bluuebunny/crossref_metadata_2025 huggingface dataset:
Synonymous mutations can alter protein dimerization through localized interface misfolding involving self-entanglements
Authors: Dang Lan Pham , Nissley Daniel Allen , Sitarik Ian , Van Quyen Vu , Jiang Yang , Li Mai Suan , O’Brien Edward P.
Published: October 2021

Synonymous mutations in messenger RNAs (mRNAs) can reduce protein-protein binding affinities by more than half despite leaving the protein’s amino acid sequence unaltered. Here, we use coarse-grain simulations of protein synthesis, ejection from the ribosome, post-translational dynamics, and dimerization to understand how synonymous mutations can influence the dimerization of the two E. coli homodimers oligoribonuclease and ribonuclease T. We synthesize each protein from its wildtype, fastest- and slowest-translating synonymous mRNAs and calculate the ensemble-average interaction energy between the resulting dimers. We find, similar to experiments with other dimers, that oligoribonuclease’s dimerization is altered by synonymous mutations. Relative to wildtype, the dimer interaction energy becomes 4% and 10% stronger, respectively, when translated from its fastest- and slowest-translating mRNAs. Ribonuclease T dimerization, however, is insensitive to synonymous mutations. The structural and kinetic origin of these changes are misfolded states containing non-covalent lasso-entanglements, many of which structurally perturb the dimer interface, whose probability of occurrence depends on translation speed. Translation of the fast- and slow-translating mRNAs of oligoribonuclease decreases the population of these misfolded states relative to wildtype. For ribonuclease T, however, these misfolded populations are insensitive to synonymous mutations. Entanglements cause altered dimerization energies for oligoribonuclease as there is a significant association (odds ratio: 50) between non-native self-entanglements and weak-binding dimer conformations. These conclusions are independent of model resolution, as entangled structures persist in long-time-scale all-atom simulations. Thus, non-native changes in entanglement is a mechanism through which oligomer structure and function can be altered.

SIGNIFICANCE STATEMENT

Synonymous mutations affect a range of post-translational protein functions, including dimerization, without altering the amino acid sequence of the encoded protein. This suggests that proteins somehow retain a “memory” of their translation-elongation kinetics long after synthesis is complete. Here, we demonstrate that synonymous mutations can change the likelihood that nascent proteins misfold into self-entangled conformations. These self-entangled structures are similar to the native state but with key conformational perturbations that disrupt the dimer interface, reducing their ability to dimerize. Rearrangement of such self-entangled states to the native state is a slow process, offering a structural explanation for how translation-elongation kinetics can influence long-time-scale protein-protein binding affinities.
Antigen experience relaxes the organisational structure of the T cell receptor repertoire
Authors: Mark Michal , Reich-Zeliger Shlomit , Greenstein Erez , Reshef Dan , Madi Asaf , Chain Benny , Friedman Nir
Published: October 2021

The creation and evolution of the T cell receptor repertoire within an individual combines stochastic and deterministic processes. We systematically examine the structure of the repertoire in different T cell subsets in young, adult and LCMV infected mice, from the perspective of variable gene usage, nucleotide sequences and amino acid motifs. Young individuals share a high level of organization, especially in the frequency distribution of variable genes and amino acid motifs. In adult mice, this structure relaxes and is replaced by idiotypic evolution of the effector and regulatory repertoire. The repertoire of CD4+ regulatory T cells was more similar to naïve cells in young mice, but became more similar to effectors with age. Finally, we observed a dramatic restructuring of the repertoire following infection with LCMV. We hypothesize that the stochastic process of recombination and thymic selection initially impose a strong structure to the repertoire, which gradually relaxes following asynchronous responses to different antigens during life.
Building control (amendment) regulations 2014: integration and compliance in large Irish construction organisations
Authors: Dennehy Gavin , Kennedy Bobby , Spillane John
Published: October 2021

Purpose

The purpose of this study is to identify the factors relating to the integration and compliance of Building Control (Amendment) Regulations 2014 (BC(A)R 2014) in large Irish construction organisations.

Design/methodology/approach

To achieve the aim, a mixed method approach is adopted, initially, providing a critique of the literature review, followed by a combination of 7 semi-structured interviews and 30 questionnaires from industry practitioners.

Findings

Findings demonstrate that BC(A)R has had a significant positive effect on the industry, eliminating previous bad practice, by increasing the accountability for professionals signing-off on new buildings, and highlights the emphasis on certification in successfully achieving practical completion on projects.

Practical implications

The findings provide further justification on the need for compliance, and integration, of BC(A)R in the Irish construction sector, offering further evidence, where needed, on the benefit of its adoption.

