bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy
Authors: Li Qing , Wang Chengfeng , Li Wei , Zhang Zaiqiang , Wang Shanshan , Wupuer Autongsha , Hu Xiao , Wumaier Kalibinuer , Zhu Yi , Li Hongyan , Yu Wengui
Published: August 2021

Pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.
Lattice duality for coupling pairs admitting polytope duality with trivial toric contribution
Authors: Mase Makiko
Published: August 2021

We study a lattice duality among families of K3 surfaces associated to coupling pairs that admit polytope duality with trivial toric contribution.
Use of walking modifications, perceived walking difficulty and changes in outdoor mobility among community-dwelling older people during COVID-19 restrictions
Authors: Leppä Heidi , Karavirta Laura , Rantalainen Timo , Rantakokko Merja , Siltanen Sini , Portegijs Erja , Rantanen Taina
Published: August 2021

Background

Outdoor mobility enables participation in essential out-of-home activities in old age.

Aim

To compare changes in different aspects of outdoor mobility during COVID-19 restrictions versus two years before according to self-reported walking.

Methods

Community-dwelling participants of AGNES study (2017–2018, initial age 75–85) responded to AGNES-COVID-19 postal survey in spring 2020 (N = 809). Life-space mobility, autonomy in participation outdoors, and self-reported physical activity were assessed at both time points and differences according to self-reported walking modifications and difficulty vs. intact walking at baseline were analyzed.

Results

Life-space mobility and autonomy in participation outdoors had declined (mean changes -11.4, SD 21.3; and 6.7, SD 5.3, respectively), whereas physical activity had increased (5.5 min/day, SD 25.1) at follow-up. Participants perceiving walking difficulty reported the poorest baseline outdoor mobility, a steeper decline in life-space mobility (p = 0.001), a smaller increase in physical activity (p < 0.001), and a smaller decline in autonomy in participation outdoors (p = 0.017) than those with intact walking. Those with walking modifications also reported lower baseline life-space mobility and physical activity, a steeper decline in life-space mobility and a smaller increase in physical activity those with intact walking (p < 0.001 for both).

Discussion

Participants reporting walking modifications remained the intermediate group in outdoor mobility over time, whereas those with walking difficulty showed the steepest decline in outdoor mobility and hence potential risk for accelerated further functional decline.

Conclusion

Interventions should target older people perceiving walking difficulty, as they may be at the risk for becoming homebound when environmental facilitators for outdoor mobility are removed.
Caring for nursing home residents with COVID-19: a “hospital-at-nursing home” intermediate care intervention
Authors: Benvenuti Enrico , Rivasi Giulia , Bulgaresi Matteo , Barucci Riccardo , Lorini Chiara , Balzi Daniela , Faraone Antonio , Fortini Giacomo , Vaccaro Gabriele , Del Lungo Ilaria , Gangemi Salvatore , Giardini Sante , Piga Cecilia , Barghini Eleonora , Boni Serena , Bulli Giulia , Carrai Paolo , Crociani Andrea , Lo Forte Aldo , Martella Letizia , Pupo Simone , Marozzi Irene , Bandini Giulia , Buscemi Primo , Cosma Claudia , Stacchini Lorenzo , Baggiani Lorenzo , Ungar Andrea , Mossello Enrico , Bonaccorsi Guglielmo , Landini Giancarlo
Published: August 2021

Background

Nursing home (NH) residents have been dramatically affected by COVID-19, with extremely high rates of hospitalization and mortality.

Aims

To describe the features and impact of an assistance model involving an intermediate care mobile medical specialist team (GIROT, Gruppo Intervento Rapido Ospedale Territorio) aimed at delivering “hospital-at-nursing home” care to NH residents with COVID-19 in Florence, Italy.

Methods

The GIROT activity was set-up during the first wave of the pandemic (W1, March–April 2020) and became a structured healthcare model during the second (W2, October 2020–January 2021). The activity involved (1) infection transmission control among NHs residents and staff, (2) comprehensive geriatric assessment including prognostication and geriatric syndromes management, (3) on-site diagnostic assessment and protocol-based treatment of COVID-19, (4) supply of nursing personnel to understaffed NHs. To estimate the impact of the GIROT intervention, we reported hospitalization and infection lethality rates recorded in SARS-CoV-2-positive NH residents during W1 and W2.

Results

The GIROT activity involved 21 NHs (1159 residents) and 43 NHs (2448 residents) during W1 and W2, respectively. The percentage of infected residents was higher in W2 than in W1 (64.5% vs. 38.8%), while both hospitalization and lethality rates significantly decreased in W2 compared to W1 (10.1% vs 58.2% and 23.4% vs 31.1%, respectively).

Discussion

Potentiating on-site care in the NHs paralleled a decrease of hospital admissions with no increase of lethality.

Conclusions

An innovative “hospital-at-nursing home” patient-centred care model based on comprehensive geriatric assessment may provide a valuable contribution in fighting COVID-19 in NH residents.
Influences of target congruence and lifestyles on victimization trajectories: An Autoregressive Latent Trajectory Modeling approach to overlap between bullying and victimization
Authors: Park Insun , Cho Sujung
Published: August 2021

Introduction

Relative to the general victimization literature, a small body of literature has examined the longitudinal process of overlap between bullying perpetration and bullying victimization. To address this gap, this study assesses the dynamic process of bullying perpetration and victimization from a developmental perspective and examine the applicability of target congruence and lifestyle‐routine activities approach.

