bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac lipid metabolism, mitochondrial function, and heart failure
Authors: Da Dalt Lorenzo , Cabodevilla Ainara G , Goldberg Ira J , Norata Giuseppe Danilo
Published: June 2023

A fine balance between uptake, storage, and the use of high energy fuels, like lipids, is crucial in the homeostasis of different metabolic tissues. Nowhere is this balance more important and more precarious than in the heart. This highly energy-demanding muscle normally oxidizes almost all the available substrates to generate energy, with fatty acids being the preferred source under physiological conditions.

In patients with cardiomyopathies and heart failure, changes in the main energetic substrate are observed; these hearts often prefer to utilize glucose rather than oxidizing fatty acids. An imbalance between uptake and oxidation of fatty acid can result in cellular lipid accumulation and cytotoxicity. In this review, we will focus on the sources and uptake pathways used to direct fatty acids to cardiomyocytes. We will then discuss the intracellular machinery used to either store or oxidize these lipids and explain how disruptions in homeostasis can lead to mitochondrial dysfunction and heart failure. Moreover, we will also discuss the role of cholesterol accumulation in cardiomyocytes. Our discussion will attempt to weave in vitro experiments and in vivo data from mice and humans and use several human diseases to illustrate metabolism gone haywire as a cause of or accomplice to cardiac dysfunction.
Lipocalin 10 is essential for protection against inflammation-triggered vascular leakage by activating LDL receptor-related protein 2-slingshot homologue 1 signalling pathway
Authors: Zhao Hongyan , Wang Peng , Wang Xiaohong , Du Wa , Yang Hui-Hui , Liu Yueying , Cui Shu-Nan , Huang Wei , Peng Tianqing , Chen Jing , Gao Chen , Wang Yigang , Sadayappan Sakthivel , Ma Chengen , Fan Yanbo , Wang Chunting , Fan Guo-Chang
Published: June 2023

Aims

Systemic inflammation occurs commonly during many human disease settings and increases vascular permeability, leading to organ failure, and lethal outcomes. Lipocalin 10 (Lcn10), a poorly characterized member of the lipocalin family, is remarkably altered in the cardiovascular system of human patients with inflammatory conditions. Nonetheless, whether Lcn10 regulates inflammation-induced endothelial permeability remains unknown.

Methods and results

Systemic inflammation models were induced using mice by injection of endotoxin lipopolysaccharide (LPS) or caecal ligation and puncture (CLP) surgery. We observed that the expression of Lcn10 was dynamically altered only in endothelial cells (ECs), but not in either fibroblasts or cardiomyocytes isolated from mouse hearts following the LPS challenge or CLP surgery. Using in vitro gain- and loss-of-function approaches and an in vivo global knockout mouse model, we discovered that Lcn10 negatively regulated endothelial permeability upon inflammatory stimuli. Loss of Lcn10 augmented vascular leakage, leading to severe organ damage and higher mortality following LPS challenge, compared to wild-type controls. By contrast, overexpression of Lcn10 in ECs displayed opposite effects. A mechanistic analysis revealed that both endogenous and exogenous elevation of Lcn10 in ECs could activate slingshot homologue 1 (Ssh1)-Cofilin signalling cascade, a key axis known to control actin filament dynamics. Accordingly, a reduced formation of stress fibre and increased generation of cortical actin band were exhibited in Lcn10-ECs, when compared to controls upon endotoxin insults. Furthermore, we identified that Lcn10 interacted with LDL receptor-related protein 2 (LRP2) in ECs, which acted as an upstream factor of the Ssh1-Confilin signalling. Finally, injection of recombinant Lcn10 protein into endotoxic mice showed therapeutic effects against inflammation-induced vascular leakage.

Conclusion

This study identifies Lcn10 as a novel regulator of EC function and illustrates a new link in the Lcn10-LRP2-Ssh1 axis to controlling endothelial barrier integrity. Our findings may provide novel strategies for the treatment of inflammation-related diseases.
Coronary microevaginations characterize culprit plaques and their inflammatory microenvironment in a subtype of acute coronary syndrome with intact fibrous cap: results from the prospective translational OPTICO-ACS study
Authors: Seppelt Claudio , Abdelwahed Youssef S , Meteva Denitsa , Nelles Gregor , Stähli Barbara E , Erbay Aslihan , Kränkel Nicolle , Sieronski Lara , Skurk Carsten , Haghikia Arash , Sinning David , Dreger Henryk , Knebel Fabian , Trippel Tobias D , Krisper Maximilian , Gerhardt Teresa , Rai Himanshu , Klotsche Jens , Joner Michael , Landmesser Ulf , Leistner David M
Published: June 2023

Aims

Coronary microevaginations (CMEs) represent an outward bulge of coronary plaques and have been introduced as a sign of adverse vascular remodelling following coronary device implantation. However, their role in atherosclerosis and plaque destabilization in the absence of coronary intervention is unknown. This study aimed to investigate CME as a novel feature of plaque vulnerability and to characterize its associated inflammatory cell–vessel–wall interactions.

