bluuebunny/crossref_metadata_2025 huggingface dataset:
HIV-1 Vpr combats the PU.1-driven antiviral response in primary human macrophages
Authors: Virgilio Maria C. , Ramnani Barka , Chen Thomas , Disbennett W. Miguel , Lubow Jay , Welch Joshua D. , Collins Kathleen L.
Published: March 2023

HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.
Dynamic lid domain ofChloroflexus aurantiacusMalonyl-CoA Reductase controls the reaction
Authors: Kabasakal Burak V. , Cotton Charles A. R. , Murray James W.
Published: March 2023

Malonyl-Coenzyme A Reductase (MCR) inChloroflexus aurantiacus, a characteristic enzyme of the 3-hydroxypropionate (3-HP) cycle, catalyses the reduction of malonyl-CoA to 3-HP. MCR is a bi-functional enzyme; in the first step, malonyl-CoA is reduced to the free intermediate malonate semialdehyde by the C-terminal region of MCR, and further reduced to 3-HP by the N-terminal region of MCR. Here we present the crystal structures of both N-terminal and C-terminal regions of the split MCR fromC. aurantiacus. A catalytic mechanism is suggested by ligand and substrate bound structures, and structural and kinetic studies of MCR variants. Both MCR structures reveal one catalytic, and one non-catalytic SDR (short chain dehydrogenase/reductase) domain. C-terminal MCR has a lid domain which undergoes a conformational change and controls the reaction. In the proposed mechanism of the C-terminal MCR, the conversion of malonyl-CoA to malonate semialdehyde is based on the reduction of malonyl-CoA by NADPH, followed by the decomposition of the hemithioacetal to produce malonate semialdehyde and coenzyme A. Conserved arginines, Arg734 and Arg773 are proposed to play key roles in the mechanism and conserved Ser719, and Tyr737 are other essential residues forming an oxyanion hole for the substrate intermediates.
Induction of osteogenic differentiation of MSCs by GSK3β knockdown through GSK3β siRNAs transfection
Authors: Galitsyna Elena V. , Buianova Anastasiia A. , Bukharova Tatiana B. , Krivosheeva Irina A. , Skoblov Mikhail Yu. , Goldshtein Dmitriy V.
Published: March 2023

The development of effective strategies for the treatment of bone defects is based on gene therapy methods aimed at regulating the differentiation of osteoprogenitor cells. One approach is the development of knockdown systems of inhibitory genes of osteogenic cell differentiation using siRNA molecules. In this work, we developed approaches to induce osteogenic differentiation of mesenchymal stem cells (MSCs) by knockdown ofGSK3βusing siRNAs in cultures of MSCs derived from human adipose tissue (AD-MSCs). For this purpose, we performed a comparative evaluation of the efficacy of lipoplexes and polyplexes formed with one of the 4 siRNA molecules and 5 commercial transfection agents most commonly used in laboratory practice. The most effective transfection agent appeared to be PEI, which demonstrated high cytocompatibility in free form and as part of polyplexes even when maximum concentrations were used. Using the polyplexes formed by siRNA molecule designed for the first time and PEI, we developed a highly efficientGSK3βgene knockdown system, which showed its effectiveness in cultures of AD-MSCs. As a result, we demonstrated the osteoinductive properties of GSK3β siRNA molecules in these cultures. The results obtained can be applied in the development of gene therapy strategies based on siRNA molecules in human bone tissue diseases.
The RBPome of influenza A virus mRNA reveals a role for TDP-43 in viral replication
Authors: Dupont Maud , Krischuns Tim , Giai-Gianetto Quentin , Paisant Sylvain , Bonazza Stefano , Brault Jean-Baptiste , Douché Thibaut , Perez-Perri Joel I , Hentze Matthias W , Cusack Stephen , Matondo Mariette , Isel Catherine , Courtney David G , Naffakh Nadia
Published: March 2023

Recent technical advances have significantly improved our understanding of the RNA-binding protein (RBP) repertoire present within eukaryotic cells, with a particular focus on the RBPs that interact with cellular polyadenylated mRNAs. However, recent studies utilising the same technologies have begun to tease apart the RBP interactome of viral mRNAs, notably SARS-CoV-2, revealing both similarities and differences between the RBP profiles of viral and cellular mRNAs. Herein, we comprehensively identified the RBPs that associate with the NP mRNA of an influenza A virus. Moreover, we provide evidence that the viral polymerase is essential for the recruitment of RPBs to viral mRNAs through direct polymerase-RBP interactions during transcription. We show that loss of TDP-43, which associates with the viral mRNAs, results in lower levels of viral mRNAs within infected cells, and a decreased yield of infectious viral particles. Overall, our results uncover an important role for TDP-43 in the influenza A virus replication cycle via a direct interaction with viral mRNAs, and point to a role of the viral polymerase in orchestrating the assembly of viral mRNPs.
Multimodal acoustic-electric trigeminal nerve stimulation modulates conscious perception
Authors: Wu Min , Auksztulewicz Ryszard , Riecke Lars
Published: March 2023

