bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune signatures of bone marrow cells can independently predict prognosis in patients with myelodysplastic syndrome
Authors: Wang Yu‐Hung , Lin Chien‐Chin , Yao Chi‐Yuan , Hsu Chia‐Lang , Tsai Cheng‐Hong , Hou Hsin‐An , Chou Wen‐Chien , Tien Hwei‐Fang
Published: September 2021

Increasing evidence supports the role of the immune microenvironment and associated signalling in the pathogenesis of myelodysplastic syndromes (MDS). Nevertheless, the clinical relevancy of immune signals in patients with MDS remains elusive. To address this, we used single‐sample gene‐set enrichment analysis to score immune signatures of bone marrow (BM) samples from 176 patients with primary MDS. Enhanced signatures of ‘immature dendritic cells’ and ‘natural killer cells with cluster of differentiation (CD)56bright’ were correlated with better overall survival (OS), whilst higher ‘CD103+ signature’ was associated with reduced survival. An MDS‐Immune‐Risk (MIR) scoring system was constructed based on the weighted sums derived from Cox regression analysis. High MIR scores were correlated with higher revised International Prognostic Scoring System (IPSS‐R) scores and mutations in ASXL transcriptional regulator 1 (ASXL1), Runt‐related transcription factor 1 (RUNX1), and tumour protein p53 (TP53). High‐score patients had significantly inferior leukaemia‐free survival (LFS) and OS than low‐score patients. The prognostic significance of MIR scores for survival remained valid across IPSS‐R subgroups and was validated in two independent cohorts. Multivariable analysis revealed that a higher MIR score was an independent adverse risk factor for LFS and OS. We further proposed a model with the combination of MIR score and gene mutations to be complementary to IPSS‐R for the prognostication of LFS and OS of patients with MDS.
Lomustine and nimustine exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance
Authors: Yamamuro Shun , Takahashi Masamichi , Satomi Kaishi , Sasaki Nobuyoshi , Kobayashi Tatsuya , Uchida Eita , Kawauchi Daisuke , Nakano Tomoyuki , Fujii Takashi , Narita Yoshitaka , Kondo Akihide , Wada Kojiro , Yoshino Atsuo , Ichimura Koichi , Tomiyama Arata
Published: September 2021

Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ‐resistant GBM (TMZ‐R‐GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ‐R‐GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ‐R‐GBM. As a model of TMZ‐R‐GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ‐R‐cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ‐R‐cells after the administration of each drug, the antitumor effects of TMZ against TMZ‐R‐cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ‐R‐cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ‐R‐cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ‐R‐cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ‐R‐GBM.
Cross‐sectional study on exhaled nitric oxide in relation to upper airway inflammatory disorders with regard to asthma and perennial sensitization
Authors: Krantz Christina , Accordini Simone , Alving Kjell , Corsico Angelo G. , Demoly Pascal , Ferreira Diogenes S. , Forsberg Bertil , Garcia‐Aymerich Judith , Gislason Thorarinn , Heinrich Joachim , Jõgi Rain , Johannessen Ane , Leynaert Bénédicte , Marcon Alessandro , Martínez‐Moratalla Rovira Jesús , Nerpin Elisabet , Nowak Dennis , Olin Anna‐Carin , Olivieri Mario , Pereira‐Vega Antonio , Raherison‐Semjen Chantal , Real Francisco Gómez , Sigsgaard Torben , Squillacioti Guilia , Janson Christer , Malinovschi Andrei ,   the European Community Respiratory Health Survey III
Published: September 2021

Background

Fractional exhaled nitric oxide (FeNO) is a well‐known marker of type‐2 inflammation. FeNO is elevated in asthma and allergic rhinitis, with IgE sensitization as a major determinant.

Objective

We aimed to see whether there was an independent association between upper airway inflammatory disorders (UAID) and FeNO, after adjustment for asthma and sensitization, in a multi‐centre population‐based study.

Methods

A total of 741 subjects with current asthma and 4155 non‐asthmatic subjects participating in the second follow‐up of the European Community Respiratory Health Survey (ECRHS III) underwent FeNO measurements. Sensitization status was based on measurement of IgE against airborne allergens; information on asthma, UAID and medication was collected through interview‐led questionnaires. Independent associations between UAID and FeNO were assessed in adjusted multivariate regression models and test for interaction with perennial sensitization and asthma on the relation between UAID and FeNO were made.

Results

UAID were associated with higher FeNO after adjusting for perennial sensitization, asthma and other confounders: with 4.4 (0.9–7.9) % higher FeNO in relation to current rhinitis and 4.8 (0.7–9.2) % higher FeNO in relation to rhinoconjunctivitis. A significant interaction with perennial sensitization was found in the relationship between current rhinitis and FeNO (p = .03) and between rhinoconjunctivitis and FeNO (p = .03). After stratification by asthma and perennial sensitization, the association between current rhinitis and FeNO remained in non‐asthmatic subjects with perennial sensitization, with 12.1 (0.2–25.5) % higher FeNO in subjects with current rhinitis than in those without.