Originality/value

The originality and value of this research lies in the limited number of studies in the area, particularly in the context of large Irish construction projects, which this study aims to fulfil.
Objective evaluation of optical illusion skirt based on image texture features
Authors: Wei Wenda , Liu Chengxia , Wang Jianing
Published: October 2021

Purpose

Nowadays, most methods of illusion garment evaluation are based on the subjective evaluation of experienced practitioners, which consumes time and the results are too subjective to be accurate enough. It is necessary to explore a method that can quantify professional experience into objective indicators to evaluate the sensory comfort of the optical illusion skirt quickly and accurately. The purpose of this paper is to propose a method to objectively evaluate the sensory comfort of optical illusion skirt patterns by combining texture feature extraction and prediction model construction.

Design/methodology/approach

Firstly, 10 optical illusion sample skirts are produced, and 10 experimental images are collected for each sample skirt. Then a Likert five-level evaluation scale is designed to obtain the sensory comfort level of each skirt through the questionnaire survey. Synchronously, the coarseness, contrast, directionality, line-likeness, regularity and roughness of the sample image are calculated based on Tamura texture feature algorithm, and the mean, contrast and entropy are extracted of the image transformed by Gabor wavelet. Both are set as objective parameters. Two final indicators T1 and T2 are refined from the objective parameters previously obtained to construct the predictive model of the subjective comfort of the visual illusion skirt. The linear regression model and the MLP neural network model are constructed.

Findings

Results show that the accuracy of the linear regression model is 92%, and prediction accuracy of the MLP neural network model is 97.9%. It is feasible to use Tamura texture features, Gabor wavelet transform and MLP neural network methods to objectively predict the sensory comfort of visual illusion skirt images.

Originality/value

Compared with the existing uncertain and non-reproducible subjective evaluation of optical illusion clothing based on experienced experts. The main advantage of the authors' method is that this method can objectively obtain evaluation parameters, quickly and accurately obtain evaluation grades without repeated evaluation by experienced experts. It is a method of objectively quantifying the experience of experts.
Business model adaptation as a strategic response to crises: navigating the COVID-19 pandemic
Authors: Chanyasak Teerawut , Koseoglu Mehmet Ali , King Brian , Aladag Omer Faruk
Published: October 2021

Purpose

This study aims to explore how hotels adapt their business models as a strategic response to crisis situations. It sheds light on the processes and methods of business model adaptation during severe crisis situations, such as the COVID-19 outbreak.

Design/methodology/approach

A single-case study was conducted. Data were collected from the owner/manager of a boutique hotel chain in Chiang Mai, Thailand through an extensive interviewing process. The authors also examined corporate documents. The authors then re-organized the material as a coherent narrative about how the company navigated the COVID-19 crisis.

Findings

The findings show that the hotels in the study adapted their business models by cutting costs through stopping non-essential operations, increasing non-room revenues and adding new revenue channels, bringing in cash from advance bookings, securing financial support from creditors, leveraging government support and training staff for the “new normal.”

Originality/value

Few previous studies have focused on business model adaptation during the COVID-19 crisis. The investigation of this largely neglected area provides two main contributions. First, it extends the literature on crisis management in hospitality firms by examining business model adaptation patterns and processes during unprecedented crisis conditions. Second, it provides managerial insights and a business model adjustment framework to help practitioners in urban settings in their efforts toward recovery from the COVID crisis.
Perceived organizational politics, knowledge hiding and diminished promotability: how do harmony motives matter?
Authors: De Clercq Dirk , Sofyan Yunita , Shang Yufan , Espinal Romani Luis
Published: October 2021

Purpose

This study aims to investigate an underexplored behavioral factor, knowledge hiding, that connects employees’ perceptions of organizational politics (POP) with their diminished promotability, while also considering the moderating role of employees’ harmony motives in this process.

Design/methodology/approach

The research hypotheses are tested with multisource, three-round data collected among employees and their supervisors.

Findings

Employees’ beliefs about self-serving organizational decision-making increase their propensity to hide knowledge, which, in turn, diminishes their promotability. This intermediate role of knowledge hiding is more prominent when their disintegration avoidance motive is strong but less prominent when their harmony enhancement motive is strong.

Practical implications

A refusal to share knowledge with organizational colleagues, as a covert response to POP, can create a negative cycle for employees. They are frustrated with decision-making practices that are predicated on favoritism, but by choosing seemingly subtle ways to respond, they compromise their own promotion prospects. To avoid this escalation, employees should adopt an active instead of passive approach toward maintaining harmony in their work relationships.

Originality/value

This research contributes to extant research by detailing a hitherto overlooked reason that employees’ frustrations with dysfunctional politics may escalate into an enhanced probability to miss out on promotion opportunities. They respond to this situation by engaging in knowledge hiding. As an additional contribution, this study details how the likelihood of this response depends on employees’ harmony motives.
Green marketing and perceived SME profitability: the meditating effect of green purchase behaviour
Authors: Martins Albert
Published: October 2021

Purpose

The concept of green marketing has emerged as a panacea for reducing the negative impact of business activities on the environment. Many studies have investigated the impact of green marketing on green purchase behavior, sustainable competitive advantage, etc., without much being explored about how green marketing translates into firms' profitability, particularly among small and medium enterprises (SMEs) in emerging markets. This study, therefore, investigates the influence of green marketing on perceived SME profitability alongside the mediating effect of green purchase behaviour.

