bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of Antimicrobial Agent Cetylpyridinium Chloride Mitochondrial Toxicity in Rodent and Primary Human Cells: Super-resolution Microscopy Reveals Nanostructural Disruption
Authors: Weller Sasha R. , Burnell John E. , Aho Brandon M. , Obeng Bright , Ledue Emily L. , Shim Juyoung K. , Hess Samuel T. , Gosse Julie A.
Published: September 2022

People are exposed to high concentrations of antibacterial agent cetylpyridinium chloride (CPC) via personal care and food products, despite little information regarding CPC effects on eukaryotes. CPC is used as an antibacterial agent via a detergent mechanism when above ∼600- 900 μM. While three previous studies suggested CPC mitochondrial toxicity, this phenomenon is not well-studied. Here, we show that low-micromolar CPC inhibits mitochondrial ATP production in primary human keratinocytes, mouse NIH-3T3 fibroblasts, and rat RBL-2H3 immune mast cells, in galactose media, which causes cells to produce ATP via mitochondria. ATP inhibition via CPC (EC501.7LJµM) is nearly as potent as that caused by canonical mitotoxicant CCCP (EC501.2LJµM). CPC inhibition of oxygen consumption rate (OCR) tracks with that of ATP: OCR is halved due to 1.75 μM CPC in RBL-2H3 cells and 1.25 μM in primary human keratinocytes. Here we demonstrate that CPC is more potent as a mitotoxicant than as an immune mast cell signaling inhibitor, an effect published previously. Mitochondrial [Ca2+] changes can cause mitochondrial dysfunction. Here we show, using a novel plate reader assay with reporter CEPIA2mt, that CPC causes mitochondrial Ca2+efflux from mast cells via an ATP-inhibition mechanism. Using super-resolution microscopy (fluorescence photoactivation localization) in live cells, we have discovered that CPC causes mitochondrial nanostructural defects in fibroblasts, including the formation of spherical structures with donut-like cross section, as quantified by novel Fourier transform analysis. This work reveals CPC as a mitotoxicant despite widespread use, highlighting the importance of further research into its toxicological safety.
Twist1 and balanced retinoic acid signaling act to suppress cortical folding in mice
Authors: Ho-Nguyen Khue-Tu , Jain Manav , Matrongolo Matt J. , Ang Phillip S. , Schaper Samantha , Tischfield Max A.
Published: September 2022

Evolution of cortical folding in gyrencephalic animals enabled higher cognitive functions and complex behaviors. Gene expression patterns and signaling molecules that control cortical folding have only recently been described and thus are still not well understood. In transgenic mouse models with induced cortical folding, amplification of neuroprogenitor cells or loss of their adhesion from the apical ventricular surface leads to gyri formation, whereas decreased cell adhesion in migrating projection neurons causes abnormal neuronal clustering and development of cortical fissures that resemble sulci. We now report that loss ofTwist1expression in the primitive meninx results in cortical folding and sulci formation in the dorsolateral telencephalon. In developing sulcal regions, generation of apical and basal neuroprogenitor cells is normal. Instead, cell proliferation in the developing meninges is reduced, leading to loss of arachnoid fibroblasts that express Raldh2, an enzyme required for retinoic acid synthesis. Maternal retinoic acid supplementation rescues cortical folding and sulci formation. Our results suggest that balanced retinoic acid signaling from the meninges is required to maintain lissencephaly in mice, and in a manner independent from neuroprogenitor cell amplification.
Combinatorial control of biofilm development by quorum-sensing and nutrient-sensing regulators inPseudomonas aeruginosa
Authors: Chen Gong , Fanouraki Georgia , Rangarajan Aathmaja Anandhi , Winkelman Bradford T. , Winkelman Jared T. , Waters Christopher M. , Mukherjee Sampriti
Published: September 2022

The human pathogenPseudomonas aeruginosa, a leading cause of hospital-acquired infections, inhabits and forms sessile antibiotic-resistant communities called biofilms in a wide range of biotic and abiotic environments. In this study, we examined how two global sensory signaling pathways – the RhlR quorum-sensing system and the CbrA/CbrB nutritional adaptation system – intersect to control biofilm development. Previous work has shown that individually these two systems repress biofilm formation. Here, we used biofilm analyses, RNA-seq, and reporter assays to explore the combined effect of information flow through RhlR and CbrA on biofilm development. We find that the ΔrhlRΔcbrAdouble mutant exhibits a biofilm morphology and an associated transcriptional response distinct from wildtype and the parent ΔrhlR andΔcbrAmutants indicating codominance of each signaling pathway. The ΔrhlRΔcbrAmutant rapidly gains suppressor mutations that map to the carbon catabolite repression protein Crc. The combined absence of RhlR and CbrA leads to drastic reduction in the abundance of the Crc antagonist small RNA CrcZ. Thus, CrcZ acts as the molecular convergence point for quorum- and nutrient-sensing cues. Furthermore, in the absence of antagonism by CrcZ, Crc promotes the expression of biofilm matrix components – Pel exopolysaccharide, and CupB and CupC fimbriae. Therefore, this study uncovers a regulatory link between nutritional adaption and quorum sensing with potential implications for anti-biofilm targeting strategies.

