthermore, the expression is markedly increased in cancerous/non-cancerous skin samples with the hyperproliferation of keratinocytes. We herein examined the role of TCHHL1 in normal human keratinocytes (NHKs) and squamous cell carcinoma (SCC). The knockdown of TCHHL1 by transfection with TCHHL1 siRNA significantly inhibited proliferation and induced the early apoptosis of NHKs. In TCHHL1-knockdown NHKs, the level of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was markedly decreased. In addition, the slight inhibition of v-akt murine thymoma viral oncogene homolog (AKT) phosphorylation and upregulation of forkhead box-containing protein O1(FOXO1), B-cell lymphoma2 (BCL2) and Bcl2-like protein 11 (BCL2L11) was observed. Skin-equivalent models built by TCHHL1-knockdown NHKs showed a markedly hypoplastic epidermis. These findings highlight that TCHHL1 plays an important role in homeostasis of the normal epidermis. TCHHL1 was expressed in the growing cells of cutaneous SCC; therefore, we next examined an association with the cell growth in HSC-1 cells (a human SCC line). In HSC-1 cells, the knockdown of TCHHL1 also suppressed cell proliferation and induced apoptosis. These cells showed an inhibition of phosphorylation of ERK1/2, AKT and signal transducers and activator of transcription 3, and the significant upregulation of FOXO1, BCL2, and BCL2L11. Accordingly, TCHHL1 is associated with survival of cutaneous SCC. In addition, we hypothesize that TCHHL1 may be a novel therapeutic target in cutaneous SCC.
Towards a global-scale soil climate mitigation strategy
Authors: Amelung W. , Bossio D. , de Vries W. , Kögel-Knabner I. , Lehmann J. , Amundson R. , Bol R. , Collins C. , Lal R. , Leifeld J. , Minasny B. , Pan G. , Paustian K. , Rumpel C. , Sanderman J. , van Groenigen J. W. , Mooney S. , van Wesemael B. , Wander M. , Chabbi A.
Published: October 2020

Sustainable soil carbon sequestration practices need to be rapidly scaled up and implemented to contribute to climate change mitigation. We highlight that the major potential for carbon sequestration is in cropland soils, especially those with large yield gaps and/or large historic soil organic carbon losses. The implementation of soil carbon sequestration measures requires a diverse set of options, each adapted to local soil conditions and management opportunities, and accounting for site-specific trade-offs. We propose the establishment of a soil information system containing localised information on soil group, degradation status, crop yield gap, and the associated carbon-sequestration potentials, as well as the provision of incentives and policies to translate management options into region- and soil-specific practices.
Global warming due to loss of large ice masses and Arctic summer sea ice
Authors: Wunderling Nico , Willeit Matteo , Donges Jonathan F. , Winkelmann Ricarda
Published: October 2020

Several large-scale cryosphere elements such as the Arctic summer sea ice, the mountain glaciers, the Greenland and West Antarctic Ice Sheet have changed substantially during the last century due to anthropogenic global warming. However, the impacts of their possible future disintegration on global mean temperature (GMT) and climate feedbacks have not yet been comprehensively evaluated. Here, we quantify this response using an Earth system model of intermediate complexity. Overall, we find a median additional global warming of 0.43 °C (interquartile range: 0.39−0.46 °C) at a CO2 concentration of 400 ppm. Most of this response (55%) is caused by albedo changes, but lapse rate together with water vapour (30%) and cloud feedbacks (15%) also contribute significantly. While a decay of the ice sheets would occur on centennial to millennial time scales, the Arctic might become ice-free during summer within the 21st century. Our findings imply an additional increase of the GMT on intermediate to long time scales.
Capturing human categorization of natural images by combining deep networks and cognitive models
Authors: Battleday Ruairidh M. , Peterson Joshua C. , Griffiths Thomas L.
Published: October 2020

