bluuebunny/crossref_metadata_2025 huggingface dataset:
Wisely Frugal: Ensuring sustainable funding for novel cancer therapeutics using cost-effectiveness thresholds in resource limited settings
Authors: Joseph Nuradh , Peiris Vimukthini , Bamunuarachchi Vodathi , Abeysinghe Prasad , Jeyakumaran Nadarajah , Jayathilake Devinda , Perera Kanthi , Fernandopulle Rohini , Gunasekera Sanjeeva
Published: February 2023

Introduction

Cancer care in Sri Lanka is predominantly provided through its public funded state health system which is free at the point of delivery. The health system faced unprecedented funding restrictions brought about by the post-pandemic recession. We performed a cost-effectiveness analysis of novel cancer drugs with a view to prioritising novel cancer therapeutics to its sustainability during these challenging times.

Methods

The direct cost of drug procurement was obtained, and the cost per life year gained was computed for each indication. Two thresholds - per capita GDP per life year gained (GDPx1) and three times per capita GDP per life year gained (GDPx3) were considered to determine cost effectiveness. The cumulative annual cost of these treatments were then determined by multiplying the cost per treatment course per patient by the estimated number of treated patients per year for each indication.

Results

Data obtained on 42 novel cancer drugs spanning across 90 indications were included in the analysis. The cumulative annual treatment cost when the threshold was set at GDPx1 was US$ 6 million and it increased to US$ 16.3 million if the threshold was expanded GDPx3. Only 28 indications met the GDPx3 threshold while there were 18 drugs that did not meet the thresholds for any indication. Without a threshold, if every eligible patient were to receive the indicated currently used novel drugs, the total cost of treatment would reach almost US$ 300 million per year.

Conclusion

Cost-effectiveness thresholds will lead to considerable savings and help prioritise procurement and supply of cost-effective novel agents in the state health system in Sri Lanka.

Advances in Knowledge

In this work, we show that significant savings can be achieved by performing simple cost-effectiveness analyses and defining thresholds. The absence of robust quality of life and costing data should not deter policy makers from such conducting analyses from available information.
Prognostic value of Coronary artery calcium score for the prediction of atherosclerotic cardiovascular disease in participants with nonalcoholic fatty liver disease: Results from the Multi-Ethnic Study of Atherosclerosis
Authors: Ichikawa Keishi , Hansen Spencer , Manubolu Venkat S. , Pourafkari Leili , Fazlalizadeh Hooman , Aldana-Bitar Jairo , VanWagner Lisa B , Krishnan Srikanth , Budoff Matthew J.
Published: February 2023

Background

Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) events, thus a diagnostic approach to help identify NAFLD patients at high risk is needed. In this study, we hypothesized that coronary artery calcium (CAC) screening could help stratify the risk of ASCVD events in NAFLD patients.

Methods

A total of 718 NAFLD participants from Multi-Ethnic Study of Atherosclerosis (MESA) without previous cardiovascular events were followed for the occurrence of incident ASCVD. NAFLD was defined using non-enhanced computed tomography and liver/spleen attenuation ratio <1. Cox proportional hazards regression models were used to estimate hazard ratios (HR). C-statistic and net reclassification improvement were used to compare incremental contributions of CAC score when added to the clinical risk factors.

Results

In multivariable analyses, CAC score was found to be independently associated with incident ASCVD (HR = 1.33, 95% CI = 1.22–1.44, p < 0.001). The addition of CAC score to clinical risk factors increased the C-statistic from 0.677 to 0.739 (p < 0.001) and the net reclassification index was 0.721 (95% CI = 0.494–0.977). In subgroup analyses, the incremental prognostic value of CAC score was more significant in NAFLD participants with low/borderline- (<7.5%) and intermediate- (7.5–20%) 10–year ASCVD risk score.

Conclusions

The inclusion of CAC score in global risk assessment was found to significantly improve the classification of incident ASCVD events in participants with NAFLD, indicating a potential role for CAC screening in risk assessment.

Clinical Perspective

With the increasing prevalence of nonalcoholic fatty liver disease (NAFLD) individuals, there is an unmet need for a diagnostic approach to identify NAFLD individuals who are at higher risk for atherosclerotic cardiovascular disease (ASCVD) events. This study showed that higher coronary artery calcium (CAC) score was associated with ASCVD events during follow-up and improved the discriminative ability for future events in NAFLD individuals. Our study suggests routine CAC screening can be useful in assessing the risk of future ASCVD events. Future studies are needed to explore the therapeutic implications of CAC screening in this population.
Simulating Rumen Conditions using an Anaerobic Dynamic Membrane Bioreactor to Enhance Hydrolysis of Lignocellulosic Biomass
Authors: Fonoll Xavier , Zhu Kuang , Aley Lucy , Shrestha Shilva , Raskin Lutgarde
Published: February 2023