Methods

Using data from 2,378 Korean youths collected from 2012 to 2016, the current study has conducted a Parallel Process Latent Growth Curve Modeling (PPLGCM) analysis to examine co‐development and sequentially contingent processes of bullying and victimization, and Autoregressive Latent Trajectory Modeling (ALTM) to examine the time‐lagged effect of bullying on victimization.

Results

Results from the PPLGCM revealed a significant and positive relationship between the initial levels of bullying and victimization as well as a reciprocal and cumulative influence over time. The ALTM analysis indicated that increased victimization in the previous year was associated with increased victimization in the following year. Further, time‐concurrent and time‐lagged effects of bullying on victimization were significant and positive. Finally, target congruence and risky lifestyle variables predicted the longitudinal process of victimization, indicating the cross‐cultural generalizability of the theory.

Conclusions

The findings offer support for a complex and dynamic relationship between bullying and victimization, and thus call for developmentally sensitive prevention strategies.
Physics and Computation
Authors: Duwell Armond
Published: August 2021

This Element has three main aims. First, it aims to help the reader understand the concept of computation that Turing developed, his corresponding results, and what those results indicate about the limits of computational possibility. Second, it aims to bring the reader up to speed on analyses of computation in physical systems which provide the most general characterizations of what it takes for a physical system to be a computational system. Third, it aims to introduce the reader to some different kinds of quantum computers, describe quantum speedup, and present some explanation sketches of quantum speedup. If successful, this Element will equip the reader with a basic knowledge necessary for pursuing these topics in more detail.
The Burden of Communicable Diseases in Lebanon: Trends in the Past Decade
Authors: Hammoud Sahar , Onchonga David , Amer Faten , Kocsis Béla
Published: August 2021

The present study aims to review the main communicable diseases that experienced an upsurge in the past decade in Lebanon and to highlight the reasons behind this increase. Data of reported communicable diseases from 2010 till 2019 were obtained from the Lebanese Ministry of Public Health (LMOPH) epidemiological surveillance database. Tuberculosis, measles, mumps, leishmaniasis, and hepatitis A were the main communicable diseases that showed a sharp increase in the past 10 y. Measles outbreaks occurred in 2013 and 2018, leishmaniasis outbreak in 2013, and mumps and hepatitis A outbreaks in 2014. The highest percentages of reported diseases were from Beqaa and North governorates. The massive influx of Syrian refugees to Lebanon, together with the poor water management system, poor sanitation, deprived living conditions, and limited health-care access in rural areas might have contributed to the upsurge of communicable diseases. Although the LMOPH succeeded in containing the outbreaks, further efforts are needed to improve the identified gaps to avoid future outbreaks.
Dung beetle community assemblages in a southern African landscape: niche overlap between domestic and wild herbivore dung
Authors: Sands B. , Mgidiswa N. , Curson S. , Nyamukondiwa C. , Wall R.
Published: August 2021

Dung beetles provide important ecosystem functions in semiarid environments, improving the physiochemical characteristics of the soil through tunnelling and burying nutrient-rich dung. In sub-Saharan Africa, diverse indigenous mammal communities support highly abundant dung beetle populations in savannah ecosystems. However, the conversion of landscapes to livestock agriculture may result in changes in the abundance and diversity of wild mammal species. This is likely to have significant impacts on dung beetle communities, particularly because domestic livestock dung may be contaminated with toxic residues of veterinary parasiticides. The environmental impact is likely to be affected by the degree of niche overlap between the beetle communities that colonize cattle dung and those that colonize the dung of wild mammals. We compared dung beetle communities between a pristine national park habitat dominated by large wild herbivores, and a pastoral farming community dominated by domestic livestock. Diurnal dung beetles were attracted to cattle dung in greater abundance and diversity compared to elephant, zebra or giraffe dung. Nocturnal/crepuscular dung beetles were attracted to non-ruminant dung (elephant and zebra) in higher abundance compared to ruminant dung (cattle and giraffe). Although there were no clear trophic specializations, three diurnal species showed an association with cattle dung, whereas eight nocturnal/crepuscular species showed an association with non-ruminant (elephant and zebra) dung. Diurnal species may be at greater risk from the toxic effects of residues of veterinary parasiticides in domestic livestock dung. Although many species showed trophic associations with wild herbivore dung, these beetles can utilize a wide range of dung and will readily colonize cattle dung in the absence of other options. As more land is converted to livestock agriculture, the contamination of dung with toxic residues from veterinary parasiticides could therefore negatively impact the majority of dung beetle species.
The Continued Criminality of Selling Sex: A Trajectory of South African Sex Work Law Reform
Authors: Spies Amanda
Published: August 2021

This article explores the regulation of sex work in South Africa and follows the trajectory of the South African Law Reform Commission (SALRC) in investigating whether sex work should be decriminalized. The legal regulation of sex work is a hotly contested topic. South Africa currently criminalizes the selling and buying of sex, but policy reform has been on the cards since the SALRC launched its project on the topic in the early 2000s. As most sex work policy responses are grounded in feminist theory, the article analyses the main theoretical ideologies and questions the influence of these ideologies in structuring sex work law reform in the South African context. The author calls for a more inclusive understanding of feminism and sex work, and the need to acknowledge the importance of rights discourse in furthering political growth and protecting sex workers’ constitutional rights.
Hear me out: rethinking internal auditory meatus magnetic resonance imaging in primary care. A cohort evaluation
Authors: Sajid I M , Frost K
Published: August 2021

Background

Imaging detects acoustic neuroma, a rare pathology associated with asymmetric sensorineural hearing loss and tinnitus, that is mostly managed conservatively. Scanning indication is debatable, without evaluation in primary care, despite the high burden of audiovestibular symptoms and commissioning of general practitioner imaging.