Human categorization is one of the most important and successful targets of cognitive modeling, with decades of model development and assessment using simple, low-dimensional artificial stimuli. However, it remains unclear how these findings relate to categorization in more natural settings, involving complex, high-dimensional stimuli. Here, we take a step towards addressing this question by modeling human categorization over a large behavioral dataset, comprising more than 500,000 judgments over 10,000 natural images from ten object categories. We apply a range of machine learning methods to generate candidate representations for these images, and show that combining rich image representations with flexible cognitive models captures human decisions best. We also find that in the high-dimensional representational spaces these methods generate, simple prototype models can perform comparably to the more complex memory-based exemplar models dominant in laboratory settings.
Genetically engineered magnetic nanocages for cancer magneto-catalytic theranostics
Authors: Zhang Yang , Wang Xiaoyong , Chu Chengchao , Zhou Zijian , Chen Biaoqi , Pang Xin , Lin Gan , Lin Huirong , Guo Yuxin , Ren En , Lv Peng , Shi Yesi , Zheng Qingbing , Yan Xiaohui , Chen Xiaoyuan , Liu Gang
Published: October 2020

The clinical applications of magnetic hyperthermia therapy (MHT) have been largely hindered by the poor magnetic-to-thermal conversion efficiency of MHT agents. Herein, we develop a facile and efficient strategy for engineering encapsulin-produced magnetic iron oxide nanocomposites (eMIONs) via a green biomineralization procedure. We demonstrate that eMIONs have excellent magnetic saturation and remnant magnetization properties, featuring superior magnetic-to-thermal conversion efficiency with an ultrahigh specific absorption rate of 2390 W/g to overcome the critical issues of MHT. We also show that eMIONs act as a nanozyme and have enhanced catalase-like activity in the presence of an alternative magnetic field, leading to tumor angiogenesis inhibition with a corresponding sharp decrease in the expression of HIF-1α. The inherent excellent magnetic-heat capability, coupled with catalysis-triggered tumor suppression, allows eMIONs to provide an MRI-guided magneto-catalytic combination therapy, which may open up a new avenue for bench-to-bed translational research of MHT.
Dispersion state phase diagram of citrate-coated metallic nanoparticles in saline solutions
Authors: Franco-Ulloa Sebastian , Tatulli Giuseppina , Bore Sigbjørn Løland , Moglianetti Mauro , Pompa Pier Paolo , Cascella Michele , De Vivo Marco
Published: October 2020

The fundamental interactions underlying citrate-mediated chemical stability of metal nanoparticles, and their surface characteristics dictating particle dispersion/aggregation in aqueous solutions, are largely unclear. Here, we developed a theoretical model to estimate the stoichiometry of small, charged ligands (like citrate) chemisorbed onto spherical metallic nanoparticles and coupled it with atomistic molecular dynamics simulations to define the uncovered solvent-accessible surface area of the nanoparticle. Then, we integrated coarse-grained molecular dynamics simulations and two-body free energy calculations to define dispersion state phase diagrams for charged metal nanoparticles in a range of medium’s ionic strength, a known trigger for aggregation. Ultraviolet-visible spectroscopy experiments of citrate-capped nanocolloids validated our predictions and extended our results to nanoparticles up to 35 nm. Altogether, our results disclose a complex interplay between the particle size, its surface charge density, and the ionic strength of the medium, which ultimately clarifies how these variables impact colloidal stability.
Circulating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma
Authors: Escudero Laura , Llort Anna , Arias Alexandra , Diaz-Navarro Ander , Martínez-Ricarte Francisco , Rubio-Perez Carlota , Mayor Regina , Caratù Ginevra , Martínez-Sáez Elena , Vázquez-Méndez Élida , Lesende-Rodríguez Iván , Hladun Raquel , Gros Luis , Ramón y Cajal Santiago , Poca Maria A. , Puente Xose S. , Sahuquillo Juan , Gallego Soledad , Seoane Joan
Published: October 2020