An anaerobic dynamic membrane bioreactor (AnDMBR) was used to mimic rumen conditions to enhance the hydrolysis of lignocellulosic materials and the production of volatile fatty acids (VFA) when treating food waste. The AnDMBR was inoculated with cow rumen content and operated at a 0.5-day hydraulic retention time, 2 to 4-day solids retention time, a temperature of 39 °C, and a pH of 6.3, characteristics similar to those of a rumen. An operational strategy of repeating settle-permeate-mix cycles was utilized to simulate the regurgitation of ruminant animals. Removal rates of neutral detergent fiber (NDF) and acid detergent fiber (ADF) of 58.9 ± 8.4 % and 69.0 ± 8.6 %, respectively, and a VFA yield of 0.55 ± 0.12 g VFA/g CODfedwere observed when operating at an organic loading rate of 18 ± 2 kg VS/m3/day. Sequencing results of both 16S rRNA gene and 16S rRNA revealed that a microbial community resistant to both disruption and reinoculation developed six weeks after inoculation. Up to 66.7 ± 5.7 % of the active microbial populations (based on 16S rRNA sequence data) and 51.0 ± 7.0 % of the total microbial populations (based on 16S rRNA gene sequence data) present in the rumen-mimicking AnDMBR originated from the rumen inoculum. This study offers a reliable strategy to leverage the unique features of a rumen; the rumen-mimicking AnDMBR achieved high hydrolysis and acidogenesis rates even when treating substrates drastically different from those fed to ruminants.
A Metabolomics Study of Thrombosis after Cardiac Surgery in Children with Congenital Heart Disease
Authors: Li Shengxu , Watson Dave , Jorgenson Alissa , Adelekan Zainab , Tang Weihong , Garland Kathleen , Zupancich Leah , Dassenko David , Edens R. Erik , Overman David M. , Huntley Marnie T.
Published: February 2023

Objective

Thrombosis is a major complication after cardiac surgery in children with congenital heart disease (CHD). The mechanisms underlying thrombosis development remain poorly understood. We aimed to identify novel circulating metabolites before cardiac surgery that are associated with the development of thrombosis after surgery in children with CHD.

Approach and results

All blood samples were drawn right before surgical incision and after the induction of anesthesia, and plasma was separated immediately under 4 °C. Untargeted metabolomic data were measured by Metabolon in plasma from children (age range: 0 days-18 years) with CHD undergoing cardiac surgery. The primary outcome was thrombosis within 30 days of surgery or before discharge. Associations of individual metabolites with thrombosis were assessed with logistic regression with false discovery rate (FDR) correction for multiple comparison and adjustment for clinical characteristics; elastic net regression was used to select a prediction model. Out of 1,115 metabolites measured in samples from 203 children, 776 met the quality control criteria. In total, 26 children (12.8%) developed thrombosis. Among the 776 metabolites, 195 were significantly associated with thrombosis (FDR q-value < 0.05). The top three metabolites showing the strongest associations with thrombosis were eicosapentaenoate, steroid monosulfate C19H28O6S, and formiminoglutamate (FDR = 0.01 for all). Pathway analysis showed that the pathways of nicotinate and nicotinamide metabolism (P = 0.0007) and glycerophospholipid metabolism (P = 0.002) were enriched and had significant impacts on the development of thrombosis. In elastic net regression analysis, the area under the receiver operating-characteristic curve of a prediction model for thrombosis was 0.94 in the training sample (70% of the total sample) and 0.84 in the testing sample (the remaining 30%).

Conclusion

We have identified promising novel metabolites and metabolic pathways associated with thrombosis. Future studies are warranted to confirm the findings and examine the mechanistic pathways to thrombosis.
Acute and Subacute Ischemia of Lower Limbs: Angiography and Peripheral Hemodynamics
Authors: Bulvas Miroslav , Sommerová Zuzana
Published: February 2023

Objective

To identify pretreatment characteristics related to ischemia severity and symptoms duration in patients with acute (ALI) and subacute lower limb ischemia (SLI).

Methods

Comparative study, a part of prospective, single-arm, single-center trial of 316 consecutive patients with threatened extremities (all-comers, mean age: 70.9±12.0 years, range: 23-96; 184 men) of whom 99. 4 % suffered from acute or subacute supratibial occlusions (target occlusions).

Results

Multisegmental (supratibial plus infrapopliteal) arterial occlusions were documented in 90.6 % of ALI patients and in 78.1 % of SLI patients with threatened lower extremity. The value of ABI related to the number of occluded tibial arteries. Occlusion locations associated with ALI (IIA+IIB) were the aortoiliac segment and/or profunda femoris. Furthermore, ALI subjects presented additional infrapopliteal occlusion (acute and/or subacute), smaller number of patent tibial arteries and lower ABI.

Conclusion

Anatomically, the most important factor related to the ischemia severity and symptoms duration was the status of infrapopliteal vascular bed. The number of acutely, subacutely or chronically occluded tibial vessels was related to clinical categories of ALI and SLI and to ABI. This suggests that tibial reperfusion can be essential for the salvage of threatened limb and should be always considered.
Associations between SARS-CoV-2 infection and incidence of new chronic condition diagnoses: a systematic review
Authors: Gaudet Lindsay A. , Pillay Jennifer , Saba Sabrina , Zakaria Dianne , Cheta Nicholas , Gardiner Hélène , Shaver Larry , Middleton Jacqueline , Tan Maria , Vandermeer Ben , Hartling Lisa
Published: February 2023

