bluuebunny/crossref_metadata_2025 huggingface dataset:
Institutional Activism and Ethnic Intermediation in Post-Communist Romania
Authors: Fittante Daniel
Published: May 2021

Existing studies on legal approaches to ethnic minority representation often highlight different systems’ strengths and weaknesses. While this scholarship provides important insights into the growing body of literature on minority representation, the topic remains largely under-theorized. Because systems of ethnic minority representation clarify the organizations and philosophies of diverse states, more theoretical analyses can enrich the descriptive literature. Building on the existing scholarship, this article assesses Romania’s particular version of proportional representation regarding designated national minorities. It applies two theoretical models: (1) institutional activism and (2) ethnic intermediation. The former clarifies the establishment of Romania’s post-communist constitutional provisions regarding minority organizations, and the latter explains how small yet influential minority populations make claims to and reallocate resources from the Romanian state. Through a unique, understudied case study – the Armenian community of Romania – this article attempts to broaden ethnic minority representation scholarship by refining the theoretical frameworks of institutional activism and ethnic intermediation.
Can neuroscience help to understand narcissism? A systematic review of an emerging field
Authors: Jauk Emanuel , Kanske Philipp
Published: May 2021

Narcissism is a Janusian personality construct, associated with both grandiose self-assuredness and dominance, as well as vulnerable insecurity and reactivity. Central questions of intra- and interpersonal functioning in narcissism are still a matter of debate. Neuroscience could help to understand the paradoxical patterns of experience and behavior beyond the limitations of self-reports. We provide a systematic review of 34 neuroscience studies on grandiose, vulnerable, pathological narcissism, and Narcissistic Personality Disorder (NPD), spanning experimental investigations of intra- and interpersonal mechanisms, research on neurophysiological and neuroendocrine aspects of baseline function, and brain structural correlates. While neuroscience has scarcely directly studied vulnerable narcissism, grandiose narcissism is associated with heightened vigilance to ego threat and stress responses following ego threat, as well as heightened stress indicators in baseline measures. Such responses are not commonly observed in self-reports, highlighting the potential of neuroscience to augment our understanding of self-regulatory dynamics in narcissism. Interpersonal functioning is characterized by deficits in social–affective processes. Both involve altered activity within the salience network, pointing to a double dissociation regarding the expression of narcissism and self/other oriented situational focus. Findings are summarized in an integrative model providing testable hypotheses for future research along with methodological recommendations.
Smoking Clubs in Graphic Satire and the Anglicizing of Tobacco in Eighteenth-Century Britain
Authors: Roman Cynthia
Published: May 2021

Focusing onA smoking club(1793/7) by James Gillray, this essay presents satiric representations of smoking clubs in late eighteenth- and early nineteenth-century British prints, arguing that they reflect and mediate contemporary understandings of tobacco as an intoxicant in British associational life. The breadth of potential cultural connotations – from political and social parody to light-hearted humour – is traced through the content and imagery of selected prints. These prints rely on the familiarity of contemporary audiences with political and social knowledge, as well as a visual iconography iconically realized in William Hogarth'sA midnight modern conversation(1732).
Women in Diplomacy in Late Eighteenth-Century Istanbul
Authors: Do Paço David
Published: May 2021

This article identifies the different roles played by women in the diplomatic corps of the Pera embassies of Christian-ruled states. It focuses on women operating in and from the Habsburg embassy during the last two decades of the eighteenth century, a period marked by the revolutionary wars and the beginning of the ‘Eastern Question’. Using a microhistorical approach, this article analyses how women facilitated the embedding of individual members of the diplomatic corps in Pera's diplomatic social scene, the social integration of young diplomats, and the development of the trans-imperial networks of influence upon which diplomats heavily depended. It shifts the focus from states to actors and invites a more systematic development of a diplomatic history based on networks of non-official agents, thus enabling an improved understanding of the family, social, and urban dynamics that led to the development of political elites. This article draws on a set of private sources and parish sources in order to emphasize the role of households in the diplomacy of empires, the agenda of women in the management of patronage and power networks, and the diversity of their social affiliation.
Geometric particle-in-cell methods for the Vlasov–Maxwell equations with spin effects
Authors: Crouseilles Nicolas , Hervieux Paul-Antoine , Li Yingzhe , Manfredi Giovanni , Sun Yajuan
Published: May 2021

We propose a numerical scheme to solve the semiclassical Vlasov–Maxwell equations for electrons with spin. The electron gas is described by a distribution function

$f(t,{\boldsymbol x},{{{\boldsymbol p}}}, {\boldsymbol s})$

that evolves in an extended 9-dimensional phase space

$({\boldsymbol x},{{{\boldsymbol p}}}, {\boldsymbol s})$

, where

$\boldsymbol s$

represents the spin vector. Using suitable approximations and symmetries, the extended phase space can be reduced to five dimensions:

$(x,{{p_x}}, {\boldsymbol s})$

. It can be shown that the spin Vlasov–Maxwell equations enjoy a Hamiltonian structure that motivates the use of the recently developed geometric particle-in-cell (PIC) methods. Here, the geometric PIC approach is generalized to the case of electrons with spin. Total energy conservation is very well satisfied, with a relative error below

$0.05\,\%$

. As a relevant example, we study the stimulated Raman scattering of an electromagnetic wave interacting with an underdense plasma, where the electrons are partially or fully spin polarized. It is shown that the Raman instability is very effective in destroying the electron polarization.
Maternal characteristics influence infant feeding styles in Caribbean women
Authors: Wright Amika S , Tulloch-Reid Marshall K , Chang Susan M , Walker Susan P
Published: May 2021

Objective:

To examine associations between maternal characteristics and feeding styles in Caribbean mothers.

