bluuebunny/crossref_metadata_2025 huggingface dataset:
The functional cooperation of 5-HT1A and mGlu4R in HEK-293 cell line
Authors: Burnat Grzegorz , Brański Piotr , Solich Joanna , Kolasa Magdalena , Chruścicka Barbara , Dziedzicka-Wasylewska Marta , Pilc Andrzej
Published: May 2020

Background

The serotonin 5-HT1A receptor (5-HT1AR) and metabotropic glutamate receptor 4 (mGlu4) have been implicated as sites of antipsychotic drug action. 5-HT1AR belongs to the A class of G protein-coupled receptors (GPCRs); mGlu4 is a representative of class C GPCRs. Both receptors preferentially couple with Gi protein to inhibit cAMP formation. The present work aimed to examine the possibility of mGlu4 and 5-HT1A receptor cross-talk, the phenomenon that could serve as a molecular basis of the interaction of these receptor ligands observed in behavioral studies.

Methods

First, in vitro studies were performed to examine the pharmacological modulation of interaction of the mGlu4 and 5-HT1A receptors in the T-REx 293 cell line using SNAP- or HALO–tag and cAMP accumulation assay. Next, the colocalization of these two receptors was examined in some regions of the mouse brain by applying RNAScope dual fluorescence in situ hybridization, immunohistochemical labeling, and proximity ligation assay (PLA).

Results

The ex vivo and in vitro results obtained in the present work suggest the existence of interactions between mGlu4 and 5-HT1A receptors. The changes were observed in cAMP accumulation assay and were dependent on expression and activation of mGlu4R in T-REx 293cell line. Moreover, the existence of spots with proximity expression of both receptors were showed by PLA, immunofluorescence labeling and RNAscope methods.

Conclusion

The existence of interactions between mGlu4 and 5-HT1A receptors may represent another signaling pathway involved in the development and treatment psychiatric disorders such as schizophrenia or depression.
Statistical stability of mostly expanding diffeomorphisms
Authors: Vásquez Carlos H. , Andersson Martin
Published: May 2020

We study how physical measures vary with the underlying dynamics in the open class of

C^{r}

,

r > 1

, strong partially hyperbolic diffeomorphisms for which the central Lyapunov exponents of every Gibbs

u

-state is positive. If transitive, such a diffeomorphism has a unique physical measure that persists and varies continuously with the dynamics.

A main ingredient in the proof is a new Pliss-like Lemma which, under the right circumstances, yields frequency of hyperbolic times close to one. Another novelty is the introduction of a new characterization of Gibbs

cu

-states. Both of these may be of independent interest.

The non-transitive case is also treated: here the number of physical measures varies upper semi-continuously with the diffeomorphism, and physical measures vary continuously whenever possible.

Nous étudions comment les mesures physiques varient avec la dynamique sous-jacente, dans la classe ouverte des difféomorphismes

C^{r}

,

r > 1

, fortement partiellement hyperboliques pour lesquelles les exposants de Lyapunov centraux de tout

u

-état de Gibbs sont positifs. Lorsque transitifs, de tels difféomorphismes possédent une unique mesure physique qui persiste et varie continûment avec la dynamique.

Un des ingrédients principaux de la preuve est un nouveau lemme de type Pliss qui, appliqué dans le contexte adéquat, implique que la fréquence des temps hyperboliques est proche de un. Une autre nouveauté est l'introduction d'une nouvelle caractérisation des

cu

-états de Gibbs. Chacun de ses deux aspects ayant leur propre intérêt.

Le cas non transitif est aussi traité : dans ce contexte, le nombre de mesures physiques est une fonction semi-continue supérieure du difféomorphisme, et les mesures physiques varient continûment sous des hypothèses naturelles.
A 3600-year record of drought in southern Pacific Costa Rica
Authors: Taylor Zachary P. , Lane Chad S. , Horn Sally. P.
Published: May 2020

We analyzed the δ2H composition ofn-alkanes isolated from Laguna Zoncho, a small lake in southern Pacific Costa Rica, to reconstruct paleohydrology. Using a core that spans the past 3600 years, we found evidence of dry periods, most notably during the Terminal Classic Drought (TCD; ~1200 cal yr BP) and the Little Ice Age (~400 cal yr BP). Previous work at Laguna Zoncho, using bulk sedimentary δ13C and geochemical analysis, found that agriculture began to decline during the TCD. Our δ2H records confirm the occurrence of arid conditions coincident with the TCD at Laguna Zoncho and show that, despite receiving more than 3000 mm of precipitation per year, this region is susceptible to multidecadal droughts.
Management of diet in gastrointestinal cancer
Authors: Shaw Clare
Published: May 2020

Nutrition and gastrointestinal cancer are inextricably linked. The metabolic effects of cancer along with changes in dietary intake, the development of cancer cachexia and the presence of sarcopenia can influence changes in body composition. These have a negative impact on quality of life and tolerance to cancer treatment. Treatment for cancer presents some significant nutritional challenges as nutrition impact symptoms may develop, be exacerbated by treatment and may contribute to a worsening in nutritional status. Nutrition screening and assessment should be an integral part of holistic patient care. The provision of appropriate, evidence-based dietary advice should occur before, during and after cancer treatment. Appropriate and timely methods of nutritional support across the spectrum of gastrointestinal cancer are needed to ensure that people are adequately supported during courses of treatment that can span weeks and months. These can range from standard approaches of supplementing oral intake to complex interventions such as managing high output intestinal stomas. The gastrointestinal tract is particularly susceptible to impact from systemic anti-cancer treatments and radiotherapy. Gastrointestinal late effects of cancer treatment are now recognised to present particular challenges in terms of both medical and nutritional management. These late effects have a significant impact on the individual and their quality of life in addition to implications for the health service. Dietary intake following cancer treatment has an impact on quality of life and future research may demonstrate its influence on the risk of recurrence of gastrointestinal cancer.
Effect of theTc13Tul antigen fromTrypanosoma cruzion splenocytes fromnaïvemice
Authors: Tasso Laura Mónica , Bruballa Andrea Cecilia , Garavaglia Patricia Andrea , Esteva Mónica Inés , Albareda María Cecilia , García Gabriela Andrea
Published: May 2020