Method

Cohort evaluation of two years' internal auditory meatus magnetic resonance imaging in primary care.

Results

Of 200 scans requested by 77 general practitioners, only 33 per cent conformed to guideline indications. Most were referred to specialists, regardless of result. Only 10.5 per cent were appropriately imaged to rule out neuroma without specialist referral. One neuroma was detected (diagnostic yield 0.5 per cent) in a patient already referred. Incidental findings were shown in 44.5 per cent, triggering low-value cascades in 18 per cent. Whilst fewer than 1 in a 1000 imaged patients may improve through surgery, 1 in 5 can suffer negative imaging cascades.

Conclusion

Considering the bi-directional relationship between distress and audio-vestibular symptoms, anxiety-provoking imaging overuse should be minimised. In low-prevalence primary care, retrocochlear imaging could be limited to those with asymmetric sensorineural hearing loss. Alternatively, assessment and imaging could be shifted to audiologist-led settings, with a wider therapeutic offer, likely more beneficial and cost-effective than conventional surgical pathways.
A child case of Kawasaki with giant coronary aneurysm: percutaneous coronary intervention due to anterior myocardial infarction
Authors: Türe Mehmet , Akın Alper , Ertaş Faruk , Akın Oğuz Aylin
Published: August 2021

Kawasaki disease is usually self-limited, but it can lead to aneurysm, stenosis, thrombosis, and myocardial infarction in the coronary arteries. The most important complication of Kawasaki disease is coronary artery aneurysm. Coronary artery aneurysm or ectasia may be seen in 15–25% of patients who do not receive treatment. It develops in 5% of children who receive intravenous immunoglobulin at the appropriate time. Acute myocardial infarction is the most important cause of morbidity and mortality in Kawasaki patients with giant aneurysms. We present a 10-year-old girl who had a history of giant aneurysm in the coronary arteries and underwent percutaneous coronary intervention due to anterior myocardial infarction.
Improvisational Listening:Audiowalk – St Enda’s Park
Authors: Eadie Jimmy
Published: August 2021

This article discusses the affordance of headphone listening as a sensory experience within a responsive, interactive and improvisational site-specific audiowalk. The intention here is to elucidate how correlational and dialectic tensions between improvisation and listening have informed an approach to creating the geolocative project:Audiowalk – St Enda’s Park. Initially using the concept of soundwalking, as both a touchstone and a springboard, I explore some of the theoretical and dialogic underpinnings that have grounded this process-orientated work. The discussion is then extended into a phenomenological application of improvisational listening and walking in this form of somatic art, and particularly how this can impact the immersive experience for the participant/performer. The theoretical grounding and telos are explored in terms of the improvisational ‘flow’ state and how this accentuates and engenders an awareness of a soundscape through contextual and ethnographic aural histories. Critical reflection and analysis will be discussed throughout in attaining greater epistemological efficacy dealing with concepts of place and memory within this site-specific work.
Donohue+: Developing performer-specific electronic improvisatory accompaniment for instrumental improvisation
Authors: Gillies Sam , Sappho Donohue Maria
Published: August 2021

Electronic systems designed to improvise with a live instrumental performer are a constant mediation of musical language and artificial decision-making. Often these systems are designed to elicit a reaction in a very broad way, relying on segmenting and playing back audio material according to a fixed or mobile set of rules or analysis. As a result, such systems can produce an outcome that sounds generic across different improvisers, or restrict meaningful electroacoustic improvisation to those performers with a matching capacity for designing improvisatory electroacoustic processing. This article documents the development of an improvisatory electroacoustic instrument for pianist Maria Donohue as a collaborative process for music-making. The Donohue+ program is a bespoke electroacoustic improvisatory system designed to augment the performance capabilities of Maria, enabling her to achieve new possibilities in live performance. Through the process of development, Maria’s performative style, within the broader context of free improvisation, was analysed and used to design an interactive electronic system. The end result of this process is a meaningful augmentation of the piano in accordance with Maria’s creative practice, differing significantly from other improvising electroacoustic instruments she has previously experimented with. Through the process of development, Donohue+ identifies a practice for instrument design that engages not only with a performer’s musical materials but also with a broader free improvisation aesthetic.
Towards a Practice of Palimpsestic Listening
Authors: Cross Richard
Published: August 2021

