bluuebunny/crossref_metadata_2025 huggingface dataset:
Coronary sinus for cardiac resynchronization therapy: leave it alone and go for the branch! a case report
Authors: Dell’Era Gabriele , Veroli Alessandro , Degiovanni Anna , Patti Giuseppe
Published: November 2022

Background

Coronary sinus is the target of an increasing number of percutaneous interventional procedures. Thus, in some patients, conventional cardiac resynchronization therapy (CRT) may not be feasible or preferable, and ‘alternative’ CRT approaches should be applied.

Case summary

We present the case of a successful CRT via direct left bundle branch permanent pacing (LBBP) in a patient with relative contraindication to conventional CRT because of previous percutaneous indirect mitral annuloplasty.

Discussion

LBBP is emerging as a promising technique for physiological cardiac pacing and CRT. It may represent the technique of choice when coronary sinus is not viable for the implant of a conventional left ventricular catheter.
Characterization of myocardial mechanics and its prognostic significance in patients with severe aortic stenosis undergoing aortic valve replacement
Authors: Bi Xiaojun , Yeung Darwin F , Thaden Jeremy J , Nhola Lara F , Schaff Hartzell V , Pislaru Sorin V , Pellikka Patricia A , Pochettino Alberto , Greason Kevin L , Nkomo Vuyisile T , Villarraga Hector R
Published: November 2022

Aims

Aortic stenosis (AS) induces characteristic changes in left ventricular (LV) mechanics that can be reversed after aortic valve replacement (AVR). We aimed to comprehensively characterize LV mechanics before and after AVR in patients with severe AS and identify predictors of short-term functional recovery and long-term survival.

Methods and results

We prospectively performed comprehensive strain analysis by 2D speckle-tracking echocardiography in 88 patients with severe AS and LV ejection fraction ≥50% (mean age 71 ± 12 years, 42% female) prior to and within 7 days after AVR. Patients were followed for up to 5.2 years until death from any cause or last encounter. Within days after AVR, we observed an absolute increase in global longitudinal strain (GLS) (−16.0 ± 2.0% vs. −18.5 ± 2.1%, P<0.0001) and a decrease in apical rotation (10.5 ± 4.0° vs. 8.3 ± 2.8°, P = 0.0002) and peak systolic twist (18.2 ± 5.0° vs. 15.5 ± 3.8°, P = 0.0008). A baseline GLS is less negative than −16.2% was 90% sensitive and 67% specific in predicting a ≥ 20% relative increase in GLS. During a median follow-up of 3.8 years, a global circumferential systolic strain rate (GCSRs) less negative than −1.9% independently predicted lower survival.

Conclusion

In patients with severe AS, a reversal in GLS, apical rotation, and peak systolic twist abnormalities towards normal occurs within days of AVR. Baseline GLS is the strongest predictor of GLS recovery but neither was associated with long-term survival. In contrast, abnormal baseline GCSRs are associated with worse outcomes.
Occurrence and significance of fluoroquinolone-resistant and ESBL-producingEscherichia coliandKlebsiella pneumoniaecomplex of the rectal flora in Ghanaian patients undergoing prostate biopsy
Authors: Labi Appiah-Korang , Obeng-Nkrumah Noah , Dayie Nicholas T K D , Addo Ben Molai , Osei Mary-Magdalene , Fenny Ama , Egyir Beverly , Mensah James Edward
Published: November 2022

Background

Reports suggest that fluoroquinolone (FQ)-resistant and ESBL-producing rectal flora are associated with infectious complications in men undergoing transrectal ultrasound-guided prostate needle biopsy (TRUS-B)

Objectives

We investigated the relationship between carriage of FQ-resistant and ESBL-producing Escherichia coli and Klebsiella pneumoniae complex of the rectal flora, and the 30 day incidence rate of post-TRUS-B infectious complications.

Methods

From 1 January 2018 to 30 April 2019, rectal swabs of 361 patients were cultured pre-TRUS-B for FQ-resistant and ESBL-producing flora. Patients were followed up for 30 days for infectious complications post-biopsy. Multivariable logistic regression analyses were used to identify risk factors.

Results

Overall, 86.4% (n = 312/361) and 62.6% (n = 226/361) of patients carried FQ-resistant and ESBL-producing E. coli and K. pneumoniae complex, respectively. Approximately 60% (n = 289/483) of the FQ-resistant and 66.0% (n = 202/306) of the ESBL-positive isolates exhibited in vitro resistance to the pre-biopsy prophylactic antibiotic regimen of levofloxacin and gentamicin. Amikacin and meropenem were the most effective antibiotics against the MDR rectal E. coli and K. pneumoniae complex (78.7% and 84.3%, respectively). The 30 day incidence rate for post-biopsy infections was 3.1% (n = 11/361), with an overall high probability (96.9%) of staying free of infections within the 30 day period post-TRUS-B. Antibiotic use in the previous 3 months was a risk factor for rectal carriage of FQ-resistant and ESBL-positive isolates. Rectal colonization by ESBL-positive E. coli and K. pneumoniae complex comprised an independent risk factor for post-biopsy infectious complications.