Methods and results

A total of 557 patients from the translational OPTICO-ACS study programme underwent optical coherence tomography imaging of the culprit vessel and simultaneous immunophenotyping of the culprit lesion (CL). Two hundred and fifty-eight CLs had a ruptured fibrous cap (RFC) and one hundred had intact fibrous cap (IFC) acute coronary syndrome (ACS) as an underlying pathophysiology. CMEs were significantly more frequent in CL when compared with non-CL (25 vs. 4%, P < 0.001) and were more frequently observed in lesions with IFC-ACS when compared with RFC-ACS (55.0 vs. 12.7%, P < 0.001). CMEs were particularly prevalent in IFC-ACS-causing CLs independent of a coronary bifurcation (IFC-ICB) when compared with IFC-ACS with an association to a coronary bifurcation (IFC-ACB, 65.4 vs. 43.7%, P = 0.030). CME emerged as the strongest independent predictor of IFC-ICB (relative risk 3.36, 95% confidence interval 1.67–6.76, P = 0.001) by multivariable regression analysis. IFC-ICB demonstrated an enrichment of monocytes in both culprit blood analysis (culprit ratio: 1.1 ± 0.2 vs. 0.9 ± 0.2, P = 0.048) and aspirated culprit thrombi (326 ± 162 vs. 96 ± 87 cells/mm2, P = 0.017), while IFC-ACB confirmed the accumulation of CD4+ T cells, as recently described.

Conclusion

This study provides novel evidence for a pathophysiological involvement of CME in the development of IFC-ACS and provides first evidence for a distinct pathophysiological pathway for IFC-ICB, driven by CME-derived flow disturbances and inflammatory activation involving the innate immune system.

Trial registration

Registration of the study at clinicalTrials.gov (NCT03129503).
Cardiovascular risks of continuing vs. initiating NSAIDs after first-time myocardial infarction or heart failure: a nationwide cohort study
Authors: Schmidt Morten , Hallas Jesper , Ernst Martin Thomsen , Pottegård Anton
Published: June 2023

Aims

It is unknown whether the cardiovascular risks associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) shortly after first-time myocardial infarction (MI) or heart failure (HF) differ between patients continuing and initiating use.

Methods and results

Using nationwide health registries, we conducted a cohort study of all patients with first-time MI or HF during 1996–2018 (n = 273 682). NSAID users (n = 97 966) were categorized as continuing (17%) and initiating (83%) users according to prescription fillings < 60 days before index diagnosis. The primary outcome was a composite of new MI, HF admission, and all-cause death. Follow-up started 30 days after the index discharge date. We used Cox regression to compute hazard ratios (HRs) with 95% confidence intervals (CIs) comparing NSAID users vs. non-users. The most commonly filled NSAIDs were ibuprofen (50%), diclofenac (20%), etodolac (8.5%), and naproxen (4.3%). The composite outcome HR of 1.25 (CI: 1.23–1.27) was driven by initiators (HR = 1.39, 1.36–1.41) and not continuing users (HR = 1.03, 1.00–1.07). The lack of association among continuing users was also observed for individual NSAIDs (ibuprofen and naproxen), except diclofenac (HR = 1.11, 95% CI: 1.05–1.18). Among initiators, the HR was 1.63 (CI: 1.57–1.69) for diclofenac, 1.31 (CI: 1.27–1.35) for ibuprofen, and 1.19 (CI: 1.08–1.31) for naproxen. The results were consistent for both MI and HF patients, the individual components of the composite outcome, and various sensitivity analyses.

Conclusion

NSAID initiators were more susceptible to adverse cardiovascular outcomes after first-time MI or HF than continuing users.
Coronary microcirculatory dysfunction can be assessed by positive dicrotic wave and amplitude index on resting distal coronary pressure waveform, a newly developed index
Authors: Fujimori Yoshiharu , Hashimoto Satoshi , Takahashi Miki , Hoshino Hirotada , Shimizu Kenji , Terasawa Yuya , Wakabayashi Tadamasa , Imai Taku
Published: June 2023

Aims

Some lesions have high resting distal coronary pressure/aortic pressure (Pd/Pa) despite low fractional flow reserve (FFR). This study aimed to assess microcirculatory dysfunction as a possible basal mechanism.

Methods and results

Patients were grouped into two according to coffee intake (caffeine 222 mg) before coronary angiography. Through an adenosine-induced Pd/Pa decrease, amplitude index was calculated by dividing the difference between the highest pressure after the inflection point and the minimal diastolic pressure by the pulse pressure on the Pd waveform. In 130 coronary lesions (caffeine group, n = 69; non-caffeine group, n = 61) from 113 patients, the amplitude index through the adenosine-induced Pd/Pa decrease in all lesions was 0.54 ± 0.11 at resting Pd/Pa and 0.44 ± 0.12 at FFR (P < 0.0001). The positive dicrotic wave distribution on a maximal hyperaemia (FFRnicr)–resting Pd/Pa graph was analysed. In lesions with FFRnicr <0.80 on the FFRnicr–resting Pd/Pa graph, the resting Pd/Pa was divided into three zones based on Pd/Pa values: high-remaining, intermediate, and low. The high-remaining zone had a higher amplitude index than the intermediate zone (0.60 ± 0.09 vs. 0.48 ± 0.12; P < 0.005); the low zone lesions had no inflection point (no amplitude index). The high-remaining zone correlated with a larger positive dicrotic wave than the intermediate zone (94 vs. 30%; P < 0.005). Most lesions in the high-remaining zone corresponded to the caffeine group.

Conclusion

In severe coronary stenosis, a high-remaining resting Pd/Pa with a high amplitude index or a positive dicrotic wave on the resting Pd waveform suggests microcirculatory dysfunction, such as insufficient arteriolar dilation reactive to myocardial ischaemia.