The molecular characterisation of medulloblastoma, the most common paediatric brain tumour, is crucial for the correct management and treatment of this heterogenous disease. However, insufficient tissue sample, the presence of tumour heterogeneity, or disseminated disease can challenge its diagnosis and monitoring. Here, we report that the cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) recapitulates the genomic alterations of the tumour and facilitates subgrouping and risk stratification, providing valuable information about diagnosis and prognosis. CSF ctDNA also characterises the intra-tumour genomic heterogeneity identifying small subclones. ctDNA is abundant in the CSF but barely present in plasma and longitudinal analysis of CSF ctDNA allows the study of minimal residual disease, genomic evolution and the characterisation of tumours at recurrence. Ultimately, CSF ctDNA analysis could facilitate the clinical management of medulloblastoma patients and help the design of tailored therapeutic strategies, increasing treatment efficacy while reducing excessive treatment to prevent long-term secondary effects.
Impact of wet-dry cycling on the phase behavior and compartmentalization properties of complex coacervates
Authors: Fares Hadi M. , Marras Alexander E. , Ting Jeffrey M. , Tirrell Matthew V. , Keating Christine D.
Published: October 2020

Wet-dry cycling on the early Earth is thought to have facilitated production of molecular building blocks of life, but its impact on self-assembly and compartmentalization remains largely unexplored. Here, we investigate dehydration/rehydration of complex coacervates, which are membraneless compartments formed by phase separation of polyelectrolyte solutions. Solution compositions are identified for which tenfold water loss results in maintenance, disappearance, or appearance of coacervate droplets. Systems maintaining coacervates throughout the dehydration process are further evaluated to understand how their compartmentalization properties change with drying. Although added total RNA concentrations increase tenfold, RNA concentration within coacervates remains steady. Exterior RNA concentrations rise, and exchange rates for encapsulated versus free RNAs increase with dehydration. We explain these results in light of the phase diagram, with dehydration-driven ionic strength increase being particularly important in determining coacervate properties. This work shows that wet-dry cycling can alter the phase behavior and protocell-relevant functions of complex coacervates.
Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s
Authors: Oba Takaaki , Long Mark D. , Keler Tibor , Marsh Henry C. , Minderman Hans , Abrams Scott I. , Liu Song , Ito Fumito
Published: October 2020

The ability of cancer cells to ensure T-cell exclusion from the tumor microenvironment is a significant mechanism of resistance to anti-PD-1/PD-L1 therapy. Evidence indicates crucial roles of Batf3-dependent conventional type-1 dendritic cells (cDC1s) for inducing antitumor T-cell immunity; however, strategies to maximize cDC1 engagement remain elusive. Here, using multiple orthotopic tumor mouse models resistant to anti-PD-L1-therapy, we are testing the hypothesis that in situ induction and activation of tumor-residing cDC1s overcomes poor T-cell infiltration. In situ immunomodulation with Flt3L, radiotherapy, and TLR3/CD40 stimulation induces an influx of stem-like Tcf1+ Slamf6+ CD8+ T cells, triggers regression not only of primary, but also untreated distant tumors, and renders tumors responsive to anti-PD-L1 therapy. Furthermore, serial in situ immunomodulation (ISIM) reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, and establishes tumor-specific immunological memory. These findings provide new insights into cDC1 biology as a critical determinant to overcome mechanisms of intratumoral T-cell exclusion.
Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression
Authors: Yee Patricia P. , Wei Yiju , Kim Soo-Yeon , Lu Tong , Chih Stephen Y. , Lawson Cynthia , Tang Miaolu , Liu Zhijun , Anderson Benjamin , Thamburaj Krishnamoorthy , Young Megan M. , Aregawi Dawit G. , Glantz Michael J. , Zacharia Brad E. , Specht Charles S. , Wang Hong-Gang , Li Wei
Published: October 2020

Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.
Modeling early stage atherosclerosis in a primary human vascular microphysiological system
Authors: Zhang Xu , Bishawi Muath , Zhang Ge , Prasad Varun , Salmon Ellen , Breithaupt Jason J. , Zhang Qiao , Truskey George A.
Published: October 2020