Multimodal stimulation has the potential to reverse pathological neural activity and alleviate symptoms in neuropsychiatric diseases. However, the reliability of this approach and the mechanisms through which it improves consciousness remain largely unknown. We investigated the effects of multimodal stimulation combining music stimulation with electrical trigeminal nerve stimulation in healthy human participants. We assessed conscious perception before and after acoustic-electric stimulation and investigated the mechanisms underlying the putative stimulation effects. Our results show that (1) acoustic-electric stimulation improves conscious tactile perception in healthy human participants without a concomitant change in auditory perception, (2) this improvement is caused by the interplay of the acoustic and electric stimulation rather than any of the unimodal stimulation alone, and (3) the effect of acoustic-electric stimulation on conscious perception correlates with inter-regional connection changes in a recurrent neural processing model. These findings provide evidence that multimodal acoustic-electric stimulation can promote conscious perception and offer insights into its underlying mechanisms.
Paying attention to natural scenes in area V1
Authors: Lazar Andreea , Klein Liane , Klon-Lipok Johanna , Bányai Mihály , Orbán Gergő , Singer Wolf
Published: March 2023

Natural scene responses in the primary visual cortex are modulated simultaneously by attention and by contextual signals about scene statistics stored across the connectivity of the visual processing hierarchy. Here, we hypothesized that attentional and contextual top-down signals interact in V1, in a manner that primarily benefits the representation of natural visual stimuli, rich in high-order statistical structure. Recording from two macaques engaged in a spatial attention task, we found that attention enhanced the decodability of stimulus identity from population responses evoked by natural scenes but, critically, not by synthetic stimuli in which higher-order statistical regularities were eliminated. Population analysis revealed that neuronal responses converged to a low dimensional subspace for natural but not for synthetic images. Critically, we determined that the attentional enhancement in stimulus decodability was captured by the dominant low dimensional subspace, suggesting an alignment between the attentional and natural stimulus variance. The alignment was pronounced for late evoked responses but not for early transient responses of V1 neurons, supporting the notion that top-down feedback was required. We argue that attention and perception share top-down pathways, which mediate hierarchical interactions optimized for natural vision.
The value of time in the invigoration of human movements when interacting with a robotic exoskeleton
Authors: Verdel Dorian , Bruneau Olivier , Sahm Guillaume , Vignais Nicolas , Berret Bastien
Published: March 2023

Time and effort are critical factors that are thought to be subjectively balanced during the planning of goal-directed actions, thereby setting the vigor of volitional movements. Theoretical models predicted that the value of time should then amount to relatively high levels of effort. However, the time-effort tradeoff has so far only been studied for a narrow range of efforts. Therefore, the extent to which humans can invest in a time-saving effort remains largely unknown. To address this issue, we used a robotic exoskeleton which significantly varied the energetic cost associated with a certain vigor during reaching movements. In this situation, minimizing the time-effort tradeoff would lead to high and low human efforts for upward and downward movements respectively. Consistent with this prediction, results showed that all participants expended substantial amounts of energy to pull on the exoskeleton during upward movements and remained essentially inactive by harnessing the work of gravity to push on the exoskeleton during downward movements, while saving time in both cases. These findings show that a common tradeoff between time and effort can determine the vigor of reaching movements for a wide range of efforts, with time cost playing a pivotal role.
Structure of Dimeric Lipoprotein Lipase Reveals a Pore for Hydrolysis of Acyl Chains
Authors: Gunn Kathryn H. , Neher Saskia B.
Published: March 2023

Lipoprotein lipase (LPL) hydrolyzes triglycerides from circulating lipoproteins, releasing free fatty acids. Active LPL is needed to prevent hypertriglyceridemia, which is a risk factor for cardiovascular disease (CVD). Using cryogenic electron microscopy (cryoEM), we determined the structure of an active LPL dimer at 3.9 Å resolution. This is the first structure of a mammalian lipase with an open, hydrophobic pore adjacent to the active site. We demonstrate that the pore can accommodate an acyl chain from a triglyceride. Previously, it was thought that an open lipase conformation was defined by a displaced lid peptide, exposing the hydrophobic pocket surrounding the active site. With these previous models after the lid opened, the substrate would enter the active site, be hydrolyzed and then released in a bidirectional manner. It was assumed that the hydrophobic pocket provided the only ligand selectivity. Based on our structure, we propose a new model for lipid hydrolysis, in which the free fatty acid product travels unidirectionally through the active site pore, entering and exiting opposite sides of the protein. By this new model, the hydrophobic pore provides additional substrate specificity and provides insight into how LPL mutations in the active site pore may negatively impact LPL activity, leading to chylomicronemia. Structural similarity of LPL to other human lipases suggests that this unidirectional mechanism could be conserved but has not been observed due to the difficulty of studying lipase structure in the presence of an activating substrate. We hypothesize that the air/water interface formed during creation of samples for cryoEM triggered interfacial activation, allowing us to capture, for the first time, a fully open state of a mammalian lipase. Our new structure also revises previous models on how LPL dimerizes, revealing an unexpected C-terminal to C-terminal interface. The elucidation of a dimeric LPL structure highlights the oligomeric diversity of LPL, as now LPL homodimer, heterodimer, and helical filament structures have been elucidated. This diversity of oligomerization may provide a form of regulation as LPL travels from secretory vesicles in the cell, to the capillary, and eventually to the liver for lipoprotein remnant uptake. We hypothesize that LPL dimerizes in this active C-terminal to C-terminal conformation when associated with mobile lipoproteins in the capillary.
RNase R Controls Membrane Fatty Acid Composition inStreptococcus pneumoniae
Authors: Filipe Alípio André , Bárria Cátia , Pobre Vânia , Matos Rita , Amblar Mónica , Maria Arraiano Cecília , Domingues Susana
Published: March 2023

