bluuebunny/crossref_metadata_2025 huggingface dataset:
In silico modelling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms
Authors: Dall’Armellina Filippo , Stagi Massimiliano , Swan Laura E.
Published: July 2022

The VPS13 protein family constitutes a novel class of bridge-like lipid transferases. Autosomal recessive inheritance of mutations in VPS13 genes is associated with the development of neurodegenerative diseases in humans. Bioinformatic approaches previously recognised the domain architecture of these proteins. In this study, we model the first ever full-length structures of the four human homologs VPS13A, VPS13B, VPS13C, and VPS13D in association with model membranes, to investigate their lipid transfer ability and potential structural association with membrane leaflets. We analyse the evolutionary conservation and physicochemical properties of these proteins, focusing on conserved C-terminal amphipathic helices that disturb organelle surfaces and that, adjoined, resemble a traditional Venetian gondola. The gondola domains share significant structural homology with lipid droplet surface-binding proteins. We introduce in silico protein-membrane models displaying the mode of association of VPS13A, VPS13B, VPS13C, and VPS13D to donor and target membranes, and present potential models of action for protein-mediated lipid transfer.
GENOMIC INVESTIGATIONS OF ACUTE HEPATITIS OF UNKNOWN AETIOLOGY IN CHILDREN
Authors: Morfopoulou Sofia , Buddle Sarah , Torres Montaguth Oscar Enrique , Atkinson Laura , Guerra-Assunção José Afonso , Storey Nathaniel , Roy Sunando , Lennon Alexander , Lee Jack C D , Williams Rachel , Williams Charlotte A , Tutill Helena , Bayzid Nadua , Bernal Luz Marina Martin , Moore Catherine , Templeton Kate , Neill Claire , Holden Matt , Gunson Rory , Shepherd Samantha J , Shah Priyen , Cooray Samantha , Voice Marie , Steele Michael , Fink Colin , Whittaker Thomas E , Santilli Giorgia , Gissen Paul , Brown Rachel , Kaufer Benedikt B , Reich Jana , Andreani Julien , Simmonds Peter , Alrabiah Dimah K. , Hereza Sergi Castellano ,   DIAMONDS and PERFORM consortia, Andrade Catarina , Anderson Glenn , Kelgeri Chayarani , Waddington Simon N , Diaz Juan F Antinao , Hatcher James , De Surjo , Chiozzi Riccardo Zenezini , Thalassinos Konstantinos , Jacques Thomas S , Hoschler Katja , Talts Tiina , Celma Cristina , Gonzalez Suam , Gallagher Eileen , Simmons Ruth , Watson Conall , Mandal Sema , Zambon Maria , Chand Meera , Campos Luis , Martin Joanne , Thomson Emma , Ushiro-Lumb Ines , Levin Michael , Brown Julianne R , Breuer Judith
Published: July 2022

Since the first reports of hepatitis of unknown aetiology occurring in UK children, over 1000 cases have been reported worldwide, including 268 cases in the UK, with the majority younger than 6 years old. Using genomic, proteomic and immunohistochemical methods, we undertook extensive investigation of 28 cases and 136 control subjects. In five cases who underwent liver transplantation, we detected high levels of adeno-associated virus 2 (AAV2) in the explanted livers. AAV2 was also detected at high levels in blood from 10/11 non-transplanted cases. Low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), both of which enable AAV2 lytic replication, were also found in the five explanted livers and blood from 15/17 and 6/9 respectively, of the 23 non-transplant cases tested. In contrast, AAV2 was detected at low titre in 6/100 whole bloods from child controls from cohorts with presence or absence of hepatitis and/or adenovirus infection. Our data show an association of AAV2 at high titre in blood or liver tissue, with unexplained hepatitis in children infected in the recent HAdV-F41 outbreak. We were unable to find evidence by electron microscopy, immunohistochemistry or proteomics of HAdV or AAV2 viral particles or proteins in explanted livers, suggesting that hepatic pathology is not due to direct lytic infection by either virus. The potential that AAV2, although not previously associated with disease, may, together with HAdV-F41 and/or HHV-6, be causally implicated in the outbreak of unexplained hepatitis, requires further investigation.
Allosteric Regulation of Aptamer Affinity through Mechano-Chemical Coupling
Authors: Qu Hao , Zheng Manyi , Ma Qihui , Wang Lu , Mao Yu , Eisenstein Michael , Soh Hyongsok Tom , Zheng Lei
Published: July 2022

The capacity to precisely modulate aptamer affinity is important for a wide variety of applications. However, most such engineering strategies entail laborious trial-and-error testing or require prior knowledge of an aptamer’s structure and ligand-binding domain. We describe here a simple and generalizable strategy for allosteric modulation of aptamer affinity by employing a double-stranded molecular clamp that destabilizes aptamer secondary structure through mechanical tension. We demonstrate the effectiveness of the approach with a thrombin-binding aptamer and show that we can alter its affinity by as much as 65-fold. We also show that this modulation can be rendered reversible by introducing a restriction enzyme cleavage site into the molecular clamp domain and describe a design strategy for achieving even more finely-tuned affinity modulation. This strategy requires no prior knowledge of the aptamer’s structure and binding mechanism and should thus be generalizable across aptamers.
Transcriptome analysis of protein kinase MoCK2 affect acetyl-CoA metabolism and import of CK2 interacting mitochondrial proteins into mitochondria in rice blast fungus Magnaporthe oryzae
Authors: Zhang Lianhu , Shan Chonglei , Zhang Yifan , Miao Wenjing , Bing Xiaoli , Kuang Weigang , Wang Zonghua , Cui Ruqiang , Olsson Stefan
Published: July 2022