Trypanosoma cruzi, the etiological agent of Chagas disease, releases factors, including antigens from thetrans-sialidase (TS) superfamily, which modulate the host immune responses.Tc13 antigens belong to group IV of TSs and are characterized by C-terminal EPKSA repeats. Here, we studied the effect of theTc13 antigen from the Tulahuén strain,Tc13Tul, on primary cultures of splenocytes fromnaïveBALB/c mice. RecombinantTc13Tul increased the percentage of viable cells and induced B (CD19+) lymphocyte proliferation.Tc13Tul stimulation also induced secretion of non-specific IgM and interferon-γ(IFN-γ). The same effects were induced byTc13Tul on splenocytes fromnaïveC3H/HeJ mice.In vivoadministration ofTc13Tul tonaïveBALB/c mice increased non-specific IgG in sera. In addition,in vitrocultured splenocytes fromTc13Tul-inoculated mice secreted a higher basal level of non-specific IgM than controls and thein vitro Tc13Tul stimulation of these cells showed an enhanced effect on IgM and IFN-γsecretion. Our results indicate thatTc13Tul may participate in the early immunity inT. cruziinfection by favouring immune system evasion through B-cell activation and non-specific Ig secretion. In contrast, as IFN-γis an important factor involved inT. cruziresistance, this may be considered aTc13Tul effect in favour of the host.
Expert Knowledge by Perception
Authors: Ransom Madeleine
Published: May 2020

Does the scope of beliefs that people can form on the basis of perception remain fixed, or can it be amplified with learning? The answer to this question is important for our understanding of why and when we ought to trust experts, and also for assessing the plausibility of epistemic foundationalism. The empirical study of perceptual expertise suggests that experts can indeed enrich their perceptual experiences through learning. Yet this does not settle the epistemic status of their beliefs. One might hold that the background knowledge of experts is the cause of their enriched perceptual experience – what is known as cognitive permeation – and so their subsequent beliefs are only mediately justified because they are epistemically dependent on this background knowledge. I argue against this view. Perceptual expertise is not the result of cognitive permeation but is rather the result of perceptual learning, and perceptual learning does not involve cognition in a way that entails cognitive permeation. Perceptual expertise thus provides a means of widening the scope of the immediately justified beliefs that experts can form.
There is No (Sui Generis) Norm of Assertion
Authors: Greenberg Alexander
Published: May 2020

There are norms on action and norms on assertion. That is, there are things we should and shouldn't do, and things we should and shouldn't say. How do these two kinds of norm relate? Are norms on assertion reducible to norms on action? Many philosophers think they are not. These philosophers claim there is a sui generis norm specific to assertion, a norm which is also often claimed to be constitutive of assertion. Both claims, I argue, should be rejected. The phenomenon claimed to support them – the intuitive wrongness of certain assertions – does not in fact support them. Because assertion is an action, the wrongness of assertions can be explained purely by norms on action. And the specifically epistemic wrongness an assertion norm is typically supposed to explain can be explained by an uncontroversial norm on action: one shouldn't act on epistemically faulty beliefs. No additional sui generis norm on assertion is needed.
Motivational and cognitive factors linked to community integration in homeless veterans: Study 2 – clinically diverse sample
Authors: Wynn Jonathan K. , Gabrielian Sonya , Hellemann Gerhard , Horan William P. , Kern Robert S. , Lee Junghee , Marder Stephen R. , Sugar Catherine A. , Green Michael F.
Published: May 2020

Background

In an initial study (Study 1), we found that motivation predicted community integration (i.e. functional recovery) 12 months after receiving housing in formerly homeless Veterans with a psychotic disorder. The current study examined whether the same pattern would be found in a broader, more clinically diverse, homeless Veteran sample without psychosis.

Methods

We examined four categories of variables as potential predictors of community integration in non-psychotic Veterans: perception, non-social cognition, social cognition, and motivation at baseline (after participants were engaged in a permanent supported housing program but before receiving housing) and a 12-month follow-up. A total of 82 Veterans had a baseline assessment and 41 returned for testing after 12 months.

Results

The strongest longitudinal association was between an interview-based measure of motivation (the motivation and pleasure subscale from the Clinical Assessment Interview for Negative Symptoms) at baseline and measures of social integration at 12 months. In addition, cross-lagged panel analyses were consistent with a causal influence of general psychiatric symptoms at baseline driving social integration at 12 months, and reduced expressiveness at baseline driving independent living at 12 months, but there were no significant causal associations with measures of motivation.