Conclusions & Clinical Relevance

Current rhinitis and rhinoconjunctivitis was associated with higher FeNO, with an interaction with perennial sensitization. This further highlights the concept of united airway disease, with correlations between symptoms and inflammation in the upper and lower airways and that sensitization needs to be accounted for in the relation between FeNO and rhinitis.
Does aluminium in sunscreens cause dermatitis in children with aluminium contact allergy: A repeated open application test study
Authors: Hoffmann Stine S. , Elberling Jesper , Thyssen Jacob P. , Hansen Kirsten S. , Johansen Jeanne D.
Published: September 2021

Background

Parents report that children with aluminium contact allergy and vaccination granulomas may react to aluminium‐containing sunscreen following application.

Objectives

To evaluate whether contact dermatitis develops following repeated application of aluminium‐containing sunscreens in children with aluminium sensitization and vaccination granulomas.

Methods

Sixteen children aged 2‐9 years (mean age 5 years) with vaccination granulomas and a positive patch test reaction to aluminium chloride hexahydrate 2%/10% petrolatum completed a blinded repeated open application test (ROAT) with two daily applications of two sunscreens for 14 days. One cream contained aluminium and the other did not. The children served as their own controls.

Results

Sixteen children completed the study. Only one child (6%) had a positive skin reaction during ROAT on day 2 to the sunscreen with aluminium. None reacted to the sunscreen without aluminium.

Conclusions

Use of aluminium‐containing sunscreens may on a case basis lead to allergic contact dermatitis in aluminium allergic children.
The use of radiomic analysis of magnetic resonance imaging in predicting distant metastases of rectal carcinoma following surgical resection: A systematic review and meta‐analysis
Authors: Davey Martin S. , Davey Matthew G. , Ryan Éanna J. , Hogan Aisling M. , Kerin Michael J. , Joyce Myles
Published: September 2021

Aim

Estimating prognosis in rectal carcinoma (RC) is challenging, with distant recurrence (DR) occurring in up to 30% of cases. Radiomics is a novel field using diagnostic imaging to investigate the tumour heterogeneity of cancers and may have the potential to predict DR. The aim of the study was to perform a systematic review of the current literature evaluating the use of radiomics in predicting DR in patients with resected RC.

Methods

A systematic review was performed as per PRISMA guidelines to identify studies reporting radiomic analysis of magnetic resonance imaging (MRI) to predict DR in patients diagnosed with RC. Sensitivity and specificity of radiomic analyses were included for meta‐analysis.

Results

A total of seven studies including 1497 patients (998 males) were included, seven, five and one of whom reported radiomics, respectively. The overall pooled rate of DR from all included studies was 17.1% (256/1497), with 15.6% (236/1497), 1.3% (19/1497) and 0.2% (3/1497) of patients having hepatic, pulmonary and peritoneal metastases. Meta‐analysis demonstrated that radiomics correctly predicted DR with pooled sensitivities and specificities of MRI 0.76 (95% CI: 0.73, 0.78) and 0.85 (95% CI: 0.83, 0.88), respectively.

Conclusion

This systematic review suggests the benefit of radiomic analysis of preoperative MRI in identifying patients with resected RC at an increased risk of DR. Our findings warrant validation in larger prospective studies as modalities to predict DR is a significant unmet need in RC. Radiomics may allow for tailored therapeutic strategies for high‐risk groups.
Appropriate use criteria for ancillary diagnostic testing in dermatopathology: New recommendations for 11 tests and 220 clinical scenarios from the American Society of Dermatopathology Appropriate Use Criteria Committee
Authors:   AUC Committee Members, Fung Maxwell A. , Vidal Claudia I. , Armbrecht Eric A. , Andea Aleodor A. , Cassarino David S. , Comfere Nneka I. , Emanuel Patrick O. , Ferringer Tammie , Hristov Alexandra C. , Kim Jinah , Lauer Scott R. , Linos Konstantinos , Missall Tricia A. , Motaparthi Kiran , Novoa Roberto A. , Patel Rajiv , Shalin Sara C. , Sundram Uma ,   Rating Panel, Calame Antoanella , Bennett Daniel D. , Duncan Lyn M. , Elston Dirk M. , Hosler Gregory A. , Hurley Yadira M. , Lazar Alexander J. , Lowe Lori , Messina Jane , Myles Jonathan , Plaza Jose A. , Prieto Victor G. , Reddy Vijaya , Schaffer András , Subtil Antonio
Published: September 2021

Background

Appropriate use criteria (AUC) provide patient‐centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests.

Methods

RAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2.

Results

For 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid‐Schiff, Gömöri methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated “usually appropriate” or “rarely appropriate” and 45 of 148 (30%), “appropriateness uncertain.” Limitations: The study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded.

Conclusions

AUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery.
Predicting range shifts of pikas (Mammalia, Ochotonidae) in China under scenarios incorporating land use change, climate change and dispersal limitations
Authors: Ma Liang , Mi Chun‐rong , Qu Jia‐peng , Ge De‐yan , Yang Qi‐sen , Wilcove David S.
Published: September 2021

Aim

Two of the most important forces affecting biodiversity are land use change (LUC) and global climate change (GCC). Previous studies have modelled their impacts on species separately, and together, but few have done so for multiple species with dispersal limitations incorporated into the models.

Location

Qinghai–Tibet plateau region.

