bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing Ambiguities: Municipalities, Francophone Minority Communities and Immigration in Canada
Authors: Fourot Aude-Claire
Published: January 2021

This article analyzes the implication of municipal governments and civil society actors in immigration through multilevel and collaborative governance arrangements. It argues that studying the roles of ambiguities is critical to understanding the activism of political entities with ill-defined status and mandates, such as municipalities and francophone minority communities (FMCs). This research adds to the literature on the “local turn” by highlighting that ambiguities are both a condition—that is, a driver that makes collaborative and multilevel arrangements work—and an outcome of collaboration practices, characterized by ambiguities regarding the balance of power, the aims of collaboration in a competitive sector and conflicting forms of accountabilities. The article identifies three approaches that actors use to deal with these ambiguities in a context where resources are not equitably distributed and where the role of the federal government is critical. In this configuration, municipalities and FMCs develop adaptive, rather than transformative, approaches to ambiguities.
Women's Municipal Electoral Performance: An Introduction to the Canadian Municipal Elections Database
Authors: Lucas Jack , Merrill Reed , Blidook Kelly , Breux Sandra , Conrad Laura , Eidelman Gabriel , Koop Royce , Marciano Daniella , Taylor Zack , Vallette Salomé
Published: January 2021

This research note describes the Canadian Municipal Elections Database (CMED), a new publicly available and actively maintained dataset of more than 24,000 municipal elections in Canada. We describe the need for high-quality election results data for municipal politics research and describe the content, sources and construction of the CMED. To illustrate the value of the CMED, we estimate gender differences in municipal electoral performance for the first time, finding that women are, on average, more likely than men to win municipal elections in Canada.
The interaction of host and nematode galectins influences the outcome of gastrointestinal nematode infections
Authors: Donskow-Łysoniewska Katarzyna , Maruszewska-Cheruiyot Marta , Stear Michael
Published: January 2021

Galectins are a family of proteins that bind β-galactosides and play key roles in a variety of cellular processes including host defence. They have been well studied in hosts but less so in gastrointestinal nematodes. Both host and parasite galectins are present in the gastrointestinal tract following infection. Parasite galectins can both bind antibody, especially highly glycosylated IgE and be bound by antibody. Parasite galectins may act as molecular sponges that soak up antibody. Host galectins promote mast cell degranulation while parasite galectins inhibit degranulation. Host and parasite galectins can also bind mucins and influence mucus viscosity. As the protective response against gastrointestinal nematode infection is partly dependent on IgE mediated mast cell degranulation and mucus, the interactions between host and parasite galectins play key roles in determining the outcome of infection.
COMBINING EXPLICIT AND SENSITIVE INDICES FOR MEASURING L2 VOCABULARY LEARNING THROUGH CONTEXTUALIZED INPUT AND WORD-FOCUSED INSTRUCTION
Authors: Vandenberghe Bert , Perez Maribel Montero , Reynvoet Bert , Desmet Piet
Published: January 2021

This study combines explicit (pen-and-paper) and sensitive (time-pressured) measures to gauge the impact of three instructional interventions (contextualized input with meaning-focused activities, contextualized input with word-focused activities, and decontextualized input with word-focused exercises) on the learning of 20 L2 French target verbs. Participants (N = 313, L1 = Dutch) completed a combination of explicit (form recognition, meaning recall, grammatical preference) and time-pressured sensitive tests (lexical decision, semantic relatedness, grammaticality judgment) as immediate and delayed posttests. Explicit posttests show the beneficial effects of word-focused instruction, and underline the efficiency of context for meaning-related knowledge. Sensitive posttests generally confirm the explicit results, but reveal differences between both word-focused conditions related to lexical processing and strength of knowledge. This study suggests that combining explicit and sensitive measures can provide a more complete picture about the effects of L2 vocabulary instruction and shows that contextualized and decontextualized word-focused instruction benefit vocabulary learning in a complementary way.
Powder X-ray diffraction of escitalopram oxalate oxalic acid hydrate, (C20H21FN2O)2(C2O4)(H2C2O4)(H2O)0.16
Authors: Kaduk James A. , Gindhart Amy M. , Blanton Thomas N.
Published: January 2021

Commercial escitalopram oxalate crystallizes as a hydrated adduct with oxalic acid, in the space group P21 with a = 8.029897(21), b = 25.09397(6), c = 11.138930(31) Å, β = 106.7759(2)°, V = 2148.992(7) Å3, and Z = 4. The agreement of the Rietveld and previous single-crystal structures is excellent; the root-mean-square Cartesian displacements of the non-H atoms of the two independent cations are 0.076 and 0.067 Å, respectively. The water molecule refined to a slightly different position and occupancy. The pattern is included in the Powder Diffraction File™ (PDF®) as entry 00-064-1507.
Crystal structure of loteprednol etabonate Form II, C24H31ClO7
Authors: Kaduk James A. , Gindhart Amy M. , Blanton Thomas N.
Published: January 2021

