bluuebunny/crossref_metadata_2025 huggingface dataset:
Spheroid-induced heterogeneity and plasticity of uveal melanoma cells
Authors: Chen Yao , Lu Xiaoqin , Gao Ling , Dean Douglas C. , Liu Yongqing
Published: April 2022

Purpose

The mechanism underlying cancer heterogeneity and plasticity remains elusive, in spite of the fact that multiple hypotheses have been put forward. We intended to clarify this heterogeneity in uveal melanoma (UM) by looking for evidence of cancer stem cell involvement and a potential role of ZEB1 in cancer cell plasticity.

Methods

Spheroids derived from human UM cells as well as xenograft tumors in nude mice were dissected for signs of heterogeneity and plasticity. Two human UM cell lines were studied: the epithelioid type C918 cell line and the spindle type OCM1 cell line. We knocked down ZEB1 in both cell lines to investigate its involvement in the regulation of stem-like cell formation and vascularization by qRT-PCR, immunohistochemistry, flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays.

Results

We found that a small side population (SP) in OCM1 showed stem cell-like properties such as heterogeneity, remote dissemination and nuclear dye exclusion after spheroid formation in vitro. ZEB1 regulated UM stem cell generation indirectly by promoting cell proliferation to form large size tumors in vivo and spheroid in vitro, and directly by binding to stemness genes such as TERT and ABCB1. In addition, we found that ZEB1 participates in vasculogenic mimicry system formation through the regulation of CD34 and VE-cadherin expression.

Conclusions

From our data we conclude that cancer stem cells may contribute to UM heterogeneity and plasticity and that ZEB1 may play a regulatory role in it.
The dose makes the poison: feeding of antibiotic-treated winter honey bees, Apis mellifera, with probiotics and b-vitamins
Authors: Brown Andrew , Rodriguez Victor , Pfister Judith , Perreten Vincent , Neumann Peter , Retschnig Gina
Published: April 2022

Honey stores of Apis mellifera colonies are replaced with sugar water by beekeepers, which may result in malnutrition. Nutritional supplements have been developed, but the importance of bacterial probiotics and vitamins is poorly understood. Given that supplementary feeding with vitamins and probiotics may enhance worker weight and longevity, this might suggest a feasible approach to mitigate winter colony losses. Here, we conducted a laboratory hoarding cage study with freshly emerged winter bees, which were treated with the antibiotic tetracycline to reduce gut bacteria obtained post-emergence and subsequently assigned to feeding regimes: sucrose only, sucrose + pollen, probiotics (low and high dosage), probiotics + pollen (low and high dosage), or b-vitamins (low and high dosage) (N = 8 treatments, 29 workers/cage × 8 replicates). In parallel, another age cohort of bees remained on their frame (= Frame) to establish their gut microbiota and were subsequently fed with sucrose only or sucrose + pollen (N = 2 treatments, 29 workers/cage × 4 replicates). The most beneficial effects on body weights were found in workers given ad libitum access to pollen, notably in the Frame Sucrose + Pollen group, confirming the inherent importance of post-emergent gut flora inoculation and the role of gut bacteria in protein digestion. Furthermore, both Frame groups and the antibiotic-treated workers fed with probiotic low + pollen survived longer than all other groups, highlighting a fundamental host-microbial relationship. On the other hand, our current treatments alone, post-tetracycline, did not yield any positive results. In contrast, high dosages of both probiotic and b-vitamins significantly reduced lifespan compared to their low concentration counterparts, probably due to dysbiosis and toxicity, suggesting that the outcome was dose-dependent. These results highlight that bacterial and b-vitamin supplementation can alter longevity with advisable caution since harmful concentrations appear to exist.
Möglichkeiten und Grenzen der Einschätzung des Delirrisikos: ein Scoping Review zu den Gütekriterien der Skala Recognizing Acute Delirium As part of your Routine
Authors: Schumacher Petra , Schmied Marten , Schiller Michael , Voyer Philippe , Müller Gerhard
Published: April 2022

Hintergrund

Die Diagnose eines Delirs beruht primär auf der Erfassung der klinischen Symptomatik mit akutem Beginn und fluktuierendem Verlauf. In der Literatur werden 5 pflegerische Screeninginstrumente zur Delirrisikoeinschätzung beschrieben, eines davon ist die Skala Recognizing Acute Delirium As part of your Routine (RADAR). Bisher wurde noch keine Literaturübersichtsarbeit zu den Gütekriterien der Skala durchgeführt.

Ziel

Die Literatur zu RADAR zu sichten, um einen Überblick über die testtheoretischen und anwendungsbezogenen Gütekriterien aufzuzeigen.

Methode

Das Scoping Review wurde in MEDLINE via PubMed sowie CINAHL und Academic Search Elite via EBSCOhost in der Zeit vom Juni 2019 bis Juli 2019 u. a. mit den Suchbegriffendelir*, screening tool, psychometric propertiesdurchgeführt. Die Checkliste Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews mit ihren 9 Schritten wurde verwendet, um über die angewandte Methode dieses Scoping Review zu berichten.

Ergebnis

Die Interrater-Reliabilität der RADAR variiert zwischen 82 und 92 % (κ = 0,34–1). Die konvergente Validität mit der Confusion Assessment Method liegt zwischen 36 und 85 % (κ = 0,08–0,42). Die prädiktive Validität wird mit einer Sensitivität von 54,4–100 % und einer Spezifität von 72–85,5 % angegeben (PPV = 12,5–71 %,NPV = 94,2–100 %). Die RADAR ist einfach zu verstehen und kann in weniger als 6 min ausgefüllt werden. Die Akzeptanz wird als hoch angegeben.