Methods

We integrate species distribution models plus a dispersal model to predict LUC and GCC impacts on the ranges of five species of pikas in the Qinghai–Tibet plateau region of China. Pikas are sensitive to land use and climate change and have limited dispersal abilities.

Results

The predicted impacts of LUC and GCC on pikas vary between species as well as between LUC and GCC projections. Incorporation of dispersal limitations appreciably restricts the amount of colonized habitat. For all five species, the amount of habitat abandoned or colonized when LUC and GCC are modelled together is less than the sum of LUC and GCC modelled separately. Three of the five species experience a net increase in occupied habitat by 2080 relative to their current ranges under all modelled projections. However, relative to a “Dispersal Only” baseline scenario that assumes no environmental change but continued range expansion into suitable, unoccupied habitat, all five species suffer a net loss of occupied habitat by 2080 under some or all projections.

Main conclusions

Predictions of future distributions of species based solely on LUC or GCC, as well as predictions assuming additive impacts, can be misleading. Inclusion of dispersal limitations in models markedly alters predicted future distributions of species. The use of a “Dispersal Only” scenario provides a different and perhaps more accurate way to gauge net impacts to species. Future work should consider incorporating all these parameters to better predict the impacts of LUC and GCC on biodiversity.
Developmental delay in infants and toddlers with sickle cell disease: a systematic review
Authors: Hoyt Catherine R , Varughese Taniya E , Erickson Jeni , Haffner Natalie , Luo Lingzi , L’Hotta Allison J , Yeager Lauren , King Allison A
Published: September 2021

Aim

To summarize developmental delay among infants and toddlers with sickle cell disease (SCD).

Method

This systematic review included studies that reported developmental outcomes of children with SCD between 0 months and 48 months of age and followed standards set forth by the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines.

Results

Ten studies were included, describing 596 unique developmental assessments. The rate of developmental delay ranged from 17.5% to 50% and increased with age. Cognition was the only domain included in all studies and the most frequently identified delay. One study reported that more severe SCD genotypes predicted worse development, while five studies reported no difference in rates of developmental delay across genotypes.

Interpretation

These findings emphasize the need for standardized screening to identify children with SCD at risk of delay at a young age to facilitate appropriate referrals for therapeutic intervention. Frequent and comprehensive developmental screening is necessary among all SCD genotypes.
Hope, hype, cures, and persons with cerebral palsy
Authors: Turner Leigh
Published: September 2021

This commentary is on the invited review by Honan et al. on pages 49–55 of this issue.
Temporal trend of small nerve fibre degeneration in people with and without type 2 diabetes mellitus
Authors: Ekman Linnéa , Pourhamidi Kaveh , Englund Elisabet , Lagali Neil , Rolandsson Olov , Dahlin Lars B.
Published: September 2021

Aims

We investigated the long‐term temporal trend of intraepidermal nerve fibre density (IENFD) and the association between changes in IENFD and metabolic factors in individuals with and without type 2 diabetes.

Methods

A total of 66 participants were enrolled in this longitudinal population‐based study, at baseline consisting of 35 individuals (median 61 years) without diabetes and 31 individuals with type 2 diabetes mellitus. Participants underwent clinical and electrophysiological examinations, as well as a skin biopsy both at baseline and at the follow‐up visit (mean 8.1 ± 0.5 years). IENFD was assessed in thin sections of 5 μm, stained with the protein gene product 9.5‐antibody and compared between the groups.

Results

IENFD decreased during the period in both groups, with a greater decline in the group without diabetes than in type 2 diabetes (−2.3 and −0.6 fibres/mm respectively; p < 0.001). While IENFD at baseline was significantly reduced in type 2 diabetes relative to people without (p < 0.001), no difference in IENFD was found between groups at the follow‐up (p = 0.183). Linear mixed model analysis indicated that age, weight and HbA1c were associated with decrease in IENFD in the total population (p < 0.007). IENFD also decreased with increasing age and weight, but not with HbA1c, in the separate groups (p < 0.049).

Conclusions

Despite lower IENFD levels at baseline in type 2 diabetes, IENFD was equal between the groups at follow‐up. A decrease in IENFD is to a limited extent affected by body weight, and HbA1c, but age seems to be the long‐term determinant of IENFD in an elderly population.
Does weight management after gestational diabetes mellitus diagnosis improve pregnancy outcomes? A multi‐ethnic cohort study
Authors: Barnes Robyn A. , Flack Jeff R. , Wong Tang , Ross Glynis P. , Griffiths Michelle M. , Stephens Megan , Kourloufas Laura , Smart Carmel E. , Collins Clare E. , MacDonald‐Wicks Lesley
Published: September 2021

Aims

To assess the impact of achieving an Institute of Medicine based personalised weight target in addition to conventional glycaemic management after gestational diabetes mellitus diagnosis on maternal and neonatal outcomes.

Methods

A retrospective audit of clinical data (2016–2019) for singleton gestational diabetes pregnancies was conducted in a multi‐ethnic cohort. Logistic regression analyses assessed relationships between achieving, exceeding and gaining less than a personalised weight target provided after gestational diabetes diagnosis and rates of large for gestational age, small for gestational age infants, insulin therapy initiation and neonatal outcomes. Adjusted odds ratios (aOR) were adjusted for glucose 2‐h post‐glucose load value, family history of type 2 diabetes, previous gestational diabetes, macrosomia in a previous pregnancy, and East and South‐East Asian ethnicity.