AUTHOR SUMMARY

Bacterial pathogens often form multicellular communities encased in an extra cytoplasmic matrix called biofilms as a virulence strategy. Biofilm development is controlled by various environmental stimuli that are decoded and converted into appropriate cellular responses. How information from two or more stimuli is integrated is poorly understood. UsingPseudomonas aeruginosabiofilm formation as a model, we studied the intersection of two global sensory signaling pathways – quorum sensing and nutritional adaptation. We find parallel regulation by each pathway that converges on the abundance of a small RNA. Thus, we describe a regulatory link betweenP. aeruginosaquorum-sensing and nutritional adaptation pathways that allows integration of information from each system into the control of biofilm development. These results expand our understanding of the genetic regulatory strategies that allowP. aeruginosato successfully colonize host during chronic infections.
Common population codes produce extremely nonlinear neural manifolds
Authors: De Anandita , Chaudhuri Rishidev
Published: September 2022

Populations of neurons represent sensory, motor and cognitive variables via patterns of activity distributed across the population. The size of the population used to encode a variable is typically much greater than the dimension of the variable itself, and thus the corresponding neural population activity occupies lower-dimensional subsets of the full set of possible activity states. Given population activity data with such lower-dimensional structure, a fundamental question asks how close the low-dimensional data lies to a linear subspace. The linearity or non-linearity of the low-dimensional structure reflects important computational features of the encoding, such as robustness and generalizability. Moreover, identifying such linear structure underlies common data analysis methods such as Principal Component Analysis. Here we show that for data drawn from many common population codes the resulting point clouds and manifolds are exceedingly nonlinear, with the dimension of the best-fitting linear subspace growing at least exponentially with the true dimension of the data. Consequently, linear methods like Principal Component Analysis fail dramatically at identifying the true underlying structure, even in the limit of arbitrarily many data points and no noise.
L1 retrotransposition is regulated post-transcriptionally In High-Grade Serous Ovarian Cancer
Authors: Pradhan Barun , Zhang Kaiyang , Li Yilin , Lavikka Kari , Muranen Taru , Huhtinen Kaisa , Badge Richard , Burns Kathleen H. , Hynninen Johanna , Hietanen Sakari , Oikkonen Jaana , Hautaniemi Sampsa , Kauppi Liisa
Published: September 2022

L1 retrotransposons are the only protein-coding active transposable elements in the human genome. Although silenced during normal conditions, they are highly expressed in human epithelial cancers including high-grade serous ovarian cancer (HGSC), where they transcribe to form L1 mRNA and subsequently integrate into the genome by a process called retrotransposition. Despite of high L1 protein expression in the earliest phases of HGSC, these tumors do not accrue many somatic L1 insertions. To understand this unexplained disconnect, we monitored the transcription and retrotransposition activity of two frequently expressed retrotransposition-competent (RC)-L1 (RC-L1) in 64 clinical tumor specimens from 34 HGSC patients and found that despite the presence of RC-L1 mRNA, a third of samples did not acquire somatic L1 insertions. In addition to high inter-patient variability in retrotransposition frequency, there was remarkable intra-patient heterogeneity in L1 insertion patterns between tumor sites, indicating that L1 retrotransposition is highly dynamic in vivo. Comparison of genomic and transcriptomic features of L1-null tumors with L1-high tumors (those with ≥5 somatic L1 insertions) showed that retrotransposition was favored by increased rate of cell proliferation.
CDK4/6 inhibition and dsRNA sensor agonism co-operate to enhance anti-cancer effects through ER stress and immune modulation of tumour cells
Authors: Roulstone Victoria , Kyula Joan , Wright James , Yu Lu , Alonso Aida Barreiro , Melake Miriam , Choudhary Jyoti , Elliott Richard , Lord Christopher J. , Mansfield David , Matthews Nik , Chauhan Ritika , Jennings Victoria , Chan Charleen , Baldock Holly , Butera Francesca , Appleton Elizabeth , Nenclares Pablo , Pederson Malin , Foo Shane , Patin Emmanuel C. , Rullan Antonio , Tenev Tencho , Meier Pascal , Van Vloten Jacob , Vile Richard , Pandha Hardev , Melcher Alan , McLaughlin Martin , Harrington Kevin
Published: September 2022

Cytoplasmic pattern recognition receptors (PRRs) for double-stranded RNA (RIG-I/MDA5) are key mediators of anti-viral responses. PRR agonists, such as dsRNA oncolytic Reovirus type 3 Dearing (Rt3D), potently activate RNA sensors. We used an unbiased cytotoxicity screen to reveal synergistic drug-virotherapy combinations and found potent effects of Rt3D combined with the CDK4/6 inhibitor, palbociclib. The combination augmented oncolytic virus-induced endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and the expression and activation/signaling of RNA sensors. Combined Rt3D-palbociclib treatment potently increased interferon production and signaling, and knockdown studies implicated key UPR proteins and the RNA sensor, RIG-I, as essential to the phenotype observed. Further experiments, using canonical RIG-I agonists and an ER stress inducer, thapsigargin, confirmed cross-talk between RNA sensing and ER stress pathways that augmented cancer cell death and interferon production. Combined Rt3D-palbociclib also increased innate immune activation within tumour cells and IFN-induced HLA expression. Analysis of the immunopeptidome revealed changes to HLA-captured peptides with Rt3D-palbociclib, including altered expression of peptides from cancer/testis antigens (CTA) and endogenous retroviral elements (ERVs). Our findings highlight cross-talk between UPR signaling and RNA-mediated PRR activation as a means of enhancing anti-cancer efficacy with potential pro-immunogenic consequences. This has implications for future clinical development of PRR agonists and oncolytic viruses, and broadens the therapeutic remit of CDK4/6 inhibitors to include roles as both ER stress and dsRNA PRR sensitizers.
Permeability transition pore-related changes in the proteome and channel activity of ATP synthase dimers and monomers
Authors: Nikiforova Anna B. , Baburina Yulia L. , Borisova Marina P. , Surin Alexey K. , Kharechkina Ekaterina S. , Krestinina Olga V. , Suvorina Maria Y. , Kruglova Svetlana A. , Kruglov Alexey G.
Published: September 2022

