bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of classical versus non classical papillary thyroid carcinoma subtypes from cytology of nodules classified according to TIRADS
Authors: Scappaticcio Lorenzo , Trimboli Pierpaolo , Bellastella Giuseppe , Ferrazzano Pamela , Clery Eduardo , Cozzolino Immacolata , Montella Marco , Fasano Morena , Pirozzi Mario , Ferrandes Sonia , Docimo Giovanni , Ciardiello Fortunato , Franco Renato , Esposito Katherine
Published: November 2023

Purpose

Our purposes were: 1) to estimate the prediction performance (PP) of cytology in identifying papillary thyroid carcinoma (PTC) subtypes; 2) to explore how the PTC subtypes distribute among the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) categories.

Methods

Nodules were included if both the histology with the PTC subtype report and the cytology report with the possible PTC subtype were available. The PP was calculated by making the proportion of True positives/False positives+false negatives.

Results

309 cytologically “suspicious for malignancy” and “malignant” thyroid nodules with PTC histology were evaluated. ACR TI-RADS categorization for classical PTC was significantly different from non-classical PTC (p-value 0.02). For the whole cohort the PP of cytologically classical cases was 0.74, while that of cytologically non classical cases was 0.41. ACR TI-RADS categorization was not significantly different for aggressive vs non-aggressive PTC subtypes (p-value 0.1). When considering only aggressive or non-aggressive PTC subtypes, the PP of cytologically classical cases was respectively 0.86 and 0.87, while that of cytologically non classical cases was respectively 0.27 and 0.22. The PP of cytologically classical cases was 0.73 and 0.79, respectively for macroPTCs and microPTCs, while that of cytologically non classical cases was 0.55 and 0.33, respectively for macroPTCs and microPTCs.

Conclusion

Cytology examination reliably performed in predicting classical PTC versus non classical PTC subtypes. ACR TI-RADS categorization was significantly different among classical PTC versus non classical PTC subtypes.
Improved guidance is needed to optimise diagnostics and treatment of patients with thyroid cancer in Europe
Authors: de la Fouchardière Christelle , Fugazzola Laura , Locati Laura D. , Alvarez Clara V. , Peeters Robin P. , Camacho Pilar , Simon Iris M. , Jarząb Barbara , Netea-Maier Romana
Published: November 2023

Although thyroid cancer (TC) is generally associated with a favourable prognosis, there are certain high-risk groups with a clear unmet therapeutic need. Unravelling the genomic landscape of TC has recently led to the development of novel effective targeted treatments. To date, these treatments have mostly been evaluated in non-randomised single-arm phase II clinical trials and are consequently non-reimbursed in several countries. Furthermore, most of these agents must be tailored to individual patient molecular characteristics, a context known as personalised cancer medicine, necessitating a requirement for predictive molecular biomarker testing. Existing guidelines, both in Europe and internationally, entail mostly therapeutic rather than molecular testing recommendations. This may reflect ambiguity among experts due to lack of evidence and also practical barriers in availability of the preferred molecular somatic screening and/or targeted treatments. This article reviews existing European recommendations regarding advanced/metastatic TC management with a special focus on molecular testing, and compares findings with real-world practice based on a recent survey involving TC experts from 18 European countries. Significant disparities are highlighted between theory and practice related to variable access to infrastructure, therapies and expertise, together with the insufficient availability of multidisciplinary tumour boards. In particular, practitioners’ choice of what, how and when to test is shown to be influenced by the expertise of the available laboratory, the financing source and the existence of potential facilitators, such as clinical trial access. Overall, the need of a collaborative initiative among European stakeholders to develop standardised, accessible molecular genotyping approaches in TC is underscored.
Parenting Competences Among Migrant Families Living at Psychosocial Risk in Spain
Authors: Martins Marco , Pinto Rita , Živković Marija , Jiménez Lucía
Published: November 2023