The rice pathogen Magnaporthe oryzae causes severe losses to rice production. Previous studies have shown protein kinase MoCK2 essential for pathogenesis, and this ubiquitous eukaryotic might affect several processes in the fungus needed for infection. To better understand which cellular processes are affected by the MoCK2 activity, we performed a detailed RNAseq analysis of deletions MoCK2-beta1 and beta2 components in relation to the background strain Ku80 and connected this analysis with the abundance of substrates for proteins in a previous pulldown of the essential CKa subunit of CK2 to estimate effects on proteins directly interacting with CK2. The results showed that MoCK2 seriously affected carbohydrate metabolism, fatty acid metabolism, amino acid metabolism and related transporters and reduced acetyl-CoA production. CK2 phosphorylation can affect the folding of proteins and especially the effective formation of protein complexes by intrinsically disordered or mitochondrial import by destabilizing soluble alpha helixes. Upregulated genes found in the pulldown of the b1 and b2 mutants indicate that proteins directly interacting with CK2 are compensatory upregulated depending on their pulldown. A similar correlation was found for mitochondrial proteins. Taken together, the classes of proteins and the change in regulation in the b1 and b2 mutants suggest that CK2 has a central role in mitochondrial metabolism, secondary metabolism, and ROS resistance, in addition to the previously suggested role in the formation of new ribosomes, all processes central to efficient non-self responses as innate immunity.

Importance

The protein kinase CK2 is highly expressed and essential for plants, animals, and fungi affecting fatty acid-related metabolism. In addition, it directly affects the import of essential mitochondrial proteins into mitochondria. These effects mean CK2 is essential for lipid metabolism and mitochondrial function and, as shown before, crucial for making new translation machinery proteins. Taken together, our new results combined with previous published indicate that CK2 is an essential protein necessary for the capacity to launch efficient innate immunity responses and withstand the negative effect of such responses necessary for general resistance against invading bacteria and viruses as well as to interact with plants and withstand plant immunity responses and kill plant cells.

Protein kinase CK2, highly expressed and essential for plants, animals, and fungi, affects fatty acid-related metabolism and mitochondrial proteins, making it essential for the capacity to launch efficient innate immunity responses and plant pathogenicity
Formation of contact and multiple cyclic cassiterite twins in SnO2-based ceramics co-doped with cobalt and niobium oxides
Authors: Daneu Nina , Dražič Goran , Mazaj Matjaž , Barou Fabrice , Padrón-Navarta José Alberto
Published: July 2022

Contact and multiple cyclic twins of cassiterite commonly form in SnO2-based ceramics when SnO2 is sintered with small additions of cobalt and niobium oxides (dual doping). In this work, it is shown that the formation of twins is a two-stage process that starts with epitaxial growth of SnO2 on CoNb2O6 and Co4Nb2O9 seeds (twin nucleation stage) and continues with the fast growth of (101) twin contacts (twin growth stage). Both secondary phases form below the temperature of enhanced densification and SnO2 grain growth; CoNb2O6 forms at ∼700°C and Co4Nb2O9 at ∼900°C. They are structurally related to the rutile-type cassiterite and can thus trigger oriented (epitaxial) growth (local recrystallization) of SnO2 domains in different orientations on a single seed particle. While oriented growth of cassiterite on columbite-type CoNb2O6 grains can only result in the formation of contact twins, the Co4Nb2O9 grains with a structure comparable with that of corundum represent suitable sites for the nucleation of contact and multiple cyclic twins with coplanar or alternating morphology. The twin nucleation stage is followed by fast densification accompanied by significant SnO2 grain growth above 1300°C. The twin nuclei coarsen to large twinned grains as a result of the preferential and fast growth of the low-energy (101) twin contacts. The solid-state diffusion processes during densification and SnO2 grain growth are controlled by the formation of point defects and result in the dissolution of the twin nuclei and the incorporation of Nb5+ and Co2+ ions into the SnO2 matrix in the form of a solid solution. In this process, the twin nuclei are erased and their role in the formation of twins is shown only by irregular segregation of Co and Nb to the twin boundaries and inside the cassiterite grains, and Co,Nb-enrichment in the cyclic twin cores.
Crystal structure, Hirshfeld surface analysis and DFT calculations of (E)-3-[1-(2-hydroxyphenylanilino)ethylidene]-6-methylpyran-2,4-dione
Authors: Faraj Imane , Oubella Ali , Chkirate Karim , Al Mamari Khalil , Hökelek Tuncer , Mague Joel T. , El Ghayati Lhoussaine , Sebbar Nada Kheira , Essassi El Mokhtar
Published: July 2022

