bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential antidiabetic phytochemicals in plant roots: a review of in vivo studies
Authors: Ardalani Hamidreza , Hejazi Amiri Fatemeh , Hadipanah Amin , Kongstad Kenneth T.
Published: July 2021

Background

Medicinal plants are used to treat various disorders, including diabetes, globally in a range of formulations. While attention has mainly been on the aerial plant parts, there are only a few review studies to date that are focused on the natural constituents present in the plant roots with health benefits. Thus, the present study was performed to review in vivo studies investigating the antidiabetic potential of the natural compounds in plant roots.

Methods

We sorted relevant data in 2001–2019 from scientific databases and search engines, including Web of Knowledge, PubMed, ScienceDirect, Medline, Reaxys, and Google Scholar. The class of phytochemicals, plant families, major compounds, active constituents, effective dosages, type of extracts, time of experiments, and type of diabetic induction were described.

Results

In our literature review, we found 104 plants with determined antidiabetic activity in their root extracts. The biosynthesis pathways and mechanism of actions of the most frequent class of compounds were also proposed. The results of this review indicated that flavonoids, phenolic compounds, alkaloids, and phytosteroids are the most abundant natural compounds in plant roots with antidiabetic activity. Phytochemicals in plant roots possess different mechanisms of action to control diabetes, including inhibition ofα-amylase andα-glucosidase enzymes, oxidative stress reduction, secretion of insulin, improvement of diabetic retinopathy/nephropathy, slow the starch digestion, and contribution against hyperglycemia.

Conclusion

This review concludes that plant roots are a promising source of bioactive compounds which can be explored to develop against diabetes and diabetes-related complications.

Graphical abstract
Die Offenheit für interethnische Freundschaften von Jugendlichen in marginalisierten Wohngebieten
Authors: Zdun Steffen
Published: July 2021

Obwohl interethnische Freundschaften seit Jahren in der deutschen Soziologie thematisiert werden, handelt es sich meist eher um Defizitdiskurse bzw. eine Beschäftigung mit interethnischen Begegnungen in verschiedenen Settings und deren Auswirkungen auf das Individuum. Hingegen ist die darüber hinausgehende Offenheit für interethnische Freundschaften von Jugendlichen in marginalisierten Stadtteilen eine relativ neue Entwicklung hierzulande und deshalb auch ein empirisch relativ blinder Fleck. Der vorliegende Beitrag widmet sich diesem Trend auf der Datengrundlage einer qualitativen Explorativstudie, in deren Rahmen 45 Jugendliche aus sechs deutschen Städten befragt wurden. Die Ergebnisse geben Einblick in diese Offenheit der Jugendlichen und das Selbstverständnis, mit dem sie in Freundschaften mit lokalen Peers praktiziert wird.
Factors associated with daily opioid use among aged home care clients: a cross-sectional analysis of Resident Assessment Instrument data
Authors: Mörttinen-Vallius Heidi , Hartikainen Sirpa , Huhtala Heini , Seinelä Lauri , Jämsen Esa
Published: July 2021

Purpose

To examine which client characteristics and other factors, including possible adverse effects, identified in the Resident Assessment Instrument—Home Care (RAI-HC) are associated with daily opioid use among aged home care clients.

Methods

The study sample comprised 2584 home care clients aged ≥ 65 years, of which 282 persons used opioids daily. Clients using opioids less than once daily were excluded. The cross-sectional data were gathered from each client’s first assessment with the RAI-HC during 2014. Multivariable logistic regression was used to study associations of daily opioid use with the clients’ characteristics and symptoms.

Results

Cognitive impairment was associated with less frequent opioid use after adjusting for pain-related diseases, disabilities and depressive symptoms (OR 0.43, 95% CI 0.32–0.58). The association was not explained by the estimated severity of pain. Osteoporosis, cancer within previous 5 years and greater disabilities in Instrumental Activities of Daily Living (IADL) were associated with daily opioid use regardless of the estimated severity of pain. Depressive symptoms and Parkinson’s disease were associated with daily opioid use only among clients with cognitive impairment, and disabilities in Activities of Daily Living, cancer, arthritis, fractures and pressure ulcers only among clients without cognitive impairment. Constipation was the only adverse effect associated with daily opioid use.

Conclusion

The pain of home care clients with cognitive impairment may not be treated optimally, whereas there might be prolonged opioid use without a sufficient evaluation of current pain among clients with osteoporosis, cancer within previous 5 years and disabilities in IADLs.
Forschung partizipativ und inklusiv gestalten? Ethische Reflexionen zu Interviews mit Kindern unter besonderer Berücksichtigung von Erwachsenheit
Authors: Velten Katrin , Höke Julia
Published: July 2021

Im Beitrag wird mit Fokus auf vier Ansprüche an die Erfassung von Kinderperspektiven der methodische Zugang des Interviews daraufhin reflektiert, wie im Kontext von kindlichem Eigensinn und generationaler Ordnung die Erwachsenheit der Forscher*innen aus forschungsethischer Sicht betrachtet werden kann und muss. In der sequenzanalytischen Re-Analyse von konflikthaften und weniger ergiebig erscheinenden Interviewsequenzen werden sog. Ad-hoc-Praktiken deutlich, in denen Forscher*innen in der Einmaligkeit der konkreten Interviewsituation Erwachsenheit und generationale Ordnung bei gleichzeitigem Interesse am Eigensinn des Kindes (re)produzieren. Diese sog. „Turning Points“ bieten Impulse für die Justierung des Begriffs der Angemessenheit und die Erweiterung von individuellen Forschungskompetenzen bei Kinderbefragungen.
Adolescent depressed mood and difficulties with emotion regulation: Concurrent trajectories of change
Authors: Defayette Annamarie B. , Whitmyre Emma D. , López Roberto , Brown Bradley , Wolff Jennifer C. , Spirito Anthony , Esposito‐Smythers Christianne
Published: July 2021