Results

Of 1034 women, 44% (n = 449) achieved their personalised weight target. Women who exceeded their personalised weight target had significantly and higher mean insulin doses (28.8 ± 21.5 units vs. 22.7 ± 18.7, p = 0.006) and higher rates of large for gestational age infants (19% vs. 9.8%, p < 0.001), with aOR of 1.99 [95% CI 1.25–3.15] p = 0.004, but no difference in rates of small for gestational age infants (5.3% vs. 8.0%) (aOR 0.77 [0.41–1.44] p = 0.41). Lower rates of large for gestational age infants occurred in those who gained below their personalised weight target (aOR 0.48 [0.25–0.95] p = 0.034), but rates of small for gestational age infants concurrently increased (aOR 1.9 [1.19–3.12] p = 0.008).

Conclusions

Weight management after gestational diabetes diagnosis does not appear to be too late to confer additional benefits to glucose‐lowering treatment, resulting in lower mean insulin doses, and lower rates of large for gestational age infants without increasing the risk of small for gestational age infants.
Becoming a central bank: The development of the Bank of England's private sector lending policies during the Restriction
Authors: Sissoko Carolyn
Published: September 2021

This article studies the changes that took place in the Bank of England's Restriction‐era policies governing private sector lending. The findings show that the Bank was adapting to novel monetary circumstances, created both by the evolution of the English financial system and by the Restriction itself, and that, although the process was far from smooth, the Bank was learning to act as a central bank: during this period the Bank transformed its internal operating procedures to put regulation‐based constraints on its private sector lending, established regular reviews of its policies and their effects on the money market, and adopted a distinct crisis‐orientated lending policy. In addition to establishing that these core central bank activities developed over this period, the article also shows that for 18 months starting in 1809 the Bank's policies were destabilizing, and that the Bullion Committee probably played a role in a shift in Bank lending policies that took place in mid‐1810. Overall, this study finds that the 1810 crisis was a turning point in the Bank's understanding of its role in the economy: the Bank directors both acknowledged privately the Bank's duty to the public, and restructured its discount policies with a view to promoting financial and monetary stability.
Dental students’ perceptions of the long case
Authors: Paul Natasha L. , Adam Lee A. , Moffat Susan M.
Published: September 2021

Introduction

The long case examination is used to assess clinical competency in dental education. However, the academic literature, much of which is in medical education, highlights concerns regarding the relevancy and authenticity of the long case. To date, dental students’ experiences of the long case have been under‐researched. This study examines students’ experiences and perceptions of the long case examination at an Australasian dental school.

Materials and Methods

This study was a qualitative investigation. Students participated in interviews to discuss their perceptions and experiences of the long case examination. The interviews were voice‐recorded and transcribed, and a thematic inductive analysis was undertaken.

Results

Three main themes emerged from the data: stress, where students described stressors before, during and after the long case; fairness, where students positioned the long case as either fair or not fair; and confusion, where students spoke about their perceived lack of understanding of the examination process and procedures.

Conclusion

The concerns students raised regarding stress, fairness and confusion are considered and ways in which the long case might be developed in order to support students’ learning are presented. Alternative structures or practices that might be explored include greater calibration of examiners and cases, and enhancements to how students are prepared for and prepare for the examination. The results of this research will inform ongoing development of assessment practices.
Carfilzomib and dexamethasone maintenance following salvage ASCT in multiple myeloma: A randomised phase 2 trial by the Nordic Myeloma Study Group
Authors: Gregersen Henrik , Peceliunas Valdas , Remes Kari , Schjesvold Fredrik , Abildgaard Niels , Nahi Hareth , Andersen Niels Frost , Vangsted Annette Juul , Klausen Tobias Wirenfeldt , Helleberg Carsten , Carlson Kristina , Frølund Ulf Christian , Axelsson Per , Stromberg Olga , Blimark Cecilie Hveding , Crafoord Jacob , Tsykunova Galina , Eshoj Henrik Rode , Waage Anders , Hansson Markus , Gulbrandsen Nina
Published: September 2021

Objective

We investigated the efficacy and safety of carfilzomib‐containing induction before salvage high‐dose melphalan with autologous stem‐cell transplantation (salvage ASCT) and maintenance with carfilzomib and dexamethasone after salvage ASCT in multiple myeloma.

Methods

This randomised, open‐label, phase 2 trial included patients with first relapse of multiple myeloma after upfront ASCT who were re‐induced with four cycles of carfilzomib, cyclophosphamide and dexamethasone. Two months after salvage, ASCT patients were randomised to either observation or maintenance therapy with iv carfilzomib 27 → 56 mg/sqm and p.o. dexamethasone 20 mg every second week. The study enrolled 200 patients of which 168 were randomised to either maintenance with carfilzomib and dexamethasone (n = 82) or observation (n = 86).