Registration

UMIN000046883.
Left ventricular functional recovery after atrial fibrillation catheter ablation in heart failure: a prediction model
Authors: Bergonti Marco , Ascione Ciro , Marcon Lorenzo , Pambrun Thomas , Della Rocca Domenico G , Ferrero Teba Gonzalez , Pannone Luigi , Kühne Michael , Compagnucci Paolo , Bonomi Alice , Gevaert Andreas B , Anselmino Matteo , Casella Michela , Krisai Philipp , Tondo Claudio , Rodríguez-Mañero Moises , Derval Nicolas , Chierchia Gian-Battista , de Asmundis Carlo , Heidbuchel Hein , Jaïs Pierre , Sarkozy Andrea
Published: June 2023

Aims

Management of patients with atrial fibrillation (AF) and concomitant heart failure (HF) remains complex. The Antwerp score, based on four parameters [QRS >120 ms (2 points), known aetiology (2 points), paroxysmal AF (1 point), severe atrial dilation (1 point)] adequately estimated the probability of left ventricular ejection fraction (LVEF) recovery after AF ablation in a single-centre cohort. The present study aims to externally validate this prediction model in a large European multi-centre cohort.

Methods and results

A total of 605 patients (61.1 ± 9.4 years, 23.8% females, 79.8% with persistent AF) with HF and impaired LVEF (<50%) undergoing AF ablation in 8 European centres were retrospectively identified. According to the LVEF changes at 12-month echocardiography, 427 (70%) patients fulfilled the ‘2021 Universal Definition of HF’ criteria for LVEF recovery and were defined as ‘responders’. External validation of the score yielded good discrimination and calibration {area under the curve 0.86 [95% confidence interval (CI) 0.82–0.89], P < .001; Hosmer–Lemeshow P = .29}. Patients with a score < 2 had a 93% probability of LVEF recovery as opposed to only 24% in patients with a score > 3. Responders experienced more often positive ventricular remodelling [odds ratio (OR) 8.91, 95% CI 4.45–17.84, P < .001], fewer HF hospitalizations (OR 0.09, 95% CI 0.05–0.18, P < .001) and lower mortality (OR 0.11, 95% CI 0.04–0.31, P < .001).

Conclusion

In this multi-centre study, a simple four-parameter score predicted LVEF recovery after AF ablation in patients with HF and discriminated clinical outcomes. These findings support the use of the Antwerp score to standardize shared decision-making regarding AF ablation referral in future clinical studies.
Evaluating power to detect recurrent selective sweeps under increasingly realistic evolutionary null models
Authors: Soni Vivak , Johri Parul , Jensen Jeffrey D
Published: June 2023

The detection of selective sweeps from population genomic data often relies on the premise that the beneficial mutations in question have fixed very near the sampling time. As it has been previously shown that the power to detect a selective sweep is strongly dependent on the time since fixation as well as the strength of selection, it is naturally the case that strong, recent sweeps leave the strongest signatures. However, the biological reality is that beneficial mutations enter populations at a rate, one that partially determines the mean wait time between sweep events and hence their age distribution. An important question thus remains about the power to detect recurrent selective sweeps when they are modeled by a realistic mutation rate and as part of a realistic distribution of fitness effects, as opposed to a single, recent, isolated event on a purely neutral background as is more commonly modeled. Here we use forward-in-time simulations to study the performance of commonly used sweep statistics, within the context of more realistic evolutionary baseline models incorporating purifying and background selection, population size change, and mutation and recombination rate heterogeneity. Results demonstrate the important interplay of these processes, necessitating caution when interpreting selection scans; specifically, false-positive rates are in excess of true﻿-positive across much of the evaluated parameter space, and selective sweeps are often undetectable unless the strength of selection is exceptionally strong.
Parental experiences and opinions regarding the management of acute otitis media in Finland—a comparative questionnaire between 2006 and 2019
Authors: Jokinen Sylvia , Ruohola Aino , Tähtinen Paula A
Published: June 2023

Background

Treatment guidelines for acute otitis media (AOM) have changed over the past 20 years. Watchful waiting is often recommended as an option for antibiotic treatment and the use of proper pain medication is emphasised.

Objective

To study parental experiences and opinions regarding the management of AOM and compare our findings with our previous questionnaire submitted in 2006.

Methods

We sent an online survey link through day-care centres and Facebook parental groups in Turku area. Children <4 years of age attending day care were included in the analysis. We asked about the child’s history of AOM, parental opinions about AOM treatment, and antibiotic resistance. Results of 2019 were compared with those of 2006.

Results

Altogether 84% (320/381) and 83% (568/681) of children had had at least 1 episode of AOM in 2019 and 2006, respectively. In 2019, more children had been treated without antibiotics (30% vs. 13%, P < 0.001) and fewer parents thought that antibiotics are necessary for the treatment of AOM (70% vs. 85%, P < 0.001) compared with 2006. The use and knowledge of painkillers had increased over the past 13 years. Painkillers had been given at least once to 93% (296/320) of children in 2019 and 80% (441/552) of children in 2006 (P < 0.001).