Novel atherosclerosis models are needed to guide clinical therapy. Here, we report an in vitro model of early atherosclerosis by fabricating and perfusing multi-layer arteriole-scale human tissue-engineered blood vessels (TEBVs) by plastic compression. TEBVs maintain mechanical strength, vasoactivity, and nitric oxide (NO) production for at least 4 weeks. Perfusion of TEBVs at a physiological shear stress with enzyme-modified low-density-lipoprotein (eLDL) with or without TNFα promotes monocyte accumulation, reduces vasoactivity, alters NO production, which leads to endothelial cell activation, monocyte accumulation, foam cell formation and expression of pro-inflammatory cytokines. Removing eLDL leads to recovery of vasoactivity, but not loss of foam cells or recovery of permeability, while pretreatment with lovastatin or the P2Y11inhibitor NF157 reduces monocyte accumulation and blocks foam cell formation. Perfusion with blood leads to increased monocyte adhesion. This atherosclerosis model can identify the role of drugs on specific vascular functions that cannot be assessed in vivo.
Flow-induced order–order transitions in amyloid fibril liquid crystalline tactoids
Authors: Almohammadi Hamed , Bagnani Massimo , Mezzenga Raffaele
Published: October 2020

Liquid crystalline droplets, also known as tactoids, forming by nucleation and growth within the phase diagram region where isotropic and nematic phases coexist, challenge our understanding of liquid crystals under confinement due to anisotropic surface boundaries at vanishingly small interfacial tension, resulting in complex, non-spherical shapes. Little is known about their dynamical properties, since they are mostly studied under quiescent, quasi-equilibrium conditions. Here we show that different classes of amyloid based nematic and cholesteric tactoids undergo order–order transitions by flow-induced deformations of their shape. Tactoids align under extensional flow, undergoing extreme deformation into highly elongated prolate shapes, with the cholesteric pitch decreasing as an inverse power-law of the tactoids aspect ratio. Free energy functional theory and experimental measurements are combined to rationalize the critical elongation above which the director-field configuration of tactoids transforms from bipolar and uniaxial cholesteric to homogenous and to debate on the thermodynamic nature of these transitions.
Force-clamp spectroscopy identifies a catch bond mechanism in a Gram-positive pathogen
Authors: Mathelié-Guinlet Marion , Viela Felipe , Pietrocola Giampiero , Speziale Pietro , Alsteens David , Dufrêne Yves F.
Published: October 2020

Physical forces have profound effects on cellular behavior, physiology, and disease. Perhaps the most intruiguing and fascinating example is the formation of catch-bonds that strengthen cellular adhesion under shear stresses. Today mannose-binding by the Escherichia coli FimH adhesin remains one of the rare microbial catch-bond thoroughly characterized at the molecular level. Here we provide a quantitative demonstration of a catch-bond in living Gram-positive pathogens using force-clamp spectroscopy. We show that the dock, lock, and latch interaction between staphylococcal surface protein SpsD and fibrinogen is strong, and exhibits an unusual catch-slip transition. The bond lifetime first grows with force, but ultimately decreases to behave as a slip bond beyond a critical force (~1 nN) that is orders of magnitude higher than for previously investigated complexes. This catch-bond, never reported for a staphylococcal adhesin, provides the pathogen with a mechanism to tightly control its adhesive function during colonization and infection.
A protein tertiary structure mimetic modulator of the Hippo signalling pathway
Authors: Adihou Hélène , Gopalakrishnan Ranganath , Förster Tim , Guéret Stéphanie M. , Gasper Raphael , Geschwindner Stefan , Carrillo García Carmen , Karatas Hacer , Pobbati Ajaybabu V. , Vazquez‐Chantada Mercedes , Davey Paul , Wassvik Carola M. , Pang Jeremy Kah Sheng , Soh Boon Seng , Hong Wanjin , Chiarparin Elisabetta , Schade Dennis , Plowright Alleyn T. , Valeur Eric , Lemurell Malin , Grossmann Tom N. , Waldmann Herbert
Published: October 2020

Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein–protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but hampered by the difficulties associated with the targeting of PPIs, in particular when extended and flat protein interfaces are involved. Peptidomimetics have been applied to inhibit PPIs, however with variable success, as for certain interfaces the mimicry of a single secondary structure element is insufficient to obtain high binding affinities. Here, we describe the design and characterization of a stabilized protein tertiary structure that acts as an inhibitor of the interaction between the transcription factor TEAD and its co-repressor VGL4, both playing a central role in the Hippo signalling pathway. Modification of the inhibitor with a cell-penetrating entity yielded a cell-permeable proteomimetic that activates cell proliferation via regulation of the Hippo pathway, highlighting the potential of protein tertiary structure mimetics as an emerging class of PPI modulators.
Local community assembly mechanisms shape soil bacterial β diversity patterns along a latitudinal gradient
Authors: Zhang Xiao , Liu Shirong , Wang Jingxin , Huang Yongtao , Freedman Zachary , Fu Shenglei , Liu Kuan , Wang Hui , Li Xiangzhen , Yao Minjie , Liu Xiaojing , Schuler Jamie
Published: October 2020

Biodiversity patterns across geographical gradients could result from regional species pool and local community assembly mechanisms. However, little has been done to separate the effects of local ecological mechanisms from variation in the regional species pools on bacterial diversity patterns. In this study, we compare assembly mechanisms of soil bacterial communities in 660 plots from 11 regions along a latitudinal gradient in eastern China with highly divergent species pools. Our results show that β diversity does not co-vary with γ diversity, and local community assembly mechanisms appear to explain variation in β diversity patterns after correcting for variation in regional species pools. The variation in environmental conditions along the latitudinal gradient accounts for the variation in β diversity through mediating the strength of heterogeneous selection. In conclusion, our study clearly illustrates the importance of local community assembly processes in shaping geographical patterns of soil bacterial β diversity.
Disease burden and clinical severity of the first pandemic wave of COVID-19 in Wuhan, China
Authors: Yang Juan , Chen Xinhua , Deng Xiaowei , Chen Zhiyuan , Gong Hui , Yan Han , Wu Qianhui , Shi Huilin , Lai Shengjie , Ajelli Marco , Viboud Cecile , Yu Prof Hongjie
Published: October 2020

The novel coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, where the initial wave of intense community transmissions was cut short by interventions. Using multiple data sources, here we estimate the disease burden and clinical severity by age of COVID-19 in Wuhan from December 1, 2019 to March 31, 2020. Our estimates account for the sensitivity of the laboratory assays, prospective community screenings, and healthcare seeking behaviors. Rates of symptomatic cases, medical consultations, hospitalizations and deaths were estimated at 796 (95% CI: 703–977), 489 (472–509), 370 (358–384), and 36.2 (35.0–37.3) per 100,000 persons, respectively. The COVID-19 outbreak in Wuhan had a higher burden than the 2009 influenza pandemic or seasonal influenza in terms of hospitalization and mortality rates, and clinical severity was similar to that of the 1918 influenza pandemic. Our comparison puts the COVID-19 pandemic into context and could be helpful to guide intervention strategies and preparedness for the potential resurgence of COVID-19.
Structure of human steroid 5α-reductase 2 with the anti-androgen drug finasteride
Authors: Xiao Qingpin , Wang Lei , Supekar Shreyas , Shen Tao , Liu Heng , Ye Fei , Huang Junzhou , Fan Hao , Wei Zhiyi , Zhang Cheng
Published: October 2020

Human steroid 5α-reductase 2 (SRD5A2) is an integral membrane enzyme in steroid metabolism and catalyzes the reduction of testosterone to dihydrotestosterone. Mutations in theSRD5A2gene have been linked to 5α-reductase deficiency and prostate cancer. Finasteride and dutasteride, as SRD5A2 inhibitors, are widely used antiandrogen drugs for benign prostate hyperplasia. The molecular mechanisms underlying enzyme catalysis and inhibition for SRD5A2 and other eukaryotic integral membrane steroid reductases remain elusive due to a lack of structural information. Here, we report a crystal structure of human SRD5A2 at 2.8 Å, revealing a unique 7-TM structural topology and an intermediate adduct of finasteride and NADPH as NADP-dihydrofinasteride in a largely enclosed binding cavity inside the transmembrane domain. Structural analysis together with computational and mutagenesis studies reveal the molecular mechanisms of the catalyzed reaction and of finasteride inhibition involving residues E57 and Y91. Molecular dynamics simulation results indicate high conformational dynamics of the cytosolic region that regulate NADPH/NADP+exchange. Mapping disease-causing mutations of SRD5A2 to our structure suggests molecular mechanisms for their pathological effects. Our results offer critical structural insights into the function of integral membrane steroid reductases and may facilitate drug development.
Origin of rebound virus in chronically SIV-infected Rhesus monkeys following treatment discontinuation
Authors: Liu Po-Ting , Keele Brandon F. , Abbink Peter , Mercado Noe B. , Liu Jinyan , Bondzie Esther A. , Chandrashekar Abishek , Borducchi Erica N. , Hesselgesser Joseph , Mish Michael , Chin Gregory , Bekerman Elena , Geleziunas Romas , Barouch Dan H.
Published: October 2020