Monomers, dimers, and individual FOF1-ATP synthase subunits are, presumably, involved in the formation of the mitochondrial permeability transition pore (PTP), which molecular structure, however, is still unknown. We hypothesized that upon the Ca2+-dependent assembly of PTP complex, F-ATP synthase (subunits) recruits mitochondrial proteins that do not interact or weakly interact with F-ATP synthase under normal conditions. Therefore, we examined whether the PTP opening in mitochondria before the separation of supercomplexes by BN-PAGE will increases the channel stability and channel-forming capacity of isolated F-ATP synthase dimers and monomers in planar lipid membranes. Besides, we studied the specific activity and protein composition of F-ATP synthase dimers and monomers from rat liver and heart mitochondria before and after PTP opening. By contrast to our expectations, preliminary PTP opening dramatically suppressed the high-conductance channel activity of F-ATP synthase dimers and monomers and decreased their specific “in gel” activity. The decline in the channel-forming activity correlated with the reduced levels of as few as two proteins in the bands: methylmalonate-semialdehyde dehydrogenase and prohibitin 2. These data indicate that proteins accompanying F-ATP synthase may be important players in the PTP formation and stabilization.
A full computational model of cell motility: Early spreading, cell migration and competing taxis
Authors: Betorz Joel , Bokil Gaurav R. , Deshpande Shreyas M. , Kulkarnic Shardool , Rolando Daniel , Venturini Chiara , Saez Pablo
Published: September 2022

Cell motility represents one of the most fundamental function in mechanobiology. Cell motility is directly implicated in development, cancer or tissue regeneration, but it also plays a key role in the future of tissue and biomedical engineering. Here, we derived a computational model of cell motility that incorporates the most important mechanisms toward cell motility: cell protrusion, polarization and retrograde flow. We first validate our model to explain two important types of cell migration, i.e. confined and ameboid cell migration, as well as all phases of the latter cell migration type, i.e. symmetric cell spreading, cell polarization and latter migration. Then, we use our model to investigate durotaxis and chemotaxis. The model predicts that chemotaxis alone induces larger migration velocities than durotaxis and that durotaxis is activated in soft matrices but not in stiff ones. More importantly, we analyze the competition between chemical and mechanical signals. We show that chemotaxis rules over durotaxis in most situations although durotaxis diminishes chemotaxis. Moreover, we show that inhibiting the effect of GTPases in actin polymerization at the cell front may allow durotaxis to take control over chemotaxis in soft substrates. Understanding how the main forces in cell motility cooperate, and how a precise manipulation of external cues may control directed cell migration is not only key for a fundamental comprehension of cell biology but also to engineer better biomimetic tissues. To this end, we provide a freely-available platform to predict all phases and modes of cell motility analyzed in this work.
Chemotaxonomy ofTapinomaand some Dolichoderinae ants from Europe and North Africa
Authors: Lenoir Alain , Perdereau Elfie , Berville Laurence
Published: September 2022

Cuticular hydrocarbons of some Dolichoderinae species from France and various places like Spain, North Africa, and Italy were studied. TheTapinoma nigerrimumgroup was particularly analyzed and replaced in the genusTapinoma. All species were correctly discriminated and a new hydrocarbons profile was found in Spanish mountains in theT. nigerrimumgroup, which was provisionally namedT. sp. Spain. We added numerous unknown spots for the distribution of these ants. We also tested aggression between someT. magnumcolonies and it appeared that this species forms supercolonies like other invasive species, but does not form giant supercolonies like the Argentine ant
Comparative Study of State-Dependent Cholesterol Binding Sites in Adenosine A2A and A1 Receptors Using Coarse-Grained Molecular Dynamics Simulations in Biologically Relevant Membranes
Authors: Tzortzini Efpraxia , Corey Robin A. , Kolocouris Antonios
Published: September 2022

In this study we used coarse-grained molecular dynamics (CG MD) simulations to study protein-cholesterol interactions for different activation states of the A2A adenosine receptor (A2AR) and A1 adenosine receptor (A1R). Three different membranes were used, of which a plasma mimetic membrane best matched cholesterol binding sites previously detected in X-ray structures and computationally for the inactive state of A2AR. Here, cholesterol binds stably between TM5 and TM6 in the intracellular leaf and between the extracellular part of TM6 and TM7. The stability of the identified binding sites to A1R with CG MD simulations were further investigated using potential of mean force calculations combined with umbrella sampling.

Cholesterol binding to certain cavities in active or inactive state can stabilize a conformation of active or inactive state respectively and is important to identify these cavities. For the active state the cholesterol binding sites have much longer residence times compared to the inactive state for both A2AR and A1R.