Abstract

Previous studies on RNase R have highlighted significant effects of this ribonuclease in several processes ofStreptococcus pneumoniaebiology. In this work we have studied the global impact of RNase R by comparing the transcriptional landscape of a deleted RNase R mutant to that of the wild-type strain, and this led us investigate specific targets affected by RNase R. RNA-Seq showed that RNase R deletion affects transcripts from several different biological processes. Of particular interest, elimination of RNase R results in overexpression of most of the genes encoding the components of type II fatty acid biosynthesis (FAS-II) cluster. We demonstrate that RNase R governs the turnover of most of genes from this pathway, affecting the outcome of the whole FAS-II cluster, and leading to an unbalanced membrane fatty acid composition. Our results show that the membrane of the deleted strain contains a higher proportion of unsaturated and long-chained fatty acids than the wild type strain. This leads to a higher fluidity of the Δrnrmutant membrane, which is probably related with the increased sensitivity to detergent observed in this strain. We demonstrate that RNase R expression is induced in cells challenged with H2O2, which is suggestive of a role for this ribonuclease on the regulation of membrane homeostasis under oxidative stress. Reprogramming of membrane fluidity is an adaptative cell response crucial for bacterial survival in constantly changing environmental conditions. The fact that RNase R controls the expression of several essential genes to the fatty acid synthesis unveils a new important function of this enzyme.
BCG administration promotes the long-term protection afforded by a single-dose intranasal adenovirus-based SARS-CoV-2 vaccine
Authors: Perera Dilhan J. , Domenech Pilar , Babuadze George Giorgi , Naghibosadat Maedeh , Alvarez Fernando , Koger-Pease Cal , Labrie Lydia , Stuible Matthew , Durocher Yves , Piccirillo Ciriaco A. , Lametti André , Fiset Pierre Olivier , Elahi Seyyed Mehdy , Kobinger Gary P. , Gilbert Rénald , Olivier Martin , Kozak Robert , Reed Michael B. , Ndao Momar
Published: March 2023

Despite medical interventions and several approved vaccines, the COVID-19 pandemic is continuing into its third year. Recent publications have explored single-dose intranasal (i.n.) adenovirus-based vaccines as an effective strategy for curbing SARS-CoV-2 in naïve animal models. However, the effects of prior immunizations and infections have yet to be considered within these models. Here, we investigate the immunomodulatory effects ofMycobacterium bovisBCG pre-immunization on a subsequent S-protein expressing i.n. Ad vaccination, termed Ad(Spike). We found that Ad(Spike) alone conferred long-term protection from severe SARS-CoV-2 pathology within a mouse model, yet it was unable to limit initial infection 6 months post-vaccination. While i.n. Ad(Spike) retains some protective effect after 6 months, a single administration of BCG-Danish prior to Ad(Spike) vaccination potentiates its ability to control viral replication of the B.1.351 SARS-CoV-2 variant within the respiratory tract. Though BCG-Danish had no effect on the ability of Ad(Spike) to generate and maintain humoral immunity, it promoted the generation of cytotoxic and Th1 responses over suppressive FoxP3+TREGcells in the lungs of infected mice. These data demonstrate a novel vaccination strategy that may prove useful in limiting future viral pandemics by potentiating the long-term efficacy of next generation mucosal vaccines within the context of the safe and widely distributed BCG vaccine.

One sentence summary

BCG enhances anti-SARS-CoV-2 immunity and protection afforded by a novel adenovirus-vectored vaccine.
An opinion paper on requirement for a practitioner's handbook designed for business continuity and resilience in government: a South African context
Authors: Ferguson Clifford Stanley
Published: March 2023

Purpose

This paper aims to find a suitable structure for a practitioner's handbook that addresses the structural elements of the business continuity (BC) practice.

Design/methodology/approach

The case study using the mixed method, quantitative with a questionnaire and conceptual research approach was what has been chosen. The four steps to the research process are outlined: one, choosing the topic, two, collecting relevant literature, three, identifying specific variables and four, generating a structure. The design brought on by years of experience, should be put into an organised system and handbook that can be reused, without having to reinvent the wheel.

Findings

A BC handbook should be as relevant to the executives and management as to their employees. By adopting a BC practice in a government department, state-owned entity, agency or municipality. Assurance will be ascertained for reliable, improved service delivery and reputation with much less interruption. Therefore a handbook with a “cradle to the grave” BC approach should outline, with examples of standards, awareness, policy, BC programme plan, BC structures, business impact and risk analysis, strategy, budgets, scorecards, monitoring and evaluation, recovery and BC plans, together with the audit and an International Standards Organization (ISO) 22301 certification process.