Introduction

Adolescent depression is a significant mental health concern. Emotion regulation difficulties have been associated with subsequent depressive symptoms, though different facets of emotion regulation are rarely compared. This study examined the degree to which trajectories of change in different facets of emotion regulation (goal‐directed behavior, impulse control, and regulation strategies) and depressive symptoms were associated across twelve months in a clinical adolescent sample.

Methods

Participants included 110 adolescents from the US who were enrolled in a randomized trial that tested a cognitive‐behavioral treatment for youth with co‐occurring mental health and substance use concerns (Mage = 15.71 years; 57.3% male). Assessments were conducted at baseline, 3‐, 6‐, and 12‐month follow‐ups. Three separate bivariate latent basis growth curve analyses were conducted. Correlations between latent intercepts and latent slopes, as well as overall model fit, were examined.

Results

Impulse control and goal‐directed behavior were each associated with depressive symptoms at baseline. Additionally, change in impulse control over time was significantly associated with change in depressive symptoms. However, the same was not true for goal‐directed behavior. Overall fit indices for models of emotion regulation strategies were below acceptable levels and thus could not be interpreted.

Conclusions

Findings from the present study indicate that adolescents’ depressive symptoms appear to improve as their perceived ability to control impulses improves. These results suggest that addressing impulse control difficulties may be an important step in treating adolescent depression and co‐occurring disorders.
Itraconazole Improves Vulvodynia in Fungus Culture-Negative Patients Post Fluconazole Failure
Authors: Rothenberger Rodger , Jones Wendy , MacNeill Colin
Published: July 2021

Introduction

Vulvodynia is a difficult condition to treat due to both the uncertain etiology of the disorder and poorly available therapies. This difficulty leads to a disproportionately high prevalence and cost of treatment for this condition. Candida vulvovaginitis is a frequent co-present diagnosis in vulvodynia patients. Whether through treatment of co-present, candida vulvovaginitis or by systemic interaction, itraconazole has been proposed as a treatment for vulvodynia.

Aim

To describe objective change in vulvodynia pain in a cohort of patients treated with itraconazole.

Methods

This study was a retrospective cohort study comprised of women diagnosed with vulvodynia who were treated with itraconazole between January 1, 2011 and October 17, 2017. Patients had failed fluconazole treatment and had negative fungus cultures for >2 months before itraconazole treatment. All other vulvovaginal disorders were excluded.

Main outcome measure

The main outcome measure was the change in pain before and after treatment as measured by cotton swab testing.

Results

106 patients met inclusion criteria. Average pain reduction for the entire cohort was 60.7%. Patients who continued itraconazole for 5 to 8 weeks demonstrated a 69.6% reduction in cotton swab test pain. Pain reduction as a percentage of total patients showed complete resolution of pain in 37.7% of patients and >50% reduction in 66.0% of patients. Two-sample paired T-tests for means analysis of pain scores disproved the null hypothesis (P < .01, α = 0.01) and showed a 50% reduction in pain to be significant (P = 0.043, α = 0.05). Two-tailed Wilcoxon signed rank test also demonstrated rejection of the null hypothesis (α = 0.05).

Conclusions

Itraconazole therapy is associated with a significant reduction in vulvovaginal pain in patients with negative fungus cultures and no other identifiable disease in this pilot study. A randomized placebo-controlled trial is warranted.
Semantics with Assignment Variables
Authors: Silk Alex
Published: July 2021

This pioneering study combines insights from philosophy and linguistics to develop a novel framework for theorizing about linguistic meaning and the role of context in interpretation. A key innovation is to introduce explicit representations of context - assignment variables - in the syntax and semantics of natural language. The proposed theory systematizes a spectrum of 'shifting' phenomena in which the context relevant for interpreting certain expressions depends on features of the linguistic environment. Central applications include local and non-local contextual dependencies with quantifiers, attitude ascriptions, conditionals, questions, and relativization. The result is an innovative philosophically informed compositional semantics compatible with the truth-conditional paradigm. At the forefront of contemporary interdisciplinary research into meaning and communication, Semantics with Assignment Variables is essential reading for researchers and students in a diverse range of fields.
A systems approach to enable effective team science from the internal research program of the National Center for Advancing Translational Sciences
Authors: Vogel Amanda L. , Knebel Ann R. , Faupel-Badger Jessica M. , Portilla Lili M. , Simeonov Anton
Published: July 2021