Results

Median time to progression (TTP) after randomisation was 25.1 months (22.5‐NR) in the carfilzomib‐dexamethasone maintenance group and 16.7 months (14.4–21.8) in the control group (HR 0.46, 95% CI 0.30–0.71; P = .0004). The most common adverse events during maintenance were thrombocytopenia, anaemia, hypertension, dyspnoea and bacterial infections.

Conclusion

In summary, maintenance therapy with carfilzomib and dexamethasone after salvage ASCT prolonged TTP with 8 months. The maintenance treatment was in general well‐tolerated with manageable toxicity.
The N400 ERP component reflects an error‐based implicit learning signal during language comprehension
Authors: Hodapp Alice , Rabovsky Milena
Published: September 2021

The functional significance of the N400 evoked‐response component is still actively debated. An increasing amount of theoretical and computational modelling work is built on the interpretation of the N400 as a prediction error. In neural network modelling work, it was proposed that the N400 component can be interpreted as the change in a probabilistic representation of meaning that drives the continuous adaptation of an internal model of the statistics of the environment. These results imply that increased N400 amplitudes should correspond to greater adaptation, which can be measured via implicit memory. To investigate this model derived hypothesis, the current study manipulated expectancy in a sentence reading task to influence N400 amplitudes and subsequently presented the previously expected vs. unexpected words in a perceptual identification task to measure implicit memory. As predicted, reaction times in the perceptual identification task were significantly faster for previously unexpected words that induced larger N400 amplitudes in the previous sentence reading task. Additionally, it could be demonstrated that this adaptation seems to specifically depend on the process underlying N400 amplitudes, as participants with larger N400 differences during sentence reading also exhibited a larger implicit memory benefit in the perceptual identification task. These findings support the interpretation of the N400 as an implicit learning signal driving adaptation in language processing.
Serine/threonine kinase 17b (STK17B) signalling regulates Purkinje cell dendritic development and is altered in multiple spinocerebellar ataxias
Authors: Wu Qin‐Wei , Kapfhammer Josef P.
Published: September 2021

Serine/threonine kinase 17b (STK17B, also known as DRAK2) is known to be a downstream effector of protein kinase C (PKC) in the immune system, in particular T lymphocytes. PKC activity also plays a critical role for dendritic development and synaptic maturation and plasticity in cerebellar Purkinje cells. We present evidence that STK17B is strongly expressed in mouse cerebellar Purkinje cells starting in the early postnatal period and remaining highly expressed throughout adult stages and that STK17B is a target of PKC phosphorylation in the cerebellum. STK17B overexpression potentiates the morphological changes of Purkinje cells seen after PKC activation, suggesting that it is a downstream effector of PKC. A phosphorylation mimetic STK17B variant induced a marked reduction of Purkinje cell dendritic tree size, whereas the inhibition of STK17B with the novel compound 16 (Cpd16) could partially rescue the morphological changes of the Purkinje cell dendritic tree after PKC activation. These findings show that STK17B signalling is an important downstream effector of PKC activation in Purkinje cells. Furthermore, STK17B was identified as a molecule being transcriptionally downregulated in mouse models of SCA1, SCA7, SCA14 and SCA41. The reduced expression of STK17B in these mouse models might protect Purkinje cell dendrites from the negative effects of overactivated PKC signalling. Our findings provide new insights in the role of STK17B for Purkinje cell dendritic development and the pathology of SCAs.
Persistent DNA damage alters the neuronal transcriptome suggesting cell cycle dysregulation and altered mitochondrial function
Authors: Vazquez‐Villasenor Irina , Garwood Claire J. , Simpson Julie E. , Heath Paul R. , Mortiboys Heather , Wharton Stephen B.
Published: September 2021

Oxidative DNA damage induces changes in the neuronal cell cycle and activates a DNA damage response (DDR) to promote repair, but these processes may be altered under a chronic oxidative environment, leading to the accumulation of unrepaired DNA damage and continued activation of a DDR. Failure to repair DNA damage can lead to apoptosis or senescence, which is characterized by a permanent cell cycle arrest. Increased oxidative stress and accumulation of oxidative DNA damage are features of brain ageing and neurodegeneration, but the effects of persistent DNA damage in neurons are not well characterized. We developed a model of persistent oxidative DNA damage in immortalized post‐mitotic neurons in vitro by exposing them to a sublethal concentration of hydrogen peroxide following a ‘double stress’ protocol and performed a detailed characterization of the neuronal transcriptome using microarray analysis. Persistent DNA damage significantly altered the expression of genes involved in cell cycle regulation, DDR and repair mechanisms, and mitochondrial function, suggesting an active DDR response to replication stress and alterations in mitochondrial electron transport chain. Quantitative polymerase chain reaction (qPCR) and functional validation experiments confirmed hyperactivation of mitochondrial Complex I in response to persistent DNA damage. These changes in response to persistent oxidative DNA damage may lead to further oxidative stress, contributing to neuronal dysfunction and ultimately neurodegeneration.
Response to Comment on ‘Soil carbon persistence governed by plant input and mineral protection at regional and global scales’
Authors: Chen Leiyi , Yang Yuanhe
Published: September 2021