The crystal structure of loteprednol etabonate Form II has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. Loteprednol etabonate Form II crystallizes in the space group P21 (#4) with a = 11.96312(6), b = 14.91862(5), c = 6.75715(3) Å, β = 94.1584(3)°, V = 1202.796(6) Å3, and Z = 2. The crystal structure is characterized by herringbone layers in the ab-plane. The anisotropic displacement ellipsoid of the Cl atom is not oriented in a way which corresponds to a chemically sensible motion of this atom. The sample suffered damage in the X-ray beam, probably involving photolysis of the C–Cl bond. The most prominent hydrogen bond is the O–H⋯O hydrogen bond between the hydroxyl group and the carbonyl group of the steroid A ring. This hydrogen bond links the molecules into C1,1(9) chains along the b-axis. The powder pattern is included in the Powder Diffraction File™ (PDF®) as entry 00-066-1602; this study will allow inclusion of the atomic coordinates to the PDF entry.
Surviving COVID-19 in Bergamo province: a post-acute outpatient re-evaluation
Authors: Venturelli Serena , Benatti Simone Vasilij , Casati Monica , Binda Francesca , Zuglian Gianluca , Imeri Gianluca , Conti Caterina , Biffi Ave Maria , Spada Maria Simonetta , Bondi Emi , Camera Giorgia , Severgnini Roberta , Giammarresi Andrea , Marinaro Claudia , Rossini Alessandro , Bonaffini Pietro Andrea , Guerra Giovanni , Bellasi Antonio , Cesa Simonetta , Rizzi Marco
Published: January 2021

Bergamo province was badly hit by the coronavirus disease 2019 (COVID-19) epidemic. We organised a public-funded, multidisciplinary follow-up programme for COVID-19 patients discharged from the emergency department or from the inpatient wards of ‘Papa Giovanni XXIII’ Hospital, the largest public hospital in the area. As of 31 July, the first 767 patients had completed the first post-discharge multidisciplinary assessment. Patients entered our programme at a median time of 81 days after discharge. Among them, 51.4% still complained of symptoms, most commonly fatigue and exertional dyspnoea, and 30.5% were still experiencing post-traumatic psychological consequences. Impaired lung diffusion was found in 19%. Seventeen per cent had D-dimer values two times above the threshold for diagnosis of pulmonary embolism (two unexpected and clinically silent pulmonary thrombosis were discovered by investigating striking D-dimer elevation). Survivors of COVID-19 exhibit a complex array of symptoms, whose common underlying pathology, if any, has still to be elucidated: a multidisciplinary approach is fundamental, to address the different problems and to look for effective solutions.
Glucagon-like peptide-1 regulation by food proteins and protein hydrolysates
Authors: Miguéns-Gómez Alba , Casanova-Martí Àngela , Blay M. Teresa , Terra Ximena , Beltrán-Debón Raúl , Rodríguez-Gallego Esther , Ardévol Anna , Pinent Montserrat
Published: January 2021

Glucagon-like peptide-1 (GLP-1) is an enterohormone with a key role in several processes controlling body homeostasis, including glucose homeostasis and food intake regulation. It is secreted by the intestinal cells in response to nutrients, such as glucose, fat and amino acids. In the present review, we analyse the effect of protein on GLP-1 secretion and clearance. We review the literature on the GLP-1 secretory effects of protein and protein hydrolysates, and the mechanisms through which they exert these effects. We also review the studies on protein from different sources that has inhibitory effects on dipeptidyl peptidase-4 (DPP4), the enzyme responsible for GLP-1 inactivation, with particular emphasis on specific sources and treatments, and the gaps there still are in knowledge. There is evidence that the protein source and the hydrolytic processing applied to them can influence the effects on GLP-1 signalling. The gastrointestinal digestion of proteins, for example, significantly changes their effectiveness at modulating this enterohormone secretion in both in vivo and in vitro studies. Nevertheless, little information is available regarding human studies and more research is required to understand their potential as regulators of glucose homeostasis.
Characterization of the effects of age and childhood maltreatment onELOVL2DNA methylation
Authors: Ramo-Fernández Laura , Karabatsiakis Alexander , Boeck Christina , Bach Alexandra M. , Gumpp Anja M. , Mavioglu R. Nehir , Ammerpohl Ole , Kolassa Iris-Tatjana
Published: January 2021

DNA methylation of the elongation of very long chain fatty acids protein 2 (ELOVL2) was suggested as a biomarker of biological aging, while childhood maltreatment (CM) has been associated with accelerated biological aging. We investigated the association of age and CM experiences withELOVL2methylation in peripheral blood mononuclear cells (PBMC). Furthermore, we investigatedELOVL2methylation in the umbilical cord blood mononuclear cells (UBMC) of newborns of mothers with and without CM. PBMC and UBMC were isolated from 113 mother–newborn dyads and genomic DNA was extracted. Mothers with and without CM experiences were recruited directly postpartum. Mass array spectrometry and pyrosequencing were used for methylation analyses ofELOVL2intron 1, and exon 1 and 5′ end, respectively.ELOVL25′ end and intron 1 methylation increased with higher age but were not associated with CM experiences. On the contrary, overallELOVL2exon 1 methylation increased with higher CM, but these changes were minimal and did not increase with age. Maternal CM experiences and neonatal methylation ofELOVL2intron 1 or exon 1 were not significantly correlated. Our study suggests region-specific effects of chronological age and experienced CM onELOVL2methylation and shows that the epigenetic biomarker for age within theELOVL2gene does not show accelerated biological aging years after CM exposure.
Divergence of dose–response with asenapine: a cluster analysis of randomized, double-blind, and placebo control study
Authors: Takekita Yoshiteru , Hiraoka Shuichi , Iwama Yasuhiro , Sunada Naotaka , Aoki Nobuatsu , Ogata Haruhiko , Funatsuki Toshiya , Takano Chikashi , Yanagida Tomoyo , Koshikawa Yosuke , Naito Minami , Yamamoto Atsuko , Kato Masaki , Kinoshita Toshihiko
Published: January 2021

Background

Differences in psychiatric background and dose–response to asenapine in patients with schizophrenia were examined based on efficacy and safety, using data obtained in a double-blind, placebo-controlled trial.