We observed for the active A1R two cholesterol binding sites in the extracellular membrane leaf in a cavity between TM2/TM3 and along TM3 in the intracellular leaf. We found a partially overlapped binding area between TM6 and TM7 in the extracellular membrane leaf for active state and inactive A1R state which can be antagonized by cholesterol molecules although the site has a much longer residence time for active A1R. For the active A2AR we predicted a high residence time cholesterol position between TM1 and TM7 in the middle region of TMD which is different from the binding sites calculated in active or inactive A1R and for the inactive A2AR. For the inactive A2AR cholesterol binds to the same extracellular area between TM6 and TM7 as in the inactive A1R.

The differences in stable, long residence time cholesterol binding sites between active and inactive states of A1R and for A2AR can be important for functional activity and orthosteric agonist or antagonist affinity and can be used for the design of allosteric modulators which can bind through lipid pathways.
A robust numerical method for drawing the fluid flux-barrier geometry in the inner and outer rotor radial flux synchronous reluctance machines based on the finite difference method
Authors: Jamali Fard Ali , Mirsalim Mojtaba
Published: September 2022

Purpose

Rotor shape optimization is crucial in designing synchronous reluctance machines (SynRMs) because the machine performance is directly proportional to the rotor’s magnetic saliency ratio. The rotor geometry in synchronous reluctance machines is complex, and many geometrical parameters must be optimized. When fluid flux-barrier geometry is desirable, using analytic equations to prepare the rotor geometry for finite element analysis could be tedious. This paper aims to provide a robust numerical procedure to draw the fluid flux-barrier geometry in transversally laminated radial flux inner and outer rotor SynRMs by directly solving the magnetic vector potential equation using the finite difference method..

Design/methodology/approach

In this paper, the goal is to have a robust procedure for drawing the rotor geometry for an arbitrary number of slots (Ns), poles (p) and flux-barrier layers (Nfb). Therefore, this paper targeted several combinations to investigate the performance of the proposed algorithm. The MATLAB software is used to implement the proposed algorithm. The ANSYS Maxwell software is used for counterpart finite element simulation to check the correctness of the results derived by the proposed method.

Findings

Several inner and outer rotor SynRMs considering a different number of poles and a different number of flux-barrier layers per pole are studied to investigate the performance of the proposed algorithm. Results corresponding to each case are presented, and it is shown that the method is robust, flexible and fast enough, which could be used for the generation of the rotor geometry for the finite element analysis effectively.

Originality/value

The value of the proposed algorithm is its simplicity and straightforwardness in its implementation for the preparation of the rotor geometry with the desired fluid flux-barrier layer curvature resolution suitable for the finite element analysis. The procedure presented in this paper is based on the ideal magnetic loading concept, and in future works, a similar idea could be used for linear and axial flux SynRMs.
Monetary penalties for refusal of mandatory Covid-19 vaccination: state’s right to regulate vs people’s rights and freedom in health care
Authors: Sefriani Sefriani , Mahardhika Nur Gemilang
Published: September 2022

Purpose

The Covid-19 pandemic has persisted for almost three years. States have since then enforced laws, policies and measures believed to be the most effective to handle the global pandemic. Along this line, the Indonesian Government opted to implement mandatory vaccination and refusal of which entails monetary penalties. Hence, this study aims to analyze two legal issues that touch upon the realm of International Human Rights Law: first, whether state has the authority to implement the said mandatory vaccine program to those who refuse to be vaccinated, and second, how is the more appropriate legal policy to obligate vaccination but without coercive sanction.

Design/methodology/approach

This is a normative legal research that uses a qualitative method with case studies, conceptual, historical and comparative approaches. A descriptive-analytical deduction process was used in analyzing the issue.

Findings

The results present, as part of state’s right to regulate, it has the authority to enact mandatory vaccination with monetary penalties to fulfil its obligation to protect public health in times of emergency; this is legal and constitutional but only if it satisfies the requirements under the International Human Rights Law: public health necessity, reasonableness, proportionality and harm avoidance. Alternatively, herd immunity is achievable without deploying unnecessary coercive sanctions, such as improving public channels of communication and information, adopting legal policies that incentivize people’s compliance like exclusion from public services, subsidies revocation, employment restrictions, higher health insurance premiums, etc.

Research limitations/implications

This study analyzes in depth the following issues: of whether the government has the authority to apply mandatory vaccination laws enforced through monetary penalties for those who refused to be vaccinated and how does the government implement the appropriate legal policy to enforce mandatory vaccination without imposing penalties for non-compliance while maintaining a balance between the interests of protecting public health and the human rights of individuals to choose medical treatment for themselves, including whether they are willing to be vaccinated. Hence, the political affairs, economic matters and other non-legal related issues are excluded from this study.

Originality/value

This paper hence offers a suggestive insight for state in formulating a policy relating to the mandatory vaccination program. Although the monetary penalties do not directly violate the rule of law, a more non-coercive approach to the society would be more favorable.
Risk reporting and earnings smoothing: signaling or managerial opportunism?
Authors: Monjed Hend , Ibrahim Salma , Jørgensen Bjørn N.
Published: September 2022

Purpose

The purpose of this study is to examine the association between two reporting mechanisms used by managers to communicate risk information to the capital market: risk disclosure and earnings smoothing.