The asymmetric unit of the title compound, C14H13NO4, contains three independent molecules, which differ slightly in conformation. Each contains an intramolecular N—H...O hydrogen bond. In the crystal, O—H...O hydrogen bonds form chains of molecules, which are linked into corrugated sheets parallel to (\overline{1}03) plane by C—H...O hydrogen bonds together with π interactions between the carbonyl groups and the 2-hydroxyphenyl rings. The layers are linked by further C—H...O hydrogen bonds. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H...H (49.0%), H...O/O...H (28.3%) and H...C/C...H (10.9%) interactions. van der Waals interactions are the dominant interactions in the crystal packing. Moreover, density functional theory (DFT) optimized structures at the B3LYP/ 6–311 G(d,p) level are compared with the experimentally determined molecular structure in the solid state. The HOMO–LUMO behavior was elucidated to determine the energy gap of 4.53 eV.
Is conflict useful after all? A scenario experiment on the antecedents and consequences of task and relationship conflict in military settings
Authors: Telecan Maria Ioana , Rus Claudia Lenuța , Curșeu Petru Lucian
Published: July 2022

Purpose

Using a within-subject vignette experiment, this study aims to disentangle the differential effect of task and relationship conflict on team effectiveness and interpersonal outcomes. In addition, the authors aimed to test the moderating role of the conflict inducing person’s gender on task and relationship conflict outcomes.

Design/methodology/approach

Data were collected using four vignettes administered to 151 participants from an Air Force military organization.

Findings

Relationship conflict was more damaging than task conflict for team effectiveness, the harmonious interpersonal relations and the expected positive affective team climate. Task conflict triggers more positive emotions than relationship conflict and, in consequence, team effectiveness is higher in scenarios with the task rather than relationship conflict. The groups in which conflict is induced by a woman are not expected to perform better than groups in which the conflict is induced by a man. The similarity between participant’s gender and the gender of the person that generated the conflict accentuates rather than attenuates the effectiveness decline associated with relationship conflict. Task conflict triggers cooperative, while relationship conflict triggers assertive conflict management strategies.

Research limitations/implications

This study provided only a snapshot on how task and relationship conflict are perceived to relate to the various team and individual-level outcomes, particularly in military settings.

Originality/value

The findings evidence the differential effect of task and relationship conflict not only on team effectiveness but also on attitudinal and emotional team and individual-level outcomes.
All that glistens is not (green) gold: historicising the contemporary chlorophyll fad through a multimodal analysis of Swedish marketing, 1950–1953
Authors: O'Hagan Lauren Alex
Published: July 2022

Purpose

This paper aims to historicise the contemporary chlorophyll trend through the first academic study of its early marketing in Sweden (1950–1953). Using multimodal critical discourse analysis, it demonstrates how brands used advertisements to convince female consumers of chlorophyll’s necessity to fulfil certain aspirational goals.

Design/methodology/approach

In all, 150 advertisements for chlorophyll products were collected from the Swedish Historical Newspaper Archive, as well as 600 additional advertisements for the three most popular products (toothpaste/mouthwash, sanitary towels and soap) from 1940 to 1950 and from 1954 to 1964. Then, multimodal critical discourse analysis was used to investigate how the products were marketed before, during and after the chlorophyll trend, identifying the general themes and linguistic/semiotic structures of the advertisements.

Findings

This paper shows how the commercial use of chlorophyll offered a lucrative opportunity for marketers, acting as a “tabula rasa” on which they could use discourses of science, nature, idealised femininity and luxury to draw connections with health, modernity and beauty, despite the product having no real purpose or value.

Originality/value

Viewing this fad from a historical perspective emphasises how brands, marketers and influencers continue to capitalise on the anxieties of female consumers with promises around beauty, hygiene and health. It, thus, offers us critical distance to reflect on contemporary claims about chlorophyll’s health benefits to make informed choices.
Understanding the key drivers in using mobile payment among Generation Z
Authors: Lisana Lisana
Published: July 2022

Purpose

This quantitative study aims to examine the determinants that impact the behavioral intention to use mobile payment (m-payment) among Generation Z (Gen Z) customers in Indonesia.

Design/methodology/approach

The theoretical model comprises seven latent variables: effort expectancy, performance expectancy, social influence, facilitating conditions, promotional activities, perceived security and behavioral intention. In addition, the two moderating factors of education and gender are used to investigate the significant effect of the determinants on intention to adopt m-payment. This study obtained the final data size of 430 respondents. The data analysis is conducted using structural equation modeling.

Findings

The results substantiate the significance of promotional activities, perceived security, performance expectancy, effort expectancy and social influence, on the behavioral intention to accept m-payment systems. Gender is revealed to significantly moderate two constructs: social influence and promotional activities, on the m-payment usage intention. Meanwhile, education moderates the effect of perceived security on behavioral intention.

Originality/value

This research is expected to fill the gap because only a few studies discuss the determinants affecting m-payment usage in Indonesia, especially among Gen Z-ers. Furthermore, the new findings associated with the role of two moderating factors become important practical implications because most of the prior studies often ignore the moderating factors.
Cotton fibre selection based on quality value using measurement of alternatives and ranking according to compromise solution (MARCOS) method
Authors: Mitra Ashis
Published: July 2022

Purpose

Cotton fibre lots are graded and selected for yarn spinning based on their quality value which is a function of certain fibre properties. Cotton grading and selection has created a domain of emerging interest among the researchers. Several researchers have addressed the said issue using a few exponents of multi-criteria decision-making (MCDM) technique. The purpose of this study is to demonstrate a cotton selection problem using a recently developed measurement of alternatives and ranking according to compromise solution (MARCOS) method which can handle almost any decision problem involving a finite number of alternatives and multiple conflicting decision criteria.