Schlussfolgerung

Die RADAR-Skala scheint ein valides und akzeptiertes Instrument zur Delirrisikoeinschätzung zu sein. Für die deutschsprachige Version werden weitere Validierungsstudien empfohlen.
Design of ECM Functionalized Polycaprolactone Aligned Nanofibers for Peripheral Nerve Tissue Engineering
Authors: Nune Manasa , Bhat Mahima , Nagarajan Aishwarya
Published: April 2022

Purpose

Peripheral nerve injury (PNI) and its regeneration continue to remain a significant medical burden worldwide. The current treatment strategies used to treat PNI are often associated with multiple complications and yet do not achieve complete motor and sensory functions. Recently, synthetic biodegradable nerve conduits have become one the most commonly used conduits to repair small gaps in nerve injury. But they have not shown better results than nerve grafts possibly because of the lack of biological microenvironment required for axonal growth. Schwann cells play a very crucial role in peripheral nerve regeneration where activated SCs produce multiple neurotrophic factors that help in remyelination and immune modulation during nerve repair. Studies have shown that nanofibrous scaffolds have better bioactivity and more closely mimic the native structure of the extracellular matrix. Therefore, the present study was focused on designing a nanofibrous scaffold that would cover the roles of both structural support for the cells that can provide a microenvironment with biological cues for nerve growth and regeneration.

Methods

Decellularized Schwann cell ECM were spin-coated on polycaprolactone random and aligned nanofibrous scaffolds and their compatibility was evaluated using Schwann cells.

Results

Schwann cells displayed growth in the direction of the aligned PCL nanofibers and ACM treated exhibited appropriate bipolar morphology indicating that these modified fibers could provide directional cues making them highly suitable for neuronal cell growth.

Conclusion

Our results indicate that the fabricated aligned SC-ACM treated PCL scaffolds would be a potential biomaterial to treat peripheral nerve injuries and promote regeneration.

Graphical Abstract
Protein–chromophore interactions controlling photoisomerization in red/green cyanobacteriochromes
Authors: Rockwell Nathan C. , Moreno Marcus V. , Martin Shelley S. , Lagarias J. Clark
Published: April 2022

Photoreceptors in the phytochrome superfamily use 15,16-photoisomerization of a linear tetrapyrrole (bilin) chromophore to photoconvert between two states with distinct spectral and biochemical properties. Canonical phytochromes include master regulators of plant growth and development in which light signals trigger interconversion between a red-absorbing 15Z dark-adapted state and a metastable, far-red-absorbing 15E photoproduct state. Distantly related cyanobacteriochromes (CBCRs) carry out a diverse range of photoregulatory functions in cyanobacteria and exhibit considerable spectral diversity. One widespread CBCR subfamily typically exhibits a red-absorbing 15Z dark-adapted state similar to that of phytochrome that gives rise to a distinct green-absorbing 15E photoproduct. This red/green CBCR subfamily also includes red-inactive examples that fail to undergo photoconversion, providing an opportunity to study protein–chromophore interactions that either promote photoisomerization or block it. In this work, we identified a conserved lineage of red-inactive CBCRs. This enabled us to identify three substitutions sufficient to block photoisomerization in photoactive red/green CBCRs. The resulting red-inactive variants faithfully replicated the fluorescence and circular dichroism properties of naturally occurring examples. Converse substitutions restored photoconversion in naturally red-inactive CBCRs. This work thus identifies protein–chromophore interactions that control the fate of the excited-state population in red/green cyanobacteriochromes.
Understanding Metaphors in the Life Sciences
Authors: Reynolds Andrew S.
Published: April 2022

Covering a range of metaphors from a diverse field of sciences, from cell and molecular biology to evolution, ecology, and biomedicine, Understanding Metaphors in the Life Sciences explores the positive and negative implications of the widespread use of metaphors in the biological and life sciences. From genetic codes, programs, and blueprints, to cell factories, survival of the fittest, the tree of life, selfish genes, and ecological niches, to genome editing with CRISPR's molecular scissors, metaphors are ubiquitous and vital components of the modern life sciences. But how exactly do metaphors help scientists to understand the objects they study? How can they mislead both scientists and laypeople alike? And what should we all understand about the implications of science's reliance on metaphorical speech and thought for objective knowledge and adequate public policy informed by science? This book will literally help you to better understand the metaphorical dimensions of science.
Beyond consumption: a qualitative investigation of hospital clinician attitudes to receiving feedback on antimicrobial prescribing quality
Authors: Hughes Gerry , O’ Toole Eilis , Coleman Una , Talento Alida Fe , Doyle Keith , O’ Leary Aisling , Bergin Colm
Published: April 2022

Background:

Feedback on optimal antimicrobial prescribing to clinicians is an important strategy to ensure antimicrobial stewardship (AMS) in the hospital setting.

Objective:

To explore the perceptions of antimicrobial prescribing feedback among clinicians in acute care.

Study design:

Prospective qualitative design.

Setting:

A large inner-city tertiary referral center in Dublin, Ireland.

Participants:

Clinicians were recruited from the hospital clinician population.

Methods:

A qualitative study was conducted with a purposive sample of multidisciplinary clinicians. Focus groups and semistructured interviews were used to collect data that were analyzed inductively to identify themes.

Results:

In total, 30 clinicians from medical, surgical, nursing and pharmacy professions participated in the study. We identified 5 themes: (1) antimicrobial consumption perceived as a proxy measure for prescribing quality; (2) lack of connection between antimicrobial prescribing and patient outcomes; (3) relevance and impact of antimicrobial prescribing feedback associated with professional role; (4) attitudes regarding feedback as an AMS strategy; and (5) knowledge regarding AMS, including antimicrobial prescribing quality measures.