Design/methodology/approach

This study juxtaposes two competing hypotheses, the “opportunistic” and the “signaling”, and empirically investigates whether one dominates the other for a sample of large UK firms for the period 2005–2015. This study also uses the global financial crisis as an arguably exogenous shock on overall risk in the economy to investigate its effect on managers' joint use of textual risk disclosures and earnings smoothing.

Findings

This study finds that risk disclosure and earnings smoothing are negatively associated. This finding supports that managers with incentives to mask the firm’s true underlying risk through smoothing earnings provide lower levels of risk-related disclosures. This study documents that the trade-off between risk disclosure and earnings smoothing is more pronounced during the global financial crisis period than before and after the crisis period. Further, this study demonstrates a more negative association for firms with higher volatility of cash flows. This negative association is robust to various model specifications, additional corporate governance related controls and an alternative measure of earnings smoothing.

Originality/value

The findings provide new empirical evidence about the association between risk disclosure and earnings smoothing and support the opportunistic hypothesis, especially when firms are faced with increased risk.
Sporadic, non‐functional, gastrin‐producing duodenal neuroendocrine tumors: A retrospective study of an infrequent disease
Authors: de Jorge Huerta Lucía , Solares Fernández Isabel , Sánchez‐Moreno Beatriz , Males Maldonado David , de Ibarrola Andrés Carolina , Díaz‐Simón Raquel
Published: September 2022

Objectives

Non‐functioning gastrin‐producing neuroendocrine neoplasms (NEN) of the duodenum are rare gastrointestinal tumors without a clinical syndrome due to gastrin production. Their incidence has significantly increased as an incidental finding during endoscopic studies. The aim of this study was to describe the characteristics and prognostic factors of this emergent and infrequent neoplasm.

Methods

We performed a retrospective observational study based on the duodenal NENs samples with positive staining for gastrin at the Department of Pathology, University Hospital 12‐de‐Octubre (Madrid, Spain) between 2000 and 2017. Patients with clinically functional tumors ([Zollinger–Ellison syndrome] or gastrin >1000 pg/mL), with previously diagnosed multiple endocrine neoplasia (MEN) syndrome or synchronous neoplasia were excluded. Clinicopathological and therapeutic variables, follow‐up, recurrence, and mortality data were collected.

Results

In all, 21 patients were included. Most of the tumors were diagnosed incidentally as a single small polypoid lesion limited to mucosa/submucosa and with a low histological grade. Four (19.0%) patients presented with metastatic involvement at diagnosis (lymphatic and/or hepatic). These four patients also had a high or intermediate mitotic grade and infiltration further than submucosa. Local resection was applied in most cases as curative treatment. There were two cases of tumor recurrence and two tumor‐related deaths with a 5‐year disease‐free survival of 81.0%.

Conclusions

The majority of these tumors were diagnosed at a localized stage and had a good prognosis with treatment. Nevertheless, given the potential metastatic risk, a close follow‐up is necessary, especially in those with aggressive pathological factors such as deep infiltration or high histological grade.
A network theoretic method for the basic reproductive number for infectious diseases
Authors: Sisk Anna , Fefferman Nina
Published: September 2022

When an outbreak of an infectious disease occurs, whether it is COVID‐19 in humans, pine wilt in trees or canine distemper in dogs, quick and decisive actions need to be taken to contain it. One tool that can help both the scientific and applied management communities understand the infection risk during an outbreak is the basic reproductive number, .

In this paper, we use a network method to calculate and analyse the basic reproductive number, specifically flow network theory. We convert traditional compartmental models to flow networks and then apply the fundamental Max‐Flow Min‐Cut Theorem to calculate the basic reproductive number.

We show that this method is equivalent to the traditional next generation matrix method for the calculation of , and thus a valid alternative. Then we provide step‐by‐step instructions and illustrate how to apply this method to epidemic models.

The current methods available for calculating are complicated, requiring mathematical training. This can act as a barrier to understanding and cause delays in a real‐time response. Our new approach drastically reduces the mathematical complexity of the calculation and is far more accessible to the broader scientific community. It also allows for novel insights and can be applied to models/situations where traditional methods fail.
Letter: should we have to include baclofen in the GORD therapy armamentarium?
Authors: Ribolsi Mentore , Savarino Edoardo
Published: September 2022

LINKED CONTENT

This article is linked to Pauwels et al papers. To view these articles, visit https://doi.org/10.1111/apt.17068 and https://doi.org/10.1111/apt.17214
Letter: a hidden cause of chronic abdominal pain—opioid‐induced adrenal insufficiency. Authors' reply
Authors: Coffin Benoit , Duboc Henri
Published: September 2022

LINKED CONTENT

This article is linked to Choe et al papers. To view these articles, visit https://doi.org/10.1111/apt.17064 and https://doi.org/10.1111/apt.17172
Editorial: natural history of irritable bowel syndrome in inflammatory bowel disease—authors' reply
Authors: Fairbrass Keeley M. , Hamlin P. John , Gracie David J. , Ford Alexander C.
Published: September 2022

LINKED CONTENT

This article is linked to Fairbrass et al papers. To view these articles, visit https://doi.org/10.1111/apt.17193 and https://doi.org/10.1111/apt.17211
Editorial: wireless pH‐monitoring ‐ is it time to put away the pH‐impredance catheters: Authors' response
Authors: Yadlapati Rena , Gawron Andrew J. , Pandolfino John E.
Published: September 2022