Research limitations/implications

The research was limited to literature, questionnaires and identified variables pertaining to BC management (BCM) in the South African Government.

Practical implications

The implications of the case study is that out of the variables identified and the relevant literature and standards, a structure for a relevant post-COVID-19 government practitioner's handbook could be made available.

Social implications

The use of a BCM handbook for government would assist in the continuation of services through manmade and natural disasters. The service to the citizen, including but not limited to water, electricity, sanitation, medical and health services, and the food supply chain are just a few areas that can be positively impacted upon by good BCM. By implication the reliance of government structure are treated most in time of disasters as experienced through the two year period of the COVID-19 pandemic.

Originality/value

The government departments in South Africa do not have or have not implemented BCM due to the lack of clear guidelines. The COVID-19 pandemic however had accelerated the requirement for a top down BCM approach. To ensure that the scope of BCM is not limited, the possibility of having a set handbook for the government practitioner will ensure that service quality remains intact. Such a handbook related to government BCM practice is long outstanding.
A qualitative study of diversity management practices in Iran's private sector organizations
Authors: Ganji Seyedeh Fatemeh Ghasempour , Rahimnia Fariborz , Ahanchian Mohammad Reza , Syed Jawad
Published: March 2023

Purpose

This paper aims to examine diversity management (DM) practices in leading private-sector organizations in Iran.

Design/methodology/approach

The study draws on in-depth interviews with 23 human resource management (HRM) executives and supervisors in nine private sector companies in Iran, and presents the analysis conducted using MAXQDA software.

Findings

The results categorize DM practices into four subsystems of HRM, i.e. recruitment and selection, training, performance management, and reward management. These practices indicate the inclusion of diversity-sensitive criteria and consideration of equal opportunity in the HRM subsystems.

Originality/value

The findings advance a contextual understanding of DM in a developing country. Considering DM practices in HRM subsystems may provide an effective way to help managers address workforce diversity in organizations.
Re-expatriation inclinations among skilled female self-initiated repatriates in Asia's rapidly emerging markets
Authors: Ho Nga Thi Thuy , Seet Pi-Shen , Jones Janice , Hoang Hung Trong
Published: March 2023

Purpose

Integrating identity theory and role theory, this study examines the re-expatriation inclinations of highly-skilled professional female self-initiated repatriates (SIRs) in an Asian rapidly emerging market (REM) and the reasons underlying these inclinations.

Design/methodology/approach

The authors conducted a survey on a sample of highly-skilled professional female SIRs in Vietnam (N = 248). Structural equation modelling was used to evaluate the model.

Findings

The study found that female SIRs' career identity, family identity and social identity have a significant influence on their inclinations to re-expatriate. Attitude towards re-expatriation fully mediates the influence of family identity and career identity on re-expatriation inclinations.

Research limitations/implications

This research was limited to female SIRs in one REM, namely Vietnam, and may lack generalisability in countries and contexts.

Originality/value

By delineating the identity-related factors that contribute to skilled female SIRs' inclinations to re-expatriate and recognising gender as a complex, multifaceted social construct, the authors broaden the way expatriation is conceptualised and isolate factors that can inform practices for recruitment and retention of this important sub-set of international talent.
The optimal carbon emission reduction and advertising strategy with dynamic market share in the supply chain
Authors: Tan Yong , Zhou Huini , Wu Peng , Huang Liling
Published: March 2023

Purpose

As the quality of the environment decreases, enterprises and consumers' awareness of environmental protection is constantly improving. More and more enterprises begin to increase their investment in carbon emission reduction and attract environmentally friendly consumers to buy low-carbon products through advertising. The purpose of this paper is to utilize a realistic differential game model to provide dynamic carbon emission reduction strategies, advertising strategies and cooperation methods for complex supply chain members from a long-term perspective.

Design/methodology/approach

This paper uses the extend Vidale-Wolfe model (V-W model) to discuss the dynamic joint emission reduction strategy in the supply chain.

Findings

(1) When consumers' awareness of environmental protection increases, on the whole, carbon emission reduction and profit of products show an upward trend. (2) From a long-term perspective, the manufacturer's advertising subsidy to one of the retailers is the best choice. If the strength of the two retailers is unbalanced, the manufacturer will choose to cooperate with the dominant retailer. (3) Advertising, as a marketing means for retailers to promote low-carbon products, can alleviate the adverse effects of prisoner's dilemma in a semi-cooperative state, but it cannot achieve the Pareto optimization result.

Research limitations/implications

This paper focuses on the analysis of the situation that when the manufacturer is the leader and thinks that consumers are active advocates of low-carbon products.

Originality/value

The results of this paper can provide theoretical basis for the joint emission strategy of supply chain members in low-carbon environment.
Exploitative leadership and constructive voice: the role of employee adaptive personality and organizational identification
Authors: Bajaba Abdulah , Bajaba Saleh , Alsabban Abdullah
Published: March 2023

Purpose

The purpose of this paper is to examine the mediating role of organizational identification (OI) and the moderating role of adaptive personality (AP) between exploitative leadership (EL) and constructive voice (CV) relationship.