Conclusions

The findings suggest that a change in prophylactic antibiotics to a more targeted regimen may be warranted in our institution.
Function and inhibition of Haspin kinase: targeting multiple cancer therapies by antimitosis
Authors: Liu Yongjian , Yang Hongliu , Fang Yongsheng , Xing Yantao , Pang Xinxin , Li Yang , Zhang Yuanyuan , Liu Yonggang
Published: November 2022

Objectives

Haploid germ cell-specific nuclear protein kinase (Haspin) is a serine/threonine kinase as an atypical kinase, which is structurally distinct from conventional protein kinases.

Key findings

Functionally, Haspin is involved in important cell cycle progression, particularly in critical mitosis regulating centromeric sister chromatid cohesion during prophase and prometaphase, and subsequently ensuring proper chromosome alignment during metaphase and the normal chromosome segregation during anaphase. However, increasing evidence has demonstrated that Haspin is significantly upregulated in a variety of cancer cells in addition to normal proliferating somatic cells. Its knockdown or small molecule inhibition could prevent cancer cell growth and induce apoptosis by disrupting the regular mitotic progression. Given the specificity of its expressed tissues or cells and the uniqueness of its current known substrate, Haspin can be a promising target against cancer. Consequently, selective synthetic and natural inhibitors of Haspin have been widely developed to determine their inhibitory power for various cancer cells in vivo and in vitro.

Here our perspective includes a comprehensive review of the roles and structure of Haspin, its relatively potent and selective inhibitors and Haspin’s preliminary studies in a variety of cancers.
Constructive and mechanised meta-theory of IEL and similar modal logics
Authors: Hagemeier Christian , Kirst Dominik
Published: November 2022

Artemov and Protopopescu proposed intuitionistic epistemic logic (IEL) to capture an intuitionistic conception of knowledge. By establishing completeness, they provided the base for a meta-theoretic investigation of IEL, which was continued by Krupski with a proof of cut-elimination, and Su and Sano establishing semantic cut-elimination and the finite model property. However, no analysis of these results in a constructive meta-logic has been conducted, arguably impeding the intuitionistic justification of IEL. We aim to close this gap and investigate IEL in the constructive-type theory of the Coq proof assistant. Concretely, we present a constructive and mechanised completeness proof for IEL, employing a syntactic decidability proof based on cut-elimination to constructivise the ideas from the literature. Following Su and Sano, we then also give constructive versions of semantic cut-elimination and the finite model property. Given our constructive and mechanised setting, all these results now bear executable algorithms. Our particular strategy to establish constructive completeness exploiting syntactic decidability can be used for similar modal logics, which we illustrate with the examples of the classical modal logics K, D and T. For modal logics including the four axioms, however, the method seems not to apply immediately.
Birth characteristics and risk of meningioma in a population-based study in California
Authors: Cote David J , Wang Rong , Morimoto Libby M , Metayer Catherine , Stempel Jessica , Zada Gabriel , Ma Xiaomei , Wiemels Joseph L
Published: November 2022

Background

We evaluated the potential role of birth characteristics in the etiology of early-onset meningioma.

Methods

Leveraging a population-based linkage of California birth records (from 1978 to 2015) and cancer registry data (from 1988 to 2015), we identified 362 nonmalignant meningioma cases aged 0–37 years and selected 18 100 controls matched on year of birth. Cases and controls were compared with regard to birth characteristics, with adjusted odds ratios (ORs) and 95% confidence intervals (CIs) estimated from unconditional multivariable logistic regression models. We also conducted stratified analyses by race/ethnicity and age.

Results

Female sex (compared to male: OR = 1.43, 95% CI: 1.16 to 1.79; P < .01) and Black race (compared to White: OR = 1.46, 95% CI: 1.02 to 2.07; P = .04) were associated with higher risk of meningioma. Higher birth order (OR = 0.90, 95% CI: 0.81 to 0.99 per additional birth position; P = .04) was associated with a lower risk. No significant associations were observed between birthweight, gestational age, delivery mode, maternal age, or maternal education and meningioma risk. In the non-Latino White subgroup, higher birthweight was associated with a higher risk of meningioma (OR = 1.20, 95% CI: 1.02 to 1.41 per 500 grams; P = .03), but this was not recapitulated in the Latino subgroup. In age-stratified analyses, female sex was a risk factor for those diagnosed at the age of 20–37 years but not among younger individuals.

Conclusions

In this large population-based study less prone to selection and recall bias, higher birth order was associated with a reduced risk of early-onset meningioma, while female sex and Black race were linked to an increased risk. There were also indications of differential associations by race/ethnicity and age of diagnosis.
A New Classification of Lysin Motif Receptor-Like Kinases in Lotus japonicus
Authors: Ruman Hafijur , Kawaharada Yasuyuki
Published: November 2022