Conclusions

Today, more parents accept watchful waiting as a treatment option for AOM and give painkillers to their children, which indicates that the education about optimal management of AOM has reached parents.
Automated characterization of forest canopy vertical layering for predicting forest inventory attributes by layer using airborne LiDAR data
Authors: Penner Margaret , White Joanne C , Woods Murray E
Published: June 2023

Forest canopy vertical layering influences stand development and yield and is critical information for forest management planning and wood supply analysis. It is also relevant for other applications including habitat modelling, forest fuels management and assessing forest resilience. Forest inventories that use coincident airborne Light Detection and Ranging (LiDAR) data and field plots (i.e. area-based approach) to predict forest attributes generally do not consider the multi-layer canopy structure that may be found in many natural and managed forest stands. With airborne LiDAR, it is possible to separate single-layer and multi-layer stands. This information can be used to allocate predictions of forest attributes such as timber volume (m3 ha−1), by canopy layer. In this study, we used single-photon LiDAR data to automate the mapping of vertical stand layering in a temperate mixedwood forest with a variety of forest types and vertical complexities. We first predicted whether each 25 × 25 m grid cell had one or two canopy layers, and then partitioned inventory attributes (e.g. basal area (BA), gross total stem volume (GTV)) by canopy layer. We compared two methods for estimating attributes by layer at the stand level using nine independent validation stands. Overall agreement between the reference and predicted structure for the calibration plots was 74% (n = 266). At the grid-cell level, attributes were generally underestimated for the upper layer and overestimated for the lower layer. For the validation stands, the relative height of the lower layer was under-predicted compared to the reference data (46–52% versus 57%), while the proportion of BA and GTV in the lower layer were very similar to the reference values (17–19% versus 18% for BA and 12–15% versus 12% for GTV). Overall, the approach showed promise in distinguishing single- and two-layered stand conditions and partitioning estimates of inventory attributes such as BA and GTV by layer—both for grid cells and at the stand level. The inclusion of forest information by canopy layer enhances the utility of LiDAR-derived forest inventories for forest management in forest areas with complex, multi-layer stand conditions.
Prediction of chronological age and its applications in forensic casework: methods, current practices, and future perspectives
Authors: Refn Mie Rath , Kampmann Marie-Louise , Morling Niels , Tfelt-Hansen Jacob , Børsting Claus , Pereira Vania
Published: June 2023

Estimating an individual’s age can be relevant in several areas primarily related to the clinical and forensic fields. In the latter, estimation of an individual’s chronological age from biological material left by the perpetrator at a crime scene may provide helpful information for police investigation. Estimation of age is also beneficial in immigration cases, where age can affect the person’s protection status under the law, or in disaster victim identification to narrow the list of potential missing persons. In the last decade, research has focused on establishing new approaches for age prediction in the forensic field. From the first forensic age estimations based on morphological inspections of macroscopic changes in bone and teeth, the focus has shifted to molecular methods for age estimation. These methods allow the use of samples from human biological material that does not contain morphological age features and can, in theory, be investigated in traces containing only small amounts of biological material. Molecular methods involving DNA analyses are the primary choice and estimation of DNA methylation levels at specific sites in the genome is the most promising tool. This review aims to provide an overview of the status of forensic age prediction using molecular methods, with particular focus in DNA methylation. The frequent challenges that impact forensic age prediction model development will be addressed, together with the importance of validation efforts within the forensic community.
Prevalence and determinants of diarrhoea and acute respiratory infections among children aged under five years in West Africa: evidence from demographic and health surveys
Authors: Owusu Derrick Nyantakyi , Duah Henry Ofori , Dwomoh Duah , Alhassan Yakubu
Published: June 2023

Background

Diarrhoea and pneumonia are the leading causes of morbidity and mortality in children aged <5 y (under five) globally. This study sought to investigate the prevalence and determinants of diarrhoea and acute respiratory infections (ARIs) among children under five in West Africa.

Methods

The most recent demographic and health survey (DHS) standard for 13 West African countries was used in the study. We calculated the prevalence of diarrhoea and ARIs (2 wk prior to the survey) and performed multivariable complex logistic regression analysis to identify possible predictors of diarrhoea and ARIs.

Results

The weighted prevalence of diarrhoea and ARI was 13.7% and 15.9%, respectively. The prevalence of comorbid diarrhoea and ARI was 4.4%. Children aged <2 y (p<0.001), mothers aged <30 y (p<0.003), mothers without formal education (p<0.001), poor households (p<0.001) and poor nutritional status, wasting (p=0.005) and underweight (p<0.001), were the independent predictors of diarrhoea. The independent predictors of ARIs were children with no childhood vaccinations (p=0.002), use of solid fuel in the household (p=0.007), being underweight (p=0.05) and diarrhoea (p<0.001).

Conclusions

The findings imply the need for holistic public health interventions such as increased vaccination coverage, population-based nutritional programmes and campaigns on the use of cleaner cooking fuel targeted at high-risk subgroups in the population to reduce the burden and adverse effects of diarrhoea and ARIs in the West African region.
A PROBLEM of RULES: Sexual Exploitation and UN Legitimacy
Authors: Westendorf Jasmine-Kim
Published: June 2023