The internal research program of the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health aims to fundamentally transform the preclinical translational research process to get more treatments to more people more quickly. The program develops and implements innovative scientific and operational approaches that accelerate and enhance translation across many diverse projects. Cross-disciplinary team science is a defining feature of our organization, with scientists at all levels engaged in multiple research teams. Here, we share our systems approach to nurturing cross-disciplinary team science, which leverages organizational policies, structures, and processes. Policies including the organizational mission statement, principles for ethical conduct of research, performance review criteria, and training program objectives and approaches reinforce the value of team science to achieve the program’s scientific goals. Structures including an organizational structure designed around solving translational problems, co-location of employees in a single state-of-the-art scientific facility, and shared-use laboratories, expertise and instrumentation facilitate collaboration. Processes including fluid team assembly, specialized project management, cross-agency partnerships, and decision making based on clear screening criteria and milestones enable effective team assembly and functioning. We share evidence of the impact of these approaches on the science and commercialization of findings and discuss pathways to broad adoption of similar approaches.
Rapid Assessment of COVID-19 Screening Program for Travelers in Iran: A Qualitative Study
Authors: Seddighi Hamed , Salmani Ibrahim , Baharmand Hossein , Seddighi Saeideh , Sharifi Sedeh Mehrab
Published: July 2021

Objective:

Coronavirus disease 2019 (COVID-19) screening stations set up by Iranian Red Crescent Society have been available for 17 d with the aim of identifying and treating people with coronavirus, reducing road trips, and sensitizing people to the problem. This study aims to investigate the challenges of the procedure.

Methods:

A qualitative study was used to find the challenges of the COVID-19 screening centers. Volunteers, branch managers, and headquarter managers of the Iranian Red Crescent Society participated in this study applying snowball sampling. Data were collected by means of in-depth semi-structured telephone interviews in April 2020 after completion of the fever screening plan. All interviews were recorded and transcribed verbatim, always with prior permission of interviewees.

Results:

The interviews with 20 participants in the plan indicated 6 relevant challenges, including logistics, lack of planning, lack of coordination, legal challenges, mental health, and ethical challenges.

Conclusions:

The results indicated that, although establishing fever detection centers in Iran was a rapid response to COVID-19, it had significant flaws in the structure and adversely affected volunteers’ and staff’s health and financial resources. Therefore, well-structured protocols are required for similar responses in the future.
Bias-free model fitting of correlated data in interferometry
Authors: Lachaume Régis
Published: July 2021

In optical and infrared long-baseline interferometry, data often display significant correlated errors because of uncertain multiplicative factors such as the instrumental transfer function or the pixel-to-visibility matrix. In the context of model fitting, this situation often leads to a significant bias in the model parameters. In the most severe cases, this can can result in a fit lying outside of the range of measurement values. This is known in nuclear physics as Peelle’s Pertinent Puzzle. I show how this arises in the context of interferometry and determine that the relative bias is of the order of the square root of the correlated component of the relative uncertainty times the number of measurements. It impacts preferentially large datasets, such as those obtained in medium to high spectral resolution. I then give a conceptually simple and computationally cheap way to avoid the issue: model the data without covariances, estimate the covariance matrix by error propagation using the modelled data instead of the actual data, and perform the model fitting using the covariance matrix. I also show that a more imprecise but also unbiased result can be obtained from ignoring correlations in the model fitting.
Protecting the Vote? Peacekeeping Presence and the Risk of Electoral Violence
Authors: Fjelde Hanne , Smidt Hannah M.
Published: July 2021

Democracy assistance, including the promotion of electoral security, is often a central component of contemporary peacekeeping operations. Preventing violence during post-conflict elections is critical for the war-to-democracy transition. Yet little is known about the role of peacekeepers in this effort. To fill this gap, this study provides the first comprehensive sub-national study of peacekeeping effectiveness in reducing the risk of electoral violence. It combines geo-referenced data on peacekeeping deployment across all multidimensional peacekeeping missions in Africa over the past two decades with fine-grained data on electoral violence. The analysis finds a negative association between peacekeeping presence and the risk of electoral violence. The relationship is of a similar magnitude in the pre- and post-election periods. However, the association is more strongly negative for violence perpetrated by non-state actors compared to violence perpetrated by government-affiliated actors. Analyses using two-way fixed-effects models and matching mitigate potential selection biases.
CHILDREN’S LEARNING ENVIRONMENT AND GROWTH-PROMOTING INCOME REDISTRIBUTION
Authors: Bandyopadhyay Debasis , Tang Xueli
Published: July 2021

Bénabou [(2002) Econometrica 70, 481–517.] demonstrated how progressive redistribution mitigates unequal opportunity for education to promote growth. We ask how effective that policy is when it affects the average quality of education. So, we add a learning externality in his model of human capital accumulation. It captures how knowledge diffusion through global channels—such as a national educational curriculum—influences children’s learning outcomes and, hence, growth. Whether inequality is a curse or a blessing for economic growth depends on how efficiently an economy designs these channels and to what extent they influence children’s education. The greater this efficiency, the lower is the optimal progressiveness of income redistribution for maximizing the long-run output growth rate. Interestingly, if poorly designed global channels exert greater influence in education, the optimal progressivity may increase. Our quantitative analysis reveals new implications for redistributive policies, including a surprisingly low optimal progressivity (approximately 6–7%) for the calibrated US economy.
Revamping the menu – or just offering what’s in stock? Candidate list volatility in open-list PR systems. Evidence from Finland
Authors: Koskimaa Vesa , Mattila Mikko , Papageorgiou Achillefs , von Schoultz Åsa
Published: July 2021