This article invites reflection on the ambiguity of sonic temporalities as the lines between physicality and immediacy become increasingly blurred. Through the notion that digital technologies are haunted by analogic process, I foreground the concept ofPalimpsestic Listeningto explore the musical qualities and critical resonances of sonic acts and objects in hybrid physical/digital systems that evoke layered temporalities that are ‘historically distinct nonetheless linked’. I also seek to illustrate the significance of engaging practically with this concept by discussing the methods behind my compositionD/ta Ro} – A Dialectical Trash Heap, a sound installation that interrogates the relationship between sonic materiality and digital audio processing and how acts of erasure and time-stretching might influence the layering of disparate sound materials.
Emotionsfokussierte Therapie
Authors: Herrmann Imke R. , Auszra Lars
Published: August 2021

Die Emotionsfokussierte Therapie (EFT) ist ein trans-diagnostisches Verfahren, das bei einem breiten Spektrum an psychischen Störungen Anwendung finden kann. Wirksamkeitsnachweise liegen insbesondere für die Behandlung von Depressionen und Traumafolgestörungen vor. Der Band liefert eine kompakte Darstellung der emotionsfokussierten Theorie und Beziehungsgestaltung sowie zentraler emotions-fokussierter Interventionen. Psychischen Problemen und Symptomen liegen häufig Schwierigkeiten in der emotionalen Verarbeitung zugrunde. Die EFT zielt auf die Veränderung dieser Schwierigkeiten und rückt das emotionale Erleben von Patientinnen und Patienten und ihren Umgang mit diesem Erleben in den Mittelpunkt therapeutischen Handelns. Die EFT zeigt Wege auf, wie Patientinnen und Patienten ihre Emotionen adäquat verarbeiten und flexibel zur Lösung aktueller Probleme nutzen können. Es geht darum, maladaptive Emotionen nachhaltig zu verändern und einen funktionaleren Umgang mit Emotionen zu fördern. Anhand von zahlreichen Beispielen und Therapiedialogen wird das therapeutische Vorgehen, z. B. bei der Fallformulierung, der Zwei-Stuhl-Technik und der Arbeit mit dem Leeren Stuhl, praxisorientiert beschrieben.
Parental Mediation Strategies and Their Role on Youths’ Online	Privacy Disclosure and Protection
Authors: Lo Cricchio Maria Grazia , Palladino Benedetta E. , Eleftheriou Androulla , Nocentini Annalaura , Menesini Ersilia
Published: August 2021

Abstract. The amount of personal information shared online every day by youths without control has raised concerns about their vulnerability to privacy disclosure. Parental mediation strategies have been considered as important aspects that can contribute to the reduction of online-related risks. However, research on this field has shown puzzling results and there is not a consistent investigation of the specific role of parental mediation in youths’ online privacy management. Therefore, this systematic review was aimed at examining the evidence for associations between different parental mediation strategies and aspects of both privacy disclosure and protection. The search was conducted in December 2019 in the SCOPUS and Web of Science scientific databases and resulted in 17 studies that have been included in our review. Taken together, the results confirm that mediation practices can be considered as important variables for the reduction of information disclosure and for enhancing privacy protection. However, some specificities emerged. Restrictive forms of mediation showed clear negative associations with disclosing behaviors, whereas active strategies showed more contrasting results. Moreover, restrictive practices seemed to be less linked to attitudes and beliefs of privacy protection than active forms. More research is needed concerning the role of co-viewing strategies. Findings were discussed in terms of future research and intervention.
Ocean Dust Deposition Rates Constrained in a Data‐Assimilation Model of the Marine Aluminum Cycle
Authors: Xu Hairong , Weber Thomas
Published: August 2021

Aluminum (Al) is delivered to surface ocean waters by aeolian dust, making it a promising tracer to constrain dust deposition rates and the atmospheric supply of trace metal micronutrients. Over recent years, dissolved Al has been mapped along the GEOTRACES transects, providing unparalleled coverage of the world ocean. However, inferring atmospheric input rates from these observations is complicated by a suite of additional processes that influence the Al distribution, including reversible particle scavenging, biological uptake by diatoms, hydrothermal sources, sediment resuspension. Here we employ a data‐assimilation model of the oceanic Al cycle that explicitly accounts for these processes, allowing the atmospheric signal to be extracted. We conduct an ensemble of model optimizations that test different dust deposition distributions and consider spatial variations in Al solubility, thereby inferring the atmospheric Al supply that is most consistent with GEOTRACES observations. We find that 37.2 ± 11.0 Gmol/yr of soluble Al is added to the global ocean, dominated in the Atlantic Ocean, and that Al fractional solubility varies strongly as a function of atmospheric dust concentration. Our model also suggests that 6.1 ± 2.4 Gmol Al/yr is injected from hydrothermal vents, and that vertical Al redistribution through the water column is dominated by abiotic reversible scavenging rather than uptake by diatoms. Our results have important implications for the oceanic iron (Fe) budget: based on the soluble Fe:Al ratio of dust, we infer that aeolian Fe inputs lie between 3.82 and 9.25 Gmol/yr globally, and fall short of the biological Fe demand in most ocean regions.
Earthquake Source Complexity Controls the Frequency Dependence of Near‐Source Radiation Patterns
Authors: Trugman Daniel T. , Chu Shanna X. , Tsai Victor C.
Published: August 2021