Conclusions

The findings from this study complement and reinforce those in Veterans with psychosis. Across these two studies, our findings suggest that motivational factors are associated at baseline and at 12 months and are particularly important for understanding and improving community integration in recently-housed Veterans across psychiatric diagnoses.
Impact of Dispatcher-Assisted Bystander Cardiopulmonary Resuscitation with Out-of-Hospital Cardiac Arrest: A Systemic Review and Meta-Analysis
Authors: Wang Junhong , Zhang Hua , Zhao Zongxuan , Wen Kaifeng , Xu Yaoke , Wang Daidai , Ma Qingbian
Published: May 2020

Objective:

This systemic review and meta-analysis was conducted to explore the impact of dispatcher-assisted bystander cardiopulmonary resuscitation (DA-BCPR) on bystander cardiopulmonary resuscitation (BCPR) probability, survival, and neurological outcomes with out-of-hospital cardiac arrest (OHCA).

Methods:

Electronically searching of PubMed, Embase, and Cochrane Library, along with manual retrieval, were done for clinical trials about the impact of DA-BCPR which were published from the date of inception to December 2018. The literature was screened according to inclusion and exclusion criteria, the baseline information, and interested outcomes were extracted. Two reviewers assessed the methodological quality of the included studies. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated by STATA version 13.1.

Results:

In 13 studies, 235,550 patients were enrolled. Compared with no dispatcher instruction, DA-BCPR tended to be effective in improving BCPR rate (I2 = 98.2%; OR = 5.84; 95% CI, 4.58-7.46; P <.01), return of spontaneous circulation (ROSC) before admission (I2 = 36.0%; OR = 1.17; 95% CI, 1.06-1.29; P <.01), discharge or 30-day survival rate (I2 = 47.7%; OR = 1.25; 95% CI, 1.06-1.46; P <.01), and good neurological outcome (I2 = 30.9%; OR = 1.24; 95% CI, 1.04-1.48; P = .01). However, no significant difference in hospital admission was found (I2 = 29.0%; OR = 1.09; 95% CI, 0.91-1.30; P = .36).

Conclusion:

This review shows DA-BPCR plays a positive role for OHCA as a critical section in the life chain. It is effective in improving the probability of BCPR, survival, ROSC before admission, and neurological outcome.
Household food insecurity: associations with disordered eating behaviours and overweight in a population-based sample of adolescents
Authors: Hooper Laura , Telke Susan , Larson Nicole , Mason Susan M , Neumark-Sztainer Dianne
Published: May 2020

Objective:

To examine how household food insecurity is related to adolescent weight status and disordered eating.

Design:

Cross-sectional, population-based study. Adolescents self-reported unhealthy weight control behaviours, binge eating and meal frequency; weight status was measured. Household food insecurity was assessed by asking parents to respond to the validated six-item US Household Food Security Survey Module.

Setting:

Adolescents surveyed within Minneapolis/St. Paul public middle and high schools completed surveys at school, and their parents/guardians were surveyed by mail during the 2009–2010 academic year.

Participants:

Ethnically/racially diverse, primarily low-income adolescents (mean age: 14·4 years, range: 10–22 years) and their parents/guardians (n2285 dyads).

Results:

More than one-third (38·9 %) of the adolescents experienced past-year household food insecurity, 43·2 % reported disordered eating and 39·6 % were overweight. Generalised regression models showed that food insecure (FI) compared with food secure (FS) adolescents had higher prevalence of overweight (FI: 42·3 %v. FS: 37·9 %,P= 0·039), lower breakfast consumption (FI: 4·1 times/weekv. FS: 4·4 times/week,P= 0·005) and greater use of unhealthy weight control behaviours (FI: 49·0 %v. FS: 39·5 %,P< 0·001) in unadjusted models. Models adjusted for parental education, ethnicity/race, sex and age found that food insecurity was associated with higher prevalence of unhealthy weight control behaviours (FI: 44·5 %v. FS: 37·8 %,P= 0·007), but not with weight status or other eating behaviours.

Conclusions:

These results suggest that food insecurity may be an independent risk factor for unhealthy weight control behaviours, indicating a need to approach these intersecting issues in a comprehensive manner.
Radar for projectile impact on granular media
Authors: Rech Felix , Huang Kai
Published: May 2020

From the prevention of natural disasters such as landslide and avalanches, to the enhancement of energy efficiencies in chemical and civil engineering industries, understanding the collective dynamics of granular materials is a fundamental question that are closely related to our daily lives. Using a recently developed multi-static radar system operating at 10 GHz (X-band), we explore the possibility of tracking a projectile moving inside a granular medium, focusing on possible sources of uncertainties in the detection and reconstruction processes. On the one hand, particle tracking with continuous-wave radar provides an extremely high temporal resolution. On the other hand, there are still challenges in obtaining tracer trajectories accurately. We show that some of the challenges can be resolved through a correction of the IQ mismatch in the raw signals obtained. Consequently, the tracer trajectories can be obtained with sub-millimeter spatial resolution. Such an advance can not only shed light on radar particle tracking, but also on a wide range of scenarios where issues relevant to IQ mismatch arise.
Control Strategies and Daily Affect
Authors: Knoll Nina , Keller Jan , Luszczynska Aleksandra , Scholz Urte , Röcke Christina , Schrader Mark , Heckhausen Jutta
Published: May 2020