Conclusions:

Focused feedback on antimicrobial prescribing, with clear goals for improvement, could serve as a useful AMS strategy among clinicians in the acute-care setting. The need for further education and training in AMS was also identified.
Is Teledentistry a Feasible Alternative for People Who Need Special Care?
Authors: Omezli Mehmet Melih , Torul Damla , Yilmaz Eyup Birkan
Published: April 2022

Objective:

The aim of this study is to explore the feasibility and acceptability of teledentistry as a vehicle that provides enhanced delivery of oral care for the people who need special care (PNSC).

Methods:

Between January 2018 and September 2020, PNSC who were admitted in the study were either waiting for a follow-up (F) appointment or on a waiting list. An examination via video call was carried out for initial examination (IE) and F purposes. The virtual examination was scored by the clinician who performed the examinations. The experience of the participants was evaluated with a satisfaction questionnaire.

Results:

Forty PNSC (26 females, 14 males) between ages 7 and 48 years (21.17 ± 10.62) participated in the study. According to the clinician ratings, the accuracy of the examination was rated as the lowest. The F group had higher scores when compared to the IE group regarding clinician rating. No significant differences were found in terms of the scoring of the clinician and patient/parent satisfaction regarding cooperation status and type of examination (P ≥ 0.05).

Conclusions:

Through adequate adaptation of the technology into clinical practice and overcoming the barriers for wider implementation, the teledentistry approach could be a reliable and feasible alternative in triaging, treatment planning, and F purposes for PNSC.
Landed Nation: Land Reform and Ethnic Diversity in the Interwar Polish Parliament
Authors: Marzec Wiktor
Published: April 2022

This article investigates the ethnic entanglements of the land reform debate in the first Polish Diet (1919–1922). Against the backdrop of global comparative studies, interwar Poland, haunted by land hunger, rural poverty, and high concentration of land ownership, is an odd case. Despite conditions conducive to far-reaching land reforms, that is, a high level of inter-elite conflict and semiautocratic order, the Polish reform was very moderate, if not disappointing. Unpacking the series of moves in the debate and the sequence of hairbreadth voting on its shape, I ask why, despite broad acceptance of the reform across the political spectrum, it could not attract enough support to be swiftly executed. The ethnic composition of the country triggered controversies concerning German farmers and peasants of the ethnically diversified eastern borderlands. Major political parties shared tacit Polish nationalism, but the history of political alignments made the nationalist politicians susceptible to the lobbying of the landed elite and estranged them from peasant parties. The land holdings of nobles were considered a bulwark of the nation, which effectively blocked the alternative idea of integrating the ethnic minorities via land ownership.
DHA turnover in pregnant women using the natural abundance variation of 13C: a pilot study
Authors: Simonato Manuela , Visentin Silvia , Verlato Giovanna , Cosmi Erich , Correani Alessio , Cogo Paola , Carnielli Virgilio Paolo
Published: April 2022

The importance of DHA to support fetal development and maternal health is well established. In this study, we applied the natural abundance approach to determine the contribution of 200 mg/d of DHA supplement to the plasma DHA pool in nineteen healthy pregnant women. Women received DHA, from week 20 until delivery, from an algal source (n 13, Algae group) or from fish oil (n 6, Fish group) with slightly different content of 13C. We measured plasma phospholipids DHA 13C:12C ratio (reported as δ13C) prior to supplementation (T0), after 10 (T1) and 90 days (T2) and prior to delivery (T3). The δ13C of DHA in algae and fish supplements were −15·8 (sd 0·2) mUr and −25·3 (sd 0·2) mUr (P < 0·001). DHA δ13C in the Algae group increased from −27·7 (sd 1·6) mUr (T0) to −21·9 (sd 2·2) mUr (T3) (P < 0·001), whereas there were not significant changes in the Fish group (–27·8 (sd 0·9) mUr at T0 and −27·3 (sd 1·1) mUr at T3, P = 0·09). In the Algae group, 200 mg/d of DHA contributed to the plasma phospholipid pool by a median value of 53 % (31–75 % minimum and maximum). This estimation was not possible in the Fish group. Our results demonstrate the feasibility of assessing the contribution of DHA from an algal source to the plasma DHA pool in pregnant women by the natural abundance approach. Plasma δ13C DHA did not change when consuming DHA of fish origin, with almost the same δ13C value of that of the pre-supplementation plasma δ13C DHA.
Prevalence and maternal determinants of early and late introduction of complementary foods: results from the Growing Up in New Zealand cohort study
Authors: Ferreira Sara Silva , Marchioni Dirce Maria Lobo , Wall Clare Rosemary , Gerritsen Sarah , Teixeira Juliana Araujo , Grant Cameron C. , Morton Susan M. B. , Gontijo de Castro Teresa
Published: April 2022