Design/methodology/approach

A quantitative research approach was adopted, where a cross-sectional survey design was employed to collect the data from 400 SME owners/managers in Ghana. Using Statistical Package for Social Science, the data were analysed through descriptive statistics, correlation and macro Process version 3.4.1.

Findings

The results reveal that the dimensions (environmental knowledge, environmental concern, green price, green advertising and green product) of green marketing distinctively have significant positive effect on perceived SME profitability as well as green purchase behaviour. Furthermore, green purchase behaviour significantly mediates the relationship between green marketing dimensions and perceived SME profitability such that the indirect effects are far greater than the direct effects.

Practical implications

SME managers should include the green marketing dimensions in their business plans and develop strategies to implement them in order to enhance green purchase behaviour of their products and services which will, in turn, lead to profitability.

Originality/value

In augmenting green marketing literature, this study provides an insight into how SMEs can leverage on the distinct dimensions of green marketing to influence green purchase behaviour and profitability in an emerging market context.
Covid-19 is driving fear and greed in consumer behaviour and purchase pattern
Authors: Satish Kavya , Venkatesh Abhishek , Manivannan Anand Shankar Raja
Published: October 2021

Purpose

This research aims to study the recent changes in consumer behaviour and purchase pattern during the Covid-19 pandemic. Covid-19 pandemic has forced consumers to stockpile, which has its own consequences. The article proposes the importance of “minimalism in consumption” to avoid greed in consumer behaviour.

Design/methodology/approach

The data are collected from consumers across India using an online survey during the first lockdown from March 2020 to May 2020. A simple random sampling technique is used for data collection, and the collected data are analysed using SPSS version 26.

Findings

The study states that there will be a shift in the purchase pattern of the consumers if lockdowns are imposed in the future or during any other crisis. However, at present, consumers have developed a stockpiling mentality fearing the unavailability of essentials.

Research limitations/implications

Pandemic has stimulated a drastic change in consumer behaviour, which is a situational effect. Each crisis affects consumer behaviour in a different way. In this research, we have considered only fear, greed and anxiety in the light of Covid-19. On the other hand, the research intends to draw realistic conclusions based on consumers' experiences during the lockdown.

Practical implications

The study proposes solutions that will help marketers frame exclusive strategies for a future crisis. Analysing the change in consumer behaviour and the shift in purchase patterns will emphasize the importance of market research to know consumer expectations during a crisis situation in order to cater to their new demands.

Social implications

Consumers who stockpile should realize the unavailability of goods to other consumers who are in need. They also have to understand the importance of “minimalism in consumption” during a crisis.

Originality/value

The data are collected during the most taxing crisis, the Covid-19 pandemic. Data are collected at the peak time of the first wave of Covid-19 in India, during a major shift in consumers' behaviour and purchase pattern. The article brings to the larger consciousness and also preaches a life lesson to all consumers to execute their responsibilities in consumption without over-demands and expectations.
Determining the role of service quality, trust and commitment to customer loyalty for telecom service users: a PLS-SEM approach
Authors: Kalia Prateek , Kaushal Robin , Singla Meenu , Parkash Jai
Published: October 2021

Purpose

The purpose of this paper is to determine the role of service quality (SQ), trust and commitment to customer loyalty (CL) for telecom service users. Further, the moderating role of gender, marital status and connection type within the model was tested.

Design/methodology/approach

A measurement model was created based on valid 615 responses from Indian TSUs for SQ, trust, commitment and loyalty with the help of partial least squares structural equation modeling (PLS-SEM). Multi-group analysis (MGA) was conducted to understand the moderating effect of marital status, gender and connection type within the model.

Findings

The results suggest that, out of five dimensions of SQ, only responsiveness, assurance and empathy have a significant positive relationship with both commitment and trust. Tangibility has a significant positive relationship with trust only. Both commitment and trust have a significant impact on loyalty. It was noticed that both commitment and trust act as mediators between three SQ dimensions (assurance, empathy and responsiveness) and CL. MGA revealed that empathy and responsiveness positively induce trust in telecom users who are single. Whereas, assurance increases commitment toward telecom service providers in married users. Assurance and empathy significantly contribute toward commitment and trust, respectively, in male users as compared to females. Empathy was found important for postpaid users for trust-building, whereas trust was found to be more important for prepaid users to stay loyal to the service provider.

Originality/value

This article contributes toward understanding the role of SQ, trust and commitment to CL moderated by marital status, gender and connection type in an integrated model concerning telecom service.
Populations restored using regional seed are genetically diverse and similar to natural populations in the region
Authors: Höfner Johannes , Klein‐Raufhake Theresa , Lampei Christian , Mudrak Ondrej , Bucharova Anna , Durka Walter
Published: October 2021

Ecological restoration and plant re‐introductions aim to create plant populations that are genetically similar to natural populations to preserve the regional gene pool, yet genetically diverse to allow adaptation to a changing environment. For this purpose, seeds for restoration are increasingly sourced from multiple populations in the target region. However, it has only rarely been tested whether using regional seed indeed leads to genetically diverse restored populations which are genetically similar to natural populations.