We demonstrated that ignoring the non‐linear relationship between topsoil Δ14C and plant carbon (C) input in Wu et al.’s analysis was the fundamental reason for the discrepancy between their analysis and ours. By considering such a non‐linear relationship, plant C input still predominantly governs the topsoil C turnover.
Small loci of astroglial glutamine synthetase deficiency in the postnatal brain cause epileptic seizures and impaired functional connectivity
Authors: Farina Maxwell G. , Sandhu Mani Ratnesh S. , Parent Maxime , Sanganahalli Basavaraju G. , Derbin Matthew , Dhaher Roni , Wang Helen , Zaveri Hitten P. , Zhou Yun , Danbolt Niels C. , Hyder Fahmeed , Eid Tore
Published: September 2021

Objective

The astroglial enzyme glutamine synthetase (GS) is deficient in small loci in the brain in adult patients with different types of focal epilepsy; however, the role of this deficiency in the pathogenesis of epilepsy has been difficult to assess due to a lack of sufficiently sensitive and specific animal models. The aim of this study was to develop an in vivo approach for precise and specific deletions of the GS gene in the postnatal brain.

Methods

We stereotaxically injected various adeno‐associated virus (AAV)–Cre recombinase constructs into the hippocampal formation and neocortex in 22–70‐week‐old GSflox/flox mice to knock out the GS gene in a specific and focal manner. The mice were subjected to seizure threshold determination, continuous video‐electroencephalographic recordings, advanced in vivo neuroimaging, and immunocytochemistry for GS.

Results

The construct AAV8–glial fibrillary acidic protein–green fluorescent protein–Cre eliminated GS in >99% of astrocytes in the injection center with a gradual return to full GS expression toward the periphery. Such focal GS deletion reduced seizure threshold, caused spontaneous recurrent seizures, and diminished functional connectivity.

Significance

These results suggest that small loci of GS deficiency in the postnatal brain are sufficient to cause epilepsy and impaired functional connectivity. Additionally, given the high specificity and precise spatial resolution of our GS knockdown approach, we anticipate that this model will be extremely useful for rigorous in vivo and ex vivo studies of astroglial GS function at the brain‐region and single‐cell levels.
A comprehensive nanopore sequencing methodology deciphers the complete transcriptional landscape of cyclin‐dependent kinase 4 (CDK4) in human malignancies
Authors: Adamopoulos Panagiotis G. , Athanasopoulou Konstantina , Tsiakanikas Panagiotis , Scorilas Andreas
Published: September 2021

Cyclin‐dependent kinase 4 (CDK4) is a member of the cyclin‐dependent kinases, a family of protein kinases with outstanding roles in signaling pathways, transcription regulation, and cell division. Defective or overactivated CDK4/cyclin D1 pathway leads to enhanced cellular proliferation, thus being implicated in human cancers. Although the biological role of CDK4 has been extensively studied, its pre‐mRNA processing mechanism under normal or pathological conditions is neglected. Thus, the identification of novel CDK4 mRNA transcripts, especially protein‐coding ones, could lead to the identification of new diagnostic and/or prognostic biomarkers or new therapeutic targets. In the present study, instead of using the ‘gold standard’ direct RNA sequencing application, we designed and employed a targeted nanopore sequencing approach, which offers higher sequencing depth and enables the thorough investigation of new mRNAs of any target gene. Our study elucidates for the first time the complex transcriptional landscape of the human CDK4 gene, highlighting the existence of previously unknown CDK4 transcripts with new alternative splicing events and protein‐coding capacities. The relative expression levels of each novel CDK4 transcript in human malignancies were elucidated with custom qPCR‐based assays. The presented wide spectrum of CDK4 transcripts (CDK4 v.2–v.42) is only the first step to distinguish and assemble the missing pieces regarding the exact functions and implications of this fundamental kinase in cellular homeostasis and pathophysiology.
HSC70 as a sensor of low temperature: role in cold‐triggered autoinflammatory disorders
Authors: Raghawan Akhouri Kishore , Radha Vegesna , Swarup Ghanshyam
Published: September 2021

Familial cold autoinflammatory syndrome (FCAS) is a subset of heritable autoinflammatory disorders wherein inflammatory symptoms aggravate upon exposure of the individual to subnormal temperature. In the past two decades, several mutations in various genes such as NLRP3, NLRP12, PLCG2 and NLRC4 have been identified that cause cold‐triggered inflammation. However, our understanding of the mechanisms by which cells perceive subnormal temperature, and what keeps the inflammation under check until exposure to low temperature, is very limited. We hypothesise that recognition of FCAS‐associated mutants as misfolded polypeptides by temperature‐sensitive HSC70 (HSPA8) chaperone determines the FCAS phenotype. At 37 °C, HSC70 would interact with the mutant proteins, keeping them almost inactive, and loss of interaction at low temperature due to a conformational change in HSC70 would lead to their activation. The proposed mechanism of low temperature sensing in the context of FCAS may have wider implications for HSC70 as a cold temperature sensor in various pathological conditions where symptoms get aggravated upon exposure to low temperature.
Molecular and cellular events linking variants in the histone demethylase KDM5C to the intellectual disability disorder Claes‐Jensen syndrome
Authors: Hatch Hayden A. M. , Secombe Julie
Published: September 2021