Design:

Participants were mother–child pairs enrolled in a cluster randomised trial of a parenting intervention in three Caribbean islands. Maternal characteristics were obtained by questionnaires when infants were 6–8 weeks old. Items adapted from the Toddler Feeding Behaviour Questionnaire were used to assess infant feeding styles at the age of 1 year. Feeding styles were identified using factor analysis and associations with maternal characteristics assessed using multilevel linear regression.

Setting:

Health clinics in St. Lucia (n 9), Antigua (n 10) and Jamaica (n 20).

Participants:

A total of 405 mother–child pairs from the larger trial.

Results:

Maternal depressive symptoms were associated with uninvolved (β = 0·38, 95 % CI (0·14, 0·62)), restrictive (β = 0·44, 95 % CI (0·19, 0·69)) and forceful (β = 0·31, 95 % CI (0·06, 0·57)) feeding and inversely associated with responsive feeding (β = −0·30, 95 % CI (−0·56, −0·05)). Maternal vocabulary was inversely associated with uninvolved (β = −0·31, 95 % CI (−0·57, −0·06)), restrictive (β = −0·30, 95 % CI (−0·56, −0·04)), indulgent (β = −0·47, 95 % CI (−0·73, −0·21)) and forceful (β = −0·54, 95 % CI (−0·81, −0·28)) feeding. Indulgent feeding was negatively associated with socio-economic status (β = −0·27, 95 % CI (−0·53, −0·00)) and was lower among mothers ≥35 years (β = −0·32, 95 % CI (−0·62, −0·02)). Breast-feeding at 1 year was associated with forceful feeding (β = 0·41, 95 % CI (0·21, 0·61)). No significant associations were found between maternal education, BMI, occupation and feeding styles.

Conclusion:

Services to identify and assist mothers with depressive symptoms may benefit infant feeding style. Interventions to promote responsive feeding may be important for less educated, younger and socio-economically disadvantaged mothers.
The Moral Economy of the Kolkhoz Worker, Or Why the Protest Movement in Belarus Does Not Seem to Concern the Collectivized Countryside
Authors: Hervouet Ronan
Published: May 2021

The mass protests that have shaken Belarus since August 9, 2020 are occurring not only in the capital but also in provincial towns and even in smaller municipalities in Belarus. The protest does not seem to be affecting the countryside, however. This article, based on an ethnographic survey conducted in rural Belarus between 2006 and 2013, analyzes the roots of the attachment to Lukashenka's regime in these territories. The article describes the moral economy of kolkhozes, that is, the normative bases on which these social worlds are founded: equality, solidarity, and dignity. At the same time, the analysis reveals the figures of the moral offenders that rural inhabitants identify as posing a threat to their worlds: the profiteer, the idler, and the moralist. This defines the expectations toward politics that can be identified in the countryside, which essentially boil down to the conversion or punishment of these “moral offenders.”
Belarusian Protest: Regimes of Engagement and Coordination
Authors: Gabowitsch Mischa
Published: May 2021

The Belarusian protest movement that started in August 2020 has been discussed from the point of view of strategy and objectives, and as the cradle of a new subjectivity. This essay goes beyond those two perspectives by looking at the regimes of engagement, developing in interaction with the material and technological environment, that have given the protests their distinctive style. The first part looks at coordination and representation at protest events and in producing protest symbols such as flags. The second part discusses the role of Telegram and the emergence of local protest groups. Even though the movement did not grow organically out of everyday concerns, there are some signs that it has begun to reassemble local communities from above. Yet there are also indications that politics continues to be seen as distinct from everyday life, making it uncertain that the movement will lead to a deeper transformation of society.
Analytical and Experimental Investigation of the Impact of Land Reclamation on Steady‐State Seawater Extent in Coastal Aquifers
Authors: Zhang Jia , Lu Chunhui , Werner Adrian D.
Published: May 2021

Previous studies of the effects of land reclamation on the extent of seawater in coastal aquifers have assumed that the reclaimed area penetrates to the impermeable base of aquifer, and that the seawater in the aquifer is entirely contained within reclaimed sediments. The current study extends previous research into the effects of reclamation on groundwater levels and seawater extent by developing new analytical expressions for the steady‐state heads and non‐dispersive freshwater‐seawater interface for situations where reclaimed soils overly permeable aquifer material. Situations involving reclaimed soils that are more permeable or less permeable than the original aquifer are explored. Sand‐tank experiments and associated numerical simulations (in 2D cross section) were undertaken to evaluate assumptions adopted in developing the solutions, which include an empirical correction to account for dispersion effects. Sand tank solute distributions are well matched to numerical modeling results, and provide validation of analytical solutions and the associated simplifications. Application of the new solution demonstrates that both the water level rise and the seaward shift of seawater extent caused by reclamation are modified with the inclusion of the underlying permeable layer, depending on permeability contrasts and the reclaimed area size. For example, if the reclaimed soil is less permeable than the original aquifer, water level rise and the seawater extent shift are reduced with the inclusion of an underlying permeable layer. The analytical solution developed in this study can provide rapid guidance on the changes to seawater extent and groundwater levels caused by land reclamation in otherwise permeable substrate.
Covariation of Slab Tracers, Volatiles, and Oxidation During Subduction Initiation
Authors: Brounce Maryjo , Reagan Mark K. , Kelley Katherine A. , Cottrell Elizabeth , Shimizu Kenji , Almeev Renat
Published: May 2021