Because of the large number of infected individuals, an estimate of the future burdens of the long-term consequences of SARS-CoV-2 infection is needed. This systematic review examined associations between SARS-CoV-2 infection and incidence of categories of and selected chronic conditions, by age and severity of infection (inpatient vs. outpatient/mixed care). MEDLINE and EMBASE were searched (Jan 1, 2020 to Oct 4, 2022) and reference lists scanned. We included observational studies from high-income OECD countries with a control group adjusting for sex and comorbidities. Identified records underwent a two-stage screening process. Two reviewers screened 50% of titles/abstracts, after which DistillerAI acted as second reviewer. Two reviewers then screened the full texts of stage one selections. One reviewer extracted data and assessed risk of bias; results were verified by another. Random-effects meta-analysis estimated pooled hazard ratios (HR). GRADE assessed certainty of the evidence. Twenty-five studies were included. Among the outpatient/mixed SARS-CoV-2 care group, there is high certainty of a small-to-moderate increase (i.e., HR 1.26 to 1.99) among adults ≥65 years of any cardiovascular condition, and of little-to-no difference (i.e., HR 0.75 to 1.25) in anxiety disorders for individuals <18, 18-64, and ≥65 years old. Among 18-64 and ≥65 year-olds receiving outpatient/mixed care there are probably (moderate certainty) large increases (i.e., HR ≥2.0) in encephalopathy, interstitial lung disease, and respiratory failure. After SARS-CoV-2 infection, there is probably an increased risk of diagnoses for some chronic conditions; whether the magnitude of risk will remain stable into the future is uncertain.
FitMultiCell: Simulating and parameterizing computational models of multi-scale and multi-cellular processes
Authors: Alamoudi Emad , Schälte Yannik , Müller Robert , Starruß Jörn , Bundgaard Nils , Graw Frederik , Brusch Lutz , Hasenauer Jan
Published: February 2023

Motivation

Biological tissues are dynamic and highly organized. Multi-scale models are helpful tools to analyze and understand the processes determining tissue dynamics. These models usually depend on parameters that need to be inferred from experimental data to achieve a quantitative understanding, to predict the response to perturbations, and to evaluate competing hypotheses. However, even advanced inference approaches such as Approximate Bayesian Computation (ABC) are difficult to apply due to the computational complexity of the simulation of multi-scale models. Thus, there is a need for a scalable pipeline for modeling, simulating, and parameterizing multi-scale models of multi-cellular processes.

Results

Here, we present FitMultiCell, a computationally efficient and user-friendly open-source pipeline that can handle the full workflow of modeling, simulating, and parameterizing for multi-scale models of multi-cellular processes. The pipeline is modular and integrates the modeling and simulation tool Morpheus and the statistical inference tool pyABC. The easy integration of high-performance infrastructure allows to scale to computationally expensive problems. The introduction of a novel standard for the formulation of parameter inference problems for multi-scale models additionally ensures reproducibility and reusability. By applying the pipeline to multiple biological problems, we demonstrate its broad applicability, which will benefit in particular image-based systems biology.

Availability

FitMultiCell is available open-source athttps://gitlab.com/fitmulticell/fit.

Contact

jan.hasenauer@uni-bonn.de

Supplementary information

Supplementary data are available athttps://doi.org/10.5281/zenodo.7646287online.
Plasticity of gene expression in the nervous system by exposure to environmental odorants that inhibit HDACs
Authors: Haga-Yamanaka Sachiko , Nuñez-Flores Rogelio , Scott Christi Ann , Perry Sarah , Chen Stephanie Turner , Pontrello Crystal , Nair Meera Goh , Ray Anandasankar
Published: February 2023

Eukaryotes are often exposed to microbes and respond to their secreted metabolites, such as the microbiome in animals or commensal bacteria in roots. Little is known about the effects of long-term exposure to volatile chemicals emitted by microbes, or other volatiles that we are exposed to over a long duration. Using the model systemDrosophila melanogaster,we evaluate a yeast emitted volatile, diacetyl, found in high levels around fermenting fruits where they spend long periods of time. We find that exposure to just the headspace containing the volatile molecules can alter gene expression in the antenna. Experiments showed that diacetyl and structurally related volatile compounds inhibited human histone-deacetylases (HDACs), increased histone-H3K9 acetylation in human cells, and caused wide changes in gene expression in bothDrosophilaand mice. Diacetyl crosses the blood-brain barrier and exposure causes modulation of gene expression in the brain, therefore has potential as a therapeutic. Using two separate disease models known to be responsive to HDAC-inhibitors, we evaluated physiological effects of volatile exposure. First, we find that the HDAC inhibitor also halts proliferation of a neuroblastoma cell line in culture as predicted. Next, exposure to vapors slows progression of neurodegeneration in aDrosophilamodel for Huntington’s disease. These changes strongly suggest that unbeknown to us, certain volatiles in the surroundings can have profound effects on histone acetylation, gene expression and physiology in animals.
Active site mutations of F420-dependent alkene reductases reverse stereoselectivity
Authors: Kang Suk Woo , Antoney James , Lupton David W. , Speight Robert , Scott Colin , Jackson Colin J.
Published: February 2023

Ene-reductases from the Flavin/Deazaflavin Oxidoreductase (FDOR) family have potential value in biocatalysis as they typically exhibit complementary stereoselectivity to the widely utilized Old Yellow Enzyme (OYE) family, yet they are comparatively poorly understood at a mechanistic level. Here, we use a rational design approach to generate a library of 46 active site mutants of two FDORs fromMycobacterium smegmatisand examine the effects on conversion and stereoselectivity against a panel of substrates. Analysis of the effects of these mutations on stereoselectivity across all substrates revealed that the catalytic mechanism is highly sensitive to the polarity of the immediate active site. A conserved active site tyrosine in these enzymes, which does not serve as the proton donor, strongly affects stereochemical outcomes with Cα- (but not Cβ-) substituted substrates. Notably, a Tyr-Met mutation at this position reversed the diastereomeric excess (de) with (R)-carvone from 85.3% to −17.3% (cis/trans). Additionally, this mutation significantly increases activity with (1S)- verbenone. Finally, we show that the altered stereoselectivity is not due to a “flipped” substrate binding mode in these mutants, but rather that the hydrogenation mode is altered to favorsynrelative toantiaddition. These results show that the FDORs are highly engineerable and that, despite their superficial similarity, the OYE and FDOR families differ in crucial mechanistic aspects.
Gut microbiota promotes pain chronicity in Myosin1A deficient male mice
Authors: Reynders Ana , Jhumka Z. Anissa , Gaillard Stéphane , Hoeffel Guillaume , Mantilleri Annabelle , Malapert Pascale , Salio Chiara , Ugolini Sophie , Castets Francis , Saurin Andrew J. , Serino Matteo , Moqrich Aziz
Published: February 2023