Abstract. Adjusting strategies to manage daily goal pursuit with new functional limitations may impact not only the affect of patients, but also that of their partners. Associations between patients’ control strategies and both partners’ affect were examined at the onset of patients’ incontinence following prostatectomy. Eight-day diary data from 180 heterosexual couples were used to fit two-level models. In patients, investing personal resources to keep up goal pursuit despite incontinence (selective primary control) was associated with better affect, particularly when incontinence was pronounced. Yet, partners’ decreased negative affect coincided with patients’ asking for help and using technical aids (compensatory primary control) when the incontinence was severe. Patients and partners may benefit from different control strategies used by patients, especially when their functional limitations are pronounced.
Social‐Environmental Extremes: Rethinking Extraordinary Events as Outcomes of Interacting Biophysical and Social Systems
Authors: Balch Jennifer K. , Iglesias Virginia , Braswell Anna E. , Rossi Matthew W. , Joseph Maxwell B. , Mahood Adam L. , Shrum Trisha R. , White Caitlin T. , Scholl Victoria M. , McGuire Bryce , Karban Claire , Buckland Mollie , Travis William R.
Published: May 2020

Extreme droughts, heat waves, fires, hurricanes, floods, and landslides cause the largest losses in the United States, and globally, from natural hazards linked to weather and climate. There is evidence that the frequency of such extremes is increasing, particularly for heat waves, large fires, and intense precipitation, making better understanding of the probability and consequences of these events imperative. Further, these events are not isolated, but rather interact with each other and with other social and biophysical drivers and conditions, to amplify impacts. Less is known about the nature and strength of these interactions. Natural and social science subfields frame extreme events with different definitions and analytical approaches, often neglecting interactions and the subsequent novel extremes that can arise. Here we propose a framework for social‐environmental extremes, defined as extraordinary events that emerge from interactions among biophysical and social systems. We argue that this definition is critical because it constrains the focus to major events that are capturing societal and scientific attention because of their extreme biophysical drivers and/or the extreme social outcomes. We review how different fields approach extremes as interacting phenomena and propose a synthetic framework that allows analytical separation of the multiple drivers and responses that yield extreme events and extreme effects. We conclude with a future research agenda for understanding the extreme events that matter to society. This agenda will help to identify where, when, and why communities may have high exposure and vulnerability to social‐environmental extremes—informing future mitigation and adaptation strategies.
The Observed Seasonal Cycle of Submesoscale Processes in the Antarctic Marginal Ice Zone
Authors: Biddle L. C. , Swart S.
Published: May 2020

Submesoscale flows are energetic processes in the upper ocean that occur at scales of a few kilometers. These phenomena are important to climate because they can strongly impact vertical motions of heat, carbon, and biogeochemical properties between the surface and deep ocean. Their presence and magnitude are poorly understood in the Antarctic marginal ice zone (MIZ) and under sea ice due to a lack of observations. We present tagged southern elephant seal hydrographic data from the eastern Weddell Sea, over the austral late summer to spring in 2008, to assess the magnitude and seasonality of submesoscale processes in the Antarctic MIZ. We consider the linkages between sea ice cover, ocean stress variability, and mixed layer depth and how these influence the submesoscale fluxes. We find that there is a strong seasonal cycle in the magnitude of the equivalent heat flux from submesoscale flows (240 Wm−2), with peak activity occurring in midwinter. Periods of increased variability in sea ice cover, likely associated with leads, are also linked to restratification through submesoscale fluxes in midwinter. These findings have implications for understanding the magnitude and variability of upper ocean stratification and therefore highlights the importance of developing parameterizations for submesoscale processes in the Antarctic MIZ within global climate models.
Erythemal Radiation, Column Ozone, and the North American Monsoon
Authors: Schoeberl M. R. , Pfister L. , Wang T. , Kummer J. , Dessler A. E. , Yu W.
Published: May 2020

Recently, Anderson et al. (2012, https://doi.org/10.1126/science.1222978, 2017, https://doi.org/10.1073/pnas.1619318114) and Anderson and Clapp (2018, https://doi.org/10.1039/C7CP08331A) proposed that summertime convectively injected water vapor over North America could lead to stratospheric ozone depletion through halogenic catalytic reactions. Such ozone loss would reduce the ozone column and increase erythemal daily dose (EDD). Using 10 years of observations over the North American monsoon region from the Aura Ozone Monitoring Instrument, we find that the column ozone and EDD has a ~0.8–0.9 spatial correlation with lower stratospheric water vapor measured by the Aura Microwave Limb Sounder. We show that this correlation appears to be due to the elevation of the monsoonal tropopause and associated monsoonal convection. The increase in tropopause altitude reduces the ozone column and increases EDD. We see no apparent evidence of substantial heterogeneous chemical ozone loss in lower stratospheric ozone coincident with the stratospheric monsoonal water vapor enhancement.
Gaussian Process Regression for Estimating EM Ducting Within the Marine Atmospheric Boundary Layer
Authors: Sit Hilarie , Earls Christopher J.
Published: May 2020

We show that Gaussian process regression (GPR) can be used to infer the electromagnetic (EM) duct height within the marine atmospheric boundary layer (MABL) from sparsely sampled propagation factors within the context of bistatic radars. We use GPR to calculate the posterior predictive distribution on the labels (i.e., duct height) from both noise‐free and noise‐contaminated array of propagation factors. For duct height inference from noise‐contaminated propagation factors, we compare a naïve approach, utilizing one random sample from the input distribution (i.e., disregarding the input noise), with an inverse‐variance weighted approach, utilizing a few random samples to estimate the true predictive distribution. The resulting posterior predictive distributions from these two approaches are compared to a “ground truth” distribution, which is approximated using a large number of Monte‐Carlo samples. The ability of GPR to yield accurate and fast duct height predictions using a few training examples indicates the suitability of the proposed method for real‐time applications.
Evaluation of EAR Spaced Antenna Performance Using Multiple Receiving Antennas Orientations
Authors: Aris N. A. M. , Hashiguchi H. , Yamamoto M.
Published: May 2020