Subduction‐related lavas have higher Fe3+/∑Fe than midocean ridge basalts (MORB). Hypotheses for this offset include imprint from subducting slabs and differentiation in thickened crust. These ideas are readily tested through examination of the time‐dependent evolution of slab‐derived signatures, thickening crust of the overriding plate, and evolving redox during subduction initiation. Here, we present Fe3+/ΣFe and volatile element abundances of volcanic glasses recovered from International Ocean Discovery Program (IODP) Expedition 352 to the Izu‐Bonin‐Mariana (IBM) forearc. The samples include forearc basalts (FAB) that are stratigraphically overlain by low‐ and high‐silica boninite lavas. The FAB glasses have 0.18–0.85 wt% H2O, 75–233 ppm CO2, S contents controlled by saturation with a sulfide phase (602–1,386 ppm), Ba/La from 3.9‐10, and Fe3+/ΣFe ratios from 0.136 to 0.177. These compositions are similar to MORB and suggest that decompression melting of dry and reduced mantle dominates the earliest stages of subduction initiation. Low‐ and high‐silica boninite glasses have 1.51–3.19 wt% H2O, CO2 below detection, S contents below those required for sulfide saturation (5–235 ppm), Ba/La from 11 to 29, and Fe3+/∑Fe from 0.181 to 0.225. The compositions are broadly similar to modern arc lavas in the IBM arc. These data demonstrate that the establishment of fluid‐fluxed melting of the mantle, which occurs in just 0.6–1.2 my after subduction initiation, is synchronous with the production of oxidized, mantle‐derived magmas. The coherence of high Fe3+/∑Fe and Ba/La ratios with high H2O contents in Expedition 352 glasses and the modern IBM arc rocks strongly links the production of oxidized arc magmas to signatures of slab dehydration.
Do genetic risk scores for childhood adiposity operate independent of BMI of their mothers?
Authors: Huang Lam O. , Morgen Camilla S. , Ängquist Lars , Nohr Ellen A. , Kilpeläinen Tuomas O. , Hansen Torben , Sørensen Thorkild I. A. , Schnurr Theresia M.
Published: May 2021

Objectives

Genetic predisposition and maternal body mass index (BMI) are risk factors for childhood adiposity, defined by either BMI or overweight. We aimed to investigate whether childhood-specific genetic risk scores (GRSs) for adiposity-related traits are associated with childhood adiposity independent of maternal BMI, or whether the associations are modified by maternal BMI.

Methods

We constructed a weighted 26-SNP child BMI-GRS and a weighted 17-SNP child obesity-GRS in overall 1674 genotyped children within the Danish National Birth Cohort. We applied a case-cohort (N = 1261) and exposure-based cohort (N = 912) sampling design. Using logistic regression models we estimated associations of the GRSs and child overweight at age 7 years and examined if the GRSs influence child adiposity independent of maternal BMI (per standard deviation units).

Results

In the case-cohort design analysis, maternal BMI and the child GRSs were associated with increased odds for childhood overweight [OR for maternal BMI: 2.01 (95% CI: 1.86; 2.17), OR for child BMI-GRS: 1.56 (95% CI: 1.47; 1.66), and OR for child obesity-GRS 1.46 (95% CI: 1.37; 1.54)]. Adjustment for maternal BMI did not change the results, and there were no significant interactions between the GRSs and maternal BMI. However, in the exposure-based cohort design analysis, significant interactions between the child GRSs and maternal BMI on child overweight were observed, suggesting 0.85–0.87-fold attenuation on ORs of child overweight at higher values of maternal BMI and child GRS.

Conclusion

GRSs for childhood adiposity are strongly associated with childhood adiposity even when adjusted for maternal BMI, suggesting that the child-specific GRSs and maternal BMI contribute to childhood overweight independent of each other. However, high maternal BMI may attenuate the effects of child GRSs in children.
Final results of a phase 1b study of isatuximab short-duration fixed-volume infusion combination therapy for relapsed/refractory multiple myeloma
Authors: Usmani Saad Z. , Karanes Chatchada , Bensinger William I. , D’Souza Anita , Raje Noopur , Tuchman Sascha A. , Sborov Douglas , Laubach Jacob P. , Bianchi Giada , Kanagavel Dheepak , Saleem Rao , Dubin Franck , Campana Frank , Richardson Paul G.
Published: May 2021