Viral rebound following antiretroviral therapy (ART) discontinuation in HIV-1-infected individuals is believed to originate from a small pool of CD4+ T cells harboring replication-competent provirus. However, the origin and nature of the rebound virus has remained unclear. Recent studies have suggested that rebound virus does not originate directly from individual latent proviruses but rather from recombination events involving multiple proviruses. Here we evaluate the origin of rebound virus in 16 ART-suppressed, chronically SIV-infected rhesus monkeys following ART discontinuation. We sequence viral RNA and viral DNA in these animals prior to ART initiation, during ART suppression, and following viral rebound, and we compare rebound viral RNA after ART discontinuation with near full-length viral DNA from peripheral blood and lymph node mononuclear cells (PBMC and LNMC) during ART suppression. Sequences of initial rebound viruses closely match viral DNA sequences in PBMC and LNMC during ART suppression. Recombinant viruses are rare in the initial rebound virus populations but arise quickly within 2–4 weeks after viral rebound. These data suggest that intact proviral DNA in PBMC and LNMC during ART suppression is likely the direct origin of viral rebound in chronically SIV-infected rhesus monkeys following ART discontinuation.
Maternal DNMT3A-dependent de novo methylation of the paternal genome inhibits gene expression in the early embryo
Authors: Richard Albert Julien , Au Yeung Wan Kin , Toriyama Keisuke , Kobayashi Hisato , Hirasawa Ryutaro , Brind’Amour Julie , Bogutz Aaron , Sasaki Hiroyuki , Lorincz Matthew
Published: October 2020

De novo DNA methylation (DNAme) during mammalian spermatogenesis yields a densely methylated genome, with the exception of CpG islands (CGIs), which are hypomethylated in sperm. While the paternal genome undergoes widespread DNAme loss before the first S-phase following fertilization, recent mass spectrometry analysis revealed that the zygotic paternal genome is paradoxically also subject to a low level of de novo DNAme. However, the loci involved, and impact on transcription were not addressed. Here, we employ allele-specific analysis of whole-genome bisulphite sequencing data and show that a number of genomic regions, including several dozen CGI promoters, are de novo methylated on the paternal genome by the 2-cell stage. A subset of these promoters maintains DNAme through development to the blastocyst stage. Consistent with paternal DNAme acquisition, many of these loci are hypermethylated in androgenetic blastocysts but hypomethylated in parthenogenetic blastocysts. Paternal DNAme acquisition is lost following maternal deletion of Dnmt3a, with a subset of promoters, which are normally transcribed from the paternal allele in blastocysts, being prematurely transcribed at the 4-cell stage in maternal Dnmt3a knockout embryos. These observations uncover a role for maternal DNMT3A activity in post-fertilization epigenetic reprogramming and transcriptional silencing of the paternal genome.
Publisher Correction: CryoEM structure of the type IVa pilus secretin required for natural competence in Vibrio cholera
Authors: Weaver Sara J. , Ortega Davi R. , Sazinsky Matthew H. , Dalia Triana N. , Dalia Ankur B. , Jensen Grant J.
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: Genome-wide translational profiling of amygdala Crh-expressing neurons reveals role for CREB in fear extinction learning
Authors: McCullough Kenneth M. , Chatzinakos Chris , Hartmann Jakob , Missig Galen , Neve Rachael L. , Fenster Robert J. , Carlezon William A. , Daskalakis Nikolaos P. , Ressler Kerry J.
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.