Why do parties change candidate lists between elections? Although candidate list volatility is an important indicator of the responsiveness of electoral representation, it has received little attention in research. We offer a critical case study of party list volatility in Finland, using a candidate-centred open-list proportional (PR) electoral system with ideal conditions for ‘ultra-strategic’ party behaviour. Our explorative two-stage research design begins with party elite interviews, to extract factors that can affect list volatility, which in the following step are tested in a regression analysis of 564 party lists in parliamentary elections 1983–2019. Our results show that list formation is a complex phenomenon, where demand and supply factors interact in a contingent fashion. Following trends of voter dealignment, personalization and ‘electoral-professionalization’ of parties, volatility has increased over time. Electoral defeats and declining party membership increase volatility, but a member-driven mass-party heritage that limits party elites’ strategic capacity has a stabilizing effect.
Integrated weed management in transplanted rice: options for addressing labor constraints and improving farmers’ income in Bangladesh
Authors: Ahmed Sharif , Kumar Virender , Alam Murshedul , Dewan Mahbubur Rahman , Bhuiyan Khairul Alam , Miajy Abu Abdullah , Saha Abhijit , Singh Sudhanshu , Timsina Jagadish , Krupnik Timothy J.
Published: July 2021

In Bangladesh, weeds in transplanted rice are largely controlled by labor-intensive and costly manual weeding, resulting in inadequate and untimely weed control. Labor scarcity coupled with intensive rice production has triggered increased use of herbicides. These factors warrant a cost-effective and strategic integrated weed management (IWM) approach. On-farm trials with transplanted rice were conducted during monsoon (‘Aman’) season in 2016 and 2017 and winter (‘Boro’) season in 2016 to 2017 in agroecological zones 11 and 12 with ten treatments—seven herbicide-based IWM options, one mechanical weed control-based option, and two checks (farmers’ current weed control practice and weed-free)—to assess effects on weed control, grain yield, labor use, and profitability. Compared to farmers’ practice, herbicide-based IWM options with mefenacet + bensulfuron-methyl as preemergence followed by (fb) either bispyribac-sodium or penoxsulam as postemergence fb one hand-weeding were the most profitable alternatives, with reductions in labor requirement by 11 to 25 person-days ha–1 and in total weed control cost by US$44 to 94 ha–1, resulting in net returns increases by US$54 to 77 ha–1 without compromising on grain yield. In contrast, IWM options with bispyrbac-sodium or penoxsulam as postemergence application fb one hand-weeding reduced yields by 12% to 13% and profits by US$71 to 190 ha–1. The nonchemical option with mechanical weeding fb one hand-weeding performed similarly to farmers’ practice on yield and profitability. We suggest additional research to develop feasible herbicide-free approaches to weed management in transplanted rice that can offer competitive advantages to current practices.
Tehri Reservoir Operation Modulates Seasonal Elastic Crustal Deformation in the Himalaya
Authors: Xie Lei , Xu Wenbin , Bürgmann Roland , Ding Xiaoli , Gahalaut Vineet K. , Mondal Saroj
Published: July 2021

The filling and emptying cycles of reservoir operations may change hydrological mass loading, leading to a flexural deformation of the crust that may compromise the infrastructure safety or trigger earthquakes. In this study, we investigate the seasonal crustal response of the Tehri reservoir in the Garhwal Himalaya, northern India, using interferometric synthetic aperture radar (InSAR), Global Positioning System, the Gravity Recovery and Climate Experiment, radar altimetry, and in‐situ water‐level measurements. Results show that the evolution of vertical ground deformation is modulated elastically by the reservoir operation, whereas the horizontal displacement measured near the reservoir exhibits a time lag of ∼65 days with respect to the vertical displacements and water‐level variations. The delayed deformation transients indicate that the reservoir loading/unloading cycles affect the near‐surface hydrology in its neighborhood. The broader distribution and higher amplitude of ground deformation during the loading periods revealed by the InSAR time series can be explained by water–rock interactions, which cause a decrease in the effective Young's modulus within the top 300‐m crustal layer. Our results demonstrate the potential of using space geodetic data to ensure a better understanding of the solid Earth response to regional hydrological changes.
Iran's Groundwater Hydrochemistry
Authors: Maghrebi Mohsen , Noori Roohollah , Partani Sadegh , Araghi Alireza , Barati Reza , Farnoush Hosein , Torabi Haghighi Ali
Published: July 2021

Iran's groundwater hydrochemistry has not been well understood. In this study, Iran's groundwater hydrochemistry is evaluated using a rich, ground‐trusted data sampled from 9,468 wells distributed across the country in 2011. Twelve groundwater quality parameters were analyzed in each sample, resulting in 113,616 parameters over the study period. Examination of anions‐cations shows that concentrations of sodium, calcium, chloride, and sulphate are higher than the acceptable threshold for drinking‐use suggested by the World Health Organization in about 40%, 21%, 25%, and 20% of the samples, respectively. The results of the water quality index reveal that most of the groundwater resources in the central, southern and eastern regions of Iran, which supply the majority of the domestic water for populated cities, do not meet the requirements for drinking‐use. Although the groundwater in northern parts fulfills the requirements for irrigation‐use, it is only suitable for irrigation of salinity‐friendly crops in central, eastern and southern regions. Ionic types and hydrochemistry facies indicate the dominance of mix water type in 13 out of 30 of Iran's sub‐basins, followed by sodium‐chloride water type in nine sub‐basins. Local geology and lithology are mainly attributed to the distribution of groundwater facies in Iran. In general, our findings reveal a distinctive relationship between Iran's geological‐geomorphological features and hydrochemical facies/groundwater quality. The findings can be used in the formulation of new strategies and policies for Iran's groundwater quality management in the future.
Modeling Lithospheric Deformation Using a Compressible Visco‐Elasto‐Viscoplastic Rheology and the Effective Viscosity Approach
Authors: Duretz Thibault , de Borst René , Yamato Philippe
Published: July 2021