A nationally generalisable cohort (n 5770) was used to determine the prevalence of non-timely (early/late) introduction of complementary food and core food groups and associations with maternal sociodemographic and health behaviours in New Zealand (NZ). Variables describing maternal characteristics and infant food introduction were sourced, respectively, from interviews completed antenatally and during late infancy. The NZ Infant Feeding Guidelines were used to define early (≤ 4 months) and late (≥ 7 months) introduction. Associations were examined using multivariable multinomial regression, presented as adjusted relative risk ratios and 95 % confidence intervals (RRR; 95% CI). Complementary food introduction was early for 40·2 % and late for 3·2 %. The prevalence of early food group introduction were fruit/vegetables (23·8 %), breads/cereals (36·3 %), iron-rich foods (34·1 %) and of late were meat/meat alternatives (45·9 %), dairy products (46·2 %) and fruits/vegetables (9·9 %). Compared with infants with timely food introduction, risk of early food introduction was increased for infants: breastfed < 6months (2·52; 2·19–2·90), whose mothers were < 30 years old (1·69; 1·46–1·94), had a diploma/trade certificate v. tertiary education (1·39; 1·1–1·70), of Māori v. European ethnicity (1·40; 1·12–1·75) or smoked during pregnancy (1·88; 1·44–2·46). Risk of late food introduction decreased for infants breastfed < 6 months (0·47; 0.27–0·80) and increased for infants whose mothers had secondary v. tertiary education (2·04; 1·16–3·60) were of Asian v. European ethnicity (2·22; 1·35, 3·63) or did not attend childbirth preparation classes (2·23; 1·24–4·01). Non-timely food introduction, specifically early food introduction, is prevalent in NZ. Interventions to improve food introduction timeliness should be ethnic-specific and support longer breast-feeding.
Trust and Debt Contracting: Evidence From the Backdating Scandal
Authors: Fotak Veljko , Jiang Feng (Jack) , Lee Haekwon , Lie Erik
Published: April 2022

We study the effect of trust on debt contracting. We find that, after the revelation of option backdating, borrowers that likely backdated their previous option grants pay higher interest rates on loans. This adverse effect is mitigated by CEO replacements. Results are similar for public debt, but only if a third party identified the backdaters. After the backdating revelation, firms that engaged in backdating increase their reliance on public debt, and those without access to the public debt market experience capital constraints.
Traumatic brain injury and risk of subsequent attempted suicide and violent crime
Authors: Ineson Katrine M. , Erlangsen Annette , Nordentoft Merete , Benros Michael E. , Madsen Trine
Published: April 2022

Background

Traumatic brain injury (TBI) can cause long-lasting sequelae that may increase the risk of suicidal or criminal behaviour, but large-scale longitudinal studies are lacking on the link between TBI and events of suicide attempt and violent crime. This study examined the incidence of suicide attempt and violent crime following hospital contact for TBI in a nationwide cohort study.

Methods

We used nationwide register data covering all individuals aged 10+ living in Denmark during 1980–2016 (n = 7 783 951). Of these, 587 522 individuals had a hospital contact for TBI. Incidence rate ratios (IRR) were calculated by Poisson regression analyses while adjusted for relevant covariates including other fractures and psychiatric diagnoses.

Results

Individuals with TBI had higher rates of suicide attempt (females IRR, 2.78; 95% CI 2.71–2.85; males IRR, 3.00; 95% CI 2.93–3.08) compared to individuals without TBI in adjusted analyses. Multiple TBI and temporal proximity to TBI were associated with higher rates of suicide attempt. Individuals with TBI had higher rates of violent crime (females IRR, 2.43; 95% CI 2.36–2.49; males IRR, 1.80, 95% CI 1.78–1.82) compared with individuals without TBI. Higher rates of violent crime were found after multiple TBI and temporal proximity to TBI.

Conclusions

This nationwide cohort study found higher rates of suicide attempt and violent crime among individuals with prior hospital diagnosed TBI, compared with individuals without TBI. This emphasises the need for preventive efforts immediately after TBI diagnosis, which might mitigate the risks of a trajectory toward suicidal or violent behaviours.
Use of vector formalism in the analysis of hydrophobic and electric driving forces in biological assemblies
Authors: Mozo-Villarías Angel , Cedano Juan A. , Querol Enrique
Published: April 2022

Hydrophobic forces are known to have a crucial part not only in the conformation of the three-dimensional structure of proteins, but also in the build-up of DNA–protein complexes. Electric forces also play an important role both in the tertiary as well in the quaternary structure of macromolecular associations. Sometimes both hydrophobic and electric interactions add up their strengths to accomplish these structures but in most cases they act in opposite directions. This fact, together with being overall interactions with different ranges, provides a nuanced equilibrium also modulated by the need to comply with steric hindrances and geometric frustration effects. This review focuses on the utility of using the hydrophobic and electrical dipole moment vectors to describe the interactions that give rise to the structures of biological macromolecules. Although different definitions of both electric dipole and hydrophobic moments have been described in the literature, results obtained in biological assemblies demonstrate the principle of the biological membrane model. According to this model, postulated by our group, biological macromolecules tend to associate by aligning their hydrophobic moments in a similar manner to phospholipids in a membrane. Examples of both closed and open structures are used to assess the predictability of our model. We seek agreement between our results with those described in the current literature. The review ends with possible future projections using this formalism.
Public Reporting of Performance Indicators in Long-Term Care in Canada: Does it Make a Difference?
Authors: Poldrugovac Mircha , Amuah Joseph Emmanuel , Wei-Randall Helen , Sidhom Patricia , Morris Kathleen , Allin Sara , Klazinga Niek , Kringos Dionne
Published: April 2022

Evidence of the impact of public reporting of health care performance on quality improvement is not yet sufficient for definitive conclusions to be drawn, despite the important policy implications. This study explored the association of public reporting of performance indicators of long-term care facilities in Canada with performance trends. We considered 16 performance indicators in long-term care in Canada, 8 of which are publicly reported at a facility level, whereas the other 8 are not publicly reported, between the fiscal years 2011–2012 and 2018–2019. Data from 1,087 long-term care facilities were included. Improving trends were observed among publicly reported indicators more often than among indicators that were not publicly reported. Our analysis also suggests that the association between publication of data and improvement is stronger among indicators for which there was no improvement prior to publication and among the worst performing facilities.
Affirmative Counseling for Transgender and Gender Diverse Clients
Authors: dickey lore m. , Puckett Jae A.
Published: April 2022