Lysin motif receptor-like kinases (LysM-RLKs) are a plant-specific receptor protein family that sense components from soil microorganisms, regulating innate immunity and symbiosis. Every plant species possesses multiple LysM-RLKs in order to interact with a variety of soil microorganisms; however, most receptors have not been characterized yet. Therefore, we tried to identify LysM-RLKs from diverse plant species and proposed a new classification to indicate their evolution and characteristics, as well as to predict new functions. In this study, we have attempted to explore and update LysM-RLKs in Lotus japonicus using the latest genome sequencing and divided 20 LysM-RLKs into 11 clades based on homolog identity and phylogenetic analysis. We further identified 193 LysM-RLKs from 16 Spermatophyta species including L. japonicus and divided these receptors into 14 clades and one out-group special receptor based on the classification of L. japonicus LysM-RLKs. All plant species not only have clade I receptors such as Nod factor or chitin receptors but also have clade III receptors where most of the receptors are uncharacterized. We also identified dicotyledon- and monocotyledon-specific clades and predicted evolutionary trends in LysM-RLKs. In addition, we found a strong correlation between plant species that did not possess clade II receptors and those that lost symbiosis with arbuscular mycorrhizal fungi. A clade II receptor in L. japonicus Lys8 was predicted to express during arbuscular mycorrhizal symbiosis. Our proposed new inventory classification suggests the evolutionary pattern of LysM-RLKs and might help in elucidating novel receptor functions in various plant species.
Engaging Citizens in Government Contracting: A Theoretical Approach for the Role of Social Service Nonprofits
Authors: Park Gowun , Brunjes Benjamin M
Published: November 2022

Outsourcing may lead public administrators to regard service recipients as customers to be satisfied rather than as citizens demanding access and empowerment. This research investigates the extent to which social service nonprofits might bridge the gap between citizenship and customer service to advance shared values and reinforce public institutions. Due to unique institutional and organizational features, such as value-driven commitments, restrictions to financial distribution, and special knowledge of under-represented groups, social service nonprofit contractors may offer distinct advantages over for-profit firms in contract management. We begin by analyzing the conflicting and complementary aspects of citizenship and customer service in democracy and identify the advantages of nonprofit contractors. Then, using the lenses of transaction cost economics and agency theory, we explore how nonprofits can mitigate contract risks while bolstering citizenship. We present several suggestions to guide public agencies and future scholarship on reasserting the importance of public values in modern governance.
RADIATION DETECTOR FOR THE ISRAELI FIRST RESPONDERS—METHODOLOGY OF SELECTION
Authors: Brandis Michal , Rabby Yossi , Epstein Lior , Datz Hanan , Tsvitman Eyal , Amit Gal , Hershkovich David , Krasner Esther
Published: November 2022

This paper presents the rationale and development of a methodology of selection of a radiation detector that can be used by first responders arriving to a terror event scene, not knowing if the event involves any radioactive materials. This detector can be used to detect and quantify the presence of gamma radiation. The role of this detector in a radiological terror event is reviewed via the operational concept for handling radiological terror in Israel. The development of the methodology of selection included a literature survey of relevant radiation detector categories, followed by a user-side survey of requirements based on the first responders’ experience along with the Israeli Ministry of Defense perspective on the management of radiological events, supplemented by the input from experts in aspects of radiation detection, radiation protection and dosimetry from the Israel Atomic Energy Commission’s Soreq Nuclear Research Center. The general qualitative characterisation of requirements was then quantified using a scoring method, enabling the methodological evaluation and numerical ranking of available detectors. Plans to evaluate candidate detector models according to the developed methodology are outlined. The detectors evaluation will be conducted as part of the procurement procedure of future detectors for first responders.
Ts66Yah, an upgraded Ts65Dn mouse model for Down syndrome, for only the region homologous to Human chromosome 21
Authors: Duchon Arnaud , Muñiz Moreno Maria del Mar , Chevalier Claire , Nalesso Valérie , Andre Philippe , Fructuoso-Castellar Marta , Mondino Mary , Po Chrystelle , Noblet Vincent , Birling Marie-Christine , Potier Marie-Claude , Herault Yann
Published: November 2022

Down syndrome is caused by trisomy of human chromosome 21 (Hsa21). The understanding of phenotype-genotype relationships, the identification of driver genes and various proof-of-concepts for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to the human DS features. It carries an additional minichromosome with theMir155 toZbtb21region of mouse chromosome 16 (Mmu16), homologous to Hsa21, encompassing around 90 genes, fused to the centromeric part of mouse chromosome 17 (Mmu17) fromPisd-ps2/Scaf8toPde10a, containing 46 genes, not related to Hsa21. Here, we report the investigation of a new model, Ts66Yah, generated by CrispR/Cas9 without the genomic region unrelated to Hsa21 on the minichromosome. As expected, Ts66Yah replicated DS cognitive features. However, certain phenotypes related to increased activity, spatial learning and molecular signatures, were changed suggesting genetic interactions between theMir155-Zbtb21and theScaf8-Pde10ainterval. Thus, Ts66Yah mice have a stronger construct and face validity for mimicking consequences of DS genetic overdosage. Furthermore, this report is the first to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to Hsa21.
Screening COVID-19 by Swaasa AI Platform using cough sounds: A cross-sectional study
Authors: Padmalatha P , Rudraraju Gowrisree , Sripada Narayana Rao , Mamidgi Baswaraj , Gottipulla Charishma , Jalukuru Charan , Palreddy ShubhaDeepti , Reddy Bhoge Nikhil kumar , Firmal Priyanka , Yechuri Venkat , Sudhakar PV , Devimadhavi B , Srinivas S , Prasad K K L , Joshi Niranjan
Published: November 2022