Design/methodology/approach

This study samples 154 full-time employees from Saudi Arabia and records their self-reported responses to closed-ended items in the survey. Hierarchical regression and PROCESS Macro are used for the analysis.

Findings

Utilizing social identity theory and social exchange theory, the authors demonstrate EL adversely affect CV through OI. AP also moderates EL-OI relationships. The indirect effects of EL on CV via OI are moderated by AP. In other words, adaptive employees are more likely to neutralize the adverse effects of such exploitation by adapting to the situation.

Practical implications

Human resource professionals and organizations must identify indicators of EL when evaluating job candidates. Organizations should also adopt communication systems that encourage employees to report any misconduct. Finally, organizations should speak out against exploitative leaders and educate their employees on ethics.

Originality/value

The originality is in extending the nomological network of EL to incorporate reduced employee OI and constructive deviance. It also discusses how adaptive employees mitigate exploitative behavior's negative effects.
A Behavioural Appraisal of Regulatory Financial Reforms and Implications for Corporate Management
Authors: El Hajjar Samah , Gebka Bartosz , Duxbury Darren , Su Chen
Published: March 2023

Financial markets play a vital role in shaping corporate behaviour, impacting corporate financial decisions ranging from investment and mergers/acquisitions to payout policies and management renumeration. Financial markets, however, are prone to irrational sentiments to trade, driving prices away from fundamental values, with the potential to distort corporate decisions and, hence, corporate efficiency. It is important, therefore, to examine the extent to which regulatory reforms help mitigate the influence of irrationality in financial markets. To this end, we examine the consequences of the mandatory adoption of International Financial Reporting Standards (IFRS) in Europe through the behavioural lens of investor sentiment. In country‐level analyses, we find the impact of irrational sentiment on stock markets to have significantly diminished post‐IFRS. In global pooled analyses, we compare the change in the sentiment–return relationship in countries adopting IFRS with the change in a set of non‐adopting countries to account for stock market trends: weakening of the impact of irrational sentiment on stock prices is greater in IFRS‐adopting countries. Results are robust to a battery of alternative tests and explanations. We provide strong support, therefore, for the success of IFRS in its aim of improving market efficiency, with important implications for corporate management.
Savolitinib versus crizotinib for treating MET positive non‐small cell lung cancer
Authors: Miao Kang , Zhang Xiaotong , Wang Hanping , Si Xiaoyan , Zhang Li
Published: March 2023

Background

The c‐MET protein, encoded by the mesenchymal‐epithelial transition factor (MET) gene, can regulate cell proliferation, migration and invasion. Studies have shown that it is one of the essential driver genes for non‐small cell lung cancer (NSCLC). Currently, several clinical studies have carried out objective assessments on the efficacy and safety of different types of MET tyrosine kinase inhibitors (TKIs). However, direct cross‐sectional comparisons between different agents are still not available.

Methods

Our study was a single‐center retrospective clinical study, which collected the data from MET positive NSCLC patients treated with MET TKIs at the Lung Cancer Center of Peking Union Medical College Hospital. We explored the efficacy and safety of crizotinib versus savolitinib in patients with METex14 skipping and MET amplification, separately.

Results

Patients with METex14 skipping (median PFS = 10.7 months) had a better clinical response to MET TKIs than MET amplification patients (median PFS = 4.1 months). In the METex14 skipping subgroup, savolitinib did not show better survival benefit with significance than crizotinib (p > 0.05). In the MET amplification subgroup, savolitinib (median PFS = 7.1 months) demonstrated a better progression‐free survival benefit than crizotinib (median PFS = 1.4 months), p = 0.05. The most common adverse effects of both MET TKIs were peripheral edema (41.2%), gastrointestinal reactions (23.5%), and liver injury (14.7%). The incidence rate of peripheral edema was higher in savolitinib than crizotinib.

Conclusion

In METex14 skipping NSCLC patients, the efficacy of savolitinib and crizotinib did not show significant difference. In MET amplification patients, savolitinib showed better efficacy than crizotinib.
Heterozygous OT‐I mice reveal that antigen‐specific CD8+ T cells shift from apoptotic to necrotic killers in the elderly
Authors: Zöphel Dorina , Kaschek Lea , Steiner Romy , Janku Sandra , Chang Hsin‐Fang , Lis Annette
Published: March 2023

Numerous alterations in CD8+ T cells contribute to impaired immune responses in elderly individuals. However, the discrimination between cell‐intrinsic dysfunctions and microenvironmental changes is challenging. TCR transgenic OT‐I mice are utilized to investigate CD8+ T‐cell immunity, but their immunodeficient phenotype hampers their use especially in aging. Here, we demonstrate that using a heterozygous OT‐I model minimizes the current limitations and provides a valuable tool to assess antigen‐specific T‐cell responses even at old age. We analyzed phenotypic and functional characteristics of CD8+ T cells from OT‐I+/+ and OT‐I+/− mice to prove the applicability of the heterozygous system. Our data reveal that OVA‐activated CD8+ T cells from adult OT‐I+/− mice proliferate, differentiate, and exert cytolytic activity equally to their homozygous counterparts. Moreover, common age‐related alterations in CD8+ T cells, including naive T‐cell deterioration and decreased proliferative capacity, also occur in elderly OT‐I+/− mice, indicating the wide range of applications for in vivo and in vitro aging studies. We used the OT‐I+/− model to investigate cell‐intrinsic alterations affecting the cytotoxic behavior of aged CD8+ T cells after antigen‐specific in vitro activation. Time‐resolved analysis of antigen‐directed target cell lysis confirmed previous observations that the cytotoxic capacity of CD8+ T cells increases with age. Surprisingly, detailed single cell analysis revealed that transcriptional upregulation of perforin in aged CD8+ T cells shifts the mode of target cell death from granzyme‐mediated apoptosis to rapid induction of necrosis. This unexpected capability might be beneficial or detrimental for the aging host and requires detailed evaluation.
Comparison of the effect of different glide path files on amount of apically extruded debris in curved root canals
Authors: Kurt Özge , Zengin Talip , Üstün Yakup
Published: March 2023