Deformations of the colder regions of the lithosphere mainly occur in the frictional regime. In geodynamic models, frictional plastic deformations are often highly localized (shear bands) and are used as proxies for faults. However, capturing the generation and evolution of shear bands in geodynamic models is troublesome. Indeed, mesh dependency and lack of convergence affect, to some extent, the results of geodynamic models. Here we extend the most common plasticity implementation used in geodynamic codes (effective viscosity approach [EVA]) to include the combined effects of elastic compressibility, plastic dilatancy, strain softening, and viscoplasticity. The latter acts as a regularization that cures most of the known issues of geodynamic models related to frictional plasticity. Using regularized models based on the M2Di MATLAB routines, we show that volumetric elasto‐plastic deformations can significantly impact crustal‐scale shear banding. We also show that the artificial overstress caused by viscoplasticity can be mitigated by employing power‐law models. Furthermore, we demonstrate that plasticity algorithms common in geodynamics (based on the EVA) can be as accurate as those obtained with algorithms typically used in engineering (return mapping with a consistent tangent operator). Finally, we show examples of long‐term tectonic deformations using the state‐of‐the art geodynamic code MDoodz. They indicate that viscoplastic regularization can be used efficiently to obtain reliable simulations in geodynamics.
Precursor-dependent structural diversity in luminescent carbonized polymer dots (CPDs): the nomenclature
Authors: Zeng Qingsen , Feng Tanglue , Tao Songyuan , Zhu Shoujun , Yang Bai
Published: July 2021

Carbon dots (CDs) have received immense attention in the last decade because they are easy-to-prepare, nontoxic, and tailorable carbon-based fluorescent nanomaterials. CDs can be categorized into three subgroups based on their morphology and chemical structure: graphene quantum dots (GQDs), carbon quantum dots (CQDs), and carbonized polymer dots (CPDs). The detailed structures of the materials can vary significantly, even within the same category. This property is particularly predominant in chemically synthesized CPDs, as their formation proceeds via the polymerization–carbonization of molecules or polymer precursors. Abundant precursors endow CPDs with versatile structures and properties. A wide variety of carbon nanomaterials can be grouped under the category of CPDs because of their observed diversity. It is important to understand the precursor-dependent structural diversity observed in CPDs. Appropriate nomenclature for all classes and types of CPDs is proposed for the better utilization of these emerging materials.
Disruptor of telomeric silencing 1-like promotes ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic pathways and blocking apoptosis
Authors: Chava Suresh , Bugide Suresh , Edwards Yvonne J. K. , Gupta Romi
Published: July 2021

Ovarian cancer is the leading cause of gynecological malignancy-related deaths. Current therapies for ovarian cancer do not provide meaningful and sustainable clinical benefits, highlighting the need for new therapies. We show that the histone H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is overexpressed in ovarian cancer and that a higher level of DOT1L expression correlates with shorter progression-free and overall survival (OS). Pharmacological inhibition of DOT1L (EPZ-5676, EPZ004777, and SGC0946) or genetic inhibition of DOT1L attenuates the growth of ovarian cancer cells in cell culture and in a mouse xenograft model of ovarian cancer. Transcriptome-wide mRNA expression profiling shows that DOT1L inhibition results in the downregulation of genes involved in cellular biosynthesis pathways and the upregulation of proapoptotic genes. Consistent with the results of transcriptome analysis, the unbiased large-scale metabolomic analysis showed reduced levels of several metabolites of the amino acid and nucleotide biosynthesis pathways after DOT1L inhibition. DOT1L inhibition also resulted in the upregulation of the NKG2D ligand ULBP1 and subsequent increase in natural killer (NK) cell-mediated ovarian cancer eradication. Collectively, our results demonstrate that DOT1L promotes ovarian cancer tumor growth by regulating apoptotic and metabolic pathways as well as NK cell-mediated eradication of ovarian cancer and identifies DOT1L as a new pharmacological target for ovarian cancer therapy.
Latest advances in the management of classical Hodgkin lymphoma: the era of novel therapies
Authors: Mohty Razan , Dulery Rémy , Bazarbachi Abdul Hamid , Savani Malvi , Hamed Rama Al , Bazarbachi Ali , Mohty Mohamad
Published: July 2021

Hodgkin lymphoma is a highly curable disease. Although most patients achieve complete response following frontline therapy, key unmet clinical needs remain including relapsed/refractory disease, treatment-related morbidity, impaired quality of life and poor outcome in patients older than 60 years. The incorporation of novel therapies, including check point inhibitors and antibody–drug conjugates, into the frontline setting, sequential approaches, and further individualized treatment intensity may address these needs. We summarize the current treatment options for patients with classical Hodgkin lymphoma from frontline therapy to allogeneic hematopoietic stem cell transplantation and describe novel trials in the field.
Hematopoietic stem cell transplantation in children and adolescents with GATA2-related myelodysplastic syndrome
Authors: Bortnick Rachel , Wlodarski Marcin , de Haas Valerie , De Moerloose Barbara , Dworzak Michael , Hasle Henrik , Masetti Riccardo , Starý Jan , Turkiewicz Dominik , Ussowicz Marek , Kozyra Emilia , Albert Michael , Bader Peter , Bordon Victoria , Cario Gunnar , Beier Rita , Schulte Johannes , Bresters Dorine , Müller Ingo , Pichler Herbert , Sedlacek Petr , Sauer Martin G. , Zecca Marco , Göhring Gudrun , Yoshimi Ayami , Noellke Peter , Erlacher Miriam , Locatelli Franco , Niemeyer Charlotte M. , Strahm Brigitte ,   for EWOG-MDS
Published: July 2021