The Advent of Artificial Intelligence (AI) has led to the use of auditory data for detecting various diseases, including COVID-19. SARS-CoV-2 infection has claimed more than 6 million lives till date and hence, needs a robust screening technique to control the disease spread. In the present study we developed and validated the Swaasa AI platform for screening and prioritizing COVID-19 patients based on the signature cough sound and the symptoms presented by the subjects. The cough data records collected from 234 COVID-19 suspects were subjected to validate the convolutional neural network (CNN) architecture and tabular features-based algorithm. The likelihood of the disease was predicted by combining the final output obtained from both the models. In the clinical validation phase, Swaasa was found to be 75.54% accurate in detecting the likely presence of COVID-19 with 95.45% sensitivity and 73.46% specificity. The pilot testing of Swaasa was carried out on 183 presumptive COVID subjects, out of which 82 subjects were found to be positive for the disease by Swaasa. Among them, 58 subjects were truly COVID-19 positive, which corresponds to a Positive Predictive Value of 70.73%. The currently available rapid screening methods are very costly and require technical expertise, therefore a cost effective, remote monitoring tool would be very beneficial for preliminary screening of the potential COVID-19 subject.
Rapid onset of chronic urticaria after Moderna COVID-19 booster vaccine
Authors: Duperrex Olivier , Tommasini Francesco , Muller Yannick D.
Published: November 2022

A substantial number of patients with newly onset of chronic urticaria was observed rapidly after the booster vaccine against COVID-19. This observation was unprecedented compared to the primary series of vaccination. To address this concern, we initiated an online observational study with the help of local allergists. We found a striking association between the booster dose, the Moderna vaccine, and the new onset of chronic urticaria within the following 10 days. These data were confirmed when reviewing all cases of CSU related to COVID-19 vaccination reported to Swissmedic, the Swiss regulatory agency. These data should not discourage patients from being vaccinated, as this vaccination campaign has been instrumental in reducing COVID-19 burden and preventing millions of deaths. Yet, there is an urgent need to establish appropriate guidelines and monitor this adverse event more closely, considering that a fourth dose is currently being administered.
Nasopharyngeal competition dynamics are likely to be altered following vaccine introduction: bacteriocin prevalence and diversity among Icelandic and Kenyan pneumococci
Authors: Butler Madeleine EB , Jansen van Rensburg Melissa J , Karani Angela , Mvera Benedict , Akech Donald , Akter Asma , Forrest Calum , van Tonder Andries J , Quirk Sigríður J , Haraldsson Gunnsteinn , Bentley Stephen D , Erlendsdóttir Helga , Haraldsson Ásgeir , Kristinsson Karl G , Scott J Anthony G , Brueggemann Angela B
Published: November 2022

Bacteriocins are antimicrobial peptides produced by bacteria to inhibit other bacteria in the surrounding environment.Streptococcus pneumoniaeis a leading cause of disease worldwide and colonises the healthy human nasopharynx, where it competes for space and nutrients. Pneumococcal conjugate vaccines have reduced the incidence of disease, but they also restructure the bacterial population, and this restructuring likely alters the nasopharyngeal competition dynamics. Here, the distribution of bacteriocins was examined in over 5000 carriage and disease-causing pneumococci from Iceland and Kenya, recovered before and after the introduction of pneumococcal vaccination. Overall, up to eleven different bacteriocin gene clusters were identified per pneumococcus. Significant differences in the prevalence of bacteriocins were observed before and after vaccine introduction, and among carriage and disease-causing pneumococci, which were largely explained by the bacterial population structure. Genetically similar pneumococci generally harboured the same bacteriocins although sometimes different repertoires of bacteriocins were observed, which suggested that horizontal transfer of bacteriocin clusters had occurred. These findings demonstrated that vaccine-mediated changes in the pneumococcal population altered the prevalence and distribution of bacteriocins. The consequences of this for pneumococcal colonisation and disease remain to be determined.
Critical dynamics arise during structured information presentation: analysis of embodiedin vitroneuronal networks
Authors: Habibollahi Forough , Kagan Brett J. , Duc Daniela , Burkitt Anthony N. , French Chris
Published: November 2022

Abstract

Amongst the characteristics about information processing in the brain, observations of dynamic near-critical states have generated significant interest. However, theoretical and experimental limitations have precluded a definite answer about when and why neural criticality arises. To explore this topic, we used anin vitroneural network of cortical neurons that was trained to play a simplified game of ‘Pong’. We demonstrate that critical dynamics emerge when neural networks receive task-related structured sensory input, reorganizing the system to a near-critical state. Additionally, better task performance correlated with proximity to critical dynamics. However, criticality alone is insufficient for a neuronal network to demonstrate learning in the absence of additional information regarding the consequences of previous actions. These findings have compelling implications for the role of neural criticality.
Improving the Quality of Co-evolution Intermolecular Contact Prediction with DisVis
Authors: van Keulen Siri C. , Bonvin Alexandre M.J.J.
Published: November 2022

The steep rise in available protein sequences and structures has paved the way for bioinformatics approaches to predict residue-residue interactions in protein complexes. Multiple sequence alignments are commonly used in intermolecular contact predictions to identify co-evolving residues. These contacts, however, often include false positives (FPs), which may impair their use to predict three dimensional structures of biomolecular complexes and affect the accuracy of the generated models.

Previously, we have developed DisVis to identify false positive data in mass spectrometry cross-linking data. DisVis allows to assess the accessible interaction space between two proteins consistent with a set of distance restraints. Here, we investigate if a similar approach could be applied to co-evolution predicted contacts in order to improve their precision prior to using them for modelling complexes.