We used single nucleotide polymorphism (SNP) markers to investigate genetic diversity within and differentiation among populations of Centaurea jacea and Betonica officinalis on restored and natural meadows in the White Carpathians, Czech Republic. The restoration took place 20 years ago using regional seeds propagated from a mix of multiple regional source populations. We included original regional seeds in our analysis to compare the restored populations with their origin (only in C. jacea). Additionally, we analysed conventional seeds without certified origin because these would have constituted a common alternative for restoration seeding in the absence of regional seeds.

The differentiation between restored and natural populations (mean pairwise FST = 0.018 in Centaurea and 0.021 in Betonica) was similar to the differentiation among natural populations (FST = 0.023 and 0.021), and the restored populations were slightly more genetically diverse than the natural populations. In addition, restored populations were relatively similar to their origin, the regional seeds (FST = 0.015). In contrast, conventional seeds were strongly differentiated from all regional populations (FST = 0.100 and 0.059, in Centaurea and Betonica respectively) and harboured substantially lower genetic diversity. We also found signs of gene flow via pollen or seed dispersal from natural to restored populations but not vice versa.

Policy implications. Regionally sourced seeds can produce genetically diverse populations at natural levels of genetic differentiation.
Between Microeconomics and Geopolitics: On the Reasonable Application of Competition Law
Authors: Andriychuk Oles
Published: October 2021

For decades competition law was interpreted and applied through the prism of the economic analysis of law. This approach has advantages, enabling one to master both the methodological and normative features of the field. The use of economic rationality helps one to understand the motivation of market agents. The use of advanced mathematics allows robust modelling of the wide variety of empirical and theoretical factors. The use of efficiency and consumer welfare helps one to calibrate the goals of competition law. Such a ‘standard’ perception of the discipline, however, is in a deep crisis, and – as this article explains – chiefly for the right reasons. The conceptual divide between the representatives of Law and Economics and those adhering to a more societal account of competition law has many levels and dimensions. This article investigates the foundational aspect of the divide: the divergence in epistemic perception of legal and economic expertise.
Cronkhite–Canada syndrome: An investigation in clinical features and pathogenesis
Authors: Zhu Lan Ping , Zhong Wei Long , Wang Ze Gui , Sun Kai Di , Liu Qin Ling Fei , Zhao Jing , Zhao Jing Wen , Chen Xin , Wang Bang Mao
Published: October 2021

Objective

This study aimed to investigate the clinical features and potential pathogenesis of a rare nonhereditary polyposis syndrome, Cronkhite–Canada syndrome (CCS).

Methods

Medical records of eight patients with CCS who were admitted to our hospital from January 2005 to November 2019 were reviewed. Transcriptome profiling was performed in one patient to investigate its difference between gastric polyp tissue and normal mucosa. Differentially expressed genes (DEGs) were determined for functional analysis. The expression of inhibin beta A (INHBA) was further assessed by using immunohistochemistry.

Results

All patients presented with gastrointestinal polyposis, accompanied by diarrhea, skin hyperpigmentation, hair loss and nail dystrophy. Hyperplastic polyps were observed in seven patients, tubular adenoma in two, inflammatory polyps in one and hamartomatous polyps in one, respectively. All patients underwent comprehensive treatment and five achieved clinical remission. A total of 2107 DEGs, including 1265 upregulated and 842 downregulated, were found in the gastric polyp. Gene ontology analysis showed that upregulated genes were significantly enriched in the positive regulation of cell proliferation, epithelium development and angiogenesis. A protein–protein interaction analysis suggested that INHBA was at the center of the interaction network and might play an important role in CCS. Immunohistochemistry confirmed that INHBA expression was upregulated in CCS gastric polyps.

Conclusions

CCS is a rare disease and its diagnosis mainly depends on typical clinical manifestations, endoscopic findings and histological features. INHBA upregulation may contribute to its pathogenesis.
Endorsement of specific alcohol use disorder criterion items changes with age in individuals with persistent alcohol use disorders in 2 generations of the San Diego Prospective Study
Authors: Schuckit Marc A. , Smith Tom L.
Published: October 2021

Background

Diagnostic and Statistical Manual (DSM) alcohol use disorder (AUD) criteria are written in broad enough terms to apply to diverse populations. The current analyses evaluate whether the endorsement of criteria changes with increasing age in individuals with persistent AUDs.

Methods

Data regarding AUDs persisting across 3 timepoints between average ages of 31 and 43 were gathered about every 5 years from 318 interviews for 106 San Diego Prospective Study (SDPS) AUD male probands. Similar data regarding persistent AUDs across 2 timepoints were obtained from 136 interviews with 68 SDPS AUD offspring between average ages of 21 and 27. Changes in the endorsement of each AUD criterion were evaluated using Cochran's Q test.