It is essential to create a glide path before root canal preparation with nickel–titanium rotary files to avoid file breakage and preserve the original canal structure. The aim of this study was to compare the amount of apically extruded debris after using different glide path files. A total of 96 first mandibular molars with curved mesial roots were randomly divided into six groups (n = 16) which are K‐files, Proglider, R‐Pilot, TruNatomy Glider, WaveOne Gold Glider and group without a glide path. Apically extruded debris was measured after glide path and canal preparation. The highest amount of debris was found in the control group without a glide path and using a glide path file caused less debris and significant differences were observed between R‐Pilot, TruNatomy Glider, ProGlider, WaveOne Gold Glider and K‐file groups. It may be recommended to create a glide path before root canal shaping to reduce the amount of extrusion debris from the apical. Especially in curved and narrow root canals, it is recommended to use an R‐Pilot file before root canal shaping in order to reduce the amount of apically extruded debris.
The 2022 Pakistani references from birth to 60 months for length/height, weight and body mass index
Authors: Akbar Natasha , Aslam Muhammad , Petersen Jørge Holm , Mustafa Ghulam
Published: March 2023

Aim

The present study aimed to develop age‐ and sex‐specific anthropometric reference growth curves for the Pakistani children, aged 1–60 months.

Methods

The weight and height of 60 595 children including 30 885 (50.96%) boys and 29 710 (49.04%) girls from Pakistan were collected through a cross‐sectional study. Growth reference charts about weight‐for‐age, length/height‐for‐age, and body BMI‐for‐age were constructed for boys and girls using the generalised additive model for location, scale and shape (GAMLSS) with the Box‐Cox power exponential distribution.

Results

The 3rd, 5th, 15th, 25th, 50th, 75th, 85th, 95th and 97th smoothed percentile values with L, M and S for weight, length/height, and BMI for boys and girls from aged 1 to 60 months are presented. The median percentile for all indicators increases as the age increases in both sexes. The median percentiles of the Pakistani children are lower than the WHO 2006 standards for both sexes.

Conclusion

This study provides the first references for the Pakistani children from 1 to 60 months. The reference values could be taken as a starting point for examining the secular change in the Pakistani population.
Pacific approaches to fundraising in the digital age: COVID‐19, resilience and community relational economic practices
Authors: de la Torre Parra Lorena , Movono Apisalome , Scheyvens Regina , Auckram Sophie
Published: March 2023

The aim of this paper is to discuss how community relational economic practices in virtual spaces are effective in building resilience because they are borne of and sustained by familiar traditional Fijian values of collective work and social interdependence. The researchers adopted a pandemic‐induced methodology, conducting online‐based talanoa (fluid conversations between two or more people) with a number of people leading, or involved in, these initiatives. We also engaged with online community groups behind a number of initiatives. Examples are provided of online crowdfunding, livestreaming of concerts to solicit donations, and bartering facilitated by social media sites. To conclude, we stress the enduring nature of communal bonds and traditional systems which Pacific people readily adapt and translate into different forums and forms in the face of challenges such as the restrictions and financial hardships caused by COVID‐19. The findings highlight that solesolevaki – a tradition of working together for a common cause – can also occur in the digital era: this demonstrates the deep connection of Fijian peoples and their sense of obligation to one another and to their culture, regardless of where they are in the world.
A case of accessory hepatic duct entering cystic duct successfully treated by laparoscopic cholecystectomy for cholecystolithiasis
Authors: Tomita Masahiro , Okabe Hirohisa , Masuda Toshiro , Ono Asuka , Kuroda Daisuke , Kuroki Hideyuki , Hirota Masahiko , Hibi Taizo , Baba Hideo , Sugita Hiroki
Published: March 2023