Design/methodology/approach

The MARCOS method of the MCDM technique was deployed in this study to rank 17 cotton fibre lots based on their quality values. Six apposite fibre properties, namely, fibre bundle strength, elongation, fineness, upper half mean length, uniformity index and short fibre content are considered as the six decision criteria assigning weights previously determined by an earlier researcher using analytic hierarchy process.

Findings

Among the 17 alternatives, C9 secured rank 1 (the best lot) with the highest utility function (0.704) and C7 occupied rank 17 (the worst lot) with the lowest utility function (0.596). Ranking given by MARCOS method showed high degree of congruence with the earlier approaches, as evidenced by high rank correlation coefficients (Rs > 0.814). During sensitivity analyses, no occurrence of rank reversal is observed. The correlations between the quality value-based ranking and the yarn tenacity-based rankings are better than many of the traditional methods. The results can be improved further by adopting other efficient method of weighting the criteria.

Practical implications

The properties of raw cotton have significant impact on the quality of final yarn. Compared to the traditional methods, MCDM is reported as the most viable solution in which fibre parameters are given their due importance while formulating a single index known as quality value. The present study demonstrates the application of a recently developed exponent of MCDM in the name of MARCOS for the first time to address a cotton fibre selection problem for textile spinning mills. The same approach can also be extended to solve other decision problems of the textile industry, in general.

Originality/value

Novelty of the present study lies in the fact that the MARCOS is a very recently developed MCDM method, and this is a maiden application of the MARCOS method in the domain of textile, in general, and cotton industry, in particular. The approach is very simple, highly effective and quite flexible in terms of number of alternatives and decision criteria, although highly robust and stable.
Commentary on “Development of LDPAQ: learning disability physical activity questionnaire”
Authors: Brooker Katie , Hill Jessica
Published: July 2022

Purpose

This paper aims to discuss the importance of delivering high-quality education to allied health and fitness professionals around physical activity for people with intellectual disabilities.

Design/methodology/approach

The clinical training and experience needs of allied health and fitness professionals are examined in relation to knowledge and skills around physical activity levels and people with intellectual disabilities.

Findings

The training of allied health and fitness professionals may not be adequate. Current training does not appear to provide professionals with the skill set and suitable experiences to appropriately support people with intellectual disabilities to be active.

Originality/value

Key training areas for allied health and fitness professionals are outlined.
Customer responses to airline companies' service failure and recovery strategies: the moderating role of service failure habit
Authors: Elbaz Ahmed Mohamed , Soliman Mohammad , Al-Alawi Alamir , Al-Romeedy Bassam Samir , Mekawy Moustafa
Published: July 2022

Purpose

The purpose of this study is to investigate the perceived severity of service failure (PSSF) and service recovery strategies (SRSs) as antecedents of customer forgiveness (CF), customer reconciliation, negative word-of-mouth and re-patronage intention as outcomes across two Middle Eastern countries: Egypt and Oman.

Design/methodology/approach

A quantitative technique was used, using a questionnaire, to collect data from customers of the national airline companies of Egypt and Oman. The perspectives of 1,084 airline customers were analysed using partial least squares-structural equation modelling.

Findings

The results of this study show that service failure severity has a negative influence on the effectiveness of SRSs. In turn, proper SRSs strongly and positively affect both Egyptian and Omani CF. Furthermore, the findings of this study indicate that service failure habit plays an important role in increasing the negative influence of perceived service failure severity on Egyptian, but not Omani, CF. Overall, results suggest that CF differs considerably between Egyptians and Omanis.

Originality/value

This study developed and empirically examined a comprehensive conceptual model of the drivers and outcomes of CF of airline companies. This study provides academics with meaningful insights into how social and cultural differences between customers in different countries can result in sometimes dramatically different behaviours following a service failure.
Will Listing Rule Reform Deliver Strong Public Markets for the UK?
Authors: Cheffins Brian R. , Reddy Bobby V.
Published: July 2022

There is a general consensus that the UK needs strong public equity markets. To help to ensure Britain is well‐positioned on this front, the Financial Conduct Authority reformed the London Stock Exchange's listing regime in 2021 to foster initial public offerings (IPOs). This article outlines and evaluates these IPO‐related reforms, assessing their potential to resuscitate the UK's public equity markets. The article puts the IPO‐related reforms into context by considering whether the fostering of strong equity markets is a sensible policy goal and by assessing what laws governing publicly traded companies can contribute to this endeavour. The article acknowledges that the specific IPO reforms may increase IPO activity but concludes that concerns about strong public markets will continue to exist. This is because the reforms do not address stock market exits or the ‘over’‐regulation of public companies which discourages reliance on equity markets.
Laser treatment for genitourinary syndrome of menopause
Authors: Phillips Christian , Hillard Timothy , Salvatore Stefano , Cardozo Linda , Toozs‐Hobson Philip ,   the Royal College of Obstetricians and Gynaecologists
Published: July 2022

Plain language summary

Genitourinary syndrome of menopause (GSM) is the term used to describe the group of symptoms including vaginal pain, vaginal dryness, itching, pain during sexual intercourse and fragile vaginal tissues as well as urinary symptoms including urinary frequency, urgency, incontinence, blood in the urine (haematuria) and recurrent urinary tract infections that occur due to a lack of the hormone estrogen.