Methods

Patients with schizophrenia were classified into three clusters by a cluster analysis based on the Positive and Negative Symptom Scale (PANSS) subscores at baseline, using the data from a 6-week, double-blind, placebo-controlled trial. PANSS Marder factor scores were calculated for each cluster. The efficacy of 10 or 20 mg/day of asenapine on PANSS score was used as the primary endpoint, with the incidence of adverse events evaluated as the secondary endpoint.

Results

A total of 529 asenapine-treated patients were classified into 3 clusters: Cluster-P with the higher scores in positive symptoms, disorganized thoughts, and hostility/excitement, Cluster-N with higher scores in negative symptoms, and Cluster-L with overall lower scores. In Cluster-N and Cluster-L, both 10 and 20 mg/day groups showed significant improvement in PANSS scores, while only the 20 mg/day group showed a significant difference in Cluster-P. Cluster-N and Cluster-L had differences in the incidence of adverse events, but this was not seen in Cluster-P.

Conclusions

The efficacy and safety of asenapine 10 and 20 mg/day differed between the 3 clusters of patients. This suggests that background information regarding baseline psychiatric symptoms may affect the therapeutic response in patients with schizophrenia.
Cultural adaptations of cognitive behaviour therapy for the Orthodox Jewish community: a qualitative study of therapists’ perspectives
Authors: Golker Chaim , Cioffi Maria Cristina
Published: January 2021

Cultural factors are influential in the prevalence, diagnosis and treatment efficacy of mental health conditions. Although the literature has advanced substantially towards the development of cultural adaptations of cognitive behavioural therapy (CBT) for various minority cultural groups, research into cultural adaptations of CBT for the Orthodox Jewish community has been scarce. This qualitative study interviewed five CBT therapists about their experiences working with clients from the London Orthodox Jewish community and uncovered several key practical implications for the clinical practice of CBT with this client group. This study indicates that CBT is a culturally appropriate psychological treatment for this client group that accords with Orthodox Jewish teachings and religious beliefs. CBT therapists are encouraged to become familiar with Orthodox Jewish cultural practices and beliefs and adopt a culturally sensitive approach to treatment. Despite the reduced mental health stigma within the community, this study recommends that CBT therapists normalise mental health conditions and therapy with Orthodox Jewish clients. Due to the close-knit nature of the community, it is suggested that CBT therapists display heightened confidentiality with this client group. To overcome the mistrust of their Orthodox Jewish clients, CBT therapists are advised to display cultural sensitivity and genuine respect for the Orthodox Jewish way of life, in addition to building a strong therapeutic alliance. Further qualitative research exploring different perspectives is necessary to produce evidence-based guidelines for the cultural adaptation of CBT for the Orthodox Jewish community.

Key learning aims

(1)

To explore how CBT therapists work with the religious beliefs and practices of Orthodox Jewish clients.

(2)

To discover the challenges faced by Orthodox Jewish clients when accessing psychological treatment.

(3)

To consider the ways in which CBT can be culturally adapted to meet the needs of the Orthodox Jewish community.
Russian thistle (Salsola tragus L.) control with soil-active herbicides in no-till fallow
Authors: Lyon Drew J. , Barroso Judit , Thorne Mark E. , Gourlie Jennifer , Lutcher Larry K.
Published: January 2021

The benefits of no-till fallow, which include reduced soil erosion, improved soil health, and increased stored soil water, are in jeopardy because of the widespread development of glyphosate resistance in Russian thistle. The objective of this research was to evaluate the efficacy of soil-active, residual herbicides for Russian thistle control in no-till fallow. The combinations of sulfentrazone + carfentrazone and flumioxazin + pyroxasulfone, and metribuzin alone were each applied in late fall, late winter, and split-applied in late fall and late winter at three sites: Adams, OR, in 2017–2018; Lind, WA, in 2018–2019; and Ralston, WA, in 2019–2020. All treatments provided good to excellent control of the initial flush of Russian thistle when assessed in mid-May, except the late-fall application of metribuzin at all three sites, and the late-fall application of sulfentrazone + carfentrazone at Adams. Cumulative Russian thistle densities, evaluated monthly throughout the fallow season, were lowest for the sulfentrazone + carfentrazone treatments, except for the late-fall application at Adams. However, flumioxazin + pyroxasulfone and metribuzin provided greater control of tumble mustard and prickly lettuce than did sulfentrazone + carfentazone. Sulfentrazone + carfentrazone, flumioxazin + pyroxasulfone, and metribuzin can all be used for Russian thistle control in fallow. To reduce the risk for crop injury to subsequently planted winter wheat, a late-fall application of sulfentrazone + carfentrazone may be the preferred treatment in low-rainfall regions where winter wheat–fallow is commonly practiced. A late-winter application may be preferred in higher rainfall regions where a 3-year rotation (e.g., winter wheat–spring wheat–fallow) is common. Flumioxazin + pyroxasulfone should be considered if other broadleaf weeds, such as tumble mustard or prickly lettuce, are of concern. The use of these soil-applied herbicides will reduce the need for the frequent application of glyphosate for Russian thistle control in no-till fallow.
Risk Analysis of COVID‐19 Infections in Kolkata Metropolitan City: A GIS‐Based Study and Policy Implications
Authors: Nath Bibhash , Majumder Santanu , Sen Jayanta , Rahman Mohammad Mahmudur
Published: January 2021