Twenty years ago, the UN adopted a zero-tolerance policy on sexual exploitation and abuse (SEA) by its personnel. After prohibiting sex with children and the exchange of sex for “cash, food and things,” it “strongly discourages” sexual relationships with beneficiaries because “they are based on inherently unequal power dynamics” and undermine the UN’s credibility and integrity. Taking inspiration from the critical feminist project of understanding what happens when feminist ideas and projects become institutionalised, I consider the effectiveness and unintended consequences of the policy's discouraged relationships standard. I argue that by centring an “inherent power imbalance” between peacekeepers and local people, the policy undermines the UN’s capacity to meaningfully address that imbalance in practice. Moreover, the discouraged relationships standard diminishes the policy’s perceived legitimacy among staff, with ramifications beyond the prevention and punishment of sexual misconduct. Based on research in Bosnia-Herzegovina, Timor-Leste, Geneva, and New York, this article generates insights about the persistent challenges to preventing and punishing SEA and situates them in relation to broader questions around how international missions view and interact with local populations, and how this affects the integrity and effectiveness of their work.
In vitro activity of cefiderocol against MBL-producing Gram-negative bacteria collected in North America and Europe in five consecutive annual multinational SIDERO-WT surveillance studies (2014–2019)
Authors: Takemura Miki , Wise Mark G , Hackel Meredith A , Sahm Daniel F , Yamano Yoshinori
Published: June 2023

Objectives

To evaluate the in vitro antibacterial activity of cefiderocol, a siderophore cephalosporin against MBL-producing clinical isolates.

Methods

MBL-producing strains were selected from clinical isolates of Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii complex collected in North America and Europe in five consecutive annual multinational SIDERO-WT surveillance studies from 2014 to 2019. MICs of cefiderocol and comparator agents were determined by the broth microdilution method according to the CLSI guideline.

Results

A total of 452 MBL-producing strains consisting of 200 Enterobacterales, 227 P. aeruginosa and 25 A. baumannii complex were identified. The highest number of MBL-producing Enterobacterales strains were detected in Greece. MBL-producing strains of both P. aeruginosa and A. baumannii complex were isolated most frequently in Russia. For Enterobacterales, 91.5% or 67.5% of MBL-producing strains had cefiderocol MIC values ≤4 mg/L (CLSI susceptibility breakpoint) or ≤2 mg/L (EUCAST susceptibility breakpoint), respectively. All MIC values of cefiderocol for MBL-producing P. aeruginosa strains were ≤4 mg/L (CLSI susceptibility breakpoint), and 97.4% of them had cefiderocol MIC values ≤2 mg/L (EUCAST susceptibility breakpoint). For A. baumannii complex, 60.0% or 44.0% of MBL-producing strains had cefiderocol MIC values ≤4 mg/L (CLSI susceptibility breakpoint) or ≤2 mg/L (EUCAST pharmacokinetic-pharmacodynamic susceptibility breakpoint), respectively. Against all types of MBL-producing strains, MIC distribution curves of cefiderocol were located in the lowest numerical values, compared with other β-lactams and β-lactam/β-lactamase inhibitor combinations tested and ciprofloxacin.

Conclusions

Although the types of MBL-producing strains isolated by country varied, cefiderocol showed potent in vitro activity against all types of MBL-producing Gram-negative bacteria regardless of the bacterial species.
Cooperative DNA-binding activities of Chp2 are critical for its function in heterochromatin assembly
Authors: Rahayu Anisa Fitri , Hayashi Aki , Yoshimura Yuriko , Nakagawa Reiko , Arita Kyohei , Nakayama Jun-ichi
Published: June 2023

Heterochromatin protein 1 (HP1) is an evolutionarily conserved protein that plays a critical role in heterochromatin assembly. HP1 proteins share a basic structure consisting of an N-terminal chromodomain (CD) and a C-terminal chromoshadow domain (CSD) linked by a disordered hinge region. The CD recognizes histone H3 lysine 9 methylation, a hallmark of heterochromatin, while the CSD forms a dimer to recruit other chromosomal proteins. HP1 proteins have been shown to bind DNA or RNA primarily through the hinge region. However, how DNA or RNA binding contributes to their function remains elusive. Here, we focus on Chp2, one of the two HP1 proteins in fission yeast, and investigate how Chp2's DNA-binding ability contributes to its function. Similar to other HP1 proteins, the Chp2 hinge exhibits clear DNA-binding activity. Interestingly, the Chp2 CSD also shows robust DNA-binding activity. Mutational analysis revealed that basic residues in the Chp2 hinge and at the N-terminus of the CSD are essential for DNA binding, and the combined amino acid substitutions of these residues alter Chp2 stability, impair Chp2 heterochromatin localization and lead to a silencing defect. These results demonstrate that the cooperative DNA-binding activities of Chp2 play an important role in heterochromatin assembly in fission yeast.
Crack growth degradation-based diagnosis and design of high pressure liquefied natural gas pipe via designable data-augmented anomaly detection
Authors: Yang Dabin , Lee Sanghoon , Lee Jongsoo
Published: June 2023

A new approach to anomaly detection termed “anomaly detection with designable generative adversarial network (Ano-DGAN)” is proposed, which is a series connection of a designable generative adversarial network and anomaly detection with a generative adversarial network. The proposed Ano-DGAN, based on a deep neural network, overcomes the limitations of abnormal data collection when performing anomaly detection. In addition, it can perform statistical diagnosis by identifying the healthy range of each design variable without a massive amount of initial data. A model was constructed to simulate a high-pressure liquefied natural gas pipeline for data collection and the determination of the critical design variables. The simulation model was validated and compared with the failure mode and effect analysis of a real pipeline, which showed that stress was concentrated in the weld joints of the branch pipe. A crack-growth degradation factor was applied to the weld, and anomaly detection was performed. The performance of the proposed model was highly accurate compared with that of other anomaly detection models, such as support vector machine, 1D convolutional neural network, and long short-term memory. The results provided a statistical estimate of the design variable ranges and were validated statistically, indicating that the diagnosis was acceptable.
Repeated mild closed head injury in neonatal rats results in sustained cognitive deficits associated with chronic microglial activation and neurodegeneration
Authors: Raghupathi Ramesh , Prasad Rupal , Fox Douglas , Huh Jimmy W
Published: June 2023