In this work we analyze co-evolution contact predictions with DisVis in order to identify putative FPs for a set of 26 protein-protein complexes. Next, the DisVis-reranked and the original co-evolution contacts are used to model the complexes with our integrative docking software HADDOCK using different filtering scenarios. Our results show that HADDOCK is robust with respect to the precision of the predicted contacts due to the 50% random contact removal during docking and using DisVis filtering for low precision contact data. DisVis can thus have a beneficial effect on low quality data, but overall HADDOCK can accommodate FP restraints without negatively impacting the quality of the resulting models. Other more precision-sensitive docking protocols might, however, benefit from the increased precision of the predicted contacts after DisVis filtering.
Antigen self-anchoring onto bacteriophage T5 capsid-like particles for vaccine design
Authors: Vernhes Emeline , Chérif Linda Larbi , Ducrot Nicolas , Ouldali Malika , Zig Lena , Sidibe N’diaye , Hoos Sylviane , Ramirez-Chamorro Luis , Renouard Madalena , Rossier Ombeline , England Patrick , Schoehn Guy , Boulanger Pascale , Benihoud Karim
Published: November 2022

The promises of vaccines based on virus-like particles stimulate demand for universal non-infectious virus-like platforms that can be efficiently grafted with large antigens. Here we harnessed the modularity and extreme affinity of the decoration protein pb10 for the capsid of bacteriophage T5. SPR experiments demonstrated that pb10 fused to mCherry or to the model antigen ovalbumin (Ova) retained picomolar affinity for DNA-free T5 capsid-like particles (T5-CLPs), while cryo-EM studies attested to the full occupancy of the 120 capsid binding sites. Mice immunisation with CLP-bound pb10-Ova chimeras elicited strong long-lasting anti-Ova humoral responses involving a large panel of isotypes, as well as CD8+T cell responses, without any extrinsic adjuvant. Therefore, T5-CLP constitutes the first DNA-free bacteriophage capsid able to irreversibly display a regular array of large antigens through highly efficient chemical-free anchoring. Its ability to elicit robust immune responses paves the way for further development of this novel vaccination platform.
Divergent selection for feed efficiency in pigs altered the duodenum transcriptome and DNA methylation profiles, resulting in greater responses to feed intake in the most efficient line
Authors: Devailly Guillaume , Fève Katia , Saci Safia , Sarry Julien , Valière Sophie , Lluch Jérôme , Bouchez Olivier , Ravon Laure , Billon Yvon , Gilbert Hélène , Riquet Juliette , Beaumont Martin , Demars Julie
Published: November 2022

Feed efficiency is a trait of interest in pigs as it contributes to lowering the ecological and economical costs of pig production. A divergent genetic selection experiment from a Large White pig population was performed for 10 generations, leading to pig lines with relative low-(LRFI, more efficient) and high-(HRFI, less efficient) residual feed intake (RFI). Feeding behaviour and metabolic differences have been previously reported between the two lines. We hypothesised that part of these differences could be related to differential sensing and absorption of nutrients in the proximal intestine.

Here we investigated the duodenum transcriptome and DNA methylation profiles comparing overnight fasting with ad libitum feeding in LRFI and HRFI pigs (n=24). We identified 1,106 differentially expressed genes between the two lines, notably affecting pathways of the transmembrane transport activity and related to mitosis or chromosome separation. The LRFI line showed a greater transcriptomic response to feed intake, with 2,222 differentially expressed genes before and after a meal, as compared to 61 differentially expressed genes in the HRFI line. Feed intake affected genes from both anabolic and catabolic pathways in the pig duodenum, such as rRNA production and autophagy. We noted that several nutrient transporter and tight junction genes were differentially expressed between lines and/or by short term feed intake. We also identified 409 differentially methylated regions in the duodenum mucosa between the two lines, while this epigenetic mark was less affected by feeding. However most of the differentially expressed genes were not associated with proximal changes in DNA methylation profiles.

Altogether, our findings highlighted that the genetic selection for feed efficiency in pigs changed the transcriptome profiles of the duodenum, and notably its response to feed intake, suggesting key roles for this proximal gut segment in mechanisms underlying feed efficiency.
Path analysis of intra-metastatic hypoxia in breast cancer
Authors: Rey-Keim Sergio , Schito Luana
Published: November 2022

Hypoxia (low O2) signals into the nucleus of cancer cells through hypoxia-inducible factor (HIF)-1α-dependent transcription triggering proliferative, metabolic and vascular adaptations linked to therapy resistance and mortality due to overt metastasis. In contrast with the wealth of molecular data on primary intra-tumoral hypoxia, there is a dearth of statistical modelling studies addressing the mechanisms of intra-metastatic hypoxia. In this study, we used path analysis to model intra-metastatic hypoxia (Hx), HIF-1α expression and microvascular area (MVA) as functions of metastatic cross-sectional area (MCSA) in an advanced mouse breast cancer model; in this context, we tested the effect of conventional, maximum-tolerated dose (MTD) or low-dose metronomic (LDM) chemotherapy. Iterative analysis of 34 non-isomorphic paths yielded four well-fitting, configuration-invariant models [χ2(6,171)≥ 6.12;P≥ 0.328; CFI ≥ 0.998; RMSEA ≤ 0.07]. All four models contained HIF-1α as a mediating variable within the MCSA↔Hx↔MVA path, as well as significant Hx↔MVA interactions. LDM disrupted the HIF-1α↔MCSA→Hx and HIF-1α↔MVA paths; furthermore, all LDM and MTD combinations impaired Hx↔HIF-1α. These results confirmed well-established hypoxic interactions, whilst uncovering possible differential effects of chemotherapeutic modalities upon metastatic size, hypoxia, HIF-1α and vascularisation. Our data indicate that MVA can act as a downstream readout, rather than an adaptive angiogenic mechanism alleviating intra-metastatic hypoxia. Moreover, well-fitting path models locate HIF-1α activity either upstream or downstream of hypoxia, thereby allowing us to posit the existence of bi-directional feedback loops driving vascularisation and growth in metastatic tumours, of relevance for targeted therapies.
Glutathione induces ArabidopsisPHT1;5gene via WRKY75 transcription factor to regulate phosphate homeostasis
Authors: Shee Ranjana , Shee Dibyendu , Sahid Salman , Paul Soumitra , Datta Riddhi
Published: November 2022