The spatial patterns of earthquake ground motion amplitudes are commonly represented using a double‐couple model that corresponds to shear slip on a planar fault. While this framework has proven largely successful in explaining low‐frequency seismic recordings, at higher frequencies the wavefield becomes more azimuthally isotropic for reasons that are not yet well understood. Here, we use a dense array of nodal seismometers in Oklahoma to study the radiation patterns of earthquakes in the near‐source region where the effects of wavefield scattering are limited. At these close distances, the radiation pattern is predominantly double couple at low frequencies (<15 Hz). At higher frequencies, the recorded wavefield contains significant isotropic and residual components that cannot be explained as path or site effects, implying complexity in the rupture process or local fault zone structure. These findings demonstrate that earthquake source complexity can drive variability in the ground motions that control seismic hazard.
Magnetic Field in Magnetosheath Jets: A Statistical Study of BZ Near the Magnetopause
Authors: Vuorinen Laura , Hietala Heli , Plaschke Ferdinand , LaMoury Adrian T.
Published: August 2021

Magnetosheath jets travel from the bow shock toward the magnetopause, and some of them eventually impact it. Jet impacts have recently been linked to triggering magnetopause reconnection in case studies by Hietala et al. (2018, https://doi.org/10.1002/2017gl076525) and Nykyri et al. (2019, https://doi.org/10.1029/2018ja026357). In this study, we focus on the enhancing or suppressing effect jets could have on reconnection by locally altering the magnetic shear via their own magnetic fields. Using observations from the years 2008–2011 made by the Time History of Events and Macroscale Interactions during Substorms spacecraft and solar wind OMNI data, we statistically study for the first time within jets in the Geocentric Solar Magnetospheric coordinates. We find that opposite to the prevailing interplanetary magnetic field (IMF) is roughly as common in jets as in the non‐jet magnetosheath near the magnetopause, but these observations are distributed differently. 60–70% of jet intervals contain bursts of opposite polarity in comparison to around 40 of similar non‐jet intervals. The median duration of such a burst in jets is 10 s and strength is nT. We also investigate the prevalence of the type of strong nT pulses that Nykyri et al. (2019, https://doi.org/10.1029/2018ja026357) linked to a substorm onset. In our data set, such pulses were observed in around 13% of jets. Our statistical results indicate that jets may have the potential to affect local magnetopause reconnection via their magnetic fields. Future studies are needed to determine whether such effects can be observed.
Longitudinal analyses of CLL in mice identify leukemia-related clonal changes including a Myc gain predicting poor outcome in patients
Authors: Öztürk Selcen , Paul Yashna , Afzal Saira , Gil-Farina Irene , Jauch Anna , Bruch Peter-Martin , Kalter Verena , Hanna Bola , Arseni Lavinia , Roessner Philipp M. , Schmidt Manfred , Stilgenbauer Stephan , Dietrich Sascha , Lichter Peter , Zapatka Marc , Seiffert Martina
Published: August 2021

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy mainly occurring at an advanced age with no single major genetic driver. Transgenic expression of TCL1 in B cells leads after a long latency to a CLL-like disease in aged Eµ-TCL1 mice suggesting that TCL1 overexpression is not sufficient for full leukemic transformation. In search for secondary genetic events and to elucidate the clonal evolution of CLL, we performed whole exome and B-cell receptor sequencing of longitudinal leukemia samples of Eµ-TCL1 mice. We observed a B-cell receptor stereotypy, as described in patients, confirming that CLL is an antigen-driven disease. Deep sequencing showed that leukemia in Eµ-TCL1 mice is mostly monoclonal. Rare oligoclonality was associated with inability of tumors to develop disease upon adoptive transfer in mice. In addition, we identified clonal changes and a sequential acquisition of mutations with known relevance in CLL, which highlights the genetic similarities and therefore, suitability of the Eµ-TCL1 mouse model for progressive CLL. Among them, a recurrent gain of chromosome 15, where Myc is located, was identified in almost all tumors in Eµ-TCL1 mice. Interestingly, amplification of 8q24, the chromosomal region containing MYC in humans, was associated with worse outcome of patients with CLL.
BCL9 regulates CD226 and CD96 checkpoints in CD8+ T cells to improve PD-1 response in cancer
Authors: Feng Mei , Wu Zhongen , Zhou Yan , Wei Zhuang , Tian Enming , Mei Shenglin , Zhu Yuanyuan , Liu Chenglong , He Fenglian , Li Huiyu , Xie Cao , Jin Joy , Dong Jibin , Yang Dehua , Yu Ker , Qian Junbin , Lambrechts Diether , Wang Ming-Wei , Zhu Di
Published: August 2021