The COVID‐19 pandemic has affected daily lives of people around the world. People have already started to live wearing masks, keeping a safe distance from others, and maintaining a high level of hygiene. This paper deals with an in‐depth analysis of riskness associated with COVID‐19 infections in Kolkata Municipal Corporation (KMC) at the subcity (ward) level. Attempts have been made to identify the areas with high or low risk of infections using GIS‐based geostatistical approach. Cosine Similarity Index has been used to rank different wards of KMC according to the degree of riskness. Four indices were computed to address intervention objectives and to determine “Optimized Prevention Rank” of wards for future policy decisions. The highest risk areas were located in the eastern and western part of the city, to a great extent overlapped with wards containing larger share of population living in slums and/or below poverty level. On the other hand, highly infected areas lie in central Kolkata and in several wards at the eastern and northeastern periphery of the KMC. The “Optimized Prevention Rank” have indicated that the lack of social awareness along with lack of social distancing have contributed to the increasing number of containments of COVID‐19 cases. The rankings of the wards would no doubt provide the policy makers a basis to control further spread of the disease. Since effective antiviral drugs are already in the market, the best application of our research would be in the ensuing vaccination drive against further COVID‐19 infections.
Momentum Flux Balance at the Air‐Sea Interface
Authors: Qiao Wenli , Wu Lichuan , Song Jinbao , Li Xue , Qiao Fangli , Rutgersson Anna
Published: January 2021

Ocean waves can spatiotemporally redistribute the momentum flux at the air‐sea interface, which varies with the sea state. Traditional atmosphere‐ocean coupled systems assume the ocean‐side stress (τoc) to be identical to the air‐side stress (τa); consequently, the role of ocean waves is neglected. In this study, the wave impacts on the air‐sea momentum flux are investigated based on 1‐year high‐resolution model simulations in the Baltic Sea using an atmosphere‐wave coupled model (Uppsala University‐Coupled Model, UU‐CM). The simulation results show that τoc can differ significantly from τa in both direction and magnitude. The direction difference between τoc and τa (DD(τoc, τa)) and the normalized momentum flux () decrease with increasing inverse wave age. In general, and DD(τoc, τa) are pronounced under wind‐following swell and wind‐crossing swell conditions, respectively. The occurrence frequencies of large and DD(τoc, τa) are higher nearer the coast; statistically, both decrease significantly with increasing water depth because of the joint effect of dissipation processes. Based on four selected areas, we find that alongshore winds (winds blowing parallel to the coastline) are favorable for large angular differences between τoc and τa (DD(τoc, τa) > 5°). However, onshore winds predominate at . The τa in the wave model is generally less than that obtained from the atmospheric model under low‐moderate wind conditions if the wave model feeds only the Charnock coefficient (roughness length) back to the atmospheric model in coupled systems.
Extending Collaborative Care to Independent Primary Care Practices: A Chronic Care Model
Authors: Parkhurst John T. , Ballard Rachel R. , Lavigne John V. , Von Mach Tara , Romba Courtney , Perez-Reisler Marisa , Walkup John T.
Published: January 2021

Objective: Collaborative approaches to pediatric primary care are increasingly recognized as a way to improve access to mental health care, but certain collaborative care models are not well suited for smaller, independent pediatric practices. We describe the development of the Mood, Anxiety, ADHD Collaborative Care (MAACC) program, based on the Chronic Care Model (CCM) and a hub-and-spoke organization for collaborating with such practices. Method: MAACC’s clinical team (coordinator, psychologist, psychiatrist) trained and collaborated with 46 pediatricians in 13 independent practices. Key services included a diagnostic evaluation by the psychologist, treatment planning for both psychotherapy and pharmacotherapy, tailored referrals to evidence-based therapy, pediatrician access to a psychiatrist for medication consultation, and centralized measurement-based progress monitoring. Results: During the 15-month start-up period, 234 patients were referred; 149 patients received an evaluation, 83 received a new referral for therapy, and 88 received medication recommendations for combined psychotherapy and medication. Patients experienced significant improvement in attention deficit/hyperactivity disorder and anxiety disorder symptoms. Pediatrician attitudes and access to care substantially improved. Conclusion: MAACC demonstrates the feasibility of implementing a CCM-derived model for collaborative care with independent pediatric practices.

Implications for Impact Statement

Collaboration among mental health and pediatric primary care providers is essential to addressing the substantial pediatric mental health burden. Financially sustainable extensions of collaborative care models to small, independent pediatric practices are needed. The Mood, Anxiety, ADHD Collaborative Care program is a high-quality collaborative model designed for pediatric primary care.
RETRACTED ARTICLE: PI3K/Akt pathway and Nanog maintain cancer stem cells in
sarcomas
Authors: Yoon Changhwan , Lu Jun , Yi Brendan C. , Chang Kevin K. , Simon M. Celeste , Ryeom Sandra , Yoon Sam S.
Published: January 2021