Abusive head trauma in infants is a consequence of multiple episodes of abuse and results in axonal injury, brain atrophy, and chronic cognitive deficits. Anesthetized 11-day-old rats, neurologically equivalent to infants, were subjected to 1 impact/day to the intact skull for 3 successive days. Repeated, but not single impact(s) resulted in spatial learning deficits (p < 0.05 compared to sham-injured animals) up to 5 weeks postinjury. In the first week following single or repetitive brain injury, axonal and neuronal degeneration, and microglial activation were observed in the cortex, white matter, thalamus, and subiculum; the extent of the histopathologic damage was significantly greater in the repetitive-injured animals compared to single-injured animals. At 40 days postinjury, loss of cortical, white matter and hippocampal tissue was evident only in the repetitive-injured animals, along with evidence of microglial activation in the white matter tracts and thalamus. Axonal injury and neurodegeneration were evident in the thalamus up to 40 days postinjury in the repetitive-injured rats. These data demonstrate that while single closed head injury in the neonate rat is associated with pathologic alterations in the acute post-traumatic period, repetitive closed head injury results in sustained behavioral and pathologic deficits reminiscent of infants with abusive head trauma.
Modulating moderation: a history of objectionability in Twitter moderation practices
Authors: de Keulenaar Emillie , Magalhães João C , Ganesh Bharath
Published: June 2023

With their power to shape public discourse under unprecedented scrutiny, social media platforms have revamped their speech control practices in recent years by building complex systems of content moderation. The contours of this tectonic shift are relatively clear. Yet, little work has systematically documented, examined, and theorized this process. This article uses digital methods and web history to trace the evolution of objectionable content on Twitter content moderation policies and practices between 2006 and 2022. Its conclusions suggest that, more than abandoning an Americanized view of freedom of speech, Twitter has aimed at building a crisis-resistant speech architecture that can withstand external shocks, criticisms, and shifting speech norms. This kind of modulated moderation, as we term it, hinges on a form of normative plasticity, whose goal is not necessarily adjudicating content as more or less acceptable, but moderating it on the basis of evolving and ever contingent public conceptions of objectionability.
Fragile Solidarities: Contestation and Ambiguity at European Borderzones
Authors: Monforte Pierre , Steinhilper Elias
Published: June 2023

Borders as legal, social, and material aspaces of inclusion/exclusion constantly spark resistance, by both migrants and solidarity actors. In this article, we combine the dual observation of a proliferation of border control policies and of migrant and solidarity activism to analyse how different types of border control policies affect the forms of resistance that emerge in them. We inquire on three different cases: first the Calais region at the territorial border between France and the UK; second the camps and detention centres for refugees and migrants marking borders within Europe; and third the intimate space of encounters between citizens and migrants during practices of migrant support. In our theory oriented qualitative analysis, we carve out how power relations, and thereby notions of inclusion/exclusion, deservingness and (il)legality play out differently on the ambivalent solidarities unfolding in these settings.
Loss-of-function mutations in IQCN cause male infertility in humans and mice owing to total fertilization failure
Authors: Wang Yulin , Chen Guoyong , Tang Zhenzhen , Mei Xiaoyan , Lin Chunli , Kang Jingyi , Lian Jianqing , Lu Jun , Liu Yun , Lan Fenghua , Huang Wujian , Zhang Duo
Published: June 2023

Fertilization failure is a significant manifestation of unexplained male infertility. Previous work has suggested a genetic origin. In this study, we report on a man with unexplained infertility from a large consanguineous marriage family. Whole-exome sequencing and Sanger sequencing identified a homozygous frameshift variation of the IQ motif containing N (IQCN; GenBank: NM_001145304.1; c.1061_1062delAT; p.Y354Sfs*13) in the proband and one of his two brothers, who also remained infertile. Analyses of spermatozoa by quantitative RT-PCR indicated that the level of IQCN mRNA was significantly reduced compared to fertile men and the protein could not be detected by western blotting and immunofluorescent staining in the proband. Immunofluorescent staining of spermatozoa from fertile men showed that IQCN was located in the acrosomal region and translocated to the equatorial segment after the acrosome reaction. The proband spermatozoa had abnormal morphology and function. Finally, the proband couple underwent IVF with donor sperm and a healthy baby was born. Furthermore, we developed an Iqcn-KO mouse model using the CRISPR/Cas9 technique. Sperm quality, except for sperm motility, and the fertility of male Iqcn−/− mice were consistent with those of the proband. In conclusion, the findings in humans and mice demonstrate that the homozygous frameshift variant of IQCN causes male infertility owing to autosomal-recessive fertilization failure.
Using imlifidase to elucidate the characteristics and importance of anti-GBM antibodies produced after start of treatment
Authors: Tyrberg Linnéa , Andersson Fanny , Uhlin Fredrik , Hellmark Thomas , Segelmark Mårten
Published: June 2023

Background

Autoantibodies are common in glomerulonephritis, but the clinical benefit of rapid elimination has not been determined, even in anti-glomerular basement membrane (GBM) disease. Even less is known about the importance of autoantibody characteristics, including epitope specificity and immunoglobulin G (IgG) subclass distribution. We aimed to address this by characterizing the autoantibody profile in anti-GBM patients: we utilized samples from the GOOD-IDES-01 (treating GOODpasture's disease with Imunoglobulin G Degrading Enzyme of Streptococcus pyogenous) (ClinicalTrials.gov identifier: NCT03157037) trial , where imlifidase, which cleaves all IgG in vivo within hours, was given to 15 anti-GBM patients.