Part B of this phase 1b study (ClinicalTrials.gov number, NCT02283775) evaluated safety and efficacy of a fixed-volume infusion of isatuximab, an anti-CD38 monoclonal antibody, in combination with pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma patients. Isatuximab (10 mg/kg weekly for 4 weeks, then every other week) was administered as a fixed-volume infusion of 250 mL (mL/h infusion rate) with standard doses of Pd on 28-day cycles. Patients (N = 47) had a median of three prior treatment lines (range, 1–8). Median duration of exposure was 36.9 weeks and median duration of first, second, and 3+ infusions were 3.7, 1.8, and 1.2 h, respectively. The most common non-hematologic treatment-emergent adverse events were fatigue (63.8%), infusion reactions (IRs), cough, and upper respiratory tract infection (40.4% each). IRs were all grade 2 and occurred only during the first infusion. The overall response rate was 53.2% in all patients (55.5% in response-evaluable population, 60.0% in daratumumab-naïve patients). Efficacy and safety findings were consistent with data from the isatuximab plus Pd infusion schedule in Part A of this study and also from the phase 3 ICARIA-MM study, and these new data confirm the safety, efficacy, and feasibility of fixed-volume infusion of isatuximab.
Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity
Authors: Wang Xiao-Lan , Kooijman Sander , Gao Yuanqing , Tzeplaeff Laura , Cosquer Brigitte , Milanova Irina , Wolff Samantha E. C. , Korpel Nikita , Champy Marie-France , Petit-Demoulière Benoit , Goncalves Da Cruz Isabelle , Sorg-Guss Tania , Rensen Patrick C. N. , Cassel Jean-Christophe , Kalsbeek Andries , Boutillier Anne-Laurence , Yi Chun-Xia
Published: May 2021

Microglia play a critical role in maintaining neural function. While microglial activity follows a circadian rhythm, it is not clear how this intrinsic clock relates to their function, especially in stimulated conditions such as in the control of systemic energy homeostasis or memory formation. In this study, we found that microglia-specific knock-down of the core clock gene, Bmal1, resulted in increased microglial phagocytosis in mice subjected to high-fat diet (HFD)-induced metabolic stress and likewise among mice engaged in critical cognitive processes. Enhanced microglial phagocytosis was associated with significant retention of pro-opiomelanocortin (POMC)-immunoreactivity in the mediobasal hypothalamus in mice on a HFD as well as the formation of mature spines in the hippocampus during the learning process. This response ultimately protected mice from HFD-induced obesity and resulted in improved performance on memory tests. We conclude that loss of the rigorous control implemented by the intrinsic clock machinery increases the extent to which microglial phagocytosis can be triggered by neighboring neurons under metabolic stress or during memory formation. Taken together, microglial responses associated with loss of Bmal1 serve to ensure a healthier microenvironment for neighboring neurons in the setting of an adaptive response. Thus, microglial Bmal1 may be an important therapeutic target for metabolic and cognitive disorders with relevance to psychiatric disease.
Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia–ischemia
Authors: Martinello Kathryn A. , Meehan Christopher , Avdic-Belltheus Adnan , Lingam Ingran , Mutshiya Tatenda , Yang Qin , Akin Mustafa Ali , Price David , Sokolska Magdalena , Bainbridge Alan , Hristova Mariya , Tachtsidis Ilias , Tann Cally J. , Peebles Donald , Hagberg Henrik , Wolfs Tim G. A. M. , Klein Nigel , Kramer Boris W. , Fleiss Bobbi , Gressens Pierre , Golay Xavier , Robertson Nicola J.
Published: May 2021

Background

Perinatal inflammation combined with hypoxia–ischemia (HI) exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown.

Methods

Twelve newborn piglets received a 2 µg/kg bolus and 1 µg/kg/h infusion over 52 h of Escherichia coli lipopolysaccharide (LPS). HI was induced 4 h after LPS bolus. After HI, piglets were randomized to HT (33.5 °C 1–25 h after HI, n = 6) or normothermia (NT, n = 6). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48 h. At 48 h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured.

Results

Two HT piglets died. aEEG recovery, thalamic and white matter MRS lactate/N-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation/proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT.

Conclusions

We did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. Immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI.

Impact

Acute infection/inflammation is known to exacerbate perinatal brain injury and can worsen the outcomes in neonatal encephalopathy.

Therapeutic HT is the current standard of care for all infants with NE, but the benefit in infants with coinfection/inflammation is unknown.

In a piglet model of inflammation (LPS)-sensitized HI, we observed no evidence of neuroprotection with cooling for 24 h, based on our primary outcome measures: aEEG, MRS Lac/NAA, and histological brain cell death.

Additional neuroprotective agents, with beneficial immunomodulatory effects, require exploration in IS-HI models.
PNO1 regulates autophagy and apoptosis of hepatocellular carcinoma via the MAPK signaling pathway
Authors: Han Zhiqiang , Liu Dongming , Chen Lu , He Yuchao , Tian Xiangdong , Qi Lisha , Chen Liwei , Luo Yi , Chen Ziye , Hu Xiaomeng , Li Guangtao , Zhan Linlin , Wang Yu , Li Qiang , Chen Peng , Liu Zhiyong , Guo Hua
Published: May 2021

Some studies have reported that activated ribosomes are positively associated with malignant tumors, especially in hepatocellular carcinoma (HCC). The RNA-binding protein PNO1 is a critical ribosome rarely reported in human tumors. This study aimed to explore the molecular mechanisms of PNO1 in HCC. Using 150 formalin-fixed and paraffin-embedded samples and 8 fresh samples, we found high PNO1 expression in HCC tumor tissues through Western blotting and RT-PCR. Moreover, the higher PNO1 expression was associated with poor HCC prognosis patients. In vitro and in vivo experiments indicated that PNO1 overexpression promoted the proliferation and depressed the apoptosis of HCC cells. High PNO1 expression also increased the autophagy of HCC cells. The molecular mechanisms underlying PNO1 were examined by RNA-seq analysis and a series of functional experiments. Results showed that PNO1 promoted HCC progression through the MAPK signaling pathway. Therefore, PNO1 was overexpressed in HCC, promoted autophagy, and inhibited the apoptosis of HCC cells through the MAPK signaling pathway.
Nuclear exosome HMGB3 secreted by nasopharyngeal carcinoma cells promotes tumour metastasis by inducing angiogenesis
Authors: Zhang Kaiwen , Liu Dong , Zhao Jianmei , Shi Si , He Xin , Da Peng , You Yiwen , You Bo
Published: May 2021