The self-renewal transcription factor Nanog and the phosphoinositide
3-kinase (PI3K)–Akt pathway are known to be essential for maintenance of
mesenchymal stem cells. We evaluated their contribution to the maintenance of
CD133(+) cancer stem-like cells (CSCs) and spheroid-forming cells in
patient-derived cell lines from three human sarcoma subtypes: HT1080 fibrosarcoma,
SK-LMS-1 leiomyosarcoma, and DDLS8817 dedifferentiated liposarcoma. Levels of Nanog
and activated Akt were significantly higher in sarcoma cells grown as spheroids or
sorted for CD133 expression to enrich for CSCs. shRNA knockdown of Nanog decreased
spheroid formation 10- to 14-fold, and reversed resistance to both doxorubicin and
radiation in vitro and in H1080 flank xenografts. In the HT1080 xenograft model,
doxorubicin and Nanog knockdown reduced tumor growth by 34% and 45%, respectively,
and the combination reduced tumor growth by 74%. Using a human phospho-kinase
antibody array, Akt1/2 signaling, known to regulate Nanog, was found to be highly
activated in sarcoma spheroid cells compared with monolayer cells. Pharmacologic
inhibition of Akt using LY294002 and Akt1/2 knockdown using shRNA in sarcoma CSCs
decreased Nanog expression and spheroid formation and reversed chemotherapy
resistance. Akt1/2 inhibition combined with doxorubicin treatment of HT1080 flank
xenografts reduced tumor growth by 73%. Finally, in a human sarcoma tumor
microarray, expression of CD133, Nanog, and phospho-Akt were 1.8- to 6.8-fold higher
in tumor tissue compared with normal tissue. Together, these results indicate that
the Akt1/2–Nanog pathway is critical for maintenance of sarcoma CSCs and
spheroid-forming cells, supporting further exploration of this pathway as a
therapeutic target in sarcoma.
Necrotizing enterocolitis intestinal barrier function protection by antenatal dexamethasone and surfactant-D in a rat model
Authors: Lu Lei , Lu Jing , Yu Yueyue , Claud Erika
Published: January 2021

Background

Necrotizing enterocolitis (NEC) is the most common gastrointestinal disorder in premature neonates. Possible therapeutic approaches are centered on promoting maturation of the gastrointestinal mucosal barrier. Studies have demonstrated that antenatal administration of corticosteroids can decrease NEC incidence and mortality.

Methods

Pregnant rat dams were administered dexamethasone 48 h prior to delivery. The pups were subjected to an experimental NEC-like injury protocol. Ileal tissues and sera were collected and evaluated for inflammatory cytokines, gut permeability and expressions and localizations of tight junction proteins, and surfactant protein-D by immunohistochemistry/immunofluorescent staining. Intestinal epithelial cells (IEC-6) were pretreated with SP-D to examine the effect of SP-D on tight junction protein expressions when challenged with platelet-activating factor and lipopolysaccharide to model proinflammatory insults.

Results

Antenatal dexamethasone reduced systemic inflammation, preserved intestinal barrier integrity, and stimulated SP-D expression on the intestinal mucosal surface in pups exposed to NEC-like injury. Pretreatment of SP-D blocked platelet-activating factor/lipopolysaccharide-induced tight junction disruption in IEC-6 cells in vitro.

Conclusions

Antenatal dexamethasone preserves the development of intestinal mucosal barrier integrity and reduces incidence and morbidity from an experimental NEC-like injury model. Dexamethasone upregulation of intestinal SP-D-protective effects on tight junction proteins.

Impact

Antenatal administration of dexamethasone can function in concert with intestinal surfactant protein-D to decrease systemic inflammatory responses, and protect intestinal barrier integrity in a neonatal rat model of NEC.

A novel role of intestinal SP-D in preserving tight junction protein structures under inflammatory conditions.

We describe the intestinal SP-D—an overlooked role of antenatal dexamethasone in neonatal NEC?
Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis
Authors: Nakatsuka Takuma , Tateishi Keisuke , Kato Hiroyuki , Fujiwara Hiroaki , Yamamoto Keisuke , Kudo Yotaro , Nakagawa Hayato , Tanaka Yasuo , Ijichi Hideaki , Ikenoue Tsuneo , Ishizawa Takeaki , Hasegawa Kiyoshi , Tachibana Makoto , Shinkai Yoichi , Koike Kazuhiko
Published: January 2021

While the significance of acquired genetic abnormalities in the initiation of hepatocellular carcinoma (HCC) has been established, the role of epigenetic modification remains unknown. Here we identified the pivotal role of histone methyltransferase G9a in the DNA damage-triggered initiation of HCC. Using liver-specificG9a-deficient (G9aΔHep) mice, we revealed that loss of G9a significantly attenuated liver tumor initiation caused by diethylnitrosamine (DEN). In addition, pharmacological inhibition of G9a attenuated the DEN-induced initiation of HCC. After treatment with DEN, while the induction of γH2AX and p53 were comparable in theG9aΔHepand wild-type livers, more apoptotic hepatocytes were detected in theG9aΔHepliver. Transcriptome analysis identified Bcl-G, a pro-apoptotic Bcl-2 family member, to be markedly upregulated in theG9aΔHepliver. In human cultured hepatoma cells, a G9a inhibitor, UNC0638, upregulated BCL-G expression and enhanced the apoptotic response after treatment with hydrogen peroxide or irradiation, suggesting an essential role of the G9a-Bcl-G axis in DNA damage response in hepatocytes. The proposed mechanism was that DNA damage stimuli recruited G9a to the p53-responsive element of theBcl-Ggene, resulting in the impaired enrichment of p53 to the region and the attenuation of Bcl-G expression. G9a deletion allowed the recruitment of p53 and upregulated Bcl-G expression. These results demonstrate that G9a allows DNA-damaged hepatocytes to escape p53-induced apoptosis by silencing Bcl-G, which may contribute to the tumor initiation. Therefore, G9a inhibition can be a novel preventive strategy for HCC.
Autophagy augments the self-renewal of lung cancer stem cells by the degradation of ubiquitinated p53
Authors: Wang Jianyu , Liu Doudou , Sun Zhiwei , Ye Ting , Li Jingyuan , Zeng Bin , Zhao Qiting , Rosie Xing H.
Published: January 2021