A how-to guide to affirmative counseling with transgender clients

Presents the best evidence-based care
Instructions for strategies to improve inclusivity
Illustrated with case studies
Printable tools for clinical use

Expert guidance on how to provide competent gender-affirming care to trans people

This volume provides fundamental and evidence-based information on working with transgender and gender diverse people in mental health settings. It provides background information on the historical context of
care with transgender clients, clarifying terminology, and helping the reader understand diverse experiences of gender. The expert authors outline the key qualities of competent practice with trans clients, such as the use of affirming language and providing a safe environment, and strategies for improving inclusivity and evidence-based care. dickey and Puckett provide insight into current topics, such as the proper use of pronouns, working with youth, suicide and self-injury, and problematic approaches such as conversion therapy and rapid onset gender dysphoria. Practitioners will find the printable resources invaluable for their clinical practice, including sample letters of support for trans clients who are seeking gender-affirming medical care.
The Origin of Earth's Mantle Nitrogen: Primordial or Early Biogeochemical Cycling?
Authors: Kurokawa H. , Laneuville M. , Li Y. , Zhang N. , Fujii Y. , Sakuraba H. , Houser C. , Cleaves H. J.
Published: April 2022

Earth's mantle nitrogen (N) content is comparable to that found in its N‐rich atmosphere. Mantle N has been proposed to be primordial or sourced by later subduction, yet its origin has not been elucidated. Here we model N partitioning during the magma ocean stage following planet formation and the subsequent cycling between the surface and mantle over Earth history using argon (Ar) and N isotopes as tracers. The partitioning model, constrained by Ar, shows that only about 10% of the total N content can be trapped in the solidified mantle due to N's low solubility in magma and low partitioning coefficients in minerals in oxidized conditions supported from geophysical and geochemical studies. A possible solution for the primordial origin is that Earth had about 10 times more N at the time of magma ocean solidification. We show that the excess N could be removed by impact erosion during late accretion. The cycling model, constrained by N isotopes, shows that mantle N can originate from efficient N subduction, if the sedimentary N burial rate on early Earth is comparable to that of modern Earth. Such a high N burial rate requires biotic processing. Finally, our model provides a methodology to distinguish the two possible origins with future analysis of the surface and mantle N isotope record.
Residence Time of Over‐Steepened Rock Masses in an Active Mountain Range
Authors: Li Gen K. , Moon Seulgi , Higa Justin T.
Published: April 2022

In uplifting mountains, hillslopes steepen toward a threshold angle set by substrate material strength. Hillslopes beyond the threshold angle, referred to as excess topography, are mechanically unstable. The residence time scale of rock masses in excess topography (Tex) is critical for understanding time scales of surface processes and landscape evolution in steep mountains. However, Tex remains loosely constrained for varying slopes and lithologies. Here, we calculate Tex in the eastern Tibetan mountains by quantifying excess topography across lithologies, long‐term landslide erosion rates caused by seismicity and climate, and exhumation rates. Tex increases with local slope angles and is of the same order of magnitude across different lithologies but slightly longer for metamorphic rocks. Range‐scale Tex is estimated as ∼61–157 kyr, ∼3–9% of the relief‐rejuvenation timespan of threshold topography. Similar Tex regardless of lithologies and methods suggest steady‐state construction and erosion of excess topography over thousand to million years time scales in this orogen.
A novel approach for designing efficient broadband photodetectors expanding from deep ultraviolet to near infrared
Authors: Ding Nan , Wu Yanjie , Xu Wen , Lyu Jiekai , Wang Yue , Zi Lu , Shao Long , Sun Rui , Wang Nan , Liu Sen , Zhou Donglei , Bai Xue , Zhou Ji , Song Hongwei
Published: April 2022

Broadband photodetection (PD) covering the deep ultraviolet to near-infrared (200–1000 nm) range is significant and desirable for various optoelectronic designs. Herein, we employ ultraviolet (UV) luminescent concentrators (LC), iodine-based perovskite quantum dots (PQDs), and organic bulk heterojunction (BHJ) as the UV, visible, and near-infrared (NIR) photosensitive layers, respectively, to construct a broadband heterojunction PD. Firstly, experimental and theoretical results reveal that optoelectronic properties and stability of CsPbI3PQDs are significantly improved through Er3+doping, owing to the reduced defect density, improved charge mobility, increased formation energy, tolerance factor, etc. The narrow bandgap of CsPbI3:Er3+PQDs serves as a visible photosensitive layer of PD. Secondly, considering the matchable energy bandgap, the BHJ (BTP-4Cl: PBDB-TF) is selected as to NIR absorption layer to fabricate the hybrid structure with CsPbI3:Er3+PQDs. Thirdly, UV LC converts the UV light (200–400 nm) to visible light (400–700 nm), which is further absorbed by CsPbI3:Er3+PQDs. In contrast with other perovskites PDs and commercial Si PDs, our PD presents a relatively wide response range and high detectivity especially in UV and NIR regions (two orders of magnitude increase that of commercial Si PDs). Furthermore, the PD also demonstrates significantly enhanced air- and UV- stability, and the photocurrent of the device maintains 81.5% of the original one after 5000 cycles. This work highlights a new attempt for designing broadband PDs, which has application potential in optoelectronic devices.
Association of fruit and vegetable color with incident diabetes and cardiometabolic risk biomarkers in the United States Hispanic/Latino population
Authors: Yu Zhiping , Tamez Martha , Colon Raymond , Rodriguez Judith , Hicks-Roof Kristen K. , Ford Nikki , Mattei Josiemer , Sotres-Alvarez Daniela , Van Horn Linda , Allison Matthew , Talavera Gregory A. , Castañeda Sheila F. , Daviglus Martha L.
Published: April 2022

Background

Color groups of fruits and vegetables (FV) are part of a healthy diet, but evidence for an association with cardiometabolic outcomes is inconsistent.