The widespread availability of genetic testing for those with neurodevelopmental disorders has highlighted the importance of many genes necessary for the proper development and function of the nervous system. One gene found to be genetically altered in the X‐linked intellectual disability disorder Claes‐Jensen syndrome is KDM5C, which encodes a histone demethylase that regulates transcription by altering chromatin. While the genetic link between KDM5C and cognitive (dys)function is clear, how KDM5C functions to control transcriptional programs within neurons to impact their growth and activity remains the subject of ongoing research. Here, we review our current knowledge of Claes‐Jensen syndrome and discuss important new data using model organisms that have revealed the importance of KDM5C in regulating aspects of neuronal development and function. Continued research into the molecular and cellular activities regulated by KDM5C is expected to provide critical etiological insights into Claes‐Jensen syndrome and highlight potential targets for developing therapies to improve the quality of life of those affected.
Cancers associated with human gammaherpesviruses
Authors: Wen Kwun Wah , Wang Linlin , Menke Joshua R. , Damania Blossom
Published: September 2021

Epstein–Barr virus (EBV; human herpesvirus 4; HHV‐4) and Kaposi sarcoma‐associated herpesvirus (KSHV; human herpesvirus 8; HHV‐8) are human gammaherpesviruses that have oncogenic properties. EBV is a lymphocryptovirus, whereas HHV‐8/KSHV is a rhadinovirus. As lymphotropic viruses, EBV and KSHV are associated with several lymphoproliferative diseases or plasmacytic/plasmablastic neoplasms. Interestingly, these viruses can also infect epithelial cells causing carcinomas and, in the case of KSHV, endothelial cells, causing sarcoma. EBV is associated with Burkitt lymphoma, classic Hodgkin lymphoma, nasopharyngeal carcinoma, plasmablastic lymphoma, lymphomatoid granulomatosis, leiomyosarcoma, and subsets of diffuse large B‐cell lymphoma, post‐transplant lymphoproliferative disorder, and gastric carcinoma. KSHV is implicated in Kaposi sarcoma, primary effusion lymphoma, multicentric Castleman disease, and KSHV‐positive diffuse large B‐cell lymphoma. Pathogenesis by these two herpesviruses is intrinsically linked to viral proteins expressed during the lytic and latent lifecycles. This comprehensive review intends to provide an overview of the EBV and KSHV viral cycles, viral proteins that contribute to oncogenesis, and the current understanding of the pathogenesis and clinicopathology of their related neoplastic entities.
Biomass production in mixed short rotation coppice with poplar‐hybrids (Populus spp.) and black locust (Robinia pseudoacacia L.)
Authors: Rebola‐Lichtenberg Jessica , Schall Peter , Ammer Christian
Published: September 2021

Short rotation coppice plays an important role for biomass production. Mixing fast‐growing tree species in short rotation coppices may lead to overyielding if the species have complementarity traits. The goal of this study is to analyze biomass yield of eight different poplar hybrids and black locust in mixed short rotation coppice after a rotation of 5 years. Pure and mixed stands were established at two sites of contrasting fertility as a low‐input system. After collecting a sample of trees for the data set, we fitted allometric equations to estimate the overall biomass of the stands. All poplar genotypes showed lower performance in mixtures with black locust, whereas the latter profited from the mixture. In contrast to our expectations, poplars had no advantages from black locust's nitrogen enrichment of the soil. Instead, the dominance and competitiveness of black locust drove to poorer performance of all eight poplar genotypes across both sites.

Mixing fast‐growing tree species in short rotation coppices may lead to overyielding if the species have complementarity traits. The goal of this study is to analyze biomass yield of eight different poplar hybrids and black locust in mixed short rotation coppice after a rotation of 5 years. While black locusts profited from mixed cropping, poplars had no advantaged performance. The dominance and competitiveness of black locust drove to poorer performance of all eight poplar genotypes.
Long‐term biochar application governs the molecular compositions and decomposition of organic matter in paddy soil
Authors: Sun Jiali , Li Hongbo , Zhang Deshan , Liu Ruliang , Zhang Aiping , Rengel Zed
Published: September 2021

Biochar addition can enhance soil quality and sequester carbon. However, changes in soil organic matter (SOM) molecular compositions in response to long‐term biochar addition have rarely been studied. Therefore, we quantified soil organic carbon fractions, carbon‐cycling enzyme activities, and a range of organic compounds and lignin‐derived phenols in the rhizosphere and bulk soils in different rice growth stages in the 8‐year field trial with biochar application rates of 0 (BC‐0), 4.5 (BC‐L), and 13.5 t ha−1 year−1 (BC‐H). We found that higher amounts of biochar addition (BC‐H) increased labile organic carbon (LOC), dissolved organic carbon (DOC) and particulate organic carbon (POC), and promoted activities of α‐1,4‐glucosidase, β‐D‐cellobiohydrolase and β‐1,4‐xylosidase; in contrast, BC‐L treatment reduced activities of these enzymes. The concentrations of dichloromethane/methanol‐extractable plant‐ and microbial‐derived organic compounds in the rhizosphere and bulk soils at tillering decreased significantly in the treatment with low amount of biochar addition. BC‐L also significantly altered the concentrations of extracted compounds in the rhizosphere soil at tillering and harvest. Concentration of lignin in the bulk soil was significantly reduced in BC‐L at tillering (by 19%) and harvest (by 28%). The concentrations of extracted compounds (e.g., n‐alkanols, n‐alkanoic acids, steroids, and carbohydrates) and lignin were generally significantly higher in the bulk than the rhizosphere soil at tillering and harvest. Long‐term biochar application (BC‐H) promoted lignin decomposition in the bulk soil (at tillering) and the rhizosphere soil (at harvest). Hence, biochar decreased stability of lignin in paddy soil. Our study provided evidence that long‐term biochar application changed the molecular composition and dynamics of degradation of SOM. These results deepen our understanding of the mechanisms governing SOM stability in agricultural ecosystems.
Ecological and behavioural drivers of offspring size in marine teleost fishes
Authors: Vanadzina Karina , Phillips André , Martins Bonnie , Laland Kevin N. , Webster Michael M. , Sheard Catherine
Published: September 2021