Equatorial Atmosphere Radar (EAR) is a very high frequency (VHF) Doppler radar with an active phased array antenna system operating at 47 MHz. It had originally been equipped with a single receiving channel system since its establishment in 2001 at the equator in Kototabang, West Sumatra, Indonesia (0.20°S, 100.32°E). Recent progress has enabled the implementation of a spaced antenna (SA) method on the EAR through the development of a multichannel receiver using Universal Software Radio Peripheral (USRP) and GNU Radio. However, this approach exhibits limited height observation and horizontal wind estimation accuracy. Here, we present comparison and analysis of EAR SA performance with five different orientations, taking into consideration the size of the receiving antennas and their separation distance. Experiments with the chosen configurations were carried out between April and September 2019, and the horizontal wind profiles were estimated using full correlation analysis (FCA) and compared with the EAR standard data. In addition, FCA with the least squares method is carried out for all configurations with the aim of improving the estimation accuracy. Based on the results, the configuration with the largest aperture shows a clear advantage over the other four configurations but with limited improvement in terms of maximum observable height.
The RCAN1.4-calcineurin/NFAT signaling pathway is essential for hypoxic adaption of intervertebral discs
Authors: Huang Bao , He Yongqing , Li Shengwen , Wei Xiaoan , Liu Junhui , Shan Zhi , Huang Yue , Chen Jian , Zhao Fengdong
Published: May 2020

Calcipressin-1, also known as regulator of calcineurin 1 (RCAN1), can specifically bind calcineurin at or near the calcineurin A catalytic domain and downregulate calcineurin activity. However, whether RCAN1 affects the hypoxic intervertebral disc (IVD) phenotype through the calcineurin/NFAT signaling pathway remains unclear. First, we confirmed the characteristics of the degenerative nucleus pulposus (NP) by H&E, safranin O/fast green and Alcian blue staining, and detected increased RCAN1 levels in the degenerative NP by immunohistochemistry. Then, we demonstrated that the protein level of RCAN1.4 was higher than that of RCAN1.1 and progressively elevated from the control group to the Pfirrmann grade V group. In vitro, both hypoxia (1% O2) and overexpression of HIF-1α reduced the protein level of RCAN1.4 in rat NP cells in a dose- and time-dependent manner. We further found that miRNA-124, through a nondegradative pathway (without the proteasome or lysosome), suppressed the expression of RCAN1.4. As expected, calcineurin in NP cells was activated and primarily promoted nuclear translocation of NFATc1 under hypoxia or RCAN1.4 siRNA transfection. Furthermore, SOX9, type II collagen and MMP13 were elevated under hypoxia, RCAN1.4 siRNA transfection or NFATc1 overexpression. Using chromatin immunoprecipitation (ChIP) and a luciferase reporter assay (with mutation), we clarified that NFATc1 increasingly bound the SOX9 promotor region (bp −367~−357). Interaction of HIF-1α and NFATc1 promoted MMP13 transcription. Finally, we found that FK506 reversed hypoxia-induced activation of the calcineurin/NFAT signaling pathway in NP cells and an ex vivo model. Together, these findings show that the RCAN1.4-calcineurin/NFAT signaling pathway has a vital role in the hypoxic phenotype of NP cells. RCAN1.4 might be a therapeutic target for degenerative disc diseases.
Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer
Authors: Chopra Neha , Tovey Holly , Pearson Alex , Cutts Ros , Toms Christy , Proszek Paula , Hubank Michael , Dowsett Mitch , Dodson Andrew , Daley Frances , Kriplani Divya , Gevensleben Heidi , Davies Helen Ruth , Degasperi Andrea , Roylance Rebecca , Chan Stephen , Tutt Andrew , Skene Anthony , Evans Abigail , Bliss Judith M. , Nik-Zainal Serena , Turner Nicholas C.
Published: May 2020

Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.
A genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity
Authors: Ginno Paul Adrian , Gaidatzis Dimos , Feldmann Angelika , Hoerner Leslie , Imanci Dilek , Burger Lukas , Zilbermann Frederic , Peters Antoine H. F. M. , Edenhofer Frank , Smallwood Sébastien A. , Krebs Arnaud R. , Schübeler Dirk
Published: May 2020

DNA methylation is considered a stable epigenetic mark, yet methylation patterns can vary during differentiation and in diseases such as cancer. Local levels of DNA methylation result from opposing enzymatic activities, the rates of which remain largely unknown. Here we developed a theoretical and experimental framework enabling us to infer methylation and demethylation rates at 860,404 CpGs in mouse embryonic stem cells. We find that enzymatic rates can vary as much as two orders of magnitude between CpGs with identical steady-state DNA methylation. Unexpectedly, de novo and maintenance methylation activity is reduced at transcription factor binding sites, while methylation turnover is elevated in transcribed gene bodies. Furthermore, we show that TET activity contributes substantially more than passive demethylation to establishing low methylation levels at distal enhancers. Taken together, our work unveils a genome-scale map of methylation kinetics, revealing highly variable and context-specific activity for the DNA methylation machinery.
Human ESCRT-III polymers assemble on positively curved membranes and induce helical membrane tube formation
Authors: Bertin Aurélie , de Franceschi Nicola , de la Mora Eugenio , Maity Sourav , Alqabandi Maryam , Miguet Nolwen , di Cicco Aurélie , Roos Wouter H. , Mangenot Stéphanie , Weissenhorn Winfried , Bassereau Patricia
Published: May 2020