It has been postulated that cancer stem cells (CSCs) are involved in all aspects of human cancer, although the mechanisms governing the regulation of CSC self-renewal in the cancer state remain poorly defined. In the literature, both the pro- and anti-oncogenic activities of autophagy have been demonstrated and are context-dependent. Mounting evidence has shown augmentation of CSC stemness by autophagy, yet mechanistic characterization and understanding are lacking. In the present study, by generating stable human lung CSC cell lines with the wild-type TP53 (A549), as well as cell lines in which TP53 was deleted (H1229), we show, for the first time, that autophagy augments the stemness of lung CSCs by degrading ubiquitinated p53. Furthermore, Zeb1 is required for TP53 regulation of CSC self-renewal. Moreover, TCGA data mining and analysis show that Atg5 and Zeb1 are poor prognostic markers of lung cancer. In summary, this study has elucidated a new CSC-based mechanism underlying the oncogenic activity of autophagy and the tumor suppressor activity of p53 in cancer, i.e., CSCs can exploit the autophagy-p53-Zeb1 axis for self-renewal, oncogenesis, and progression.
Direct control of store-operated calcium channels by ultrafast laser
Authors: Cheng Pan , Tian Xiaoying , Tang Wanyi , Cheng Juan , Bao Jin , Wang Haipeng , Zheng Sisi , Wang Youjun , Wei Xunbin , Chen Tunan , Feng Hua , Xue Tian , Goda Keisuke , He Hao
Published: January 2021

Ca2+ channels are essential to cell birth, life, and death. They can be externally activated by optogenetic tools, but this requires robust introduction of exogenous optogenetic genes for expression of photosensitive proteins in biological systems. Here we present femtoSOC, a method for direct control of Ca2+ channels solely by ultrafast laser without the need for optogenetic tools or any other exogenous reagents. Specifically, by focusing and scanning wavelength-tuned low-power femtosecond laser pulses on the plasma membrane for multiphoton excitation, we directly induced Ca2+ influx in cultured cells. Mechanistic study reveals that photoexcited flavins covalently bind cysteine residues in Orai1 via thioether bonds, which facilitates Orai1 polymerization to form store-operated calcium channels (SOCs) independently of STIM1, a protein generally participating in SOC formation, enabling all-optical activation of Ca2+ influx and downstream signaling pathways. Moreover, we used femtoSOC to demonstrate direct neural activation both in brain slices in vitro and in intact brains of living mice in vivo in a spatiotemporal-specific manner, indicating potential utility of femtoSOC.
Floquet spin states in OLEDs
Authors: Jamali S. , Mkhitaryan V. V. , Malissa H. , Nahlawi A. , Popli H. , Grünbaum T. , Bange S. , Milster S. , Stoltzfus D. M. , Leung A. E. , Darwish T. A. , Burn P. L. , Lupton J. M. , Boehme C.
Published: January 2021

Electron and hole spins in organic light-emitting diodes constitute prototypical two-level systems for the exploration of the ultrastrong-drive regime of light-matter interactions. Floquet solutions to the time-dependent Hamiltonian of pairs of electron and hole spins reveal that, under non-perturbative resonant drive, when spin-Rabi frequencies become comparable to the Larmor frequencies, hybrid light-matter states emerge that enable dipole-forbidden multi-quantum transitions at integer and fractional g-factors. To probe these phenomena experimentally, we develop an electrically detected magnetic-resonance experiment supporting oscillating driving fields comparable in amplitude to the static field defining the Zeeman splitting; and an organic semiconductor characterized by minimal local hyperfine fields allowing the non-perturbative light-matter interactions to be resolved. The experimental confirmation of the predicted Floquet states under strong-drive conditions demonstrates the presence of hybrid light-matter spin excitations at room temperature. These dressed states are insensitive to power broadening, display Bloch-Siegert-like shifts, and are suggestive of long spin coherence times, implying potential applicability for quantum sensing.
Dynamical strengthening of covalent and non-covalent molecular interactions by nuclear quantum effects at finite temperature
Authors: Sauceda Huziel E. , Vassilev-Galindo Valentin , Chmiela Stefan , Müller Klaus-Robert , Tkatchenko Alexandre
Published: January 2021