Aim

Our aim was to evaluate the role of ecological and life‐history factors in shaping global variation in offspring size in a marine clade with a diverse range of parental care behaviours.

Location

Global.

Time period

Data sourced from literature published from 1953 until 2019.

Major taxa studied

Marine teleost fishes.

Methods

We compiled a species‐level dataset of egg and hatch size for 1,639 species of marine fish across 45 orders. We used Bayesian phylogenetic mixed models to evaluate the relationship between offspring size and environmental factors (i.e., mean temperature, chlorophyll‐a and dissolved oxygen content together with their annual variation), as well as latitude, reproductive strategy, parental body size and fecundity. We also tested long‐standing hypotheses about the co‐evolution of offspring size and the presence of parental care in BayesTraits.

Results

After controlling for parental body size and phylogenetic history, we find that increased egg size is associated with colder and oxygen‐rich waters, while hatch size further depends on food supply and the reproductive strategy exhibited by the species. Irrespective of the initial investment in egg size, species with parental care or demersal egg development yield larger hatchlings compared to pelagic spawners. We also demonstrate that hatch size has co‐evolved with advanced forms of care in association with parental body but fail to find a relationship with other types of care.

Main conclusions

Our study shows that parental care behaviours, together with environmental context, influence the evolution of classic life‐history trade‐offs on a global scale. While the initial investment in eggs is driven primarily by temperature and oxygen content, hatch size also reflects the impact of care an offspring has received throughout development. In support of the ‘offspring‐first’ hypothesis, we find that an increase in hatch size drives the evolution of advanced care provision.
Selected physicochemical properties and sensory acceptability as affected by addition of lecithin and calcium carbonate in extruded breakfast cereals made with silkworm pupae powder and rice flour
Authors: Hirunyophat Patthama , Chalermchaiwat Parisut , On‐nom Nattira , Prinyawiwatkul Witoon
Published: September 2021

Effects of Lecithin (LC):Calcium carbonate (CaCO3) ratios (0.00:0.50, 0.10:0.40, 0.25:0.25, 0.40:0.10 and 0.50:0.00%w/w) on selected physicochemical properties and sensory acceptability of extruded breakfast cereals made with silkworm (Samia ricini D.) pupae powder and rice flour were investigated. The control sample was made without LC:CaCO3. Compared to the control, addition of LC significantly (P ≤ 0.05) reduced sectional expansion index, water solubility index and hardness, while increasing L*, bulk density and water absorption index of the samples. Increasing the CaCO3 level decreased bulk density while increased L*, ΔE*, sectional expansion index and crispness. The LC:CaCO3 interaction influenced aw, moisture, porosity and sensory liking, especially at 0.10:0.40%w/w which was suitable to produce the breakfast cereals. All samples had a protein content between 31.70% and 33.76% (dry basis), which made them qualified as a “high‐protein” source. The white malt–honey flavour coating increased liking scores of the finished product compared to the uncoated ones.
Review: Effect of the combined application of edible coatings and osmotic dehydration on the performance of the process and the quality of pear cubes
Authors: Rodriguez Anabel , Soteras Mario , Campañone Laura
Published: September 2021

The objective of the present work was to evaluate the combined effect of the application of edible coatings (sodium alginate and low methoxyl pectin) and different osmotic dehydration conditions (sucrose solution: 40 and 60 °Brix, temperatures: 20 and 40°C and times: 1, 2, 4, 8 and 16 h) on pear cubes (water loss, solid gain, performance ratio, the total colour differences, mechanical properties, phenolic content and sensory analysis). The results indicated that samples coated with low methoxyl pectin and treated under 60 °Brix for 16 h at both temperatures (20 and 40°C) presented the best process performance. Statistical analysis showed that the application of the coatings resulted in greater firmness and stiffness of the pear cubes at the end of osmotic dehydration. Besides, alginate coating best preserved the phenolic content (31.4%) than uncoated (26.04%) and pectin‐coated (20.77%) ones. However, total colour differences were not improved with the use of edible coatings (alginate or pectin). In terms of quality, the samples coated with both hydrogels had good overall acceptability by the evaluators and good mechanical properties. However, further studies are required to decrease the difference in colour and leaching of bioactive compounds in pear cubes due to the osmotic dehydration treatment.