Phosphorus is a macronutrient that regulates a wide range of physiological processes, including plant growth and development. The scarcity of bioavailable phosphate is often a constraint for plant growth in most agricultural ecosystems. Under phosphate limited conditions, plants increase phosphate acquisition or alter its distribution within tissues by activating different phosphate transporters and phosphate starvation-induced genes. Glutathione (GSH), on the other hand, is known to play a critical role in regulating iron and zinc homeostasis in Arabidopsis. However, how it regulates phosphate homeostasis under phosphate limited conditions remains unexplored. We found that the two GSH-deficient mutants,cad2-1, andpad2-1, were hypersensitive to phosphate starvation. Under phosphate-sufficient condition, the root phosphate content was lower in the mutants but significantly higher in the shoot over the Col-0 plants. The pattern was reversed under phosphate-deficient condition. Interestingly, among the different phosphate transporters analyzed, theAtPHT1;5was significantly down-regulated in the two GSH-deficient mutants. Treatment with exogenous GSH could alter phosphate accumulation in Col-0 and thepht1;5complementation lines but not in thepht1;5mutant. This observation confirmed the role of GSH in phosphate reallocation during phosphate starvation via theAtPHT1;5 transporter. Further, promoter analysis demonstrated that GSH regulates the transcription of theAtPHT1;5gene. The phosphate-responsive transcription factor (TF),AtWRKY75 was identified to interact with theAtPHT1;5promoter, and phosphate deficiency or GSH treatment enhanced its binding affinity. Together our investigation delineates that GSH regulates theAtPHT1;5 transporter via theAtWRKY75 TF to modulate phosphate distribution under altered phosphate conditions.

Summary statement

Glutathione regulates phosphate translocation in Arabidopsis under altered phosphate condition via transcriptional activation ofAtPHT1;5gene byAtWRKY75 transcription factor.
IL-17A promotes epithelial cell IL-33 production during nematode lung migration
Authors: Ajendra Jesuthas , Pearson Stella , Parkinson James E. , Chan Brian H.K. , McSorley Henry J. , Sutherland Tara E. , Allen Judith E.
Published: November 2022

The early migratory phase of pulmonary helminth infections is characterized by tissue injury leading to the release of the alarmin IL-33 and subsequent induction of type 2 immune responses. We recently described a role for IL-17A, through regulation of IFNγ, as an important inducer of type 2 responses during infection with the lung-migrating rodent nematodeNippostrongylus brasiliensis. Here, we aimed to investigate the interaction between IL-17A and IL-33 during the early lung migratory stages ofN. brasiliensisinfection. In this brief report, we demonstrate that deficiency of IL-17A leads to impaired IL-33 expression and secretion early in infection, independent of IL-17A suppression of IFNγ. Impaired IL-33 production was evident in lung epithelial cells, but not innate immune cells. Therefore, our results demonstrate that IL-17A can drive IL-33 during helminth infection, highlighting an additional mechanism through which IL-17A can regulate pulmonary type 2 immunity.
Aryl hydrocarbon receptor utilises cellular zinc signals to maintain the gut epithelial barrier
Authors: Hu Xiuchuan , Xiao Wenfeng , Lei Yuxian , Green Adam , Lee Xinyi , Maradana Muralidhara Rao , Gao Yajing , Xie Xueru , Wang Rui , Chennell George , Basson M. Albert , Kille Pete , Maret Wolfgang , Bewick Gavin A. , Zhou Yufeng , Hogstrand Christer
Published: November 2022

Both zinc and plant-derived ligands of the aryl hydrocarbon receptor (AHR) are dietary components which regulate intestinal epithelial barrier function and protect against Inflammatory Bowel Disease (IBD)1,2. Here, we explore whether zinc and AHR pathway are linked using a mouse IBD model with follow-on studies on human and mouse ileum organoids. Our data demonstrate that AHR regulates cellular zinc uptake, and that zinc is an integral part of AHR signalling processes. We show that dietary supplementation in mice with the plant-derived AHR ligand precursor, indole-3-carbinol (I3C), offers a high level of protection against dextran sulfate sodium induced IBD while protection fails in mice with AHR deleted in the intestinal epithelium. AHR agonist treatment is also ineffective in mice with a nutritional zinc deficiency. Experiments in the human Caco-2 cell line and ileum organoids showed that AHR activation increases total cellular zinc and cytosolic free Zn2+concentrations through transcriptional upregulation of severalSLC39zinc importers. As a consequence, genes for tight junction (TJ) proteins were upregulated in a zinc-dependent manner involving zinc inhibition of signalling to NF-κB and attenuated degradation of TJ proteins through zinc inhibition of calpain activity. Thus, our data indicate that AHR activation by plant-derived dietary ligands improves gut barrier function via zinc-dependent cellular pathways, suggesting that combined dietary supplementation with AHR ligands and zinc might be effective in preventing and treating inflammatory gut disorders.
Host-driven temperature dependence of viral infection in honey bees
Authors: Palmer-Young Evan C , Ryabov Eugene V , Markowitz Lindsey , Boncristiani Dawn L , Grubbs Kyle , Pawar Asha , Peterson Raymond , Evans Jay D
Published: November 2022