Methods

In the GOOD-IDES-01 trial, plasmapheresis was (re)started if anti-GBM antibodies rebounded. Serum samples were collected prospectively for 6 months and analyzed for anti-GBM epitope specificity using recombinant constructs of the EA and EB epitopes, IgG subclass using monoclonal antibodies, and anti-neutrophil cytoplasmic antibodies (ANCA). The results were correlated with clinical data.

Results

Patients with a rebound (n = 10) tended to have lower eGFR at 6 months (11 vs 34 mL/min/1.73 m2, P = .055), and patients with dialysis at 6 months had a higher EB/EA ratio at rebound (0.8 vs 0.5, P = .047). Moreover, two patients demonstrated increasing epitope restriction and several patients displayed a shift in subclass distribution at rebound. Six patients were double positive for ANCA. ANCA rebound was seen in 50% of patients; only one patient remained ANCA positive at 6 months.

Conclusions

In this study, rebound of anti-GBM antibodies, especially if directed against the EB epitope, was associated with a worse outcome. This supports the notion that all means should be used to eliminate anti-GBM antibodies. In this study ANCA was removed early and long-term by imlifidase and cyclophosphamide.
Insulin feedback is a targetable resistance mechanism of PI3K inhibition in glioblastoma
Authors: Noch Evan K , Palma Laura N , Yim Isaiah , Bullen Nayah , Qiu Yuqing , Ravichandran Hiranmayi , Kim Junbum , Rendeiro Andre , Davis Melissa B , Elemento Olivier , Pisapia David J , Zhai Kevin , LeKaye Hongbiao Carl , Koutcher Jason A , Wen Patrick Y , Ligon Keith L , Cantley Lewis C
Published: June 2023

Background

Insulin feedback is a critical mechanism responsible for the poor clinical efficacy of phosphatidylinositol 3-kinase (PI3K) inhibition in cancer, and hyperglycemia is an independent factor associated with poor prognosis in glioblastoma (GBM). We investigated combination anti-hyperglycemic therapy in a mouse model of GBM and evaluated the association of glycemic control in clinical trial data from patients with GBM.

Methods

The effect of the anti-hyperglycemic regimens, metformin and the ketogenic diet, was evaluated in combination with PI3K inhibition in patient-derived GBM cells and in an orthotopic GBM mouse model. Insulin feedback and the immune microenvironment were retrospectively evaluated in blood and tumor tissue from a Phase 2 clinical trial of buparlisib in patients with recurrent GBM.

Results

We found that PI3K inhibition induces hyperglycemia and hyperinsulinemia in mice and that combining metformin with PI3K inhibition improves the treatment efficacy in an orthotopic GBM xenograft model. Through examination of clinical trial data, we found that hyperglycemia was an independent factor associated with poor progression-free survival in patients with GBM. We also found that PI3K inhibition increased insulin receptor activation and T-cell and microglia abundance in tumor tissue from these patients.

Conclusion

Reducing insulin feedback improves the efficacy of PI3K inhibition in GBM in mice, and hyperglycemia worsens progression-free survival in patients with GBM treated with PI3K inhibition. These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in GBM and that anti-hyperglycemic therapy may enhance PI3K inhibitor efficacy in GBM patients.
Uncover rock-climbing fish's secret of balancing tight adhesion and fast sliding for bioinspired robots
Authors: Tan Wenjun , Zhang Chuang , Wang Ruiqian , Fu Yuanyuan , Chen Qin , Yang Yongliang , Wang Wenxue , Zhang Mingjun , Xi Ning , Liu Lianqing
Published: June 2023

The underlying principle of the unique dynamic adaptive adhesion capability of a rock-climbing fish (Beaufortia kweichowensis) that can resist a pull-off force of 1000 times its weight while achieving simultaneous fast sliding (7.83 body lengths per second (BL/S)) remains a mystery in the literature. This adhesion-sliding ability has long been sought for underwater robots. However, strong surface adhesion and fast sliding appear to contradict each other due to the need for high surface contact stress. The skillfully balanced mechanism of the tight surface adhesion and fast sliding of the rock-climbing fish is disclosed in this work. The Stefan force (0.1 mN/mm2) generated by micro-setae on pectoral fins and ventral fins leads to a 70 N/m2 adhesion force by conforming the overall body of the fish to a surface to form a sealing chamber. The pull-off force is neutralized simultaneously due to the negative pressure caused by the volumetric change of the chamber. The rock-climbing fish's micro-setae hydrodynamic interaction and sealing suction cup work cohesively to contribute to low friction and high pull-off-force resistance and can therefore slide rapidly while clinging to the surface. Inspired by this unique mechanism, an underwater robot is developed with incorporated structures that mimic the functionality of the rock-climbing fish via a micro-setae array attached to a soft self-adaptive chamber, a setup which demonstrates superiority over conventional structures in terms of balancing tight underwater adhesion and fast sliding.
Phase I/II Trial of Carboplatin, Nab-paclitaxel, and Pembrolizumab for Advanced Non–Small Cell Lung Cancer: Hoosier Cancer Research Network LUN13-175
Authors: Gentzler Ryan D , Mohindra Nisha A , Jalal Shadia I , Reckamp Karen L , Hall Richard D , Hanna Nasser H , Chae Young Kwang , Koczywas Marianna , Helenowski Irene B , Patel Jyoti D
Published: June 2023

Background

Combination chemotherapy and immunotherapy regimens have significantly improved survival for patients with previously untreated advanced non–small cell lung cancer (NSCLC). Improvements in overall survival (OS) in two separate pembrolizumab trials have demonstrated survival improvements over chemotherapy alone, regardless of PD-L1 status. The optimal chemotherapy backbone for combination with immunotherapy is unknown. We hypothesized nab-paclitaxel may be a well-suited platinum partner to use in combination with checkpoint inhibitor therapy for both adenocarcinoma and squamous histology and conducted a phase I/II trial to assess the efficacy of this regimen in advanced NSCLC.