Objective

To examine the association between intake of FV of different colors with incident diabetes and cardiometabolic risk biomarkers among U.S. Hispanics/Latinos.

Subjects/methods

We used data from 9206 adults ages 18–74 years who were free of diabetes at baseline (2008–2011) and had follow-up data at visit 2 (2014–2017) in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a multicenter, prospective cohort study of self-identified Hispanics/Latinos. Dietary intake was assessed using two 24 h recalls at baseline. FV were categorized into five color groups: green, white, yellow/orange, red/purple, and uncategorized. Diabetes was defined based on laboratory measures and self-reported antihyperglycemic medication. We used survey logistic regression models to evaluate the association between FV color groups and incident diabetes and survey linear regression models to evaluate the association of FV color groups with cardiometabolic risk biomarkers at visit 2.

Results

During ~6 years of follow-up, 970 incident cases of diabetes were documented. The red/purple FV color group was the least consumed (0.21 servings/day), whereas white FV were the most consumed (0.92 servings/day). For each serving of total FV intake, body mass index (BMI) was lower by 0.24% (p = 0.03) and insulin by 0.69% (p = 0.03). For each serving of red/purple FV intake, HDL was 1.59% higher (p = 0.04). For each serving of white FV intake (with potato), post-OGTT was 0.83% lower (p = 0.04) and triglycerides 1.43% lower (p = 0.04). There was no association between FV intake and incident diabetes.

Conclusions

Specific FV colors were associated with cardiometabolic benefits though the associations were of relatively small magnitudes. Dietary recommendations could consider varying colors of FV intake, especially white and red/purple color groups, for a healthy diet.
CPT1A-mediated fatty acid oxidation promotes cell proliferation via nucleoside metabolism in nasopharyngeal carcinoma
Authors: Tang Min , Dong Xin , Xiao Lanbo , Tan Zheqiong , Luo Xiangjian , Yang Lifang , Li Wei , Shi Feng , Li Yueshuo , Zhao Lin , Liu Na , Du Qianqian , Xie Longlong , Hu Jianmin , Weng Xinxian , Fan Jia , Zhou Jian , Gao Qiang , Wu Weizhong , Zhang Xin , Liao Weihua , Bode Ann M. , Cao Ya
Published: April 2022

As the first rate-limiting enzyme in fatty acid oxidation (FAO), CPT1 plays a significant role in metabolic adaptation in cancer pathogenesis. FAO provides an alternative energy supply for cancer cells and is required for cancer cell survival. Given the high proliferation rate of cancer cells, nucleotide synthesis gains prominence in rapidly proliferating cells. In the present study, we found that CPT1A is a determining factor for the abnormal activation of FAO in nasopharyngeal carcinoma (NPC) cells. CPT1A is highly expressed in NPC cells and biopsies. CPT1A dramatically affects the malignant phenotypes in NPC, including proliferation, anchorage-independent growth, and tumor formation ability in nude mice. Moreover, an increased level of CPT1A promotes core metabolic pathways to generate ATP, inducing equivalents and the main precursors for nucleotide biosynthesis. Knockdown of CPT1A markedly lowers the fraction of 13C-palmitate-derived carbons into pyrimidine. Periodic activation of CPT1A increases the content of nucleoside metabolic intermediates promoting cell cycle progression in NPC cells. Targeting CPT1A-mediated FAO hinders the cell cycle G1/S transition. Our work verified that CPT1A links FAO to cell cycle progression in NPC cellular proliferation, which supplements additional experimental evidence for developing a therapeutic mechanism based on manipulating lipid metabolism.
MFSD4A inhibits the malignant progression of nasopharyngeal carcinoma by targeting EPHA2
Authors: Yang Huiyun , Qin Guanjie , Luo Zan , Kong Xiangyun , Gan Chunqiao , Zhang Ruyun , Jiang Wei
Published: April 2022

DNA Methylation can lead to abnormal gene expression. In the present study, we investigated whether the expression of methylated MFSD4A (major facilitator superfamily domain containing 4 A) was downregulated in nasopharyngeal carcinoma (NPC) and whether it is associated with malignant progression and poor prognosis of NPC. Bioinformatic analysis, bisulfite pyrosequencing, quantitative real-time reverse transcription PCR, and western blotting assays were performed to explore the relationship between hypermethylation of MFSD4A and its expression in NPC. The role of MFSD4A in NPC was verified by Cell Cycle Kit 8, transwell assays and flow cytometry in vitro and by animal experiments in vivo. Mass spectrometry, co-immunoprecipitation, and immunofluorescence assays were applied to explore the mechanism by which MFSD4A inhibits NPC. The prognostic significance of MFSD4A or EPHA2 was investigated by immunohistochemical analysis of clinical specimens. Hypermethylation of the promoter region of MFSD4A led to decreased expression of MFSD4A. When MFSD4A expression was upregulated or downregulated, the proliferation, apoptosis, migration, and invasion abilities of NPC cells were altered accordingly. Mechanistically, MFSD4A could specifically bind to and degrade EPH receptor A2 (EPHA2) by recruiting ring finger protein 149 (RNF149), which led to alterations in the EPHA2-mediated PI3K-AKT-ERK1/2 pathway and epithelial-mesenchymal transition (EMT), thereby affecting NPC progression. Clinically, high MFSD4A expression or low-EPHA2 expression was associated with better prognosis for patients with NPC. In all, reduced MFSD4A expression in NPC is caused by promoter hypermethylation. MFSD4A or EPHA2 expression is associated with the malignant biological behavior and prognosis of NPC. MFSD4A is a promising potential therapeutic target for NPC.
Mucin 21 confers resistance to apoptosis in an O-glycosylation-dependent manner
Authors: Tian Yuan , Denda-Nagai Kaori , Tsukui Tatsuya , Ishii-Schrade Katrin B. , Okada Kyoko , Nishizono Yoshihiro , Matsuzaki Kosuke , Hafley Margarete , Bresalier Robert S. , Irimura Tatsuro
Published: April 2022