These symptoms can have a significant negative impact on psychosexual issues, sexual function and quality of life in postmenopausal women. Traditionally women have been treated with vaginal lubricants, vaginal moisturisers or low‐dose vaginal estrogens.

Lasers have been used in the cosmetic industry for collagen remodelling and repair of the skin. Therefore, it has been suggested that laser therapy may be used on the vagina as an alternative treatment for GSM. A review of all the published studies assessing the safety and efficacy of laser therapy for GSM have shown promising beneficial results. The majority of studies to date have been small, short‐term, observational studies. However, there are randomised controlled trials underway. Laser treatment may be beneficial for the symptoms of GSM but until more robust evidence is available it should not be adopted into widespread practice, and should be used as part of a research study only.
Do Surveys Change Behaviours?
Authors: Cernat Alexandru , Keusch Florian
Published: July 2022

It is well known that being observed can change our behaviour. Alexandru Cernat and Florian Keusch used digital trace data to see whether taking part in multiple political surveys made participants more interested in news and politics
Canine Confounders
Authors: Núñez Isaac
Published: July 2022

Did the dogs of Mexico City really stop their owners dying rom Covid-19? Isaac Núñez shares an astonishing tale of causal questions, selection bias and confounding
“Statisticians are Particularly Attuned to the Beauty of Uncertainty”
Authors: Britten Anna
Published: July 2022

Data visualisation fans will need no introduction to David McCandless, data journalist and author of the bestselling books Information is Beautiful and Knowledge is Beautiful as well as, most recently, Beautiful News. He is also one of the media's most called-upon advocates for statistics as art, and tells Anna Britten about his process, data viz heroes and why communication is all about context
Thoracic myopericytoma in an older adult, rare but possible: A case report
Authors: Nigro Maria Concetta , Pirini Maria Giulia , Garelli Elena , Marchi Marina , Musto Alessandra , Pantaleo Maria Abbondanza , Solli Piergiorgio , Ardizzoni Andrea , Nannini Margherita
Published: July 2022

Myopericytoma is a rare tumor generally arising from skin and soft tissues of extremities, trunk, head, and neck regions, rarely from visceral sites. An intrathoracic visceral localization may carry a broad differential diagnosis including primary lung, pleura and chest wall lesions, or metastatic lesions. To date, any radiological features have been recognized and diagnosis of myopericytoma with intrathoracic localization remains still challenging. Here, we describe the case of a subpleural lesion incidentally diagnosed in an older adult affected by gastric cancer. Radiological features did not allow a differential diagnosis between a benign lesion, a primary tumor, or a metastasis. After resection, the histological examination showed histopathological features congruent with the diagnosis of myopericytoma. This unusual presentation reflects the need to share clinical, radiological, and histopathological data about this uncommon but frequently misdiagnosed disease.
Immunomodulation by foods and microbes: Unravelling the molecular tango
Authors: Forde Brian , Yao Lu , Shaha Rupin , Murphy Sally , Lunjani Nonhlanhla , O'Mahony Liam
Published: July 2022

Metabolic health and immune function are intimately connected via diet and the microbiota. Nearly 90% of all immune cells in the body are associated with the gastrointestinal tract and these immune cells are continuously exposed to a wide range of microbes and microbial‐derived compounds, with important systemic ramifications. Microbial dysbiosis has consistently been observed in patients with atopic dermatitis, food allergy and asthma and the molecular mechanisms linking changes in microbial populations with disease risk and disease endotypes are being intensively investigated. The discovery of novel bacterial metabolites that impact immune function is at the forefront of host‐microbe research. Co‐evolution of microbial communities within their hosts has resulted in intertwined metabolic pathways that affect physiological and pathological processes. However, recent dietary and lifestyle changes are thought to negatively influence interactions between microbes and their host. This review provides an overview of some of the critical metabolite‐receptor interactions that have been recently described, which may underpin the immunomodulatory effects of the microbiota, and are of relevance for allergy, asthma and infectious diseases.
Extracellular vesicles and microRNAs are altered in response to exercise, insulin sensitivity and overweight
Authors: Doncheva Atanaska Ivanova , Romero Silvana , Ramirez‐Garrastacho Manuel , Lee Sindre , Kolnes Kristoffer J. , Tangen Daniel Steensen , Olsen Thomas , Drevon Christian A. , Llorente Alicia , Dalen Knut Tomas , Hjorth Marit
Published: July 2022

Extracellular vesicles induced by exercise have emerged as potential mediators of tissue crosstalk. Extracellular vesicles and their cargo miRNAs have been linked to dysglycemia and obesity in animal models, but their role in humans is unclear.

Aim

The aim of the study was to characterize the miRNA content in plasma extracellular vesicle isolates after acute and long‐term exercise and to study associations between extracellular vesicle miRNAs, mRNA expression in skeletal muscle and adipose tissue, and cardiometabolic risk factors.

Methods

Sedentary men with or without dysglycemia and overweight underwent an acute bicycle test and a 12‐week exercise intervention with extensive metabolic phenotyping. Gene expression in m. vastus lateralis and subcutaneous adipose tissue was measured with RNA sequencing. Extracellular vesicles were purified from plasma with membrane affinity columns or size exclusion chromatography.