Over the past decade, the gut microbiota has emerged as an important regulator of nervous system’s health and disease states1. Yet, its contribution to the pathogenesis of chronic somatic pain remains poorly documented. Chronic pain is a heavily debilitating disease affecting more than 1.5 billion people worldwide that can manifest through a long-lasting hypersensitivity to mechanical and/or thermal stimulations2,3. Maladaptive responses of dorsal root ganglia (DRG) neurons and spinal cord (SC) interneurons to tissue injuries and also of non-neuronal cells including DRG macrophages and SC microglia are acknowledged as important drivers of sensory symptoms underlying chronic pain4,3,5–7. Recent evidence shows that signals from gut microbiota are required for the initiation of injury-induced sensory hypersensitivity, via the ability to interact with the immune system8–11. However, whether and how gut microbiota promotes pain chronicity remains unknown. Here, we report that male mice lackingMyosin1a(KO)12raised under single genotype housing conditions (KO-SGH) are predisposed to develop chronic injury-induced mechanical pain. We demonstrate that this predisposition is caused by their dysbiotic gut microbiota, which sustains the immune response in the DRG following neuropathic injury. Parental antibiotic treatment modifies gut microbiota composition and completely rescues the injury-induced chronic pain and associated DRG inflammatory response in male KO-SGH offspring. Together, our data establish a causal relationship between a dysbiotic gut microbiota and the predisposition to injury-induced chronic pain.
Brain network analysis in Parkinson’s disease patients based on graph theory
Authors: Akbari Shirin , Deevband Mohammad Reza , Alvar Amin Asgharzadeh , Zadeh Emadodin Fatemi , Tabar Hashem Rafie , Kelley Patrick , Tavakoli Meysam
Published: February 2023

Development of Parkinson’s disease causes functional impairment in the brain network of Parkinson’s patients. The aim of this study is to analyze brain networks of people with Parkinson’s disease based on higher resolution parcellations and newer graphical features. The topological features of brain networks were investigated in Parkinson’s patients (19 individuals) compared to healthy individuals (17 individuals) using graph theory. In addition, four different methods were used in graph formation to detect linear and nonlinear relationships between functional magnetic resonance imaging (fMRI) signals. The functional connectivity between the left precuneus and the left amygdala, as well as between the vermis 1-2 and the left temporal lobe was evaluated for the healthy and the patient groups. The difference between the healthy and patient groups was evaluated by non-parametric t-test and U-test. Based on the results, Parkinson’s patients showed a significant decrease in centrality criterion compared to healthy subjects. Furtheremore, changes in regional features of brain network were observed. There was also a significant difference between the two groups of healthy subjects and Parkinson’s patients in different areas by applying centrality criterion and the correlation coefficients. The results obtained for topological features indicate changes in the functional brain network of Parkinson’s patients. Finally, similar areas obtained by all three methods of graph formation in the evaluation of connectivity between paired regions in the brain network of Parkinson’s patients increased the reliability of the results.
CETP inhibitor evacetrapib enters mouse brain tissue
Authors: Phénix Jasmine , Côté Jonathan , Dieme Denis , Recinto Sherilyn J , Oestereich Felix , Efrem Sasen , Haddad Sami , Bouchard Michèle , Munter Lisa Marie
Published: February 2023

High levels of plasma cholesterol, especially high levels of low-density lipoprotein-cholesterol (LDL-C), have been associated with an increased risk of Alzheimer’s disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-C in plasma. Epidemiologically, decreased CETP activity has been associated with sustained cognitive performance during aging, longevity, and a lower risk of Alzheimer’s disease. Thus, pharmacological CETP inhibitors could potentially be repurposed for the treatment of Alzheimer’s disease as they are safe and effective at lowering CETP activity and LDL-C. While CETP is mostly expressed by the liver and secreted into the bloodstream, CETP is also expressed by astrocytes in the brain. It is therefore important to determine if CETP inhibitors can enter the brain. Here, we describe pharmacokinetic parameters of the CETP inhibitor evacetrapib in plasma, liver, and brain tissues in CETP transgenic mice. We show that evacetrapib crosses the blood-brain barrier and is detectable in brain tissue 0.5 h after a 40 mg/kg i.v. injection in a nonlinear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimer’s disease.
Palmitoylation of gasdermin D directs its membrane translocation and pore formation in pyroptosis
Authors: Balasubramanian Arumugam , Ghimire Laxman , Hsu Alan Y. , Kambara Hiroto , Liu Xing , Hasegawa Tomoya , Xu Rong , Tahir Muhammad , Yu Hongbo , Lieberman Judy , Luo Hongbo R.
Published: February 2023