Results

For AUD probands across time, significant decreases were observed in the proportions endorsing 4 criteria (tolerance, withdrawal, failure to fulfill obligations, and using alcohol in hazardous situations). Increased rates of endorsement were documented for 3 criteria (drinking alcohol in higher amounts or for longer periods of time, spending a great deal of time regarding alcohol, and continued use despite social or interpersonal problems). Significant increases in rates of endorsements for offspring were seen for spending a great deal of time regarding alcohol and giving up or reducing important activities in order to drink.

Conclusions

These data indicate that the salience of many DSM AUD criterion items changed significantly with age in both SDPS generations among individuals with persistent AUDs. The current results support the need for additional systematic research to determine whether specific criterion items might need to be weighted differently in evaluating older and younger individuals with persistent AUDs.
The association between visual display terminal use and dry eye: a review
Authors: Fjærvoll Haakon , Fjærvoll Ketil , Magno Morten , Moschowits Emily , Vehof Jelle , Dartt Darlene A. , Utheim Tor P.
Published: October 2021

Background

Dry eye disease (DED) is a multifactorial disease of the tear film and ocular surface. It causes ocular symptoms, reduced quality of life and a considerable economic burden on society. Prolonged use of visual display terminals (VDTs) has been suggested as an important risk factor for DED.

Purpose

This review aims to study the association between DED and VDT use with an emphasis on the prevalence of DED among VDT users and harmful daily duration of VDT use.

Methods

A PubMed search was conducted and yielded 57 relevant articles based on a set of inclusion and exclusion criteria. The studies were subclassified according to study design.

Results

The far majority of the studies showed an association between VDT use and DED or DED‐related signs and symptoms. The prevalence of definite or probable DED in VDT and office workers ranged from 26% to 70%, with as few as 1–2 hr of VDT exposure per day being associated with DED.

Conclusion

VDT use is strongly associated with DED. VDT‐associated DED is prevalent, but the exact prevalence needs to be further elucidated using standardized DED diagnosis criteria. Furthermore, a safe lower limit of daily VDT use has yet to be established. More research is needed on the effect of digitalization and digital transformation, which are particularly high during the time of the COVID‐19 pandemic.
Letter: association between medication use and microscopic colitis—selection of controls matters
Authors: Liu Yuanbin , Chen Mingkai
Published: October 2021

LINKED CONTENT

This article is linked to Sandler et al paper. To view this article, visit https://doi.org/10.1111/apt.16594
‘Provincialising’ the Belt and Road Initiative: Theorising with Chinese narratives of the ‘Digital Silk Road’ (数字丝绸之路)
Authors: Woon Chih Yuan
Published: October 2021

This paper reflects on how the Belt and Road Initiative (BRI) can contribute to more cosmopolitan forms of theory‐making and the diversification of knowledges. It focuses on emerging Chinese narratives of the Digital Silk Road (DSR) that cast the initiative as emblematic of an improved BRI 2.0 in the (post‐)pandemic era. With subterranean fibre‐optic cables and satellite systems constituting important components of the DSR, I argue that these Chinese discourses fundamentally expose the ‘horizontal’ bias in infrastructure debates, thereby forcing an analytical re‐orientation towards the notion's volumetric possibilities. Reconceptualising infrastructures in volumetric terms opens up opportunities for interrogating issues of representational politics, power and sovereignty that matter for the DSR and beyond. Using Chinese perspectives of the DSR for the purpose of theory‐building, however, does not equate to endorsing Sinocentrism or privileging the BRI as a totalising framework for interpreting the world. Rather, it signifies an effort to ‘provincialise’ the BRI – ensuring that different voices and subjectivities can co‐exist in the ongoing and unfinished project of rethinking/reconstructing the BRI.
Impact of Depreciation Information on Capital Budgeting among Local Governments: A Survey Experiment
Authors: Kuroki Makoto
Published: October 2021

This study investigates the impact of depreciation practices on the internal decision making of local government (LG) budget officers. Prior studies focus on depreciation practices that influence decision making and policy formulation through financial performance indicators. However, such practices are also expected to affect capital asset management. Specifically, the presence of depreciation information makes it possible for budget officers to account for the burden of current and future generations such as depreciation costs and debt interests when budgeting. Thus, this study tests the impact of depreciation information on capital budgeting by conducting a survey experiment with all 1788 LGs in Japan. A questionnaire was sent to LG budget officers with two patterns of experimental groups: decision making for capital budgeting (a) without depreciation information and (b) with depreciation information. The experimental results show that budget officers’ capital budget decisions are influenced by the presence of depreciation information. This study contributes to accounting and public sector research and practice by showing the impact of depreciation information on the decision making of LG budget officers for capital budgeting.
Moving in the right direction: elucidating the mechanisms of interaction between flecainide and the cardiac ryanodine receptor
Authors: Bannister Mark L. , MacLeod Kenneth T. , George Christopher H.
Published: October 2021