Highly glycosylated mucins protect epithelial surfaces from external insults and are related to malignant behaviors of carcinoma cells. However, the importance of carbohydrate chains on mucins in the process of cellular protection is not fully understood. Here, we investigated the effect of human mucin-21 (MUC21) expression on the susceptibility to apoptosis. MUC21 transfection into HEK293 cells decreased the number of apoptotic cells in culture media containing etoposide or after ultraviolet light irradiation. We used Chinese hamster ovary (CHO) cell variants to investigate the importance of MUC21 glycosylation in the resistance to apoptosis. When MUC21 was expressed in CHO-K1 cells, it was glycosylated with sialyl T-antigen and the cells showed resistance to etoposide-induced apoptosis. MUC21 transfection into Lec2 cells, a variant of CHO cells lacking sialylation of glycans, revealed that the presence of nonsialylated T-antigen also renders cells resistant to etoposide-induced apoptosis. MUC21 was transfected into ldlD cells and the glycosylation was manipulated by supplementation to the medium. Nonsupplemented cells and cells supplemented with N-acetylgalactosamine showed no resistance to etoposide-induced apoptosis. In contrast, these cells supplemented with N-acetylgalactosamine plus galactose expressed sialyl T-antigen and exhibited resistance to etoposide-induced apoptosis. Finally, galectin-3 knockdown in MUC21 transfectants of HEK293 cells did not significantly affect MUC21-dependent induction of apoptosis resistance. The results suggest that T-antigen with or without sialic acid is essential to the antiapoptotic effect of MUC21.
Assessment of psychosocial difficulties by genetic clinicians and distress in women at high risk of breast cancer: a prospective study
Authors: Brédart Anne , Kop Jean-Luc , Tüchler Anja , De Pauw Antoine , Cano Alejandra , Dick Julia , Rhiem Kerstin , Devilee Peter , Schmutzler Rita , Stoppa-Lyonnet Dominique , Dolbeault Sylvie
Published: April 2022

We examined how often genetic clinicians correctly identify psychosocial difficulties in women at high breast cancer risk and explored effects of this assessment and the genetic test result on counselees’ distress. A prospective observational study of counselee–clinician dyads was performed in three French, German and Spanish genetic clinics, involving 709 counselees (participation rate, 83.4%) and 31 clinicians (participation rate, 100%). Counselee–clinician agreement in perceived psychosocial difficulties was measured after the pre-test genetic consultation. Multivariate mixed linear models accounting for clinicians were tested. Predicted distress levels were assessed after the pre- (T1) and post-test result disclosure consultations (T2). Depending on the difficulty domain, clinicians adequately assessed the presence or absence of difficulties in 51% (“familial issues”) to 59% (“emotions”) of counselees. When counselees’ and clinicians’ perceptions disagreed, difficulties were generally underestimated by clinicians. Counselees’ distress levels remained stable from T1 to T2, irrespective of clinicians’ appraisal adequacy, and the genetic test result disclosure. Psychological referral need were found in 20–42% of counselees, more frequently observed for difficulties in the “emotions” domain. Our findings suggest that the genetic test result is a suboptimal indicator for psychological referral. Instead, clinicians should focus on emotions expressed by counselees to appraise their needs for psychological support.
Single-cell RNA sequencing coupled to TCR profiling of large granular lymphocyte leukemia T cells
Authors: Gao Shouguo , Wu Zhijie , Arnold Bradley , Diamond Carrie , Batchu Sai , Giudice Valentina , Alemu Lemlem , Raffo Diego Quinones , Feng Xingmin , Kajigaya Sachiko , Barrett John , Ito Sawa , Young Neal S.
Published: April 2022

T-cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disease and bone marrow failure syndrome which responds to immunosuppressive therapies. We show single-cell TCR coupled with RNA sequencing of CD3+ T cells from 13 patients, sampled before and after alemtuzumab treatments. Effector memory T cells and loss of T cell receptor (TCR) repertoire diversity are prevalent in T-LGLL. Shared TCRA and TCRB clonotypes are absent. Deregulation of cell survival and apoptosis gene programs, and marked downregulation of apoptosis genes in CD8+ clones, are prominent features of T-LGLL cells. Apoptosis genes are upregulated after alemtuzumab treatment, especially in responders than non-responders; baseline expression levels of apoptosis genes are predictive of hematologic response. Alemtuzumab does not attenuate TCR clonality, and TCR diversity is further skewed after treatment. Inferences made from analysis of single cell data inform understanding of the pathophysiologic mechanisms of clonal expansion and persistence in T-LGLL.
Super-hydration and reduction of manganese oxide minerals at shallow terrestrial depths
Authors: Yun Seohee , Hwang Huijeong , Hwang Gilchan , Kim Yeongkyoo , Blom Douglas , Vogt Thomas , Post Jeffrey E. , Jeon Tae-Yeol , Shin Tae Joo , Zhang Dong-Zhou , Kagi Hiroyuki , Lee Yongjae
Published: April 2022