Distant metastasis accompanied by angiogenesis is the main cause of nasopharyngeal carcinoma (NPC)-related death. Nuclear exosomes (nEXOs) are potential tumour biomarkers. High mobility group box 3 (HMGB3), a nuclear protein, is known to be overexpressed in cancers. However, its role in NPC has not been elucidated. Here, we explore for the first time the function of nEXO HMGB3 in tumour angiogenesis involved in NPC metastasis using a series of in vitro experiments with NPC cell lines and clinical specimens and in vivo experiments with tumour xenograft zebrafish angiogenesis model. We found a high expression of HMGB3 in NPC, accompanied by the formation of micronuclei, to be associated with metastasis. Furthermore, the NPC-secreted HMGB3 expression was associated with tumour angiogenesis. Moreover, HMGB3-containing nEXOs, derived from the micronuclei of NPC cells, were ingested by the human umbilical vein endothelial cells (HUVECs), and accelerated angiogenesis in vitro and in vivo. Importantly, western blotting and flow cytometry analysis showed that circulating nEXO HMGB3 positively correlated with NPC metastasis. In summary, nEXO HMGB3 can be a significant biomarker of NPC metastasis and provide a novel basis for anti-angiogenesis therapy in clinical metastasis.
Ruler elements in chromatin remodelers set nucleosome array spacing and phasing
Authors: Oberbeckmann Elisa , Niebauer Vanessa , Watanabe Shinya , Farnung Lucas , Moldt Manuela , Schmid Andrea , Cramer Patrick , Peterson Craig L. , Eustermann Sebastian , Hopfner Karl-Peter , Korber Philipp
Published: May 2021

Arrays of regularly spaced nucleosomes dominate chromatin and are often phased by alignment to reference sites like active promoters. How the distances between nucleosomes (spacing), and between phasing sites and nucleosomes are determined remains unclear, and specifically, how ATP-dependent chromatin remodelers impact these features. Here, we used genome-wide reconstitution to probe how Saccharomyces cerevisiae ATP-dependent remodelers generate phased arrays of regularly spaced nucleosomes. We find that remodelers bear a functional element named the ‘ruler’ that determines spacing and phasing in a remodeler-specific way. We use structure-based mutagenesis to identify and tune the ruler element residing in the Nhp10 and Arp8 modules of the INO80 remodeler complex. Generally, we propose that a remodeler ruler regulates nucleosome sliding direction bias in response to (epi)genetic information. This finally conceptualizes how remodeler-mediated nucleosome dynamics determine stable steady-state nucleosome positioning relative to other nucleosomes, DNA bound factors, DNA ends and DNA sequence elements.
Impact of DNA methylation on 3D genome structure
Authors: Buitrago Diana , Labrador Mireia , Arcon Juan Pablo , Lema Rafael , Flores Oscar , Esteve-Codina Anna , Blanc Julie , Villegas Nuria , Bellido David , Gut Marta , Dans Pablo D. , Heath Simon C. , Gut Ivo G. , Brun Heath Isabelle , Orozco Modesto
Published: May 2021

Determining the effect of DNA methylation on chromatin structure and function in higher organisms is challenging due to the extreme complexity of epigenetic regulation. We studied a simpler model system, budding yeast, that lacks DNA methylation machinery making it a perfect model system to study the intrinsic role of DNA methylation in chromatin structure and function. We expressed the murine DNA methyltransferases inSaccharomyces cerevisiaeand analyzed the correlation between DNA methylation, nucleosome positioning, gene expression and 3D genome organization. Despite lacking the machinery for positioning and reading methylation marks, induced DNA methylation follows a conserved pattern with low methylation levels at the 5’ end of the gene increasing gradually toward the 3’ end, with concentration of methylated DNA in linkers and nucleosome free regions, and with actively expressed genes showing low and high levels of methylation at transcription start and terminating sites respectively, mimicking the patterns seen in mammals. We also see that DNA methylation increases chromatin condensation in peri-centromeric regions, decreases overall DNA flexibility, and favors the heterochromatin state. Taken together, these results demonstrate that methylation intrinsically modulates chromatin structure and function even in the absence of cellular machinery evolved to recognize and process the methylation signal.
High proliferation and delamination during skin epidermal stratification
Authors: Damen Mareike , Wirtz Lisa , Soroka Ekaterina , Khatif Houda , Kukat Christian , Simons Benjamin D. , Bazzi Hisham
Published: May 2021