Results

Extracellular vesicle miRNA profiling revealed a transient increase in the number of miRNAs after acute exercise. We identified miRNAs, such as miR‐652‐3p, that were associated to insulin sensitivity and adiposity. By performing explorative association analyses, we identified two miRNAs, miR‐32‐5p and miR‐339‐3p, that were strongly correlated to an adipose tissue macrophage signature.

Conclusion

Numerous miRNAs in plasma extracellular vesicle isolates were increased by exercise, and several miRNAs correlated to insulin sensitivity and adiposity. Our findings warrant future studies to characterize exercise‐induced extracellular vesicles and cargo miRNA to clarify where exercise‐induced extracellular vesicles originate from, and to determine whether they influence metabolic health or exercise adaptation.
Dose escalations in phase I studies: Feasibility of interpreting blinded pharmacodynamic data
Authors: Hassing Gerardus J. , van Esdonk Michiel J. , van Westen Gerard J. P. , Cohen Adam F. , Burggraaf Jacobus , Gal Pim
Published: July 2022

Aims

During phase I study conduct, blinded data are reviewed to predict the safety of increasing the dose level. The aim of the present study was to describe the probability that effects are observed in blinded evaluations of data in a simulated phase I study design.

Methods

An application was created to simulate blinded pharmacological response curves over time for 6 common safety/efficacy measurements in phase I studies for 1 or 2 cohorts (6 active, 2 placebo per cohort). Effect sizes between 0 and 3 between‐measurement standard deviations (SDs) were simulated. Each set of simulated graphs contained the individual response and mean ± SD over time. Reviewers (n = 34) reviewed a median of 100 simulated datasets and indicated whether an effect was present.

Results

Increasing effect sizes resulted in a higher chance of the effect being identified by the blinded reviewer. On average, 6% of effect sizes of 0.5 between‐measurement SD were correctly identified, increasing to 72% in 3.0 between‐measurement SD effect sizes. In contrast, on average 92–95% of simulations with no effect were correctly identified, with little effect of between‐measurement variability in single cohort simulations. Adding a dataset of a second cohort at half the simulated dose did not appear to improve the interpretation.

Conclusion

Our analysis showed that effect sizes <2× the between‐measurement SD of the investigated outcome frequently go unnoticed by blinded reviewers, indicating that the weight given to these blinded analyses in current phase I practice is inappropriate and should be re‐evaluated.
Low NUDT15 expression levels due to biallelic NUDT15 variants and 6‐mercaptopurine intolerance
Authors: Yoshida Masanori , Brown Scott A. , Moriyama Takaya , Nishii Rina , Tsujimoto Shin‐ichi , Yamada Yuji , Yoshida Kaoru , Shirai Ryota , Osumi Tomoo , Utano Tomoyuki , Fukano Reiji , Kudo Ko , Sakaguchi Kimiyoshi , Arakawa Yuki , Koh Katsuyoshi , Sekiguchi Masahiro , Sekimizu Masahiro , Miyamura Takako , Ishida Hisashi , Inukai Takeshi , Tomizawa Daisuke , Kiyokawa Nobutaka , Kato Motohiro , Yang Jun J.
Published: July 2022

6‐Mercaptopurine (6‐MP) is widely used for the treatment of paediatric leukaemia and lymphoma. Recently, germline variants in the NUDT15 gene have been identified as one of the major genetic causes for 6‐MP–associated adverse effects such as myelosuppression. Patients with hypomorphic NUDT15 variants accumulate excessive levels of DNA‐incorporated thioguanine in white blood cells, resulting in severe myelosuppression. Although preclinical studies suggest that these variants may influence the protein stability of NUDT15, this has not been directly characterised in patients. In this study, we report the development of a series of novel monoclonal antibodies against NUDT15, using which we quantitatively assessed NUDT15 protein levels in 37 patients with acute lymphoblastic leukaemia treated with 6‐MP, using sandwich enzyme‐linked immunosorbent assay (ELISA). The NUDT15 genotype was highly correlated with its protein levels (p < 0.0001), with homozygous and compound heterozygous patients showing exceedingly low NUDT15 expression. There was a positive correlation between NUDT15 protein level and 6‐MP tolerance (r = 0.631, p < 0.0001). In conclusion, our results point to low NUDT15 protein abundance as the biochemical basis for NUDT15‐mediated 6‐MP intolerance, thus providing a phenotypic readout of inherited NUDT15 deficiency.
HINT1 neuropathy: Expanding the genotype and phenotype spectrum
Authors: Morel Victor , Campana‐Salort Emmanuelle , Boyer Amandine , Esselin Florence , Walther‐Louvier Ulrike , Querin Giorgia , Latour Philippe , Lia Anne‐Sophie , Magdelaine Corinne , Beze‐Beyrie Pierre , Behin Anthony , Delague Valérie , Levy Nicolas , Stojkovic Tanya , Attarian Shahram , Bonello‐Palot Nathalie
Published: July 2022