GATA2 deficiency is a heterogeneous multi-system disorder characterized by a high risk of developing myelodysplastic syndrome (MDS) and myeloid leukemia. We analyzed the outcome of 65 patients reported to the registry of the European Working Group (EWOG) of MDS in childhood carrying a germlineGATA2mutation (GATA2mut) who had undergone hematopoietic stem cell transplantation (HSCT). At 5 years the probability of overall survival and disease-free survival (DFS) was 75% and 70%, respectively. Non-relapse mortality and relapse equally contributed to treatment failure. There was no evidence of increased incidence of graft-versus-host-disease or excessive rates of infections or organ toxicities. Advanced disease and monosomy 7 (−7) were associated with worse outcome. Patients with refractory cytopenia of childhood (RCC) and normal karyotype showed an excellent outcome (DFS 90%) compared to RCC and −7 (DFS 67%). Comparing outcome ofGATA2mutwithGATA2wtpatients, there was no difference in DFS in patients with RCC and normal karyotype. The same was true for patients with −7 across morphological subtypes. We demonstrate that HSCT outcome is independent ofGATA2germline mutations in pediatric MDS suggesting the application of standard MDS algorithms and protocols. Our data support considering HSCT early in the course of GATA2 deficiency in young individuals.
Re-evaluating diabetic papillopathy using optical coherence tomography and inner retinal sublayer analysis
Authors: Huemer Josef , Khalid Hagar , Ferraz Daniel , Faes Livia , Korot Edward , Jurkute Neringa , Balaskas Konstantinos , Egan Catherine A. , Petzold Axel , Keane Pearse A.
Published: July 2021

Background/Objectives

To re-evaluate diabetic papillopathy using optical coherence tomography (OCT) for quantitative analysis of the peripapillary retinal nerve fibre layer (pRNFL), macular ganglion cell layer (mGCL) and inner nuclear layer (mINL) thickness.

Subjects/Methods

In this retrospective observational case series between June 2008 and July 2019 at Moorfields Eye hospital, 24 eyes of 22 patients with diabetes and optic disc swelling with confirmed diagnosis of NAION or diabetic papillopathy by neuro-ophthalmological assessment were included for evaluation of the pRNFL, mGCL and mINL thicknesses after resolution of optic disc swelling.

Results

The mean age of included patients was 56.5 (standard deviation (SD) ± 14.85) years with a mean follow-up duration of 216 days. Thinning of pRNFL (mean: 66.26, SD ± 31.80 µm) and mGCL (mean volume: 0.27 mm3, SD ± 0.09) were observed in either group during follow-up, the mINL volume showed no thinning with 0.39 ± 0.05 mm3. The mean decrease in visual acuity was 4.13 (SD ± 14.27) ETDRS letters with a strong correlation between mGCL thickness and visual acuity (rho 0.74,p < 0.001).

Conclusion

After resolution of acute optic disc swelling, atrophy of pRNFL and mGCL became apparent in all cases of diabetic papillopathy and diabetic NAION, with preservation of mINL volumes. Analysis of OCT did not provide a clear diagnostic distinction between both entities. We suggest a diagnostic overlay with the degree of pRNFL and mGCL atrophy of prognostic relevance for poor visual acuity independent of the semantics of terminology.
Genetic influences on hub connectivity of the human connectome
Authors: Arnatkeviciute Aurina , Fulcher Ben D. , Oldham Stuart , Tiego Jeggan , Paquola Casey , Gerring Zachary , Aquino Kevin , Hawi Ziarih , Johnson Beth , Ball Gareth , Klein Marieke , Deco Gustavo , Franke Barbara , Bellgrove Mark A. , Fornito Alex
Published: July 2021

Brain network hubs are both highly connected and highly inter-connected, forming a critical communication backbone for coherent neural dynamics. The mechanisms driving this organization are poorly understood. Using diffusion-weighted magnetic resonance imaging in twins, we identify a major role for genes, showing that they preferentially influence connectivity strength between network hubs of the human connectome. Using transcriptomic atlas data, we show that connected hubs demonstrate tight coupling of transcriptional activity related to metabolic and cytoarchitectonic similarity. Finally, comparing over thirteen generative models of network growth, we show that purely stochastic processes cannot explain the precise wiring patterns of hubs, and that model performance can be improved by incorporating genetic constraints. Our findings indicate that genes play a strong and preferential role in shaping the functionally valuable, metabolically costly connections between connectome hubs.
mTORC1 activity regulates post-translational modifications of glycine decarboxylase to modulate glycine metabolism and tumorigenesis
Authors: Liu Rui , Zeng Lin-Wen , Gong Rong , Yuan Fanen , Shu Hong-Bing , Li Shu
Published: July 2021