LINKED CONTENT

This article is linked to Yadlapati et al papers. To view these articles, visit https://doi.org/10.1111/apt.17180 and https://doi.org/10.1111/apt.17204
Prevalence and clinical characteristics of patients with metabolic dysfunction‐associated fatty liver disease with hepatitis C virus infection—a population‐based study
Authors: Attia Dina , Abdel Alem Shereen , El‐Akel Wafaa , Abdel‐Razek Wael , Eslam Mohamed , Fouad Yasser , Waked Imam
Published: September 2022

Background

Metabolic‐associated fatty liver disease (MAFLD) was proposed in 2020 to identify fatty liver disease associated with metabolic risks. Metabolic abnormalities with hepatitis C virus (HCV) and MAFLD frequently co‐exist. However, data on the co‐existence are still lacking.

Aim

To explore the prevalence and characteristics of metabolic profiles among a large cohort of patients with HCV infection between 2007 and 2020 based on new diagnostic criteria

Methods

We recruited 288,222 patients with chronic HCV infection with demographic data, laboratory parameters, and ultrasound from a web‐based registry of the National Committee for Control of Viral Hepatitis in Egypt from 2007 to 2020.

Results

Among the participants, 41.9% (95% CI: 41.69–42.05) met diagnostic criteria for MAFLD, with a significant increase in the period 2014–2020 compared to 2007–2013 (43.3% vs. 19%, respectively). Participants with MAFLD had a high prevalence of obesity, diabetes mellitus and hypertension. The prevalences increased significantly over time (obesity: 66.7% vs. 76.9%, p < 0.01; diabetes mellitus: 14.6% vs. 31.5%, p < 0.01; hypertension: 0.9% vs. 7.6%, p < 0.01; prediabetes: 28.8% vs. 25.9%, p < 0.01) for the periods 2007–2013 and 2014–2020, respectively. The percentage of advanced fibrosis by fibrosis‐4 index (FIB‐4) and NAFLD fibrosis score (NFS) was significantly higher in participants with MAFLD during 2014–2020 than during 2007–2013 (FIB‐4; 18.4% vs. 8% and NFS; 17.1% vs. 7%).

Conclusion

MAFLD is highly prevalent in patients with HCV infection and has risen over time. This rising prevalence parallels the alarming rise in obesity, diabetes mellitus and hypertension. Early detection of metabolic dysfunction in patients with HCV infection is recommended to prevent MAFLD progression.
Proper use of appendiceal stump closure methods for surgical site infection in laparoscopic appendectomy
Authors: Fukuhara Sotaro , Yano Takuya , Yoshimitsu Masanori , Oshita Ko , Katsura Yuki , Ishida Michihiro , Satoh Daisuke , Choda Yasuhiro , Nakano Kanyu , Shirakawa Yasuhiro , Matsukawa Hiroyoshi , Idani Hitoshi , Shiozaki Shigehiro , Okajima Masazumi
Published: September 2022

Introduction

Although some studies have reported on the relationship between appendiceal stump closure methods and postoperative complications, there is no fixed method for this procedure. This study aimed to compare treatment outcomes of the existing procedures.

Methods

We retrospectively analyzed the records of 200 patients who underwent urgent laparoscopic surgeries and investigated whether the difference in the appendiceal stump closure method was a risk factor for surgical site infection. The patients were divided into the Endoloop and endostapler groups, and 45 propensity score‐matched patients were included. The treatment outcomes of the two groups were compared.

Results

The patients with high body temperature showed significantly developed surgical site infection in multivariate analysis (P = .036). There was no significant difference in the appendix stump methods (Endoloop vs endostapler). Regarding postoperative complications, superficial and deep incisional surgical site infection, organ/space surgical site infection, ileus, and complications of Clavien–Dindo grade IIIa or higher; there was no significant difference between the endoloop and endostapler groups after propensity score matching (P = .725, 1.000, .645 and .557, respectively).

Conclusion

By properly using the Endoloop and endostapler according to the severity of inflammation, the Endoloop can be safely performed in many cases. Inexpensive Endoloop as an option for stump closure methods should positively impact medical costs.
CXC chemokine ligand‐10 promotes the accumulation of monocyte‐like myeloid‐derived suppressor cells by activating p38 MAPK signaling under tumor conditions
Authors: Sun Yingying , Mo Yan , Jiang Shu , Shang Chao , Feng Yunpeng , Zeng Xianlu
Published: September 2022

CXC chemokine ligand‐10 (CXCL10) is a small (10 kDa) secretory protein in the CXC subfamily of cytokines. CXCL10 has been reported to play an important role in antitumor immunity as a chemotactic factor. Tumor development is always accompanied by the formation of an immunosuppressive tumor microenvironment, and the role of CXCL10 in tumor immunosuppression remains unclear. Here, we reported that CXCL10 expression was significantly upregulated in mice with melanoma, and tumor cells secreted large amounts of CXCL10. Myeloid‐derived suppressor cells (MDSCs) are an important part of the immunosuppressive tumor microenvironment. Our results showed that CXCL10 promoted the proliferation of monocyte‐like (mo)‐MDSCs by activating the p38 MAPK signaling pathway through CXCR3, which led to the abnormal accumulation of mo‐MDSCs under tumor conditions. This finding provides a new understanding of the mechanism by which a tumor‐induced immunosuppressive microenvironment forms and suggests that CXCL10 could be a potential intervention target for slowing tumor progression.
Epigenomic dynamics of early Xenopus Embryos
Authors: Zhou Jeff Jiajing , Cho Ken W. Y.
Published: September 2022