Although laparoscopic cholecystectomy is a well‐established surgical procedure, an accessory hepatic duct (AcHD) entering the cystic duct is poorly understood. A 77‐year‐old woman with symptomatic cholecystlithiasis was referred to our hospital. Abdominal ultrasonography indicated several small stones in the gall bladder. Magnetic resonance cholangiopancreatography (MRCP) did not reveal an anomalous cystic duct. Dissecting the gall bladder bed at operation, AcHD entering the cystic duct was suspected. Intraoperative cholangiography revealed that B5 branch entered the cystic duct. We ligated the AcHD, and divided it. Laparoscopic cholecystectomy was completed, and the patient was discharged without any complication. A week after the operation, MRCP showed that ventral branch of B5 was dilated. The patient showed no symptom for more than a year. The present case exhibited extremely rare AcHD entering the cystic duct, which was hardly recognized before surgery. It is possible to recognize such anomalous variants with standard laparoscopic approach based on 2018 Tokyo Guidelines and with attention to the possibilities of AcHD entering the cystic duct.
A gain‐of‐function mutation in microRNA 142 is sufficient to cause the development of T‐cell leukemia in mice
Authors: Kawano Shingo , Araki Kimi , Bai Jie , Furukawa Imari , Tateishi Keigo , Yoshinobu Kumiko , Usuki Shingo , Nimmo Rachael A. , Kaname Tadashi , Yoshihara Masaharu , Takahashi Satoru , Sashida Goro , Araki Masatake
Published: March 2023

MicroRNAs (miRNAs) play a crucial role in regulating gene expression. MicroRNA expression levels fluctuate, and point mutations and methylation occur in cancer cells; however, to date, there have been no reports of carcinogenic point mutations in miRNAs. MicroRNA 142 (miR‐142) is frequently mutated in patients with follicular lymphoma, diffuse large B‐cell lymphoma, chronic lymphocytic leukemia (CLL), and acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). To understand the role of miR‐142 mutation in blood cancers, the CRISPR‐Cas9 system was utilized to successfully generate miR‐142‐55A>G mutant knock‐in (Ki) mice, simulating the most frequent mutation in patients with miR‐142 mutated AML/MDS. Bone marrow cells from miR‐142 mutant heterozygous Ki mice were transplanted, and we found that the miR‐142 mutant/wild‐type cells were sufficient for the development of CD8+ T‐cell leukemia in mice post‐transplantation. RNA‐sequencing analysis in hematopoietic stem/progenitor cells and CD8+ T‐cells revealed that miR‐142‐Ki/+ cells had increased expression of the mTORC1 activator, a potential target of wild‐type miR‐142‐3p. Notably, the expression of genes involved in apoptosis, differentiation, and the inhibition of the Akt–mTOR pathway was suppressed in miR‐142‐55A>G heterozygous cells, indicating that these genes are repressed by the mutant miR‐142‐3p. Thus, in addition to the loss of function due to the halving of wild‐type miR‐142‐3p alleles, mutated miR‐142‐3p gained the function to suppress the expression of distinct target genes, sufficient to cause leukemogenesis in mice.
Operative management of anastomotic leak after sigmoid colectomy for left‐sided diverticular disease: Ileostomy creation may be as safe as colostomy creation
Authors: Lee Grace C. , Kanters Arielle E. , Gunter Rebecca L. , Valente Michael A. , Bhama Anuradha R. , Holubar Stefan D. , Steele Scott R.
Published: March 2023

Aim

The management of anastomotic leak after sigmoid colectomy for diverticular disease has not been well defined. Specifically, there is a lack of literature on optimal types of reoperations for leaks. The aim of this study was to describe and compare reoperative approaches and their postoperative outcomes.

Methods

We performed a retrospective cohort study using the NSQIP Colectomy Module (2012–2019) and single‐institution chart review. Patients with diverticular disease who underwent elective sigmoid colectomy were included. Primary outcomes were anastomotic leak requiring reoperation and management of anastomotic leak.

Results

Of 37,471 patients who underwent sigmoid colectomy for diverticular disease, 1003 (2.7%) suffered an anastomotic leak, of whom 583 underwent reoperation. Of the 572 patients who were not initially diverted and underwent reoperation for leak, 302 (52.8%) were managed with stoma creation – 200 (35.0%) with colostomy and 102 (17.8%) with ileostomy. The remaining 47.2% underwent colectomy with reanastomosis, suturing of large bowel, and drainage. There were no differences in length of stay, readmission, or mortality between patients who underwent ileostomy or colostomy at reoperation (p > 0.05). Single‐institution analysis demonstrated that 100% of patients with ileostomies underwent subsequent ileostomy closure, compared to 60% of patients with colostomies.

Conclusions

In patients who suffer anastomotic leaks after sigmoid colectomy for diverticular disease and undergo reoperations, ileostomy at the time of reoperation appears to be safe, with comparable results to colostomy. Ileostomies were more frequently closed than colostomies. When faced with a colorectal anastomotic leak, ileostomy creation may be considered.
Implementation of fully closed‐loop insulin delivery for inpatients with diabetes: Real‐world outcomes
Authors: Boughton Charlotte K. , Hartnell Sara , Hobday Nicola , Lake Andrea , Davenport Katy , Daly Aideen , Ward Candice , Taylor Caroline , Hovorka Roman , Bansiya Vishakha
Published: March 2023

Aims

Fully closed‐loop insulin delivery has been shown in clinical trials to be safe and improve glucose control compared with standard insulin therapy in the inpatient setting. We investigated the feasibility of implementing the approved CamAPS HX fully closed‐loop system in a hospital setting.