To date, the overall response rate of PD-1 blockade remains unsatisfactory, partially due to limited understanding of tumor immune microenvironment (TIME). B-cell lymphoma 9 (BCL9), a key transcription co-activator of the Wnt pathway, is highly expressed in cancers. By genetic depletion and pharmacological inhibition of BCL9 in tumors, we found that BCL9 suppression reduced tumor growth, promoted CD8+ T cell tumor infiltration, and enhanced response to anti-PD-1 treatment in mouse colon cancer models. To determine the underlying mechanism of BCL9’s role in TIME regulation, single-cell RNA-seq was applied to reveal cellular landscape and transcription differences in the tumor immune microenvironment upon BCL9 inhibition. CD155-CD226 and CD155-CD96 checkpoints play key roles in cancer cell/CD8+ T cell interaction. BCL9 suppression induces phosphorylation of VAV1 in CD8+ T cells and increases GLI1 and PATCH expression to promote CD155 expression in cancer cells. In The Cancer Genome Atlas database analysis, we found that BCL9 expression is positively associated with CD155 and negatively associated with CD226 expression. BCL9 is also linked to adenomatous polyposis coli (APC) mutation involved in patient survival following anti-PD-1 treatment. This study points to cellular diversity within the tumor immune microenvironment affected by BCL9 inhibition and provides new insights into the role of BCL9 in regulating CD226 and CD96 checkpoints
Histone H4 lysine 20 mono-methylation directly facilitates chromatin openness and promotes transcription of housekeeping genes
Authors: Shoaib Muhammad , Chen Qinming , Shi Xiangyan , Nair Nidhi , Prasanna Chinmayi , Yang Renliang , Walter David , Frederiksen Klaus S. , Einarsson Hjorleifur , Svensson J. Peter , Liu Chuan Fa , Ekwall Karl , Lerdrup Mads , Nordenskiöld Lars , Sørensen Claus S.
Published: August 2021

Histone lysine methylations have primarily been linked to selective recruitment of reader or effector proteins that subsequently modify chromatin regions and mediate genome functions. Here, we describe a divergent role for histone H4 lysine 20 mono-methylation (H4K20me1) and demonstrate that it directly facilitates chromatin openness and accessibility by disrupting chromatin folding. Thus, accumulation of H4K20me1 demarcates highly accessible chromatin at genes, and this is maintained throughout the cell cycle. In vitro, H4K20me1-containing nucleosomal arrays with nucleosome repeat lengths (NRL) of 187 and 197 are less compact than unmethylated (H4K20me0) or trimethylated (H4K20me3) arrays. Concordantly, and in contrast to trimethylated and unmethylated tails, solid-state NMR data shows that H4K20 mono-methylation changes the H4 conformational state and leads to more dynamic histone H4-tails. Notably, the increased chromatin accessibility mediated by H4K20me1 facilitates gene expression, particularly of housekeeping genes. Altogether, we show how the methylation state of a single histone H4 residue operates as a focal point in chromatin structure control. While H4K20me1 directly promotes chromatin openness at highly transcribed genes, it also serves as a stepping-stone for H4K20me3-dependent chromatin compaction.
MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer
Authors: Kalogirou C. , Linxweiler J. , Schmucker P. , Snaebjornsson M. T. , Schmitz W. , Wach S. , Krebs M. , Hartmann E. , Puhr M. , Müller A. , Spahn M. , Seitz A. K. , Frank T. , Marouf H. , Büchel G. , Eckstein M. , Kübler H. , Eilers M. , Saar M. , Junker K. , Röhrig F. , Kneitz B. , Rosenfeldt M. T. , Schulze A.
Published: August 2021

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.
Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor
Authors: Wang Yue , Guo Shimeng , Zhuang Youwen , Yun Ying , Xu Peiyu , He Xinheng , Guo Jia , Yin Wanchao , Xu H. Eric , Xie Xin , Jiang Yi
Published: August 2021

Ghrelin, also called “the hunger hormone”, is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature of ghrelin is its acylation, primarily with an octanoic acid, which is essential for its binding and activation of the ghrelin receptor, a G protein-coupled receptor. The multifaceted roles of ghrelin make ghrelin receptor a highly attractive drug target for growth retardation, obesity, and metabolic disorders. Here we present two cryo-electron microscopy structures of Gq-coupled ghrelin receptor bound to ghrelin and a synthetic agonist, GHRP-6. Analysis of these two structures reveals a unique binding pocket for the octanoyl group, which guides the correct positioning of the peptide to initiate the receptor activation. Together with mutational and functional data, our structures define the rules for recognition of the acylated peptide hormone and activation of ghrelin receptor, and provide structural templates to facilitate drug design targeting ghrelin receptor.
Superconductivity up to 243 K in the yttrium-hydrogen system under high pressure
Authors: Kong Panpan , Minkov Vasily S. , Kuzovnikov Mikhail A. , Drozdov Alexander P. , Besedin Stanislav P. , Mozaffari Shirin , Balicas Luis , Balakirev Fedor Fedorovich , Prakapenka Vitali B. , Chariton Stella , Knyazev Dmitry A. , Greenberg Eran , Eremets Mikhail I.
Published: August 2021

The discovery of superconducting H3S with a critical temperature Tc∼200 K opened a door to room temperature superconductivity and stimulated further extensive studies of hydrogen-rich compounds stabilized by high pressure. Here, we report a comprehensive study of the yttrium-hydrogen system with the highest predicted Tcs among binary compounds and discuss the contradictions between different theoretical calculations and experimental data. We synthesized yttrium hydrides with the compositions of YH3, YH4, YH6 and YH9 in a diamond anvil cell and studied their crystal structures, electrical and magnetic transport properties, and isotopic effects. We found superconductivity in the Im-3m YH6 and P63/mmc YH9 phases with maximal Tcs of ∼220 K at 183 GPa and ∼243 K at 201 GPa, respectively. Fm-3m YH10 with the highest predicted Tc > 300 K was not observed in our experiments, and instead, YH9 was found to be the hydrogen-richest yttrium hydride in the studied pressure and temperature range up to record 410 GPa and 2250 K.
Variational preparation of finite-temperature states on a quantum computer
Authors: Sagastizabal R. , Premaratne S. P. , Klaver B. A. , Rol M. A. , Negîrneac V. , Moreira M. S. , Zou X. , Johri S. , Muthusubramanian N. , Beekman M. , Zachariadis C. , Ostroukh V. P. , Haider N. , Bruno A. , Matsuura A. Y. , DiCarlo L.
Published: August 2021