How the embryonic genome regulates accessibility to transcription factors is one of the major questions in understanding the spatial and temporal dynamics of gene expression during embryogenesis. Epigenomic analyses of embryonic chromatin provide molecular insights into cell‐specific gene activities and genomic architectures. In recent years, significant advances have been made to elucidate the dynamic changes behind the activation of the zygotic genome in various model organisms. Here we provide an overview of the recent epigenomic studies pertaining to early Xenopus development.
Reduction in grey matter atrophy in patients with relapsing multiple sclerosis following treatment with cladribine tablets
Authors: Cortese Rosa , Battaglini Marco , Sormani Maria Pia , Luchetti Ludovico , Gentile Giordano , Inderyas Maira , Alexandri Nektaria , De Stefano Nicola
Published: September 2022

Background and purpose

Measures of atrophy in the whole brain can be used to reliably assess treatment effect in clinical trials of patients with multiple sclerosis (MS). Trials assessing the effect of treatment on grey matter (GM) and white matter (WM) atrophy are very informative, but hindered by technical limitations. This study aimed to measure GM and WM volume changes, using a robust longitudinal method, in patients with relapsing MS randomized to cladribine tablets 3.5 mg/kg or placebo in the CLARITY study.

Methods

We analysed T1‐weighted magnetic resonance sequences using SIENA‐XL, from 0 to 6 months (cladribine, n = 267; placebo, n = 265) and 6 to 24 months (cladribine, n = 184; placebo, n = 186). Mean percentage GM and WM volume changes (PGMVC and PWMVC) were compared using a mixed‐effect model.

Results

More GM and WM volume loss was found in patients taking cladribine versus those taking placebo in the first 6 months of treatment (PGMVC: cladribine: −0.53 vs. placebo: −0.25 [p = 0.045]; PWMVC: cladribine: −0.49 vs. placebo: −0.34 [p = 0.137]), probably due to pseudoatrophy. However, over the period 6 to 24 months, GM volume loss was significantly lower in patients on cladribine than in those on placebo (PGMVC: cladribine: −0.90 vs. placebo: −1.27 [p = 0.026]). In this period, volume changes in WM were similar in the two treatment arms (p = 0.52).

Conclusions

After a short period of pseudoatrophy, treatment with cladribine 3.5 mg/kg significantly reduced GM atrophy in comparison with placebo. This supports the relevance of GM damage in MS and may have important implications for physical and cognitive disability progression.
Surveillance of rhinovirus diversity among a university community identifies multiple types from all three species including an unassigned rhinovirus A genotype
Authors: Faleye Temitope O. C. , Elyaderani Amir , Skidmore Peter , Adhikari Sangeet , Smith Abriana , Kaiser Nicole , Sandrolini Helen , Finnerty Sarah , Halden Rolf U. , Varsani Arvind , Scotch Matthew
Published: September 2022

We determine the presence and diversity of rhinoviruses in nasopharyngeal swab samples from 248 individuals who presented with influenza‐like illness (ILI) at a university clinic in the Southwest United States between October 1, 2020 and March 31, 2021. We identify at least 13 rhinovirus genotypes (A11, A22, A23, A25, A67, A101, B6, B79, C1, C17, C36, and C56, as well a new genotype [AZ88**]) and 16 variants that contributed to the burden of ILI in the community. We also describe the complete capsid protein gene of a member (AZ88**) of an unassigned rhinovirus A genotype.
Rapid microwave sintering of centimetric zirconia: Scalability and electromagnetic‐thermal‐fluid‐dynamic simulation
Authors: Manière Charles , Harnois Christelle , Riquet Guillaume , Grippi Thomas , Behar‐Lafenetre Stéphanie , Marinel Sylvain
Published: September 2022

Microwave sintering is a method presenting the following advantages for flash sintering: contactless/volumetric heating, and the possibility to control the heating cycle of the microwave power. In this study, the transition from a typical 100 K/min to an ultra‐rapid heating rate of 500 K/min is studied. The heating homogeneity of the typical hybrid configuration using silicon carbide susceptors is tested up to the stability limit of the system. We show that zirconia specimens as thick as 10 mm can be heated and sintered up to 500 K/min heating rate at which thermal cracks appear. However, the centimetric size of the specimens seems to favor coarsening implying an important remaining porosity in the end. A comprehensive simulation including microwave heating and convection has allowed the determination of the heating regime transition during the flash process and the quantification of each specimen's cooling fluxes.
The elusive relation between pension discount rates and deficits
Authors: Armitage Seth , Gallagher Ronan , Xu Jiaman
Published: September 2022

The relation between defined‐benefit (DB) pension discount rates and funding status is more complex than it might first appear. Existing evidence suffers from estimation biases that make precise inference unreliable. We document the biases and quantify their impact on inference in relation to corporate window‐dressing of DB funding status. Our empirical evidence from the United Kingdom suggests that pension sponsors use discretion in the choice of pension discount rate not only to reduce reported deficits but also to reduce reported surpluses.
Feasibility of implementing a telephone‐based frailty assessment
Authors: Sison Stephanie Denise M. , Newmeyer Natalie , Arias Karla Tejada , Schoenburg Racheli , Fonseca Valencia Carolina , Cheslock Megan , Raman Vaishnavi , Driver Jane A. , Kim Dae Hyun
Published: September 2022

Background

Despite the growing literature on the importance of identifying and managing frailty, its assessment has been limited in clinical settings. With the goal of integrating frailty assessment into routine clinical practice, this quality improvement project aimed to determine the feasibility, acceptability, and utility of administering a telephone‐based frailty assessment.