Endosomal sorting complexes for transport-III (ESCRT-III) assemble in vivo onto membranes with negative Gaussian curvature. How membrane shape influences ESCRT-III polymerization and how ESCRT-III shapes membranes is yet unclear. Human core ESCRT-III proteins, CHMP4B, CHMP2A, CHMP2B and CHMP3 are used to address this issue in vitro by combining membrane nanotube pulling experiments, cryo-electron tomography and AFM. We show that CHMP4B filaments preferentially bind to flat membranes or to tubes with positive mean curvature. Both CHMP2B and CHMP2A/CHMP3 assemble on positively curved membrane tubes. Combinations of CHMP4B/CHMP2B and CHMP4B/CHMP2A/CHMP3 are recruited to the neck of pulled membrane tubes and reshape vesicles into helical “corkscrew-like” membrane tubes. Sub-tomogram averaging reveals that the ESCRT-III filaments assemble parallel and locally perpendicular to the tube axis, highlighting the mechanical stresses imposed by ESCRT-III. Our results underline the versatile membrane remodeling activity of ESCRT-III that may be a general feature required for cellular membrane remodeling processes.
Weaker neural suppression in autism
Authors: Schallmo Michael-Paul , Kolodny Tamar , Kale Alexander M. , Millin Rachel , Flevaris Anastasia V. , Edden Richard A. E. , Gerdts Jennifer , Bernier Raphael A. , Murray Scott O.
Published: May 2020

Abnormal sensory processing has been observed in autism, including superior visual motion discrimination, but the neural basis for these sensory changes remains unknown. Leveraging well-characterized suppressive neural circuits in the visual system, we used behavioral and fMRI tasks to demonstrate a significant reduction in neural suppression in young adults with autism spectrum disorder (ASD) compared to neurotypical controls. MR spectroscopy measurements revealed no group differences in neurotransmitter signals. We show how a computational model that incorporates divisive normalization, as well as narrower top-down gain (that could result, for example, from a narrower window of attention), can explain our observations and divergent previous findings. Thus, weaker neural suppression is reflected in visual task performance and fMRI measures in ASD, and may be attributable to differences in top-down processing.
Lipid Nanoparticle Formulation Increases Efficiency of DNA-Vectored Vaccines/Immunoprophylaxis in Animals Including Transchromosomic Bovines
Authors: Mucker Eric M. , Karmali Priya P. , Vega Jerel , Kwilas Steven A. , Wu Hua , Joselyn Matthew , Ballantyne John , Sampey Darryl , Mukthavaram Rajesh , Sullivan Eddie , Chivukula Pad , Hooper Jay W.
Published: May 2020

The use of nucleic acid as a drug substance for vaccines and other gene-based medicines continues to evolve. Here, we have used a technology originally developed for mRNA in vivo delivery to enhance the immunogenicity of DNA vaccines. We demonstrate that neutralizing antibodies produced in rabbits and nonhuman primates injected with lipid nanoparticle (LNP)-formulated Andes virus or Zika virus DNA vaccines are elevated over unformulated vaccine. Using a plasmid encoding an anti-poxvirus monoclonal antibody (as a reporter of protein expression), we showed that improved immunogenicity is likely due to increased in vivo DNA delivery, resulting in more target protein. Specifically, after four days, up to 30 ng/mL of functional monoclonal antibody were detected in the serum of rabbits injected with the LNP-formulated DNA. We pragmatically applied the technology to the production of human neutralizing antibodies in a transchromosomic (Tc) bovine for use as a passive immunoprophylactic. Production of neutralizing antibody was increased by >10-fold while utilizing 10 times less DNA in the Tc bovine. This work provides a proof-of-concept that LNP formulation of DNA vaccines can be used to produce more potent active vaccines, passive countermeasures (e.g., Tc bovine), and as a means to produce more potent DNA-launched immunotherapies.
Colorectal cancer is associated with increased circulating lipopolysaccharide, inflammation and hypercoagulability
Authors: de Waal Greta M. , de Villiers Willem J. S. , Forgan Timothy , Roberts Timothy , Pretorius Etheresia
Published: May 2020

Gut dysbiosis contributes to the development of a dysfunctional gut barrier, facilitating the translocation of bacteria and inflammagens, and is implicated in colorectal cancer (CRC) pathogenesis. Such ‘leaky gut’ conditions result in systemic inflammation, of which a hallmark is increased hypercoagulability. Fluorescence antibody confocal microscopy was used to determine circulating levels of lipopolysaccharide (LPS) in control and CRC populations. Here we showed that circulating levels of LPS are significantly elevated in the CRC population. We also showed that markers of inflammation and hypercoagulability are increased in this population. Furthermore, anomalous blood clotting and structural changes in blood components are presented. Importantly, the association between LPS levels, inflammation, and hematological dysfunction was analysed. Statistical regression models were applied to identify markers with strong association with CRC, and to investigate the correlation between markers. A core aim is enhanced biomarker discovery for CRC. We conclude that circulating LPS can promote systemic inflammation and contribute to the development of a pathological coagulation system, with resulting chronic inflammation and an activated coagulation system implicated in tumorigenesis. Blood-based screening tools are an emerging research area of interest for CRC screening. We propose the use of additional (novel) biomarkers to effectively screen for CRC.
Soluble HLA-G expression levels and HLA-G/irinotecan association in metastatic colorectal cancer treated with irinotecan-based strategy
Authors: Scarabel Lucia , Garziera Marica , Fortuna Sara , Asaro Fioretta , Toffoli Giuseppe , Geremia Silvano
Published: May 2020