Gasdermin D (GSDMD)-mediated macrophage pyroptosis plays a critical role in inflammation and host defense. Plasma membrane perforation elicited by caspase-cleaved GSDMD N-terminal domain (GSDMD-NT) triggers membrane rupture and subsequent pyroptotic cell death, resulting in release of pro-inflammatory IL-1β and IL-18. However, the biological processes leading to its membrane translocation and pore formation are not fully understood. Here, using a proteomics approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner and demonstrated that post-translational palmitoylation of GSDMD at Cys191/Cys192 (human/mouse) led to membrane translocation of GSDMD-NT but not full-length GSDMD. GSDMD lipidation, mediated by palmitoyl acyltransferases ZDHHC5/9 and facilitated by LPS-induced reactive oxygen species (ROS), was essential for GSDMD pore-forming activity and pyroptosis. Inhibition of GSDMD palmitoylation with palmitate analog 2-bromopalmitate or a cell permeable GSDMD-specific competing peptide suppressed pyroptosis and IL-1β release in macrophages, mitigated organ damage, and extended the survival of septic mice. Collectively, we establish GSDMD-NT palmitoylation as a key regulatory mechanism controlling GSDMD membrane localization and activation, providing a novel target for modulating immune activity in infectious and inflammatory diseases.

One Sentence Summary

LPS-induced palmitoylation at Cys191/Cys192 is required for GSDMD membrane translocation and its pore-forming activity in macrophages.
Wnt/β-catenin signaling within multiple cell types dependent uponkramerregulatesDrosophilaintestinal stem cell proliferation
Authors: Sun Hongyan , Shah Adnan Shami , Bonfini Alessandro , Buchon Nicolas S. , Baskin Jeremy M.
Published: February 2023

The gut epithelium is subject to constant renewal, a process reliant upon intestinal stem cell (ISC) proliferation that is driven by Wnt/β-catenin signaling. Despite the importance of Wnt signaling within ISCs, the relevance of Wnt signaling within other gut cell types and the underlying mechanisms that modulate Wnt signaling in these contexts remain incompletely understood. Using challenge of theDrosophilamidgut with a non-lethal enteric pathogen, we examine the cellular determinants of ISC proliferation, harnessingkramer, a recently identified regulator of Wnt signaling pathways, as a mechanistic tool. We find that Wnt signaling within Prospero-positive cells supports ISC proliferation and thatkramerregulates Wnt signaling in this context by antagonizingkelch, a Cullin-3 E3 ligase adaptor that mediates Dishevelled polyubiquitination. This work establisheskrameras a physiological regulator of Wnt/β-catenin signaling in vivo and suggests enteroendocrine cells as a new cell type that regulates ISC proliferation via Wnt/β-catenin signaling.
TET1 Catalytic Activity is Required for Reprogramming of Imprinting Control Regions and Patterning of Sperm-Specific Hypomethylated Regions
Authors: Prasasya Rexxi D. , Caldwell Blake A. , Liu Zhengfeng , Wu Songze , Leu Nicolae A. , Fowler Johanna M. , Cincotta Steven A. , Laird Diana J. , Kohli Rahul M. , Bartolomei Marisa S.
Published: February 2023

DNA methylation erasure is required for mammalian primordial germ cell reprogramming. TET enzymes iteratively oxidize 5-methylcytosine to generate 5-hyroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxycytosine to facilitate active genome demethylation. Whether these bases are required to promote replication-coupled dilution or activate base excision repair during germline reprogramming remains unresolved due to the lack of genetic models that decouple TET activities. Here, we generated two mouse lines expressing catalytically inactive TET1 (Tet1-HxD) and TET1 that stalls oxidation at 5hmC (Tet1-V).Tet1-/-,Tet1V/V, andTet1HxD/HxDsperm methylomes show that TET1Vand TET1HxDrescue mostTet1-/-hypermethylated regions, demonstrating the importance of TET1’s extra-catalytic functions. Imprinted regions, in contrast, require iterative oxidation. We further reveal a broader class of hypermethylated regions in sperm ofTet1mutant mice that are excluded fromde novomethylation during male germline development and depend on TET oxidation for reprogramming. Our study underscores the link between TET1-mediated demethylation during reprogramming and sperm methylome patterning.
3D Synaptic Organization of Layer III of the Human Anterior Cingulate and Temporopolar Cortex
Authors: Cano-Astorga Nicolás , Plaza-Alonso Sergio , DeFelipe Javier , Alonso-Nanclares Lidia
Published: February 2023

The human anterior cingulate and temporopolar cortices have been proposed as highly connected nodes involved in high-order cognitive functions, but their synaptic organization is still basically unknown due to the difficulties involved in studying the human brain. Using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) to study the synaptic organization of the human brain obtained with a short post-mortem delay allows excellent results to be obtained. We have used this technology to analyze the neuropil (where the vast majority of synapses are found) of layer III of the anterior cingulate cortex (Brodmann’s area 24) and the temporopolar cortex, including the temporal pole (Brodmann’s area 38 ventral and dorsal) and anterior middle temporal gyrus (Brodmann’s area 21). Our results, based on 6695 synapses fully reconstructed in 3D, revealed that Brodmann’s areas 24, 21 and ventral area 38 showed similar synaptic density and synaptic size, whereas dorsal area 38 displayed the highest synaptic density and the smallest synaptic size. However, the proportion of the different types of synapses (excitatory and inhibitory), the postsynaptic targets and the shapes of excitatory and inhibitory synapses were similar, regardless of the region examined. These observations indicate that certain aspects of the synaptic organization are rather homogeneous, whereas others show specific variations across cortical regions. Since not all data obtained in a given cortical region can be extrapolated to other cortical regions, further studies on the other cortical regions and layers are necessary to better understand the functional organization of the human cerebral cortex.
CLE11 and CLE10 Suppress Mycorrhizal Colonisation in Tomato
Authors: Wulf Kate , Wang Chenglei , Ho-Plagaro Tania , Kwon Choon-Tak , Velandia Karen , Correa-Lozano Alejandro , Tamayo-Navarrete María Isabel , Sun Jiacan , Reid James B. , García Garrido Jose Manuel , Foo Eloise
Published: February 2023