Flecainide is used to treat catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmia caused by disrupted cellular Ca2+ handling following β‐adrenergic stimulation. The clinical efficacy of flecainide in this context involves complex effects on multiple ion channels that may be influenced by the disease state. A compelling narrative has been constructed around flecainide's nonselective block of sarcoplasmic reticulum (SR) lumen‐to‐cytoplasm Ca2+ release through intracellular calcium release channels (RyR2). However, ion fluxes across the SR membrane during heart contraction are bidirectional, and here, we review experimental evidence that flecainide's principal action on RyR2 involves the partial block of ion flow in the cytoplasm‐to‐lumen direction (i.e., flecainide inhibits RyR2‐mediated SR ‘countercurrent’). Experimental approaches that could advance new knowledge on the mechanism of RyR2 block by flecainide are proposed. Some impediments to progress in this area, that must be overcome to enable the development of superior drugs to treat CPVT, are also considered.
A SPIDR homozygous nonsense pathogenic variant in isolated primary ovarian insufficiency with chromosomal instability
Authors: Heddar Abdelkader , Guichoux Nathalie , Auger Nathalie , Misrahi Micheline
Published: October 2021

Primary ovarian insufficiency (POI), affecting 1% of women under 40 years is a public health problem. Genes involved in meiosis/DNA repair were recently shown to be the leading family of associated causal genes, some of them also cause tumors/cancers. Here, using targeted next‐generation sequencing in an Indian POI patient with primary amenorrhea and streak ovaries, we identified a novel homozygous nonsense variant in exon 7 of SPIDR (KIAA0146) c.814C > T, R272*, predicted to lead a nonsense‐mediated mRNA decay. SPIDR was recently identified by in vitro assays as an auxiliary protein interacting with RAD51 and BLM, two major proteins involved in genome stability. Consistent with alteration of the RAD51 pathway, we observed a strong increase in mitomycin C‐induced DNA breaks and aberrant metaphases in the patient's cells compared to a control. However, sister chromatid exchanges were normal in contrast to the sharp increase characteristic of the BLM pathway. This is the first evidence of chromosomal instability associated with a SPIDR molecular defect, which supports the role of SPIDR in double‐stranded DNA damage repair in vivo in humans and its causal role in POI. Our study increases knowledge on the SPIDR function and has broad implications in the management of such patients.
GDF15 expression in glioma is associated with malignant progression, immune microenvironment, and serves as a prognostic factor
Authors: Guo Longbin , Chen Yulei , Hu Shushu , Gao Lianxuan , Tang Nan , Liu Rongping , Qin Yue , Ren Chen , Du Shasha
Published: October 2021

Aims

Growth differentiation factor 15 (GDF15) is involved in lots of crucial inflammatory and immune response. The clinical and immune features for GDF15 in glioma have not been specifically investigated so far.

Methods

Gene expression profiles obtained from public glioma datasets were used to explore the biological function of GDF15 and its impact on immune microenvironment. Interference with GDF15 in several glioma cell lines to verify its functions in vitro. Survival data were used for the survival analysis and establishment of a nomogram predictive model.

Results

GDF15 was up‐regulated in various malignant phenotypes of glioma. Function analysis and in vitro experiments revealed that GDF15 was associated with malignant progression and NF‐κB pathway. GDF15 was closely correlated to inflammatory response, infiltrating immune cells, and immune checkpoint molecules, especially in lower grade glioma (LGG). High expression level of GDF15 predicted poor survival in LGG, while the effect on glioblastoma (GBM) was not significant. A nomogram predictive model combining GDF15 and other prognostic factors was constructed and showed ideal predictive performance.

Conclusions

GDF15 could serve as an interesting prognostic biomarker for LGG. Regulating the expression of GDF15 may help solve the dilemma of immunotherapy in glioma.
Adverse events during sedation for oro‐dental trauma in an Israeli paediatric emergency department
Authors: Bilder Leon , Librov Simona , Gutmacher Zvi , Pasternak Idit , Shavit Itai
Published: October 2021

There is a paucity of data regarding the safety of the practice of sedation for oro‐dental trauma in paediatric emergency departments (ED). A previous study reported the safety of intramuscular ketamine administered as a single agent. In the paediatric ED of a tertiary trauma centre in Israel, one of two ketamine‐based regimens is used for sedating children with intraoral injuries according to the physician's discretion: a single dose of intramuscular ketamine or a combination of ketamine and propofol (KP) intravenously. The aim of this study was to assess the safety of KP sedation in children undergoing emergency treatment of oro‐dental injuries in this paediatric ED. The primary outcome was sedation adverse events that required intervention (SAERI): prolonged oxygen desaturation and apnoea, laryngospasm, hypotension, bradycardia, partial or complete airway obstruction, and pulmonary aspiration. During the 2 years study period, 17 children were sedated with KP, 20 with intramuscular ketamine and 29 with nitrous oxide. Patients who were treated with ketamine‐based sedation or with nitrous oxide sedation had a median (interquartile range, IQR) age of 3 (2–4) years and 7 (5–9) years, respectively. No SAERI occurred in patients who were sedated with intramuscular ketamine. One (3.4%) SAERI was reported in a patient who was sedated with N2O. Six/17 (35%) SAERI occurred in patients who were sedated with KP. These findings suggest that caution should be used when young children with oro‐dental injuries are sedated with KP in the ED.
Why does it matter to individuate the senses: A Brentanian approach
Authors: Fréchette Guillaume
Published: October 2021