Methods

Adult patients with previously untreated, stage IIIB/IV NSCLC (any histology) with an Eastern Cooperative Oncology Group performance status of 0-1, any PD-L1 expression, and no EGFR mutations or ALK translocations, received carboplatin area under the curve (AUC) 6 day 1, nab-paclitaxel 100 mg/m2 days 1, 8, 15, and pembrolizumab 200 mg day 1 q21 days for 4 cycles followed by maintenance pembrolizumab q3w. Co-primary endpoints were progression-free survival (PFS) and overall response rate (ORR).

Results

Forty-six evaluable patients enrolled, 14 in phase I and 32 in phase II, from June 2015 to July 2018 with a median duration of follow-up of 35.4 months. Median time from enrollment to data lock was 42 months. In the ITT population, the ORR was 35%, median PFS was 5.6 months (95% CI, 4.6-8.2), and median OS was 15.4 months (CI, 12.4-28.1). There were no statistical differences in PFS or OS by PD-L1 status. The 2- and 3-year landmark OS rates were 33% and 24%, respectively.

Conclusion

Carboplatin, nab-paclitaxel, and pembrolizumab are a safe and effective regimen for patients with both squamous and nonsquamous NSCLC. Although this study did not meet the prespecified endpoints, the median and landmark OS results are consistent with durable benefit of this regimen as seen in phase III trials for first-line treatment of advanced NSCLC.
Adhesion of dental ceramic materials to titanium and titanium alloys: a review
Authors: Parushev Ivaylo , Dikova Tsanka , Katreva Iveta , Gagov Yavor , Simeonov Simeon
Published: June 2023

In recent years, the application of titanium and its alloys for production of metal frameworks for metal–ceramic fixed partial dentures (FPDs) has been increasing. They are fabricated mainly by casting, CAD/CAM milling and selective laser melting. Manufacturing technologies affect the surface characteristics of the metal, which in turn affects the adhesion in the metal–ceramic system. Therefore, the purpose of the present article is to analyse the information about the adhesion of dental ceramics to pure titanium and its alloys, emphasizing the methods most commonly applied to improve adhesion. Based on the papers published last 10 years, the pure titanium and its alloys, the main technologies for their production and the porcelains applied in the fabrication of metal–ceramic FPDs are examined. It is summarized that the methods for increasing the adhesion strength of the porcelains to the titanium and Ti alloys can be classified into five large groups: mechanical, physical, chemical methods, application of bonding agents and combined treatments, as clear boundaries between them cannot be set. In the last decade, the successful technologies for improving the adhesion strength of Ti and its alloys to the porcelain usually consist of a combination of successive treatments of the metal surface. Abrasion of the titanium surface by sandblasting is most often used initially. At the next stage, a bonding agent or other type of intermediate layer of different coatings is applied to the metal, which further improves the adhesion strength to the porcelain.
Runx1 regulates critical factors that control uterine angiogenesis and trophoblast differentiation during placental development
Authors: Kannan Athilakshmi , Beal Jacob R , Neff Alison M , Bagchi Milan K , Bagchi Indrani C
Published: June 2023

During early pregnancy in humans and rodents, uterine stromal cells undergo a remarkable differentiation to form the decidua, a transient maternal tissue that supports the growing fetus. It is important to understand the key decidual pathways that orchestrate the proper development of the placenta, a key structure at the maternal–fetal interface. We discovered that ablation of expression of the transcription factor Runx1 in decidual stromal cells in a conditional Runx1-null mouse model (Runx1d/d) causes fetal lethality during placentation. Further phenotypic analysis revealed that uteri of pregnant Runx1d/d mice exhibited severely compromised decidual angiogenesis and a lack of trophoblast differentiation and migration, resulting in impaired spiral artery remodeling. Gene expression profiling using uteri from Runx1d/d and control mice revealed that Runx1 directly controls the decidual expression of the gap junction protein connexin 43 (also known as GJA1), which was previously shown to be essential for decidual angiogenesis. Our study also revealed that Runx1 controls the expression of insulin-like growth factor (IGF) 2 and IGF-binding protein 4 (IGFBP4) during early pregnancy. While Runx1 deficiency drastically reduced the production of IGF2 by the decidual cells, we observed concurrent elevated expression of the IGFBP4, which regulates the bioavailability of IGFs, thereby controlling trophoblast differentiation. We posit that dysregulated expression of GJA1, IGF2, and IGFBP4 in Runx1d/d decidua contributes to the observed defects in uterine angiogenesis, trophoblast differentiation, and vascular remodeling. This study therefore provides unique insights into key maternal pathways that control the early phases of maternal–fetal interactions within a critical window during placental development.