Symbioses with beneficial microbes are widespread in plants, but these relationships must balance the energy invested by the plants with the nutrients acquired. Symbiosis with arbuscular mycorrhizal (AM) fungi occurs throughout land plants but our understanding of the genes and signals that regulate colonisation levels is limited. Here, we demonstrate that in tomato two CLV3/EMBRYO-SURROUNDING REGION (CLE) peptides,SlCLE10 andSlCLE11, act to suppress AM colonisation of roots. Mutant studies and overexpression via hairy transformation indicateSlCLE11acts locally in the root to limit AM colonisation. Indeed,SlCLE11expression is strongly induced in AM colonised roots butSlCLE11is not required for phosphate suppression of AM colonisation.SlCLE11 may act through as yet uncharacterised signalling pathways, asSlCLE11does not suppress AM colonisation by acting through two previously characterised receptors with roles in regulating AM colonisation,SlFAB (CLAVATA1 orthologue) orSlCLV2.SlCLE10 appears to play a more minor or redundant role, ascle10mutants did not influence AM, although the fact that ectopic overexpression ofSlCLE10did suppress colonisation suggestsSlCLE10may play a role in regulating AM colonisation. Our findings show that CLE peptides regulate AM colonisation in the non-legume species tomato.
Early retinal deprivation crossmodally alters nascent subplate circuits and activity in the auditory cortex during the precritical period
Authors: Mukherjee Didhiti , Xue Binghan , Chen Chih-Ting , Chang Minzi , Kao Joseph P. Y. , Kanold Patrick O.
Published: February 2023

Sensory perturbation in one modality results in adaptive reorganization of neural pathways within the spared modalities, a phenomenon known as “crossmodal plasticity”, which has been examined during or after the classic ‘critical period’. Because peripheral perturbations can alter auditory cortex (ACX) activity and functional connectivity of the ACX subplate neurons (SPNs) even before the classic critical period, called the precritical period, we investigated if retinal deprivation at birth crossmodally alters ACX activity and SPN circuits during the precritical period.

We deprived newborn mice of visual inputs after birth by performing bilateral enucleation. We performed in vivo imaging in the ACX of awake pups during the first two postnatal weeks to investigate cortical activity. We found that enucleation alters spontaneous and sound-evoked activity in the ACX in an age-dependent manner. Next, we performed whole-cell patch clamp recording combined with laser scanning photostimulation in ACX slices to investigate circuit changes in SPNs. We found that enucleation alters the intracortical inhibitory circuits impinging on SPNs shifting the excitation-inhibition balance towards excitation and this shift persists after ear opening. Together, our results indicate that crossmodal functional changes exist in the developing sensory cortices at early ages before the onset of the classic critical period.
Ketosis Prevents Abdominal Aortic Aneurysm Rupture Through CCR2 Downregulation and Enhanced MMP Balance
Authors: Sastriques-Dunlop Sergio , Elizondo-Benedetto Santiago , Arif Batool , Meade Rodrigo , Zaghloul Mohamed S. , English Sean J. , Liu Yongjian , Zayed Mohamed A.
Published: February 2023

Abdominal aortic aneurysms (AAAs) are common in aging populations, and AAA rupture is associated with high morbidity and mortality. There is currently no effective medical preventative therapy for AAAs to avoid rupture. It is known that the monocyte chemoattractant protein (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis critically regulates AAA tissue inflammation, matrix-metalloproteinase (MMP) production, and in turn extracellular matrix (ECM) stability. However, therapeutic modulation of the CCR2 axis for AAA disease has so far not been accomplished. Since ketone bodies (KBs) are known to trigger repair mechanisms in response to vascular tissue inflammation, we evaluated whether systemicin vivoketosis can impact CCR2 signaling, and therefore impact AAA expansion and rupture. To evaluate this, male Sprague-Dawley rats underwent surgical AAA formation using porcine pancreatic elastase (PPE), and received daily β-aminopropionitrile (BAPN) to promote AAA rupture. Animals with formed AAAs received either a standard diet (SD), ketogenic diet (KD), or exogenous KB supplements (EKB). Animals that received KD and EKB reached a state of ketosis, and had significantly reduced AAA expansion and incidence of rupture. Ketosis also led to significantly reduced CCR2, inflammatory cytokine content, and infiltrating macrophages in AAA tissue. Additionally, animals in ketosis had improved balance in aortic wall matrix-metalloproteinase (MMP), reduced extracellular matrix (ECM) degradation, and higher aortic media Collagen content. This study demonstrates that ketosis plays an important therapeutic role in AAA pathobiology, and provides the impetus for future studies investigating the role of ketosis as a preventative strategy for individuals with AAAs.
Characterization of the growth behavior ofListeria monocytogenesinListeriasynthetic media
Authors: Schulz Lisa Maria , Konrath Alicia , Rismondo Jeanine
Published: February 2023