We here explore the soluble Human Leukocyte Antigen-G (sHLA-G) expression level as clinical biomarker in metastatic colorectal cancer (mCRC). To this aim the sHLA-G protein was measured in plasma samples of 40 patients with mCRC treated with the FOLFIRI (irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and leucovorin (LV)) regimen. The results suggest a link between HLA-G levels and irinotecan (CPT-11) pharmacokinetic, leading to hypothesize a molecular interaction between sHLA-G and CPT-11. This interaction was confirmed experimentally by fluorescence spectroscopy. HLA-G is known to exist in a number of polymorphs that affect both the protein expression levels and its peptide-binding cleft. The interaction between HLA-G polymorphs and CPT-11 was explored by means of computational modelling, confirming the hypothesis that CPT-11 could actually target the peptide binding cleft of the most common HLA-G polymorphs.
BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes
Authors: Adriaenssens Elias , Tedesco Barbara , Mediani Laura , Asselbergh Bob , Crippa Valeria , Antoniani Francesco , Carra Serena , Poletti Angelo , Timmerman Vincent
Published: May 2020

Three missense mutations targeting the same proline 209 (Pro209) codon in the co-chaperone Bcl2-associated athanogene 3 (BAG3) have been reported to cause distal myopathy, dilated cardiomyopathy or Charcot-Marie-Tooth type 2 neuropathy. Yet, it is unclear whether distinct molecular mechanisms underlie the variable clinical spectrum of the rare patients carrying these three heterozygous Pro209 mutations in BAG3. Here, we studied all three variants and compared them to the BAG3_Glu455Lys mutant, which causes dilated cardiomyopathy. We found that all BAG3_Pro209 mutants have acquired a toxic gain-of-function, which causes these variants to accumulate in the form of insoluble HDAC6- and vimentin-positive aggresomes. The aggresomes formed by mutant BAG3 led to a relocation of other chaperones such as HSPB8 and Hsp70, which, together with BAG3, promote the so-called chaperone-assisted selective autophagy (CASA). As a consequence of their increased aggregation-proneness, mutant BAG3 trapped ubiquitinylated client proteins at the aggresome, preventing their efficient clearance. Combined, these data show that all BAG3_Pro209 mutants, irrespective of their different clinical phenotypes, are characterized by a gain-of-function that contributes to the gradual loss of protein homeostasis.
Cold climate adaptation is a plausible cause for evolution of multicellular sporulation in Dictyostelia
Authors: Lawal Hajara M. , Schilde Christina , Kin Koryu , Brown Matthew W. , James John , Prescott Alan R. , Schaap Pauline
Published: May 2020

Unicellular protozoa that encyst individually upon starvation evolved at least eight times into organisms that instead form multicellular fruiting bodies with spores. The Dictyostelia are the largest and most complex group of such organisms. They can be subdivided into 4 major groups, with many species in groups 1–3 having additionally retained encystment. To understand fitness differences between spores and cysts, we measured long-term survival of spores and cysts under climate-mimicking conditions, investigated spore and cyst ultrastructure, and related fitness characteristics to species ecology. We found that spores and cysts survived 22 °C equally well, but that spores survived wet and dry frost better than cysts, with group 4 spores being most resilient. Spore walls consist of three layers and those of cysts of maximally two, while spores were also more compacted than cysts, with group 4 spores being the most compacted. Group 4 species were frequently isolated from arctic and alpine zones, which was rarely the case for group 1–3 species. We inferred a fossil-calibrated phylogeny of Dictyostelia, which showed that its two major branches diverged 0.52 billion years ago, following several global glaciations. Our results suggest that Dictyostelium multicellular sporulation was a likely adaptation to a cold climate.
Exercise efficiency impairment in metabolic myopathies
Authors: Noury Jean-Baptiste , Zagnoli Fabien , Petit François , Marcorelles Pascale , Rannou Fabrice
Published: May 2020