Nuclear quantum effects (NQE) tend to generate delocalized molecular dynamics due to the inclusion of the zero point energy and its coupling with the anharmonicities in interatomic interactions. Here, we present evidence that NQE often enhance electronic interactions and, in turn, can result in dynamical molecular stabilization at finite temperature. The underlying physical mechanism promoted by NQE depends on the particular interaction under consideration. First, the effective reduction of interatomic distances between functional groups within a molecule can enhance the n → π* interaction by increasing the overlap between molecular orbitals or by strengthening electrostatic interactions between neighboring charge densities. Second, NQE can localize methyl rotors by temporarily changing molecular bond orders and leading to the emergence of localized transient rotor states. Third, for noncovalent van der Waals interactions the strengthening comes from the increase of the polarizability given the expanded average interatomic distances induced by NQE. The implications of these boosted interactions include counterintuitive hydroxyl–hydroxyl bonding, hindered methyl rotor dynamics, and molecular stiffening which generates smoother free-energy surfaces. Our findings yield new insights into the versatile role of nuclear quantum fluctuations in molecules and materials.
Uncomputability of phase diagrams
Authors: Bausch Johannes , Cubitt Toby S. , Watson James D.
Published: January 2021

The phase diagram of a material is of central importance in describing the properties and behaviour of a condensed matter system. In this work, we prove that the task of determining the phase diagram of a many-body Hamiltonian is in general uncomputable, by explicitly constructing a continuous one-parameter family of Hamiltonians H(φ), where $$\varphi \in {\mathbb{R}}$$
φ
∈
R
, for which this is the case. The H(φ) are translationally-invariant, with nearest-neighbour couplings on a 2D spin lattice. As well as implying uncomputablity of phase diagrams, our result also proves that undecidability can hold for a set of positive measure of a Hamiltonian’s parameter space, whereas previous results only implied undecidability on a zero measure set. This brings the spectral gap undecidability results a step closer to standard condensed matter problems, where one typically studies phase diagrams of many-body models as a function of one or more continuously varying real parameters, such as magnetic field strength or pressure.
Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma
Authors: Agliardi Giulia , Liuzzi Anna Rita , Hotblack Alastair , De Feo Donatella , Núñez Nicolás , Stowe Cassandra L. , Friebel Ekaterina , Nannini Francesco , Rindlisbacher Lukas , Roberts Thomas A. , Ramasawmy Rajiv , Williams Iwan P. , Siow Bernard M. , Lythgoe Mark F. , Kalber Tammy L. , Quezada Sergio A. , Pule Martin A. , Tugues Sonia , Straathof Karin , Becher Burkhard
Published: January 2021

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4+ T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM.
Environmental signals rather than layered ontogeny imprint the function of type 2 conventional dendritic cells in young and adult mice
Authors: Papaioannou Nikos E. , Salei Natallia , Rambichler Stephan , Ravi Kaushikk , Popovic Jelena , Küntzel Vanessa , Lehmann Christian H. K. , Fiancette Remi , Salvermoser Johanna , Gajdasik Dominika W. , Mettler Ramona , Messerer Denise , Carrelha Joana , Ohnmacht Caspar , Haller Dirk , Stumm Ralf , Straub Tobias , Jacobsen Sten Eirik W. , Schulz Christian , Withers David R. , Schotta Gunnar , Dudziak Diana , Schraml Barbara U.
Published: January 2021

Conventional dendritic cells (cDC) are key activators of naive T cells, and can be targeted in adults to induce adaptive immunity, but in early life are considered under-developed or functionally immature. Here we show that, in early life, when the immune system develops, cDC2 exhibit a dual hematopoietic origin and, like other myeloid and lymphoid cells, develop in waves. Developmentally distinct cDC2 in early life, despite being distinguishable by fate mapping, are transcriptionally and functionally similar. cDC2 in early and adult life, however, are exposed to distinct cytokine environments that shape their transcriptional profile and alter their ability to sense pathogens, secrete cytokines and polarize T cells. We further show that cDC2 in early life, despite being distinct from cDC2 in adult life, are functionally competent and can induce T cell responses. Our results thus highlight the potential of harnessing cDC2 for boosting immunity in early life.
Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development
Authors: Xu Huixin , Fame Ryann M. , Sadegh Cameron , Sutin Jason , Naranjo Christopher , Della Syau  , Cui Jin , Shipley Frederick B. , Vernon Amanda , Gao Fan , Zhang Yong , Holtzman Michael J. , Heiman Myriam , Warf Benjamin C. , Lin Pei-Yi , Lehtinen Maria K.
Published: January 2021

Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation, such as hydrocephalus, can negatively affect perinatal neurodevelopment. The mechanisms regulating CSF clearance during the postnatal critical period are unclear. Here, we show that CSF K+, accompanied by water, is cleared through the choroid plexus (ChP) during mouse early postnatal development. We report that, at this developmental stage, the ChP showed increased ATP production and increased expression of ATP-dependent K+transporters, particularly the Na+, K+, Cl−, and water cotransporter NKCC1. Overexpression of NKCC1 in the ChP resulted in increased CSF K+clearance, increased cerebral compliance, and reduced circulating CSF in the brain without changes in intracranial pressure in mice. Moreover, ChP-specific NKCC1 overexpression in an obstructive hydrocephalus mouse model resulted in reduced ventriculomegaly. Collectively, our results implicate NKCC1 in regulating CSF K+clearance through the ChP in the critical period during postnatal neurodevelopment in mice.
Crystal structure of steroid reductase SRD5A reveals conserved steroid reduction mechanism
Authors: Han Yufei , Zhuang Qian , Sun Bo , Lv Wenping , Wang Sheng , Xiao Qingjie , Pang Bin , Zhou Youli , Wang Fuxing , Chi Pengliang , Wang Qisheng , Li Zhen , Zhu Lizhe , Li Fuping , Deng Dong , Chiang Ying-Chih , Li Zhenfei , Ren Ruobing
Published: January 2021