The temperature dependence of infection reflects changes in the performance of parasites and hosts. High temperatures (i.e., fever) often mitigate infection by favoring heat-tolerant hosts over heat-sensitive parasites. Honey bees exhibit an endothermic, colony-level temperature regulation that is exceptional among insects and favors resistance to several parasites. However, proliferation of viruses is heavily host-dependent, suggesting that viral infection could be linked to—not threatened by—optimum host function. To understand how temperature-driven changes in performance of viruses and hosts shape virus proliferation, we compared the temperature dependence of isolated viral enzyme activity, three honey bee traits, and infection of honey bee pupae.

Viral enzyme activity varied by <2-fold over a >30 °C interval that spanned the temperatures typical of ectothermic insects and honey bees. In contrast, metrics of honey bee performance peaked at high (≥ 35 °C) temperatures and were highly temperature-sensitive, with respiration varying 8-fold over a 20 °C interval and successful development requiring a narrow 8 °C temperature range. Although these results suggested that hosts would gain a relative advantage over viruses with increasing temperature, the temperature dependence of pupal infection matched that of pupal development, falling only near pupae’s upper thermal limits. Our results reflect the host-dependent nature of virus proliferation, suggesting that infection is accelerated—not curtailed—by optimum host function, contradicting predictions of infection based on the relative performance of parasites and hosts, and suggesting tradeoffs between infection resistance and host survival. Despite a 98% reduction in infection at the upper end of the colony temperature range, the narrow thermal safety margin for honey bee development might preclude the effectiveness of ‘fever’ for controlling viruses.
RADICAL CATION SCAVENGING ACTIVITY OF BERBERINE BRIDGE ENZYME-LIKE OLIGOSACCHARIDE OXIDASES ACTING ON SHORT CELL WALL FRAGMENTS
Authors: Scortica Anna , Scafati Valentina , Giovannoni Moira , Benedetti Manuel , Mattei Benedetta
Published: November 2022

Oligogalacturonide-oxidases (OGOXs) and cellodextrin-oxidase (CELLOX) are plant berberine bridge enzyme-like oligosaccharide-oxidases (OSOXs) that oxidize, respectively, oligogalacturonides (OGs) and cellodextrins (CDs), thereby inactivating their elicitor nature and concomitantly releasing H2O2. Little is known about the physiological role of OSOX activity. By using an ABTS•+-reduction assay, we identified a novel reaction mechanism through which the activity of OSOXs on cell wall oligosaccharides scavenged the radical cation ABTS•+with an efficiency dependent on the type and length of the oxidized oligosaccharide. In contrast to the oxidation of longer oligomers such as OGs (degree of polymerization from 10 to 15), the activity of OSOXs on short galacturonan- and cellulose-oligomers (degree of polymerization ≤ 4) successfully counteracted the radical cation-generating activity of a fungal laccase, suggesting that OSOXs can generate radical cation scavenging activity in the apoplast with a power proportional to the extent of degradation of plant cell wall, with possible implications for redox homeostasis and defense against oxidative stress.
Astrocyte-like CEPsh glia respond to stress
Authors: Chien Evangeline , Garcia Angel J. , L’Etoile Noelle D. , Chandra Rashmi
Published: November 2022

While astrocytes are known to be important for development and nourishment of the nervous system, the field is just beginning to explore how astrocytes respond to environmental stimuli. UsingCaenorhabditis elegansand their astrocyte-equivalent, CEPsh, we asked whether astrocyte-like glia respond to odor exposure. We found one day-old adultC. elegansdecreasehlh-17promoter (CEPsh glia marker) mediated fluorescent expression when trained with an innately attractive odor butanone. Moreover, the olfactory training paradigm itself affects phlh-17expression, but in a different way. This suggests astrocyte-like CEPsh glia can integrate environmental information to respond to changes in the environment, which enhances survival.
Modeling the iron storage protein ferritin reveals how residual ferrihydrite iron determines initial ferritin iron sequestration kinetics
Authors: Masison Joseph , Mendes Pedro
Published: November 2022