Glycine decarboxylase (GLDC) is a key enzyme of glycine cleavage system that converts glycine into one-carbon units. GLDC is commonly up-regulated and plays important roles in many human cancers. Whether and how GLDC is regulated by post-translational modifications is unknown. Here we report that mechanistic target of rapamycin complex 1 (mTORC1) signal inhibits GLDC acetylation at lysine (K) 514 by inducing transcription of the deacetylase sirtuin 3 (SIRT3). Upon inhibition of mTORC1, the acetyltransferase acetyl-CoA acetyltransferase 1 (ACAT1) catalyzes GLDC K514 acetylation. This acetylation of GLDC impairs its enzymatic activity. In addition, this acetylation of GLDC primes for its K33-linked polyubiquitination at K544 by the ubiquitin ligase NF-X1, leading to its degradation by the proteasomal pathway. Finally, we find that GLDC K514 acetylation inhibits glycine catabolism, pyrimidines synthesis and glioma tumorigenesis. Our finding reveals critical roles of post-translational modifications of GLDC in regulation of its enzymatic activity, glycine metabolism and tumorigenesis, and provides potential targets for therapeutics of cancers such as glioma.
Highly active and selective oxygen reduction to H2O2 on boron-doped carbon for high production rates
Authors: Xia Yang , Zhao Xunhua , Xia Chuan , Wu Zhen-Yu , Zhu Peng , Kim Jung Yoon , Bai Xiaowan , Gao Guanhui , Hu Yongfeng , Zhong Jun , Liu Yuanyue , Wang Haotian
Published: July 2021

Oxygen reduction reaction towards hydrogen peroxide (H2O2) provides a green alternative route for H2O2production, but it lacks efficient catalysts to achieve high selectivity and activity simultaneously under industrial-relevant production rates. Here we report a boron-doped carbon (B-C) catalyst which can overcome this activity-selectivity dilemma. Compared to the state-of-the-art oxidized carbon catalyst, B-C catalyst presents enhanced activity (saving more than 210 mV overpotential) under industrial-relevant currents (up to 300 mA cm−2) while maintaining high H2O2selectivity (85–90%). Density-functional theory calculations reveal that the boron dopant site is responsible for high H2O2activity and selectivity due to low thermodynamic and kinetic barriers. Employed in our porous solid electrolyte reactor, the B-C catalyst demonstrates a direct and continuous generation of pure H2O2solutions with high selectivity (up to 95%) and high H2O2partial currents (up to ~400 mA cm−2), illustrating the catalyst’s great potential for practical applications in the future.
Exchange catalysis by tapasin exploits conserved and allele-specific features of MHC-I molecules
Authors: Lan Huan , Abualrous Esam T. , Sticht Jana , Fernandez Laura Maria Arroyo , Werk Tamina , Weise Christoph , Ballaschk Martin , Schmieder Peter , Loll Bernhard , Freund Christian
Published: July 2021

The repertoire of peptides presented by major histocompatibility complex class I (MHC-I) molecules on the cell surface is tailored by the ER-resident peptide loading complex (PLC), which contains the exchange catalyst tapasin. Tapasin stabilizes MHC-I molecules and promotes the formation of stable peptide-MHC-I (pMHC-I) complexes that serve as T cell antigens. Exchange of suboptimal by high-affinity ligands is catalyzed by tapasin, but the underlying mechanism is still elusive. Here we analyze the tapasin-induced changes in MHC-I dynamics, and find the catalyst to exploit two essential features of MHC-I. First, tapasin recognizes a conserved allosteric site underneath the α2-1-helix of MHC-I, ‘loosening’ the MHC-I F-pocket region that accomodates the C-terminus of the peptide. Second, the scoop loop11–20of tapasin relies on residue L18 to target the MHC-I F-pocket, enabling peptide exchange. Meanwhile, tapasin residue K16 plays an accessory role in catalysis of MHC-I allotypes bearing an acidic F-pocket. Thus, our results provide an explanation for the observed allele-specificity of catalyzed peptide exchange.
Peta-bit-per-second optical communications system using a standard cladding diameter 15-mode fiber
Authors: Rademacher Georg , Puttnam Benjamin J. , Luís Ruben S. , Eriksson Tobias A. , Fontaine Nicolas K. , Mazur Mikael , Chen Haoshuo , Ryf Roland , Neilson David T. , Sillard Pierre , Achten Frank , Awaji Yoshinari , Furukawa Hideaki
Published: July 2021

Data rates in optical fiber networks have increased exponentially over the past decades and core-networks are expected to operate in the peta-bit-per-second regime by 2030. As current single-mode fiber-based transmission systems are reaching their capacity limits, space-division multiplexing has been investigated as a means to increase the per-fiber capacity. Of all space-division multiplexing fibers proposed to date, multi-mode fibers have the highest spatial channel density, as signals traveling in orthogonal fiber modes share the same fiber-core. By combining a high mode-count multi-mode fiber with wideband wavelength-division multiplexing, we report a peta-bit-per-second class transmission demonstration in multi-mode fibers. This was enabled by combining three key technologies: a wideband optical comb-based transmitter to generate highly spectral efficient 64-quadrature-amplitude modulated signals between 1528 nm and 1610 nm wavelength, a broadband mode-multiplexer, based on multi-plane light conversion, and a 15-mode multi-mode fiber with optimized transmission characteristics for wideband operation.
Multiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer
Authors: Lim Yiting , Arora Sonali , Schuster Samantha L. , Corey Lukas , Fitzgibbon Matthew , Wladyka Cynthia L. , Wu Xiaoying , Coleman Ilsa M. , Delrow Jeffrey J. , Corey Eva , True Lawrence D. , Nelson Peter S. , Ha Gavin , Hsieh Andrew C.
Published: July 2021