The preparation of thermal equilibrium states is important for the simulation of condensed matter and cosmology systems using a quantum computer. We present a method to prepare such mixed states with unitary operators and demonstrate this technique experimentally using a gate-based quantum processor. Our method targets the generation of thermofield double states using a hybrid quantum-classical variational approach motivated by quantum-approximate optimization algorithms, without prior calculation of optimal variational parameters by numerical simulation. The fidelity of generated states to the thermal-equilibrium state smoothly varies from 99 to 75% between infinite and near-zero simulated temperature, in quantitative agreement with numerical simulations of the noisy quantum processor with error parameters drawn from experiment.
MethylSPWNet and MethylCapsNet: Biologically Motivated Organization of DNAm Neural Networks, Inspired by Capsule Networks
Authors: Levy Joshua J. , Chen Youdinghuan , Azizgolshani Nasim , Petersen Curtis L. , Titus Alexander J. , Moen Erika L. , Vaickus Louis J. , Salas Lucas A. , Christensen Brock C.
Published: August 2021

DNA methylation (DNAm) alterations have been heavily implicated in carcinogenesis and the pathophysiology of diseases through upstream regulation of gene expression. DNAm deep-learning approaches are able to capture features associated with aging, cell type, and disease progression, but lack incorporation of prior biological knowledge. Here, we present modular, user-friendly deep-learning methodology and software, MethylCapsNet and MethylSPWNet, that group CpGs into biologically relevant capsules—such as gene promoter context, CpG island relationship, or user-defined groupings—and relate them to diagnostic and prognostic outcomes. We demonstrate these models’ utility on 3,897 individuals in the classification of central nervous system (CNS) tumors. MethylCapsNet and MethylSPWNet provide an opportunity to increase DNAm deep-learning analyses’ interpretability by enabling a flexible organization of DNAm data into biologically relevant capsules.
Environmental DNA preserved in marine sediment for detecting jellyfish blooms after a tsunami
Authors: Ogata Mizuki , Masuda Reiji , Harino Hiroya , Sakata Masayuki K. , Hatakeyama Makoto , Yokoyama Katsuhide , Yamashita Yoh , Minamoto Toshifumi
Published: August 2021

Environmental DNA (eDNA) can be a powerful tool for detecting the distribution and abundance of target species. This study aimed to test the longevity of eDNA in marine sediment through a tank experiment and to use this information to reconstruct past faunal occurrence. In the tank experiment, juvenile jack mackerel (Trachurus japonicus) were kept in flow-through tanks with marine sediment for two weeks. Water and sediment samples from the tanks were collected after the removal of fish. In the field trial, sediment cores were collected in Moune Bay, northeast Japan, where unusual blooms of jellyfish (Aurelia sp.) occurred after a tsunami. The samples were analyzed by layers to detect the eDNA of jellyfish. The tank experiment revealed that after fish were removed, eDNA was not present in the water the next day, or subsequently, whereas eDNA was detectable in the sediment for 12 months. In the sediment core samples, jellyfish eDNA was detected at high concentrations above the layer with the highest content of polycyclic aromatic hydrocarbons, reflecting tsunami-induced oil spills. Thus, marine sediment eDNA preserves a record of target species for at least one year and can be used to reconstruct past faunal occurrence.
Metagenomic characterization of swine slurry in a North American swine farm operation
Authors: Ramesh Akshaya , Bailey Emily S. , Ahyong Vida , Langelier Charles , Phelps Maira , Neff Norma , Sit Rene , Tato Cristina , DeRisi Joseph L. , Greer Annette G. , Gray Gregory C.
Published: August 2021

Modern day large-scale, high-density farming environments are inherently susceptible to viral outbreaks, inadvertently creating conditions that favor increased pathogen transmission and potential zoonotic spread. Metagenomic sequencing has proven to be a useful tool for characterizing the microbial burden in both people, livestock, and environmental samples. International efforts have been successful at characterizing pathogens in commercial farming environments, especially swine farms, however it is unclear whether the full extent of microbial agents have been adequately captured or is representative of farms elsewhere. To augment international efforts we performed metagenomic next-generation sequencing on nine swine slurry and three environmental samples from a United States of America (U.S.A.) farm operation, characterized the microbial composition of slurry, and identified novel viruses. We assembled a remarkable total of 1792 viral genomes, of which 554 were novel/divergent. We assembled 1637 Picobirnavirus genome segments, of which 538 are novel. In addition, we discovered 10 new viruses belonging to a novel taxon: porcine Statoviruses; which have only been previously reported in human, macaques, mouse, and cows. We assembled 3 divergent Posaviruses and 3 swine Picornaviruses. In addition to viruses described, we found other eukaryotic genera such as Entamoeba and Blastocystis, and bacterial genera such as Listeria, Treponema, Peptoclostridium and Bordetella in the slurry. Of these, two species Entamoeba histolytica and Listeria monocytogenes known to cause human disease were detected. Further, antimicrobial resistance genes such as tetracycline and MLS (macrolide, lincosamide, streptogramin) were also identified. Metagenomic surveillance in swine fecal slurry has great potential for novel and antimicrobial resistant pathogen detection.
Stability of diagnostic rate in a cohort of 38,813 colorectal polyp specimens and implications for histomorphology and statistical process control
Authors: Bonert Michael , Naqvi Asghar , Rahman Mozibur , Marshall John K. , Xenodemetropoulos Ted , Arora Paul , Slater Justin , Major Pierre
Published: August 2021