The development of complex stratified epithelial barriers in mammals is initiated from single-layered epithelia. How stratification is initiated and fueled are still open questions. Previous studies on skin epidermal stratification suggested a central role for perpendicular/asymmetric cell division orientation of the basal keratinocyte progenitors. Here, we use centrosomes, that organize the mitotic spindle, to test whether cell division orientation and stratification are linked. Genetically ablating centrosomes from the developing epidermis leads to the activation of the p53-, 53BP1- and USP28-dependent mitotic surveillance pathway causing a thinner epidermis and hair follicle arrest. The centrosome/p53-double mutant keratinocyte progenitors significantly alter their division orientation in the later stages without majorly affecting epidermal differentiation. Together with time-lapse imaging and tissue growth dynamics measurements, the data suggest that the first and major phase of epidermal development is boosted by high proliferation rates in both basal and suprabasally-committed keratinocytes as well as cell delamination, whereas the second phase maybe uncoupled from the division orientation of the basal progenitors. The data provide insights for tissue homeostasis and hyperproliferative diseases that may recapitulate developmental programs.
Retention time prediction using neural networks increases identifications in crosslinking mass spectrometry
Authors: Giese Sven H. , Sinn Ludwig R. , Wegner Fritz , Rappsilber Juri
Published: May 2021

Crosslinking mass spectrometry has developed into a robust technique that is increasingly used to investigate the interactomes of organelles and cells. However, the incomplete and noisy information in the mass spectra of crosslinked peptides limits the numbers of protein–protein interactions that can be confidently identified. Here, we leverage chromatographic retention time information to aid the identification of crosslinked peptides from mass spectra. Our Siamese machine learning model xiRT achieves highly accurate retention time predictions of crosslinked peptides in a multi-dimensional separation of crosslinked E. coli lysate. Importantly, supplementing the search engine score with retention time features leads to a substantial increase in protein–protein interactions without affecting confidence. This approach is not limited to cell lysates and multi-dimensional separation but also improves considerably the analysis of crosslinked multiprotein complexes with a single chromatographic dimension. Retention times are a powerful complement to mass spectrometric information to increase the sensitivity of crosslinking mass spectrometry analyses.
Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy
Authors: Bian Zhen , Shi Lei , Kidder Koby , Zen Ke , Garnett-Benson Charlie , Liu Yuan
Published: May 2021

Radiotherapy (RT)-induced tumoricidal immunity is severely limited when tumors are well-established. Here, we report that depleting SIRPα on intratumoral macrophages augments efficacy of RT to eliminate otherwise large, treatment-resistant colorectal (MC38) and pancreatic (Pan02 and KPC) tumors, inducing complete abscopal remission and long-lasting humoral and cellular immunity that prevent recurrence. SIRPα-deficient macrophages activated by irradiated tumor-released DAMPs exhibit robust efficacy and orchestrate an anti-tumor response that controls late-stage tumors. Upon RT-mediated activation, intratumoral SIRPα-deficient macrophages acquire potent proinflammatory features and conduct immunogenic antigen presentation that confer a tumoricidal microenvironment highly infiltrated by tumor-specific cytotoxic T cells, NK cells and inflammatory neutrophils, but with limited immunosuppressive regulatory T cells, myeloid derived suppressor cells and post-radiation wound-healing. The results demonstrate that SIRPα is a master regulator underlying tumor resistance to RT and provide proof-of-principle for SIRPα-deficient macrophage-based therapies to treat a broad spectrum of cancers, including those at advanced stages with low immunogenicity and metastases.
A deep learning system for detecting diabetic retinopathy across the disease spectrum
Authors: Dai Ling , Wu Liang , Li Huating , Cai Chun , Wu Qiang , Kong Hongyu , Liu Ruhan , Wang Xiangning , Hou Xuhong , Liu Yuexing , Long Xiaoxue , Wen Yang , Lu Lina , Shen Yaxin , Chen Yan , Shen Dinggang , Yang Xiaokang , Zou Haidong , Sheng Bin , Jia Weiping
Published: May 2021

Retinal screening contributes to early detection of diabetic retinopathy and timely treatment. To facilitate the screening process, we develop a deep learning system, named DeepDR, that can detect early-to-late stages of diabetic retinopathy. DeepDR is trained for real-time image quality assessment, lesion detection and grading using 466,247 fundus images from 121,342 patients with diabetes. Evaluation is performed on a local dataset with 200,136 fundus images from 52,004 patients and three external datasets with a total of 209,322 images. The area under the receiver operating characteristic curves for detecting microaneurysms, cotton-wool spots, hard exudates and hemorrhages are 0.901, 0.941, 0.954 and 0.967, respectively. The grading of diabetic retinopathy as mild, moderate, severe and proliferative achieves area under the curves of 0.943, 0.955, 0.960 and 0.972, respectively. In external validations, the area under the curves for grading range from 0.916 to 0.970, which further supports the system is efficient for diabetic retinopathy grading.
Robust learning from noisy, incomplete, high-dimensional experimental data via physically constrained symbolic regression
Authors: Reinbold Patrick A. K. , Kageorge Logan M. , Schatz Michael F. , Grigoriev Roman O.
Published: May 2021

Machine learning offers an intriguing alternative to first-principle analysis for discovering new physics from experimental data. However, to date, purely data-driven methods have only proven successful in uncovering physical laws describing simple, low-dimensional systems with low levels of noise. Here we demonstrate that combining a data-driven methodology with some general physical principles enables discovery of a quantitatively accurate model of a non-equilibrium spatially extended system from high-dimensional data that is both noisy and incomplete. We illustrate this using an experimental weakly turbulent fluid flow where only the velocity field is accessible. We also show that this hybrid approach allows reconstruction of the inaccessible variables – the pressure and forcing field driving the flow.
Integrating genomics and metabolomics for scalable non-ribosomal peptide discovery
Authors: Behsaz Bahar , Bode Edna , Gurevich Alexey , Shi Yan-Ni , Grundmann Florian , Acharya Deepa , Caraballo-Rodríguez Andrés Mauricio , Bouslimani Amina , Panitchpakdi Morgan , Linck Annabell , Guan Changhui , Oh Julia , Dorrestein Pieter C. , Bode Helge B. , Pevzner Pavel A. , Mohimani Hosein
Published: May 2021