How do we individuate the senses, what exactly do we do when we do so, and why does it matter? In the following article, I propose a general answer to these related questions based on Franz Brentano's views on the senses. After a short survey of various answers offered in the recent literature on the senses, I distinguish between two major ways of answering this question, causally and descriptively, arguing that only answers giving priority to description and to the classification involved in it are on the right track for a general answer to the related questions. In the second part of the article, I argue that Brentano's descriptive psychology is an attractive candidate for such an answer. His descriptive psychology provides a plausible account of the classification involved in description, in particular regarding the classification of sensory qualities. I close the article by briefly explaining how Brentano spells out the priority of descriptive answers over causal ones.
“The universal word speaks only in dialect”
Authors: Jahnel Claudia
Published: October 2021

Postcolonial theories announce an “exit”: the departure from the West as the world’s centre of gravity and from Eurocentric hegemonic claims of superiority, turning away from the universal, and placing unheard voices at the centre – those who are excluded from academic, public, and political discourse. Such stories and histories of the margins do not simply represent “other” stories from the “periphery.” Rather, the stories of the margins are constitutive for the history of Europe and the invention of European modernity. Today’s manifestations of global Christianity are no exception to these dynamics. There are various models of alternative universalisms and conceptions of unity, where the crucial questions are: who defines the unity of the churches and has the monopoly over interpretation and – related to this, but a little more radically – whether such a formulation of unity must necessarily repeat Western grammar or whether there are not entirely other grammars and epistemologies of unity. Postcolonial theories and postcolonial practices in particular offer promising perspectives in dealing with these questions.
Ecumenical Engagement for Human Rights
Authors: Prove Peter
Published: October 2021

This article was originally given as a keynote address on 15 June 2021 to the annual Karlsruhe Foyer Church and Law reception, which gathered church representatives, judges of the German Federal Constitutional Court and Federal Court of Justice, as well as representatives of the Federal Prosecutor's Office. After recounting the contributions made by the World Council of Churches (WCC) to the development of the international human rights framework and the evolution of its own approach to these issues, it highlights increasing challenges in recent years to this legal framework for the protection of human dignity. It concludes by looking toward the WCC’s 11th Assembly in Karlsruhe, Germany, in 2022 as an opportunity for churches to rise above these challenges and to become even more engaged in support of human rights and the legal framework developed for their promotion and protection.
Democracy at the EU level: Folly or necessity? More work for a directly elected European Parliament
Authors: Lord Christopher
Published: October 2021

It is often argued that the European Union needs legitimation by its Member State democracies. However, there is also a reverse dependence in which Member State democracies need some kind of European Union if they are to manage externalities between themselves in ways that are needed to deliver their most fundamental obligations to their own publics to secure rights, justice, freedom from arbitrary domination and democracy itself. I argue that reverse dependence provides an additional justification for a directly elected European Parliament: namely, as an aid to national democracies in their oversight of Union decisions. The future of Europe debates should consider a directly elected Parliament as a means of connecting national democracies to the Union and not just of building representative institutions at the European level.
From structure to molecular condensates: emerging mechanisms for Mediator function
Authors: Lambert Élie , Puwakdandawa Kavindu , Tao Yi Fei , Robert François
Published: October 2021

Mediator is a large modular protein assembly whose function as a coactivator of transcription is conserved in all eukaryotes. The Mediator complex can integrate and relay signals from gene‐specific activators bound at enhancers to activate the general transcription machinery located at promoters. It has thus been described as a bridge between these elements during initiation of transcription. Here, we review recent studies on Mediator relating to its structure, gene specificity and general requirement, roles in chromatin architecture as well as novel concepts involving phase separation and transcriptional bursting. We revisit the mechanism of action of Mediator and ultimately put forward models for its mode of action in gene activation.
Role of neurexin heparan sulfate in the molecular assembly of synapses – expanding the neurexin code?
Authors: Noborn Fredrik , Sterky Fredrik H.
Published: October 2021