This work sought to quantify pathologists’ diagnostic bias over time in their evaluation of colorectal polyps to assess how this may impact the utility of statistical process control (SPC). All colorectal polyp specimens(CRPS) for 2011–2017 in a region were categorized using a validated free text string matching algorithm. Pathologist diagnostic rates (PDRs) for high grade dysplasia (HGD), tubular adenoma (TA_ad), villous morphology (TVA + VA), sessile serrated adenoma (SSA) and hyperplastic polyp (HP), were assessed (1) for each pathologist in yearly intervals with control charts (CCs), and (2) with a generalized linear model (GLM). The study included 64,115 CRPS. Fifteen pathologists each interpreted > 150 CRPS/year in all years and together diagnosed 38,813. The number of pathologists (of 15) with zero or one (p < 0.05) outlier in seven years, compared to their overall PDR, was 13, 9, 9, 5 and 9 for HGD, TVA + VA, TA_ad, HP and SSA respectively. The GLM confirmed, for the subset where pathologists/endoscopists saw > 600 CRPS each(total 52,760 CRPS), that pathologist, endoscopist, anatomical location and year were all strongly correlated (all p < 0.0001) with the diagnosis. The moderate PDR stability over time supports the hypothesis that diagnostic rates are amendable to calibration via SPC and outcome data.
Tetra-gel enables superior accuracy in combined super-resolution imaging and expansion microscopy
Authors: Lee Hsuan , Yu Chih-Chieh , Boyden Edward S. , Zhuang Xiaowei , Kosuri Pallav
Published: August 2021

The accuracy of expansion microscopy (ExM) depends on the structural preservation of samples embedded in a hydrogel. However, it has been unknown to what extent gel embedding alters the molecular positions of individual labeled sites. Here, we quantified the accuracy of gel embedding by using stochastic optical reconstruction microscopy (STORM) to image DNA origami with well-defined structures. We found that embedding in hydrogels based on polyacrylamide, the most widely used chemistry in ExM, resulted in random displacements of labeled sites with a standard deviation of ~ 16 nm. In contrast, we found that embedding in tetra-gel, a hydrogel that does not depend on free-radical chain-growth polymerization, preserved labeled sites with a standard deviation of less than 5 nm. By combining tetra-gel ExM with STORM, we were able to resolve 11-nm structural features without the loss in accuracy seen with polyacrylamide gels. Our study thus provides direct measurements of the single-molecule distortions resulting from hydrogel embedding, and presents a way to improve super-resolution microscopy through combination with tetra-gel ExM.
Longitudinal study of risk factors for decreased cross-sectional area of psoas major and paraspinal muscle in 1849 individuals
Authors: Murata Yoichi , Nakamura Eiichiro , Tsukamoto Manabu , Nakagawa Toru , Takeda Masaru , Kozuma Mio , Kadomura Takayuki , Narusawa Kenichiro , Shimizu Kenji , Uchida Soshi , Hayashi Takeshi , Sakai Akinori
Published: August 2021

This 10-year retrospective observational study investigated longitudinal losses in psoas major and paraspinal muscle area in 1849 healthy individuals (1690 male, 159 female) screened using computed tomography. Logistic regression analysis revealed significant decreases in psoas major and paraspinal muscle area at 10 years relative to the baseline area regardless of age or sex, starting at 30 years of age. Only aging [≥ 50 s (odds ratio [OR]: 1.72; 95% confidence interval [CI] 1.05–2.84; p = 0.03) and ≥ 60 s (OR: 2.67; 95% CI 1.55–4.60; p < 0.001)] was a risk factor for decreases in psoas major area. Age ≥ 60 years (OR: 2.05; 95% CI 1.24–3.39; p = 0.005), body mass index ≥ 25 kg/m2 (OR: 1.32; 95% CI 1.01–1.73; p = 0.04), and visceral fat ≥ 100 cm2 (OR: 1.61; 95% CI 1.20–2.15; p = 0.001) were risk factors for decreases in paraspinal muscle area. Physical activity ≥ 900 kcal/week (OR: 0.68; 95% CI 0.50–0.94; p = 0.02) attenuated paraspinal muscle area loss in male. Our study demonstrated that walking > 45 min daily (Calories = METs (walking: 3.0) × duration of time (h) × weight (60 kg) × 1.05) can reduce paraspinal muscle loss, which may in turn decrease the risk of falls, low-back pain, and sarcopenia.