Ferritin is the primary iron storage protein in mammalian cells and is necessary for cellular iron homeostasis. Its ability to sequester iron protects cells from rising concentrations of ferrous iron limiting oxidative cell damage. The dynamics of its sequestration behavior have been studied extensively experimentally, but mostlyin vitro, rather than within mammalian cells, computational modeling efforts are lacking, and several open questions remain. The importance of FT modeling is driven by the idea that understanding the kinetics of ferritin iron sequestration and how it impacts the regulation of iron metabolism in the cells that compose the main iron regulatory tissues (eg. Kupffer cells, splenic macrophages, enterocytes, erythroblasts, etc.) is central to understanding systemic iron control. The focus of the work here is establishing a model that tractably simulates the ferritin iron sequestration kinetics in a mechanistic way for incorporation into larger cell models, in addition to contributing to the understanding of ferritin iron sequestration dynamics within cells. The model’s parameter values were determined from published kinetic and binding experiments and the model was validated against independent data not used in its construction. Simulation results indicate that FT concentration is the most impactful on overall sequestration dynamics, while the FT iron saturation (number of iron atoms sequestered per FT cage) fine tunes the initial rates. Finally, because this model has a small number of reactions and species, was built to represent important mechanistic details of FT kinetics, and has flexibility to include subtle changes in subunit composition, we propose this model to be used as a building block for models of iron metabolism in a variety of specific cell types.
Synonymous and non-synonymous transitions/transversions vividly disclose purifying selection inEscherichia colicoding sequences
Authors: Beura Pratyush Kumar , Aziz Ruksana , Sen Piyali , Das Saurav , Namsa Nima Dondu , Feil Edward J , Satapathy Siddharatha Sankar , Ray Suvendra Kumar
Published: November 2022

Transition (ti) and transversion (tv) are the major causes for genome variation. The accurate estimation oftitotvratioin genomes is crucial for understanding of mutational and selection processes in organisms as it is influenced by both codon degeneracy and pretermination codons (PTC). Therefore, we developed a method (accessible athttps://github.com/CBBILAB/CBBI.git) to estimateratio by accounting codon degeneracy as well as PTC in protein coding sequences. Our findings revealed a distinct impact of codon degeneracy and PTC on theratio in theEscherichia coligenome. We observed a decreasing order among the frequencies of different base substitutions such as synonymous transition (Sti) > synonymous transversion (Stv) > non-synonymous transition (Nti) > non-synonymous transversion (Ntv) inE. coligenome. The correlation was strong betweenStiandStvvalues (Pearsonrvalue 0.795) whereas the correlation was weak betweenStiandNti(Pearsonrvalue 0.192). Coding sequences with similarStivalues exhibited a wide range ofNtivalues. This indicated the varying strength of purifying selection acting on the coding sequences. In concordance with the assumption, the genes having higherNtivalues were observed with lower codon adaptation index (CAI) values than that of the genes having lowerNtivalues. Our approach is convenient to visualize the frequency of base substitution variation as well as selection in protein coding sequences. The proposed method is useful to estimate differentratios accurately in coding sequences and is insightful from an evolutionary perspective.

Article Summary

Genetic diversity is pivotal in evolution, with base substitution as a key driver. Transition (ti) frequency surpasses transversion (tv) frequency in genomes, makingratios a valuable metric for studying mutation bias. Our improved estimator forcalculation accounts for codon degeneracy and nonsense substitutions in pretermination codons. Additionally, we unveil insights into the frequency of different substitutions such asSti, Stv, Nti, andNtvand demonstrate the impact of selection on protein coding sequences.
Age and lead configuration matter: A comparative study of RF-induced heating of epicardial and endocardial electronic devices in adult and pediatric anthropomorphic phantoms in 1.5 T MR
Authors: Jiang Fuchang , Henry Kaylee R. , Bhusal Bhumi , Sanpitak Pia , Webster Gregory , Popescu Andrada , Bonmassar Giorgio , Laternser Christina , Kim Daniel , Golestanirad Laleh
Published: November 2022

Background

Children with congenital heart defects often have life-sustaining indications for a cardiac implantable electronic device (CIED). In children, these devices are typically sewn to the heart epicardium, but the FDA has never licensed an epicardial system as MR-Conditional due to limited data. Children’s hospitals default to either refusing MRI service to a vast majority of pediatric CIED patients or adopting a scan-all strategy based on results from adult studies. We argue that both approaches are flawed, and the risk-benefit decisions should be made on an individual basis.

Purpose

To provide evidence-based knowledge on RF-induced heating of CIEDs in children and adults with epicardial and endocardial leads of different lengths.

Study Type

Phantom

Field Strength/Sequence

1.5 T.

Assessment

120 clinically relevant epicardial and endocardial device configurations were implemented in adult and pediatric anthropomorphic phantoms. Temperature rise was recorded during RF exposure at 1.5 T.

Statistical Tests

Means comparisons were implemented using two-sample t-tests, reliability analysis using interclass correlation coefficient based on a single rating, absolute-agreement, 2-way mixed-effects model.

Results

There was significantly higher RF heating of epicardial leads compared to endocardial leads in the pediatric phantom (3.4 ± 3.0 vs. 0.6 ± 0.4 °C, p<0.001); however, there was no significant difference in the adult phantom (3.0 ± 3.2 vs. 2.0 ± 1.8, p=0.16). Endocardial leads in the pediatric phantom generated significantly less RF heating than in the adult phantom (0.6 ± 0.4 °C vs. 2.0 ± 1.8 °C, p<0.001).

Data Conclusion

Body size and lead length significantly affected RF heating. For models based on younger children with short epicardial leads (e.g., 25cm), RF heating up to 12 °C was observed, delivering a cumulative thermal dose previously associated with tissue necrosis. In contrast, RF heating in model based on children with endocardial leads was well below the heating expected from physiologic fever (3 °C).