The functional consequences of genetic variants within 5’ untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease. Here we develop a high-throughput multi-layer functional genomics method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to quantify the molecular consequences of somatic 5’ UTR mutations in human prostate cancer. We show that 5’ UTR mutations can control transcript levels and mRNA translation rates through the creation of DNA binding elements or RNA-based cis-regulatory motifs. We discover that point mutations can simultaneously impact transcript and translation levels of the same gene. We provide evidence that functional 5’ UTR mutations in the MAP kinase signaling pathway can upregulate pathway-specific gene expression and are associated with clinical outcomes. Our study reveals the diverse mechanisms by which the mutational landscape of 5’ UTRs can co-opt gene expression and demonstrates that single nucleotide alterations within 5’ UTRs are functional in cancer.
Structural basis of the membrane intramolecular transacylase reaction responsible for lyso-form lipoprotein synthesis
Authors: Olatunji Samir , Bowen Katherine , Huang Chia-Ying , Weichert Dietmar , Singh Warispreet , Tikhonova Irina G. , Scanlan Eoin M. , Olieric Vincent , Caffrey Martin
Published: July 2021

Lipoproteins serve diverse functions in the bacterial cell and some are essential for survival. Some lipoproteins are adjuvants eliciting responses from the innate immune system of the host. The growing list of membrane enzymes responsible for lipoprotein synthesis includes the recently discovered lipoprotein intramolecular transacylase, Lit. Lit creates a lipoprotein that is less immunogenic, possibly enabling the bacteria to gain a foothold in the host by stealth. Here, we report the crystal structure of the Lit enzyme fromBacillus cereusand describe its mechanism of action. Lit consists of four transmembrane helices with an extracellular cap. Conserved residues map to the cap-membrane interface. They include two catalytic histidines that function to effect unimolecular transacylation. The reaction involves acyl transfer from thesn-2 position of the glyceryl moiety to the amino group on the N-terminal cysteine of the substrate via an 8-membered ring intermediate. Transacylation takes place in a confined aromatic residue-rich environment that likely evolved to bring distant moieties on the substrate into proximity and proper orientation for catalysis.
Upstream modes and antidots poison graphene quantum Hall effect
Authors: Moreau N. , Brun B. , Somanchi S. , Watanabe K. , Taniguchi T. , Stampfer C. , Hackens B.
Published: July 2021

The quantum Hall effect is the seminal example of topological protection, as charge carriers are transmitted through one-dimensional edge channels where backscattering is prohibited. Graphene has made its marks as an exceptional platform to reveal new facets of this remarkable property. However, in conventional Hall bar geometries, topological protection of graphene edge channels is found regrettably less robust than in high mobility semi-conductors. Here, we explore graphene quantum Hall regime at the local scale, using a scanning gate microscope. We reveal the detrimental influence of antidots along the graphene edges, mediating backscattering towards upstream edge channels, hence triggering topological breakdown. Combined with simulations, our experimental results provide further insights into graphene quantum Hall channels vulnerability. In turn, this may ease future developments towards precise manipulation of topologically protected edge channels hosted in various types of two-dimensional crystals.
A clinical deep learning framework for continually learning from cardiac signals across diseases, time, modalities, and institutions
Authors: Kiyasseh Dani , Zhu Tingting , Clifton David
Published: July 2021

Deep learning algorithms trained on instances that violate the assumption of being independent and identically distributed (i.i.d.) are known to experience destructive interference, a phenomenon characterized by a degradation in performance. Such a violation, however, is ubiquitous in clinical settings where data are streamed temporally from different clinical sites and from a multitude of physiological sensors. To mitigate this interference, we propose a continual learning strategy, entitled CLOPS, that employs a replay buffer. To guide the storage of instances into the buffer, we propose end-to-end trainable parameters, termed task-instance parameters, that quantify the difficulty with which data points are classified by a deep-learning system. We validate the interpretation of these parameters via clinical domain knowledge. To replay instances from the buffer, we exploit uncertainty-based acquisition functions. In three of the four continual learning scenarios, reflecting transitions across diseases, time, data modalities, and healthcare institutions, we show that CLOPS outperforms the state-of-the-art methods, GEM1 and MIR2. We also conduct extensive ablation studies to demonstrate the necessity of the various components of our proposed strategy. Our framework has the potential to pave the way for diagnostic systems that remain robust over time.
Self-assembly using a retro Diels-Alder reaction
Authors: Park Jaeyoung , Heo Jung-Moo , Seong Sicheon , Noh Jaegeun , Kim Jong-Man
Published: July 2021

Despite their great utility in synthetic and materials chemistry, Diels-Alder (DA) and retro Diels-Alder (rDA) reactions have been vastly unexplored in promoting self-assembly processes. Herein we describe the first example of a retro Diels-Alder (rDA) reaction-triggered self-assembly method. Release of the steric bulkiness associated with the bridged bicyclic DA adduct by the rDA reaction allowed generation of two building blocks that spontaneously self-assembled to form a supramolecular polymer. By employing photopolymerizable lipid building blocks, we demonstrated the efficiency of the rDA-based self-assembly strategy. Generation of reactive functional groups (maleimide and furan) that can be used for further modification of the supramolecular polymer is an additional meritorious feature of the rDA-based approach. Advantage was taken of reactive functional groups to fabricate stimulus-responsive selective and tunable colorimetric sensors. The strategy developed in this study should be useful for the design of systems that participate in triggered molecular assembly.