Synapses are the minimal information processing units of the brain and come in many flavors across distinct circuits. The shape and properties of a synapse depend on its molecular organisation, which is thought to largely depend on interactions between cell adhesion molecules across the synaptic cleft. An established example is that of presynaptic neurexins and their interactions with structurally diverse postsynaptic ligands: the diversity of neurexin isoforms that arise from alternative promoters and alternative splicing specify synaptic properties by dictating ligand preference. The recent finding that a majority of neurexin isoforms exist as proteoglycans with a single heparan sulfate (HS) polysaccharide adds to this complexity. Sequence motifs within the HS polysaccharide may differ between neuronal cell types to contribute specificity to its interactions, thereby expanding the coding capacity of neurexin diversity. However, an expanding number of HS‐binding proteins have been found capable to recruit neurexins via the HS chain, challenging the concept of a code provided by neurexin splice isoforms. Here we discuss the possible roles of the neurexin HS in light of what is known from other HS‐protein interactions, and propose a model for how the neurexin HS polysaccharide may contribute to synaptic assembly. We also discuss how the neurexin HS may be regulated by co‐secreted carbonic anhydrase‐related and FAM19A proteins, and highlight some key issues that should be resolved to advance the field.
The isolated Erebia pandrose Apennine population is genetically unique and endangered by climate change
Authors: Sistri Ginevra , Menchetti Mattia , Santini Luca , Pasquali Lorenzo , Sapienti Sofia , Cini Alessandro , Platania Leonardo , Balletto Emilio , Barbero Francesca , Bonelli Simona , Casacci Luca Pietro , Dincă Vlad , Vila Roger , Mantoni Cristina , Fattorini Simone , Dapporto Leonardo
Published: October 2021

Climate change is causing shifts in the distribution of many species and populations inhabiting mountain tops are particularly vulnerable to these threats because they are constrained in altitudinal shifts. Apennines are a relatively narrow and low mountain chain located in Southern Europe, which hosts many isolated populations of mountain species. The butterfly Erebia pandrose was recorded for the last time in the Apennines in 1977, on the top of a single massif (Monti della Laga).

We confirmed the presence of a small, isolated population of E. pandrose in the Apennines, at a distance of more than 400 km to any other known populations. Then, we examined the cytochrome c oxidase subunit 1 mitochondrial DNA marker of this species across the Palaearctic area and estimated the potential decline over the Alps and the Apennines due to future climatic changes.

The Apennine population represents an endemic lineage characterised by eight mutations over the 658 bp analysed (1.2%). In the Alps and Apennines, this species has shifted uphill more than 3 m per year since the end of the 19th century and more than 22 m per year since 1995. Species distribution models suggested that these mountain populations will experience a generalised loss of climatic suitability, which, according to our projections, could lead to the extinction of the Apennine population in a few decades.

Erebia pandrose has the potential to become a flagship species for advertising the risk of losing unique fractions of genetic diversity for mountain species.
Butterfly colonisation of a new chalkland road cutting
Authors: Hetherington Mike , Sterling Phil , Coulthard Emma
Published: October 2021

The design of new roads has the potential to provide new habitats and increase biodiversity value. The cutting and verges of the Weymouth Relief Road, Dorset, completed in 2011, replicate low‐fertility chalk grassland in an area previously occupied by arable farmland and improved grassland.

We examine the results of post‐construction butterfly surveys carried out in 2012–2020 to test whether butterfly abundance, species richness and species diversity increased in the post‐construction period. Analysis is also undertaken of the factors affecting the colonisation of the verges by butterfly populations.

Butterfly abundance increased in the post‐construction period when assessed by two methods: mean counts per survey visit and maximum counts. Species richness also increased, but no significant trends were observed with respect to species diversity. The 30 butterfly species recorded on the verges represent 51% of Britain's resident or regularly occurring migrant species and include habitat‐restricted chalkland species.

The most significant factor affecting speed of colonisation of the cutting and verges was an index of local presence, defined as the number of 1 km squares where two or more individuals of a species had been recorded prior to road construction in a 10 km square centred on the site. The separation distance between the site and the nearest butterfly population did not significantly affect the speed of colonisation.

Our results validate the low‐fertility approach to road verge establishment and management. The experience of the Weymouth Relief Road is influencing future road verge construction and management in the United Kingdom.
A pharmacist‐physician collaborative care model in chronic kidney disease
Authors: Li Hanlin , Radhakrishnan Jai
Published: October 2021

A multidisciplinary approach, including pharmacist interventions, has improved clinical outcomes and reduced economic costs in chronic disease management. To our knowledge, this is the first study to describe the incorporation of pharmacist‐driven medication management with partnering nephrologists while capitalizing on technology to improve outcomes in a Chronic kidney disease (CKD) population. The authors created a collaborative drug therapy management agreement to enhance medication management for hypertension and diabetes mellitus. Our metrics aligned with the Healthcare Effectiveness Data and Information Set (HEDIS) measures. Most referrals to the program met the HEDIS definition of suboptimal disease control (Diabetes: 19/25 and Hypertension: 45/70). In patients with multiple pharmacy visits, achievement of diabetes targets increased from 23% to 67% and hypertension from 29% to 58%. Those who used technology tools were more likely to reach goals. The positive impact of a pharmacist‐physician collaboration and utilization of technology tools present an opportunity to improve care for CKD patients.