Methods

This implementation project was conducted in a large teaching hospital in Cambridge, UK. Healthcare professional training was multimodal including face‐to‐face workshops, online learning modules and supported by standard operating procedures. Set‐up and maintenance of closed‐loop devices were undertaken by the inpatient diabetes team. Selection of suitable patients was multidisciplinary and prioritised those with more challenging diabetes management. Demographic and clinical data were collected from electronic health records and diabetes data management platforms.

Results

In the 12 months since the closed‐loop system was implemented, 32 inpatients (mean ± SD age 61 ± 16 years, 8 females, 24 males) used closed‐loop insulin delivery during their admission, across medical and surgical wards in the hospital with a total of 555 days of closed‐loop glucose control (median [IQR]: 14 [6, 22] days per inpatient).

The time spent in target glucose range 3.9–10.0 mmol/L was 53.3 ± 18.3%. Mean glucose was 10.7 ± 1.9 mmol/L with 46.0 ± 18.2% of time spent with glucose >10.0 mmol/L. Time spent with sensor glucose below 3.9 mmol/L was low (median [IQR]: 0.38 [0.00, 0.85]). There were no episodes of severe hypoglycaemia or diabetic ketoacidosis during closed‐loop use.

Conclusions

We have demonstrated that the fully closed‐loop system can be safely and effectively implemented by a diabetes outreach team in complex medical and surgical inpatients with challenging glycaemic control.
Cranial cartilages: Players in the evolution of the cranium during evolution of the chordates in general and of the vertebrates in particular
Authors: Onai Takayuki , Aramaki Toshihiro , Takai Akira , Kakiguchi Kisa , Yonemura Shigenobu
Published: March 2023

The present contribution is chiefly a review, augmented by some new results on amphioxus and lamprey anatomy, that draws on paleontological and developmental data to suggest a scenario for cranial cartilage evolution in the phylum chordata. Consideration is given to the cartilage‐related tissues of invertebrate chordates (amphioxus and some fossil groups like vetulicolians) as well as in the two major divisions of the subphylum Vertebrata (namely, agnathans, and gnathostomes). In the invertebrate chordates, which can be considered plausible proxy ancestors of the vertebrates, only a viscerocranium is present, whereas a neurocranium is absent. For this situation, we examine how cartilage‐related tissues of this head region prefigure the cellular cartilage types in the vertebrates. We then focus on the vertebrate neurocranium, where cyclostomes evidently lack neural‐crest derived trabecular cartilage (although this point needs to be established more firmly). In the more complex gnathostome, several neural‐crest derived cartilage types are present: namely, the trabecular cartilages of the prechordal region and the parachordal cartilage the chordal region. In sum, we present an evolutionary framework for cranial cartilage evolution in chordates and suggest aspects of the subject that should profit from additional study.
MULTIMOORA‐based MCDM model for sustainable ranking of wastewater treatment technologies under picture fuzzy environment
Authors: Priyanka  , Kumar Sunil , Kalia Susheel
Published: March 2023

This study aims to provide the best vision for ranking wastewater treatment technologies using a MULTIMOORA‐based MCDM model to build a more effective technique for future generations. Nanotechnology, photocatalytic technology, automated variable filtration (AVF) technology, and membrane filtration are the technologies explored in this article. Social, monetary, and ecological elements like cost, energy utilization, water quality, capacity, environmental effect, and technical factors were considered as boundaries to extricate best from the different wastewater treatment procedures. Each technique undertook evaluation and comparison, then ranked according to the proposed MCDM model from most to least preferred. The suggested Picture fuzzy MCDM model shows that AVF (0.4081) is the most adapted technology for wastewater treatment, followed by nanotechnology (0.2657), photocatalytic technology (0.1748), and membrane filtration (−0.0962). The results of all three models (MULTIMOORA, TOPSIS, and COPRAS MCDM) showed that the AVF technology is highly effective, although other technologies are also operative.
Resilient self‐efficacy and transformative growth of poor single mothers and their children: Higher education
Authors: Geiger Brenda
Published: March 2023

Background

Poor single mothers in Israel are stigmatized in public discourse as lazy and relying on the taxpayers' money yet are seldom given the opportunity to access higher education to achieve economic independence.

Objectives

This work sought to find (a) the sources of empowerment and resilient self‐efficacy motivating poor single mothers to pursue a degree and (b) examine the transformative growth of mothers and children in the process of acquiring knowledge.

Participants and settings

Twelve poor single mothers enrolled in the Katzir antipoverty program who were about to graduate.

Methods

In‐depth private interviews and content analysis examined the similarities among these women's experiences.

Results

Motivations to pursue a bachelor's degree included mothers' desire to prove to themselves that they could complete a degree and secure a better future for their children. Although initially overwhelmed, they developed resilient self‐efficacy as they passed their exams and surmounted financial and other crises related to their children's health and lack of childcare. Relationships with their children had improved, and by sharing their progress and achievements with their children, they had become a proud team, motivating each other to achieve.

Conclusion

Given the centrality of children well‐being in mothers' motivation to study and complete a degree, children's needs for subsidized daycare and after‐school programs cannot be ignored.

Implications

Two‐generation programs that assist mothers to pursue a degree while providing daycare and after‐school programs for children must be implemented to offer fair opportunities for poor single mothers in Israel to complete a bachelor's degree.