Non-Ribosomal Peptides (NRPs) represent a biomedically important class of natural products that include a multitude of antibiotics and other clinically used drugs. NRPs are not directly encoded in the genome but are instead produced by metabolic pathways encoded bybiosynthetic gene clusters(BGCs). Since the existing genome mining tools predict many putative NRPs synthesized by a given BGC, it remains unclear which of these putative NRPs are correct and how to identify post-assembly modifications of amino acids in these NRPs in a blind mode, without knowing which modifications exist in the sample. To address this challenge, here we report NRPminer, a modification-tolerant tool for NRP discovery from large (meta)genomic and mass spectrometry datasets. We show that NRPminer is able to identify many NRPs from different environments, including four previously unreported NRP families from soil-associated microbes and NRPs from human microbiota. Furthermore, in this work we demonstrate the anti-parasitic activities and the structure of two of these NRP families using direct bioactivity screening and nuclear magnetic resonance spectrometry, illustrating the power of NRPminer for discovering bioactive NRPs.
Structure of the mature Rous sarcoma virus lattice reveals a role for IP6 in the formation of the capsid hexamer
Authors: Obr Martin , Ricana Clifton L. , Nikulin Nadia , Feathers Jon-Philip R. , Klanschnig Marco , Thader Andreas , Johnson Marc C. , Vogt Volker M. , Schur Florian K. M. , Dick Robert A.
Published: May 2021

Inositol hexakisphosphate (IP6) is an assembly cofactor for HIV-1. We report here that IP6 is also used for assembly of Rous sarcoma virus (RSV), a retrovirus from a different genus. IP6 is ~100-fold more potent at promoting RSV mature capsid protein (CA) assembly than observed for HIV-1 and removal of IP6 in cells reduces infectivity by 100-fold. Here, visualized by cryo-electron tomography and subtomogram averaging, mature capsid-like particles show an IP6-like density in the CA hexamer, coordinated by rings of six lysines and six arginines. Phosphate and IP6 have opposing effects on CA in vitro assembly, inducing formation of T = 1 icosahedrons and tubes, respectively, implying that phosphate promotes pentamer and IP6 hexamer formation. Subtomogram averaging and classification optimized for analysis of pleomorphic retrovirus particles reveal that the heterogeneity of mature RSV CA polyhedrons results from an unexpected, intrinsic CA hexamer flexibility. In contrast, the CA pentamer forms rigid units organizing the local architecture. These different features of hexamers and pentamers determine the structural mechanism to form CA polyhedrons of variable shape in mature RSV particles.
Generative modeling of single-cell time series with PRESCIENT enables prediction of cell trajectories with interventions
Authors: Yeo Grace Hui Ting , Saksena Sachit D. , Gifford David K.
Published: May 2021

Existing computational methods that use single-cell RNA-sequencing (scRNA-seq) for cell fate prediction do not model how cells evolve stochastically and in physical time, nor can they predict how differentiation trajectories are altered by proposed interventions. We introduce PRESCIENT (Potential eneRgy undErlying Single Cell gradIENTs), a generative modeling framework that learns an underlying differentiation landscape from time-series scRNA-seq data. We validate PRESCIENT on an experimental lineage tracing dataset, where we show that PRESCIENT is able to predict the fate biases of progenitor cells in hematopoiesis when accounting for cell proliferation, improving upon the best-performing existing method. We demonstrate how PRESCIENT can simulate trajectories for perturbed cells, recovering the expected effects of known modulators of cell fate in hematopoiesis and pancreatic β cell differentiation. PRESCIENT is able to accommodate complex perturbations of multiple genes, at different time points and from different starting cell populations, and is available at https://github.com/gifford-lab/prescient.
Dimerization and oligomerization of DNA-assembled building blocks for controlled multi-motion in high-order architectures
Authors: Xin Ling , Duan Xiaoyang , Liu Na
Published: May 2021

In living organisms, proteins are organized prevalently through a self-association mechanism to form dimers and oligomers, which often confer new functions at the intermolecular interfaces. Despite the progress on DNA-assembled artificial systems, endeavors have been largely paid to achieve monomeric nanostructures that mimic motor proteins for a single type of motion. Here, we demonstrate a DNA-assembled building block with rotary and walking modules, which can introduce new motion through dimerization and oligomerization. The building block is a chiral system, comprising two interacting gold nanorods to perform rotation and walking, respectively. Through dimerization, two building blocks can form a dimer to yield coordinated sliding. Further oligomerization leads to higher-order structures, containing alternating rotation and sliding dimer interfaces to impose structural twisting. Our hierarchical assembly scheme offers a design blueprint to construct DNA-assembled advanced architectures with high degrees of freedom to tailor the optical responses and regulate multi-motion on the nanoscale.
Genome-resolved metagenomics reveals role of iron metabolism in drought-induced rhizosphere microbiome dynamics
Authors: Xu Ling , Dong Zhaobin , Chiniquy Dawn , Pierroz Grady , Deng Siwen , Gao Cheng , Diamond Spencer , Simmons Tuesday , Wipf Heidi M.-L. , Caddell Daniel , Varoquaux Nelle , Madera Mary A. , Hutmacher Robert , Deutschbauer Adam , Dahlberg Jeffery A. , Guerinot Mary Lou , Purdom Elizabeth , Banfield Jillian F. , Taylor John W. , Lemaux Peggy G. , Coleman-Derr Devin
Published: May 2021