Steroid hormones are essential in stress response, immune system regulation, and reproduction in mammals. Steroids with 3-oxo-Δ4structure, such as testosterone or progesterone, are catalyzed by steroid 5α-reductases (SRD5As) to generate their corresponding 3-oxo-5α steroids, which are essential for multiple physiological and pathological processes. SRD5A2 is already a target of clinically relevant drugs. However, the detailed mechanism of SRD5A-mediated reduction remains elusive. Here we report the crystal structure of PbSRD5A fromProteobacteria bacterium, a homolog of both SRD5A1 and SRD5A2, in complex with the cofactor NADPH at 2.0 Å resolution. PbSRD5A exists as a monomer comprised of seven transmembrane segments (TMs). The TM1-4 enclose a hydrophobic substrate binding cavity, whereas TM5-7 coordinate cofactor NADPH through extensive hydrogen bonds network. Homology-based structural models of HsSRD5A1 and -2, together with biochemical characterization, define the substrate binding pocket of SRD5As, explain the properties of disease-related mutants and provide an important framework for further understanding of the mechanism of NADPH mediated steroids 3-oxo-Δ4reduction. Based on these analyses, the design of therapeutic molecules targeting SRD5As with improved specificity and therapeutic efficacy would be possible.
Over half of western United States' most abundant tree species in decline
Authors: Stanke Hunter , Finley Andrew O. , Domke Grant M. , Weed Aaron S. , MacFarlane David W.
Published: January 2021

Changing forest disturbance regimes and climate are driving accelerated tree mortality across temperate forests. However, it remains unknown if elevated mortality has induced decline of tree populations and the ecological, economic, and social benefits they provide. Here, we develop a standardized forest demographic index and use it to quantify trends in tree population dynamics over the last two decades in the western United States. The rate and pattern of change we observe across species and tree size-distributions is alarming and often undesirable. We observe significant population decline in a majority of species examined, show decline was particularly severe, albeit size-dependent, among subalpine tree species, and provide evidence of widespread shifts in the size-structure of montane forests. Our findings offer a stark warning of changing forest composition and structure across the western US, and suggest that sustained anthropogenic and natural stress will likely result in broad-scale transformation of temperate forests globally.
Jarosite formation in deep Antarctic ice provides a window into acidic, water-limited weathering on Mars
Authors: Baccolo Giovanni , Delmonte Barbara , Niles P. B. , Cibin Giannantonio , Di Stefano Elena , Hampai Dariush , Keller Lindsay , Maggi Valter , Marcelli Augusto , Michalski Joseph , Snead Christopher , Frezzotti Massimo
Published: January 2021

Many interpretations have been proposed to explain the presence of jarosite within Martian surficial sediments, including the possibility that it precipitated within paleo-ice deposits owing to englacial weathering of dust. However, until now a similar geochemical process was not observed on Earth nor in other planetary settings. We report a multi-analytical indication of jarosite formation within deep ice. Below 1000 m depth, jarosite crystals adhering on residual silica-rich particles have been identified in the Talos Dome ice core (East Antarctica) and interpreted as products of weathering involving aeolian dust and acidic atmospheric aerosols. The progressive increase of ice metamorphism and re-crystallization with depth, favours the relocation and concentration of dust and the formation of acidic brines in isolated environments, allowing chemical reactions and mineral neo-formation to occur. This is the first described englacial diagenetic mechanism occurring in deep Antarctic ice and supports the ice-weathering model for jarosite formation on Mars, highlighting the geologic importance of paleo ice-related processes on this planet. Additional implications concern the preservation of dust-related signals in deep ice cores with respect to paleoclimatic reconstructions and the englacial history of meteorites from Antarctic blue ice fields.
A self-matched leaky-wave antenna for ultrahigh-field magnetic resonance imaging with low specific absorption rate
Authors: Solomakha G. , Svejda J. T. , van Leeuwen C. , Rennings A. , Raaijmakers A. J. , Glybovski S. , Erni D.
Published: January 2021

The technology of magnetic resonance imaging is developing towards higher magnetic fields to improve resolution and contrast. However, whole-body imaging at 7 T or even higher flux densities remains challenging due to wave interference, tissue inhomogeneities, and high RF power deposition. Nowadays, proper RF excitation of a human body in prostate and cardiac MRI is only possible to achieve by using phased arrays of antennas attached to the body (so-called surface coils). Due to safety concerns, the design of such coils aims at minimization of the local specific absorption rate (SAR), keeping the highest possible RF signal in the region of interest. Most previously demonstrated approaches were based on resonant structures such as e.g. dipoles, capacitively-loaded loops, TEM-line sections. In this study, we show that there is a better compromise between the transmit signal $${{\bf{B}}}_{{\bf{1}}}^{{\boldsymbol{+}}}$$

B

1

+

and the local SAR using non-resonant surface coils generating a low electric field in the proximity of their conductors. With this aim, we propose and experimentally demonstrate a leaky-wave antenna implemented as a periodically-slotted microstrip transmission line. Due to its non-resonant radiation, it induces only slightly over half the peak local SAR compared to a state-of-the-art dipole antenna but has the same transmit efficiency in prostate imaging at 7 T. Unlike other antennas for MRI, the leaky-wave antenna does not require to be tuned and matched when placed on a body, which makes it easy-to-use in prostate imaging at 7 T MRI.