Inherited peripheral neuropathy (IPN) is a heterogeneous group of disorders due to pathogenic variation in more than 100 genes. In 2012, the first cases of IPN associated with HINT1 pathogenic variations were described in 33 families sharing the same phenotype characterized by an axonal neuropathy with neuromyotonia and autosomal recessive inheritance (NMAN: OMIM #137200). Histidine Triad Nucleotide Binding Protein 1 regulates transcription, cell‐cycle control, and is possibly involved in neuropsychiatric pathophysiology. Herein, we report seven French patients with NMAN identified by Next Generation Sequencing. We conducted a literature review and compared phenotypic and genotypic features with our cohort. We identified a new HINT1 pathogenic variation involved in NMAN: c.310G>C p.(Gly104Arg). This cohort is comparable with literature data regarding age of onset (7,4yo), neuronal involvement (sensorimotor 3/7 and motor pure 4/7), and skeletal abnormalities (scoliosis 3/7, feet anomalies 6/7). We expand the phenotypic spectrum of HINT1‐related neuropathy by describing neurodevelopmental or psychiatric features in six out of seven individuals such as generalized anxiety disorder (GAD), obsessive–compulsive disorder (OCD), mood disorder and attention deficit hyperactivity disorder (ADHD). However, only 3/128 previously described patients had neuropsychiatric symptomatology or neurodevelopmental disorder. These features could be part of HINT1‐related disease, and we should further study the clinical phenotype of the patients.
Determining a dosage threshold of drink‐driving enforcement operations: A systematic review
Authors: O'Hara Sharon E. , Paschall Mallie J. , Herd Denise A.
Published: July 2022

Issues

Policy enforcement is crucial to achieve impacts on alcohol‐related harm. It is not clear what level of enforcement intensity or ‘dosage’ is necessary for addressing drink driving and related harms. Given competing enforcement demands and agencies' resource constraints, understanding how much enforcement is sufficient to deter drink driving is critical.

Approach

This systematic literature review followed Preferred Reporting Items for Systematic Review and Meta‐Analysis Protocols (PRISMA) guidelines to examine research about dosage effects of enforcement and related visibility on drink‐driving outcomes, including motor vehicle crashes and fatalities. Risk of bias was assessed using the Cochrane Collaboration Effective Practice and Organization of Care tool and the JBI checklist.

Key Findings

The 21 studies that met the inclusion criteria for this review differed in measures of enforcement dosage and outcomes, making it difficult to synthesise results across studies and draw conclusions about a threshold or optimal level of enforcement. Although most included studies found that sustained enforcement was associated with reductions in drink driving or related harms, only two studies tested an optimal dosage. Due to study design limitations, a substantial percentage of these studies must be considered with caution.

Implications

Additional research with rigorous study designs with appropriate controls is needed to determine an optimal high visibility enforcement dosage level to help law enforcement agencies make realistic decisions about allocating enforcement resources to address drink driving.

Conclusion

Consistent evidence about a drink‐driving enforcement dosage threshold is lacking, partly due to an insufficient number of well‐designed studies. Addressing challenges of conducting rigorous studies in community settings is crucial.
Floristic homogenization as a result of the introduction of exotic species in China
Authors: Qian Hong , Qian Shenhua
Published: July 2022

Aim

The introduction of exotic plants can both increase (homogenize) and decrease (differentiate) floristic similarity between areas. We have a poor understanding of the degree to which plant species introductions tend to homogenize or differentiate floras, and relevant studies covering large spatial extent are scarce. China has been heavily invaded by exotic plants. Here, we analyse a comprehensive dataset of vascular plants to determine whether the introduction of exotic plant species has homogenized or differentiated species composition in regions across China.

Location

China.

Methods

We calculated the Jaccard index and Simpson index of similarity for each pair of province‐level regions for native and exotic species separately and jointly, and calculated a homogenization index for each pair of regional floras. We correlated species richness of native and exotic plants to climatic factors, and correlated the Jaccard index and Simpson index to geographic and climatic distances. We used variation partitioning analysis to determine the relative importance of geographic and climatic distances on species turnover. We also examined the effect of human population density on florisitic similarity of exotic species.

Results

We found that the geographic range of each species was, on average, larger for exotics than for natives; floristic similarity between regions was greater for exotics than for natives; the vast majority of pairwise regional floras have been homogenized; the introduction of exotic species has caused stronger biotic homogenization for pairwise floras with greater dissimilarity in their species composition; geographic distributions of exotic and native species were determined by different sets of climatic factors; and distributions of exotic species were determined by climatic factors more strongly, compared to those of native species. Human population density had a moderate effect on florisitic similarity of exotic species.

Main conclusions

The introduction of exotic plant species has homogenized regional floras across China. Because strong international trades between China and other countries and dramatic development of transportation systems are continuing in China, which help spread of exotic species, we predict that exotic species will continue to spread and will strengthen biotic homogenization in China.
Sulfur cycling at natural hydrocarbon and sulfur seeps in Santa Paula Creek, CA
Authors: Aronson Heidi S. , Monteverde Danielle R. , Barnes Ben Davis , Johnson Brooke R. , Zawaski Mike J. , Speth Daan R. , Wang Xingchen Tony , Wu Fenfang , Webb Samuel M. , Trower Elizabeth J. , Magyar John S. , Sessions Alex L. , Orphan Victoria J. ,   Geobiology Course 2017,   Geobiology Course 2018, Fischer Woodward W.
Published: July 2022