The foodborne pathogenListeria monocytogenescan grow in a wide range of environmental conditions. For the study of the physiology of this organism, several chemically defined media have been developed over the past decades. Here, we examined the ability ofL. monocytogeneswildtype strains EGD-e and 10403S to grow under salt and pH stress inListeriasynthetic medium (LSM). Furthermore, we determined that a wide range of carbon sources could support growth of both wildtype strains in LSM. However, for hexose phosphate sugars such as glucose-1-phosphate, bothL. monocytogenesstrains need to be pre-grown under conditions, where the major virulence regulator PrfA is active. In addition, growth of bothL. monocytogenesstrains was observed when LSM was supplemented with the amino acid sugarN-acetylmannosamine (ManNAc). We were able to show that some of the proteins encoded in the operonlmo2795-nanE, such as the ManNAc-6-phosphate epimerase NanE, are required for growth in presence of ManNAc. The first gene of the operon,lmo2795,encodes a transcriptional regulator of the RpiR family. Using electrophoretic mobility shift assays and quantitative real time PCR analysis, we were able to show that Lmo2795 binds to the promoter region of the operonlmo2795-nanEand activates its expression.

Originality-Significance Statement

Current knowledge of growth and survival of the human pathogenListeria monocytogenesunder diverse stress conditions is mostly generated in complex medium, a condition that is rarely found in the environment or host of the pathogen. Our work contributes to the characterization of the physiology ofL. monocytogenesgrown under nutrient limiting conditions and its growth requirements with regards to metabolizable carbon sources.
RIPK3-dependent necroptosis is the primary cause of RIPK1-deficient-induced immunodeficiency
Authors: Liu Xiaoyan , Zhu Xinxin , Shu Zhaoqian , Sun Liming , Wang Huayi
Published: February 2023

RIPK1 (receptor-interacting serine/threonine kinase 1) plays a pivotal role in developing the immune system—patients with homozygous loss-of-function mutations of RIPK1 present with immunodeficiency and intestinal inflammation. Here, we reported that RIPK1-deficient rats represented defects of human patients and were certified as a suitable disease model. Knocking outRipk3rather thanCaspase-8nearly completely corrected immunodeficiency disorders, developmental defects, and necroptosis in the thymus of RIPK1-deficient rats. However, inflammatory enteritis was still detected in eitherRipk1/Ripk3-orRipk1/Casp-8-double deficient rats and only rescued inRipk1/Ripk3/Caspase-8-triple deficient rats, suggesting RIPK3 mediated necroptosis and Caspase-8 dependent apoptosis contribute in different part in RIPK1-deficient caused the syndrome. Moreover, RIPK1-deficient rat dermal fibroblasts (RDFs) showed sensitive necroptosis and impaired NF-κB activation, also reported inRIPK1-deficienthuman patients. And pharmacological inhibition of NF-κB activation could sensitize necroptosis of rat cells. Since mutations that damage NF-κB activation could cause immunodeficiency in human patients, it suggested that aberrantly activated necroptosis play a vital role in certain kinds of primary immunodeficiency syndromes and pharmacological inhibition of necroptosis could be a novel therapeutic strategy for those diseases.
A flexible Bayesian approach for estimating survival probabilities from age‐at‐harvest data
Authors: Skelly Brett P. , Clipp Hannah L. , Landry Stephanie M. , Rogers Rich , Phelps Quinton , Anderson James T. , Rota Christopher T.
Published: February 2023

Understanding survival probabilities is critical for the sustainable harvest of wildlife and fisheries populations. Age‐ and stage class‐specific survival probabilities are needed to inform a suite of population models used to estimate abundance and track population trends. However, current techniques for estimating survival probabilities using age‐at‐harvest methods require restrictive assumptions or incorporate potentially unknown parameters within the model.

Using a Bayesian approach, we developed a flexible age‐at‐harvest model that incorporates either age‐ or stage‐structured populations, while accounting for uncertainty in age structure, population growth rates and relative selectivity. Survival probabilities can vary by age or stage class, as well as by environmental covariates, and both population growth rates and selectivity for each age or stage class can be specified as fixed and known or these parameters can be specified as informative priors, allowing for the incorporation of expert opinion. We evaluated our model with simulations and empirical data from harvested bobcats Lynx rufus and American paddlefish Polyodon spathula.

Models fit to simulated age‐at‐harvest data yielded unbiased estimates of survival probability when population growth rates and selectivity were centered on the data‐generating parameter. We obtained unbiased estimates of survival probability even with biased prior estimates of selectivity and random departures from the assumed stage distribution, although the latter increased uncertainty in those estimates. We found biased estimates of survival probability when the prior distribution for population growth rate was not centered on the data‐generating value. When fit to empirical harvest data, our proposed age‐at‐harvest model produced estimates of survival probability congruent to those reported in the literature within similar geographic regions.

We demonstrate the utility of a novel age‐at‐harvest model that estimates survival probability and realistically account for uncertainty in model parameters, transcending the restrictive assumptions and auxiliary data requirements of other methods. Furthermore, we advise collecting information about population trends and age structure alongside age‐at‐harvest data to help reduce bias. Although our model cannot replace more rigorous methods, we believe our model will be transformative for wildlife and fisheries practitioners who collect age‐at‐harvest data to estimate age‐ or stage‐specific survival probabilities to help inform management decisions.
A retrospective study of colonoscopic surveillance in the elderly
Authors: McGuinness Matthew J. , Joseph Nejo , Richards Simon J. G. , Speight Julian M.
Published: February 2023

Background

Aotearoa New Zealand (AoNZ) guidelines suggest surveillance colonoscopy should be carefully considered after age 75. The authors noted a cluster of patients presenting in their 8th and 9th decade of life with a new colorectal cancer (CRC) having previously been declined surveillance colonoscopy.