Metabolic myopathies are muscle disorders caused by a biochemical defect of the skeletal muscle energy system resulting in exercise intolerance. The primary aim of this research was to evaluate the oxygen cost (∆V’O2/∆Work-Rate) during incremental exercise in patients with metabolic myopathies as compared with patients with non-metabolic myalgia and healthy subjects. The study groups consisted of eight patients with muscle glycogenoses (one Tarui and seven McArdle diseases), seven patients with a complete and twenty-two patients with a partial myoadenylate deaminase (MAD) deficiency in muscle biopsy, five patients with a respiratory chain deficiency, seventy-three patients with exercise intolerance and normal muscle biopsy (non-metabolic myalgia), and twenty-eight healthy controls. The subjects underwent a cardiopulmonary exercise test (CPX Medgraphics) performed on a bicycle ergometer. Pulmonary V’O2 was measured breath-by-breath throughout the incremental test. The ∆V’O2/∆Work-Rate slope for exercise was determined by linear regression analysis. Lower oxygen consumption (peak percent of predicted, mean ± SD; p < 0.04, one-way ANOVA) was seen in patients with glycogenoses (62.8 ± 10.2%) and respiratory chain defects (70.8 ± 23.3%) compared to patients with non-metabolic myalgia (100.0 ± 15.9%) and control subjects (106.4 ± 23.5%). ∆V’O2/∆Work-Rate slope (mLO2.min−1.W−1) was increased in patients with MAD absent (12.6 ± 1.5), MAD decreased (11.3 ± 1.1), glycogenoses (14.0 ± 2.5), respiratory chain defects (13.1 ± 1.2), and patients with non-metabolic myalgia (11.3 ± 1.3) compared with control subjects (10.2 ± 0.7; p < 0.001, one-way ANOVA). In conclusion, patients with metabolic myopathies display an increased oxygen cost during exercise and therefore can perform less work for a given VO2 consumption during daily life-submaximal exercises.
Author Correction: Water molecular structure underpins extreme desiccation tolerance of the resurrection plant Haberlea rhodopensis
Authors: Kuroki Shinichiro , Tsenkova Roumiana , Moyankova Daniela , Muncan Jelena , Morita Hiroyuki , Atanassova Stefka , Djilianov Dimitar
Published: May 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
A mouse model that is immunologically tolerant to reporter and modifier proteins
Authors: Bresser Kaspar , Dijkgraaf Feline E. , Pritchard Colin E. J. , Huijbers Ivo J. , Song Ji-Ying , Rohr Jan C. , Scheeren Ferenc A. , Schumacher Ton N.
Published: May 2020

Reporter proteins have become an indispensable tool in biomedical research. However, exogenous introduction of these reporters into mice poses a risk of rejection by the immune system. Here, we describe the generation, validation and application of a multiple reporter protein tolerant ‘Tol' mouse model that constitutively expresses an assembly of shuffled reporter proteins from a single open reading frame. We demonstrate that expression of the Tol transgene results in the deletion of CD8+ T cells specific for a model epitope, and substantially improves engraftment of reporter-gene transduced T cells. The Tol strain provides a valuable mouse model for cell transfer and viral-mediated gene transfer studies, and serves as a methodological example for the generation of poly-tolerant mouse strains.
Framework with cytoskeletal actin filaments forming insect footpad hairs inspires biomimetic adhesive device design
Authors: Kimura Ken-ichi , Minami Ryunosuke , Yamahama Yumi , Hariyama Takahiko , Hosoda Naoe
Published: May 2020

Footpads allow insects to walk on smooth surfaces. Specifically, liquid secretions on the footpad mediate adhesiveness through Van der Waals, Coulomb, and attractive capillary forces. Although the morphology and function of the footpad are well defined, the mechanism underlying their formation remains elusive. Here, we demonstrate that footpad hair in Drosophila is formed by the elongation of the hair cells and assembly of actin filaments. Knockdown of Actin5C caused a malformation of the hair structure, resulting in reduced ability to adhere to smooth substrates. We determined that functional footpads are created when hair cells form effective frameworks with actin filament bundles, thereby shaping the hair tip and facilitating cuticular deposition. We adapted this mechanism of microstructure formation to design a new artificial adhesive device⁠—a spatula-like fiber-framed adhesive device supported by nylon fibers with a gel material at the tip. This simple self-assembly mechanism facilitates the energy-efficient production of low-cost adhesion devices.
Flow fields control nanostructural organization in semiflexible networks
Authors: Rosén Tomas , Mittal Nitesh , Roth Stephan V. , Zhang Peng , Lundell Fredrik , Söderberg L. Daniel
Published: May 2020

The influence of flow deformations on the Brownian rotary dynamics of dispersed nanofibrils is characterized with a novel flow-stop technique.
An atomic scale study of two-dimensional quasicrystal nucleation controlled by multiple length scale interactions
Authors: Tang Sai , Wang Zhijun , Wang Jincheng , Jiang Kai , Liang Chaoping , Ma Yunzhu , Liu Wensheng , Du Yong
Published: May 2020

Formation of quasicrystal structures has always been mysterious since the discovery of these magic structures.
Inducing mesenchymal stem cell attachment on non-cell adhesive hydrogels through click chemistry
Authors: Battigelli Alessia , Almeida Bethany , Shukla Shashank , Rocha Alicia D. , Shukla Anita
Published: May 2020

Strain-promoted bio-orthogonal click chemistry is used to initiate cell attachment on non-cell adhesive materials.
Al-doped Fe2O3 as a support for molybdenum oxide methanol oxidation catalysts
Authors: Bowker Michael , Hellier Pip , Decarolis Donato , Gianolio Diego , Mohammed Khaled M. H. , Stenner Alex , Huthwelker Thomas , Wells Peter P.
Published: May 2020

Schematic of the proposed structure for a high Al doped haematite sample with MoOx overlayers.
Combining theories and experiments to understand the sodium nucleation behavior towards safe sodium metal batteries
Authors: Wang Huan , Matios Edward , Luo Jianmin , Li Weiyang
Published: May 2020

This review assesses both theoretical and experimental knowledge on sodium nucleation for the first time towards a safe sodium battery.
Evaluation of the effect of site substitution of Pr doping in the lithium garnet system Li5La3Nb2O12
Authors: Stockham M. P. , Dong B. , Ding Y. , Li Y. , Slater P. R.
Published: May 2020

We show that Pr is a rare example of an ambi-site dopant, being able to substitute onto either the La or Nb site in Li5La3Nb2O12, with the oxidation state determined by the site substitution.