Manganese oxides are ubiquitous marine minerals which are redox sensitive. As major components of manganese nodules found on the ocean floor, birnessite and buserite have been known to be two distinct water-containing minerals with manganese octahedral interlayer separations of ~7 Å and ~10 Å, respectively. We show here that buserite is a super-hydrated birnessite formed near 5 km depth conditions. As one of the most hydrous minerals containing ca. 34.5 wt. % water, super-hydrated birnessite, i.e., buserite, remains stable up to ca. 70 km depth conditions, where it transforms into manganite by releasing ca. 24.3 wt. % water. Subsequent transformations to hausmannite and pyrochroite occur near 100 km and 120 km depths, respectively, concomitant with a progressive reduction of Mn4+ to Mn2+. Our work forwards an abiotic geochemical cycle of manganese minerals in subduction and/or other aqueous terrestrial environments, with implications for water storage and cycling, and the redox capacity of the region.
Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma
Authors: Holm Jeppe Sejerø , Funt Samuel A. , Borch Annie , Munk Kamilla Kjærgaard , Bjerregaard Anne-Mette , Reading James L. , Maher Colleen , Regazzi Ashley , Wong Phillip , Al-Ahmadie Hikmat , Iyer Gopa , Tamhane Tripti , Bentzen Amalie Kai , Herschend Nana Overgaard , De Wolf Susan , Snyder Alexandra , Merghoub Taha , Wolchok Jedd D. , Nielsen Morten , Rosenberg Jonathan E. , Bajorin Dean F. , Hadrup Sine Reker
Published: April 2022

CD8+ T cell reactivity towards tumor mutation-derived neoantigens is widely believed to facilitate the antitumor immunity induced by immune checkpoint blockade (ICB). Here we show that broadening in the number of neoantigen-reactive CD8+ T cell (NART) populations between pre-treatment to 3-weeks post-treatment distinguishes patients with controlled disease compared to patients with progressive disease in metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. The longitudinal analysis of peripheral CD8+ T cell recognition of patient-specific neopeptide libraries consisting of DNA barcode-labelled pMHC multimers in a cohort of 24 patients from the clinical trial NCT02108652 also shows that peripheral NARTs derived from patients with disease control are characterised by a PD1+ Ki67+ effector phenotype and increased CD39 levels compared to bystander bulk- and virus-antigen reactive CD8+ T cells. The study provides insights into NART characteristics following ICB and suggests that early-stage NART expansion and activation are associated with response to ICB in patients with mUC.
Designing highly multiplex PCR primer sets with Simulated Annealing Design using Dimer Likelihood Estimation (SADDLE)
Authors: Xie Nina G. , Wang Michael X. , Song Ping , Mao Shiqi , Wang Yifan , Yang Yuxia , Luo Junfeng , Ren Shengxiang , Zhang David Yu
Published: April 2022

One major challenge in the design of highly multiplexed PCR primer sets is the large number of potential primer dimer species that grows quadratically with the number of primers to be designed. Simultaneously, there are exponentially many choices for multiplex primer sequence selection, resulting in systematic evaluation approaches being computationally intractable. Here, we present and experimentally validate Simulated Annealing Design using Dimer Likelihood Estimation (SADDLE), a stochastic algorithm for design of multiplex PCR primer sets that minimize primer dimer formation. In a 96-plex PCR primer set (192 primers), the fraction of primer dimers decreases from 90.7% in a naively designed primer set to 4.9% in our optimized primer set. Even when scaling to 384-plex (768 primers), the optimized primer set maintains low dimer fraction. In addition to NGS, SADDLE-designed primer sets can also be used in qPCR settings to allow highly multiplexed detection of gene fusions in cDNA, with a single-tube assay comprising 60 primers detecting 56 distinct gene fusions recurrently observed in lung cancer.
Carbonized paramagnetic complexes of Mn (II) as contrast agents for precise magnetic resonance imaging of sub-millimeter-sized orthotopic tumors
Authors: Qin Ruixue , Li Shi , Qiu Yuwei , Feng Yushuo , Liu Yaqing , Ding Dandan , Xu Lihua , Ma Xiaoqian , Sun Wenjing , Chen Hongmin
Published: April 2022

Paramagnetic complexes containing gadolinium ions have been widely used for magnetic resonance imaging (MRI) in clinic. However, these paramagnetic complexes pose some safety concerns. There is still a demand for the development of stable MRI contrast agents that exhibit higher sensitivity and superior functionality to existing contrast agents. Here, we develop carbonized paramagnetic complexes of manganese (II) (Mn@CCs) to encapsulate Mn2+ in sealed carbonized shells with superhigh r1 relaxivity. Compared to the most common clinical contrast agent Magnevist, investigations in vivo demonstrate that the Mn@CCs cross the intact blood-brain barrier of normal health mice with minor metal deposition; preferentially target the glioma tissues distribute homogeneously with high penetration in an intracranial mouse model; delineate clear tumor margins in MRIs of ultrasmall single-nodule brain tumors, and multi-nodular liver tumors. The sensitivity, accuracy and low toxicity offer by Mn@CCs provides new opportunities for early molecular diagnostics and imaging-guided biomedical applications.