Recent studies have demonstrated that drought leads to dramatic, highly conserved shifts in the root microbiome. At present, the molecular mechanisms underlying these responses remain largely uncharacterized. Here we employ genome-resolved metagenomics and comparative genomics to demonstrate that carbohydrate and secondary metabolite transport functionalities are overrepresented within drought-enriched taxa. These data also reveal that bacterial iron transport and metabolism functionality is highly correlated with drought enrichment. Using time-series root RNA-Seq data, we demonstrate that iron homeostasis within the root is impacted by drought stress, and that loss of a plant phytosiderophore iron transporter impacts microbial community composition, leading to significant increases in the drought-enriched lineage, Actinobacteria. Finally, we show that exogenous application of iron disrupts the drought-induced enrichment of Actinobacteria, as well as their improvement in host phenotype during drought stress. Collectively, our findings implicate iron metabolism in the root microbiome’s response to drought and may inform efforts to improve plant drought tolerance to increase food security.
Mitochondrial targeted meganuclease as a platform to eliminate mutant mtDNA in vivo
Authors: Zekonyte Ugne , Bacman Sandra R. , Smith Jeff , Shoop Wendy , Pereira Claudia V. , Tomberlin Ginger , Stewart James , Jantz Derek , Moraes Carlos T.
Published: May 2021

Diseases caused by heteroplasmic mitochondrial DNA mutations have no effective treatment or cure. In recent years, DNA editing enzymes were tested as tools to eliminate mutant mtDNA in heteroplasmic cells and tissues. Mitochondrial-targeted restriction endonucleases, ZFNs, and TALENs have been successful in shifting mtDNA heteroplasmy, but they all have drawbacks as gene therapy reagents, including: large size, heterodimeric nature, inability to distinguish single base changes, or low flexibility and effectiveness. Here we report the adaptation of a gene editing platform based on the I-CreI meganuclease known as ARCUS®. These mitochondrial-targeted meganucleases (mitoARCUS) have a relatively small size, are monomeric, and can recognize sequences differing by as little as one base pair. We show the development of a mitoARCUS specific for the mouse m.5024C>T mutation in the mt-tRNAAla gene and its delivery to mice intravenously using AAV9 as a vector. Liver and skeletal muscle show robust elimination of mutant mtDNA with concomitant restoration of mt-tRNAAla levels. We conclude that mitoARCUS is a potential powerful tool for the elimination of mutant mtDNA.
Revealing the etching process of water-soluble Au25 nanoclusters at the molecular level
Authors: Cao Yitao , Liu Tongyu , Chen Tiankai , Zhang Bihan , Jiang De-en , Xie Jianping
Published: May 2021

Etching (often considered as decomposition) is one of the key considerations in the synthesis, storage, and application of metal nanoparticles. However, the underlying chemistry of their etching process still remains elusive. Here, we use real-time electrospray ionization mass spectrometry to study the reaction dynamics and size/structure evolution of all the stable intermediates during the etching of water-soluble thiolate-protected gold nanoclusters (Au NCs), which reveal an unusual “recombination” process in the oxidative reaction environment after the initial decomposition process. Interestingly, the sizes of NC species grow larger and their ligand-to-metal ratios become higher during this recombination process, which are distinctly different from that observed in the reductive growth of Au NCs (e.g., lower ligand-to-metal ratios with increasing sizes). The etching chemistry revealed in this study provides molecular-level understandings on how metal nanoparticles transform under the oxidative reaction environment, providing efficient synthetic strategies for new NC species through the etching reactions.
The IDEAL household energy dataset, electricity, gas, contextual sensor data and survey data for 255 UK homes
Authors: Pullinger Martin , Kilgour Jonathan , Goddard Nigel , Berliner Niklas , Webb Lynda , Dzikovska Myroslava , Lovell Heather , Mann Janek , Sutton Charles , Webb Janette , Zhong Mingjun
Published: May 2021

The IDEAL household energy dataset described here comprises electricity, gas and contextual data from 255 UK homes over a 23-month period ending in June 2018, with a mean participation duration of 286 days. Sensors gathered 1-second electricity data, pulse-level gas data, 12-second temperature, humidity and light data for each room, and 12-second temperature data from boiler pipes for central heating and hot water. 39 homes also included plug-level monitoring of selected electrical appliances, real-power measurement of mains electricity and key sub-circuits, and more detailed temperature monitoring of gas- and heat-using equipment, including radiators and taps. Survey data included occupant demographics, values, attitudes and self-reported energy awareness, household income, energy tariffs, and building, room and appliance characteristics. Linked secondary data comprises weather and level of urbanisation. The data is provided in comma-separated format with a custom-built API to facilitate usage, and has been cleaned and documented. The data has a wide range of applications, including investigating energy demand patterns and drivers, modelling building performance, and undertaking Non-Intrusive Load Monitoring research.