Biogeochemical cycling of sulfur is relatively understudied in terrestrial environments compared to marine environments. However, the comparative ease of access, observation, and sampling of terrestrial settings can expand our understanding of organisms and processes important in the modern sulfur cycle. Furthermore, these sites may allow for the discovery of useful process analogs for ancient sulfur‐metabolizing microbial communities at times in Earth's past when atmospheric O2 concentrations were lower and sulfide was more prevalent in Earth surface environments. We identified a new site at Santa Paula Creek (SPC) in Ventura County, CA—a remarkable freshwater, gravel‐bedded mountain stream charged with a range of oxidized and reduced sulfur species and heavy hydrocarbons from the emergence of subsurface fluids within the underlying sulfur‐ and organic‐rich Miocene‐age Monterey Formation. SPC hosts a suite of morphologically distinct microbial biofacies that form in association with the naturally occurring hydrocarbon seeps and sulfur springs. We characterized the geology, stream geochemistry, and microbial facies and diversity of the Santa Paula Creek ecosystem. Using geochemical analyses and 16S rRNA gene sequencing, we found that SPC supports a dynamic sulfur cycle that is largely driven by sulfide‐oxidizing microbial taxa, with contributions from smaller populations of sulfate‐reducing and sulfur‐disproportionating taxa. This preliminary characterization of SPC revealed an intriguing site in which to study geological and geochemical controls on microbial community composition and to expand our understanding of sulfur cycling in terrestrial environments.
Antibacterial activity and mechanism of ginger extract against Ralstonia solanacearum
Authors: Zhang Lingling , Qin Manli , Yin Junliang , Liu Xuli , Zhou Jie , Zhu Yongxing , Liu Yiqing
Published: July 2022

Aims

The current study aimed to determine the chemical compositions of ginger extract (GE) and to assess the antibacterial activities of GE against the ginger bacterial wilt pathogen Ralstonia solanacearum and to screen their mechanisms of action.

Methods and Results

A total of 393 compounds were identified by using ultra-performance liquid chromatography and tandem-mass spectrometry. The antibacterial test indicated that GE had strong antibacterial activity against R. solanacearum and that the bactericidal effect exhibited a dose-dependent manner. The minimum inhibitory concentration and minimum bactericidal concentration of R. solanacearum were 3.91 and 125 mg/ml, respectively. The cell membrane permeability and integrity of R. solanacearum were destroyed by GE, resulting in cell content leakage, such as electrolytes, nucleic acids, proteins, extracellular adenosine triphosphate and exopoly saccharides. In addition, the activity of cellular succinate dehydrogenase and alkaline phosphatase of R. solanacearum decreased gradually with an increase in the GE concentration. Scanning electron microscopy analysis revealed that GE treatment changed the morphology of the R. solanacearum cells. Further experiments demonstrated that GE delayed or slowed the occurrence of bacterial wilt on ginger.

Conclusions

GE has a significant antibacterial effect on R. solanacearum, and the antibacterial effect is concentration dependent. The GE treatments changed the morphology, destroyed membrane permeability and integrity, reduced key enzyme activity and inhibit the synthesis of the virulence factor EPS of R. solanacearum. GE significantly controlled the bacterial wilt of ginger during infection.

Significance and Impact of the Study

This research provides insight into the antimicrobial mechanism of GE against R. solanacearum, which will open a new application field for GE.
An improved, simple and field-deployable CRISPR-Cas12a assay for the detection of SARS-CoV-2
Authors: Misra Chitra S. , Rangu Shyam S. , Phulsundar Ravindra D. , Bindal Gargi , Singh Mandeep , Shashidhar Ravindranath , Saha Tushar K. , Rao Akkipeddi V. S. S. N. , Rath Devashish
Published: July 2022

Aims

The RT-PCR is the most popular confirmatory test for SARS-CoV-2. It is sensitive, but high instrumentation cost makes it difficult for use outside routine clinical setup. This has necessitated the development of alternative methods such as CRISPR-based DETECTR method which uses lateral flow technology. Although accurate and sensitive, this method is limited by complex steps and recurrent cost of high-quality lateral flow strips. The main goal of this study was to improve the Cas12a-based SARS-CoV-2 DETECTR method and develop a portable and field-deployable system to reduce the recurring consumable cost.

Methods and results

Specific regions of N and E genes from SARS-CoV-2 virus and human RNase P (internal control) were reverse transcribed (RT) and amplified by loop-mediated isothermal amplification (LAMP). The amplified products were detected by a Cas12a-based trans-cleavage reaction that generated a fluorescent signal which could be easily visualized by naked eye. Detection of internal control, RNase P gene was improved and optimized by redesigning RT-LAMP primers. A number of steps were reduced by combining the reagents related to the detection of Cas12a trans-cleavage reaction into a single ready-to-use mix. A portable, cost-effective battery-operated instrument, CRISPR-CUBE was developed to run the assay and visualize the outcome. The method and instrument were validated using both contrived and patient samples.

Conclusions

The simplified CRISPR-based SARS-CoV-2 detection and instrument developed in this study, along with improved design for internal control detection allows for easier, more definitive viral detection requiring only reagents, consumables and the battery operable CRISPR-CUBE.

Significance and impact of study

Significant improvement in Cas12 method, coupled with simple visualization of end point makes the method and instrument deployable at the point-of-care (POC) for SARS-CoV-2 detection, without any recurrent cost for the lateral flow strips which is used in other POC methods.