Methods

A 7‐year retrospective analysis was performed of patients who underwent a colonoscopy aged between 71 and 75 years in the period between 2006 and 2012. Kaplan–Meier graphs were created with survival measured from the time of index colonoscopy. Log rank tests were used to determine any difference in survival distribution. Relative risk (RR) was calculated, and 95% confidence intervals (CI) reported.

Results

A total of 623 patients met inclusion criteria; 461 (74%) had no indication for surveillance colonoscopy and 162 (26%) had an indication. Of the 162 patients with an indication, 91 (56.2%) underwent surveillance colonoscopies after the age of 75. Twenty‐three (3.7%) patients were diagnosed with a new CRC. Eighteen (78.2%) patients diagnosed with a new CRC underwent surgery. The median survival overall was 12.9 years (95% CI 12.2–13.5). This did not differ between patients with (13.1, 95% CI 12.1–14.1) or without (12.6, 95% CI 11.2–14.0) an indication for surveillance.

Conclusion

This study found one quarter of patients who had a colonoscopy between the ages of 71–75 had an indication for surveillance colonoscopy. Most patients with a new CRC underwent surgery. This study suggests it may be appropriate to update the AoNZ guidelines and consider adopting a risk stratification tool to aid decision making.
Factors associated with suicidal ideation and suicide attempts by Australian dental practitioners
Authors: Hopcraft Matthew S. , Stormon Nicole , McGrath Roisin , Parker Gordon
Published: February 2023

Introduction

To investigate factors associated with suicidal ideation and suicide attempts amongst Australian dental practitioners.

Methods

A self‐reported online survey of 1474 registered dental practitioners in Australia was conducted from October to December 2021. Participants reported thoughts of suicide in the preceding 12 months, prior to the preceding 12 months and prior suicide attempts.

Results

Overall, 17.6% reported thoughts of suicide in the preceding 12 months, 31.4% prior to the preceding 12 months, and 5.6% reported ever having made a suicide attempt. In multivariate models, the odds of suicidal ideation in the preceding 12 months were higher in dental practitioners who were male (OR = 2.01), had a current diagnosis of depression (OR = 1.62), were experiencing moderate (OR = 2.76) or severe psychological distress (OR = 3.58), had self‐reported illicit substance use (OR = 2.06) or had previous self‐reported suicide attempts (OR = 3.02). Younger dental practitioners had more than twice the odds of recent suicidal ideation than those aged 61+ years, with higher resilience having decreasing odds of suicidal ideation.

Limitations

This study did not address help seeking behaviours directly related to suicidal ideation, so it is not clear how many participants were actively seeking mental health support. The response rate was low and results may be subject to responder biases, with practitioners experiencing depression, stress and burnout being more willing to participate.

Conclusion

These finding highlight a high prevalence of suicidal ideation amongst Australian dental practitioners. It is important to continue to monitor their mental health and develop tailored programs to provide essential interventions and supports.
Impact of circadian rhythm and daytime variation on outcome after heart transplantation
Authors: Immohr Moritz Benjamin , Mehdiani Arash , Oehler Daniel , Hettlich Vincent Hendrik , Jenkins Freya Sophie , Westenfeld Ralf , Aubin Hug , Tudorache Igor , Boeken Udo , Lichtenberg Artur , Akhyari Payam
Published: February 2023

Intro

Recently, the impact of circadian rhythm and daytime variation on surgical outcomes has attracted interest. Although studies for coronary artery and aortic valve surgery report contrary results, effects on heart transplantation have not been studied.

Methods

Between 2010 and February 2022, 235 patients underwent HTx in our department. The recipients were reviewed and categorized according to the start of the HTx procedure – between 04:00 am and 11:59 am (morning, n = 79), 12:00 pm and 07:59 pm (afternoon, n = 68) or 08:00 pm and 03:59 am (night, n = 88).

Results

The incidence of high urgency status was slightly but not significantly increased (p = .08) in the morning (55.7%), compared to the afternoon (41.2%) or night (39.8%). The most important donor and recipient characteristics were comparable among the three groups. The incidence of severe primary graft dysfunction (PGD) requiring extracorporeal life support (morning: 36.7%, afternoon: 27.3%, night: 23.0%, p = .15) was also similarly distributed. In addition, there were no significant differences for kidney failure, infections, and acute graft rejection. However, the incidence of bleeding that required rethoracotomy showed an increased trend in the afternoon (morning: 29.1%, afternoon: 40.9%, night: 23.0%, p = .06). 30‐day survival (morning: 88.6%, afternoon: 90.8%, night: 92.0%, p = .82) and 1‐year survival (morning: 77.5%, afternoon: 76.0%, night: 84.4%, p = .41) were comparable between all groups.

Conclusion

Circadian rhythm and daytime variation did not affect the outcome after HTx. Postoperative adverse events as well as survival were comparable throughout day‐ and night‐time. As the timing of the HTx procedure is rarely possible and depends on the timing of organ recovery, these results are encouraging, as they allow for the continuation of the prevalent practice.