Methods

Between 9/2020 and 6/2021, we identified 169 established patients with serious illnesses in an academic primary care‐geriatric clinic. Patients were contacted via telephone, and their current medical, functional, nutritional, cognitive, and mood statuses were assessed using validated screening tools. A deficit‐accumulation frailty score was then calculated using an electronic medical record‐based frailty index calculator and standardized documentation with recommendations was generated for providers. The primary outcome was feasibility, measured as the proportion of patients successfully assessed. Secondary outcomes included completion rates of each domain, administration time, providers' perception, and clinical utility of the assessment.

Results

A total of 139 (82.2%) patients, mean age of 82 years, 63.3% frail were successfully assessed. Of the 139 assessments, medical and functional domains were completed for all, while nutrition, mood, and cognition were completed by 88.5% (n = 123), 68.3% (n = 95), and 59.7% (n = 83) of the time, respectively. Conducting the full assessment took an average (standard deviation) time of 26.1 (7.3) minutes. Without the cognitive and mood domain, assessment took an average of 15.7 (7.5) minutes. Patients' providers found the information from the assessment helpful in evaluating and managing their patients. Care plans of 51.8% and 65.0% of patients who had mobility and mind issues, respectively, addressed these domains within 30 days after the assessment.

Conclusion

Implementation of the telephone‐based frailty assessment is feasible, acceptable, and has the potential to influence the care plans of older adults. This work demonstrated how frailty assessment can be integrated with the outpatient setting.
ARK2 stabilizes the plus‐end of microtubules and promotes microtubule bundling in Arabidopsis
Authors: Lan Miao , Liu Xianan , Kang Erfang , Fu Ying , Zhu Lei
Published: September 2022

Microtubule dynamics and organization are important for plant cell morphogenesis and development. The microtubule‐based motor protein kinesins are mainly responsible for the transport of some organelles and vesicles, although several have also been shown to regulate microtubule organization. The ARMADILLO REPEAT KINESIN (ARK) family is a plant‐specific motor protein subfamily that consists of three members (ARK1, ARK2, and ARK3) in Arabidopsis thaliana. ARK2 has been shown to participate in root epidermal cell morphogenesis. However, whether and how ARK2 associates with microtubules needs further elucidation. Here, we demonstrated that ARK2 co‐localizes with microtubules and facilitates microtubule bundling in vitro and in vivo. Pharmacological assays and microtubule dynamics analyses indicated that ARK2 stabilizes cortical microtubules. Live‐cell imaging revealed that ARK2 moves along cortical microtubules in a processive mode and localizes both at the plus‐end and the sidewall of microtubules. ARK2 therefore tracks and stabilizes the growing plus‐ends of microtubules, which facilitates the formation of parallel microtubule bundles.
DSFit: a feasibility pilot study of a group exercise programme for adolescents with Down syndrome
Authors: Hojlo M. A. , Milliken A. L. , Baumer N. T. , Davidson E. J.
Published: September 2022

Background

While past research has underscored the benefits of physical activity for people with Down syndrome (DS), exercise programming that is customised to and/or accessible for children and adolescents with DS is limited. The objectives of this pilot were to (1) develop and refine an engaging exercise programme for adolescents with DS, called DSFit; (2) assess feasibility over the course of two pilot iterations; and (3) examine participant and parent feedback regarding exercise priorities and the DSFit exercise programme.

Method

Participants were 12 unique adolescents (ages 11–17 years) with DS. Both pilot iterations of the programme consisted of weekly group exercise sessions and home exercises to complete between sessions. Physical fitness and mood/behaviour were assessed at baseline and at the end of the intervention. Parent and child goal‐setting and feedback surveys were collected before and immediately after the intervention, and a 2‐month follow‐up assessed physical activity and exercise attitudes. Quality improvement methodology and participant/parent feedback were used to modify the second iteration to better meet the needs of our study population. Changes included an expanded age range, modified physical assessments, decreased burden of questionnaires, and video‐recorded group sessions for at‐home practice.

Results

Physical fitness evaluation of core/trunk strength and stability, lower‐ and upper‐body strength, balance, flexibility, and walking was feasible, and the majority of participants in both pilot iterations improved in at least one category of physical assessment between baseline and end of intervention. Assessment of symptoms of anxiety, depression and behavioural concerns was also feasible and results showed slight improvements in some participants. Both parent and participant feedback indicated that participants enjoyed the programme and appreciated the opportunity to start developing sustainable exercise habits.

Conclusions

A group exercise programme with supported at‐home components is feasible for adolescents with DS. Future iterations will continue to examine programme efficacy with improved fitness testing and larger sample sizes. Strategies to increase at‐home compliance, such as virtual sessions and parent/guardian‐guided physical fitness assessments, will also be incorporated.