The impact of parenting competences on child well-being is well-established. During the last years, parenting support initiatives have increased in several countries, namely in Spain, offering support to promote parents’ childcare resources and competences, particularly for families at psychosocial risk. Recognizing the specificities of different subgroups of families, such as migrant families, allows the development of more tailored and effective interventions in the field of family support. However, there is a gap in the literature about parenting competences in migrant families. This article explores differences and similarities in parenting competences among 492 migrant and non-migrant parents involved in family preservation services in Spain, as well as examines the impact of these competences on children’s well-being. Our findings revealed that migrant and non-migrant vulnerable families face similar needs in terms of parenting competences in domains covered by the existing family support interventions. However, we found a few differences in parenting competences between both populations, as well as in the impact of several parenting competences in children’s well-being. Implications for research and practice are discussed.
Local Geographic Variations in Children’s School Readiness - A Multilevel Analysis of the Development Gaps in England
Authors: Purdam K. , Troncoso P. , Morales-Gomez A. , Leckie G.
Published: November 2023

The educational attainment levels of children in state-funded schools in England are lower than in many countries with comparable levels of economic development. There are also striking differences at the local level across England. To understand these differences it is important to examine children’s development in their early years. This research uses multilevel analysis of the National Pupil Database to investigate child development at ages 4 and 5 years old at the individual, school and local levels including within a case study urban area. Child development is assessed using teachers’ observations to measure what is termed School Readiness. This is based on a child’s communication, literacy and numeracy skills and their physical, personal and social development. The findings reveal substantial differences in School Readiness at the individual, school and local area levels including in terms of sex, ethnic background, age in the school year, welfare benefit entitlement and local area income deprivation level. Such differences are also evident across the separate Early Learning Goals that are used to assess School Readiness. Between local areas children with similar backgrounds can vary considerably in their likelihood of being categorised as School Ready. Many children face multiple disadvantages as a consequence of different interlinked factors including where they live. The gap in the levels of School Readiness has long-term implications for the individuals themselves and for society more widely. Whilst increasing the levels of School Readiness is a key target in the UK Government’s Levelling Up policy, tackling the stark inequalities will take considerable investment, highly targeted support and engagement across the home and school learning environments.
3D printing injectable microbeads using a composite liposomal ink for local treatment of peritoneal diseases
Authors: Eugster Remo , Ganguin Aymar Abel , Seidi Amirmohammad , Aleandri Simone , Luciani Paola
Published: November 2023

The peritoneal cavity offers an attractive administration route for challenging-to-treat diseases, such as peritoneal carcinomatosis, post-surgical adhesions, and peritoneal fibrosis. Achieving a uniform and prolonged drug distribution throughout the entire peritoneal space, though, is difficult due to high clearance rates, among others. To address such an unmet clinical need, alternative drug delivery approaches providing sustained drug release, reduced clearance rates, and a patient-centric strategy are required. Here, we describe the development of a 3D-printed composite platform for the sustained release of the tyrosine kinase inhibitor gefitinib (GEF), a small molecule drug with therapeutic applications for peritoneal metastasis and post-surgical adhesions. We present a robust method for the production of biodegradable liposome-loaded hydrogel microbeads that can overcome the pharmacokinetic limitations of small molecules with fast clearance rates, a current bottleneck for the intraperitoneal (IP) administration of these therapeutics. By means of an electromagnetic droplet printhead, we 3D printed microbeads employing an alginate-based ink loaded with GEF-containing multilamellar vesicles (MLVs). The sustained release of GEF from microbeads was demonstrated. In vitro studies on an immortalized human hepatic cancer cell line (Huh-7) proved concentration-dependent cell death. These findings demonstrate the potential of 3D-printed alginate microbeads containing liposomes for delivering small drug compounds into the peritoneum, overcoming previous limitations of IP drug delivery.

Graphical abstract
Chemically Functionalized Graphene–Boron Nitride/Polypropylene Nanocomposites with Enhanced Nanomechanical and Anti-wear Properties
Authors: Uyor Uwa O. , Popoola Abimbola P. I. , Popoola Olawale M.
Published: November 2023

Polymers are soft materials with large molecular chains, which are softened during frictional wear, leading to bulk detachment of materials and poor wear resistance in addition to their low mechanical strength and hardness. This study developed polypropylene nanocomposites containing hydrothermal assembled graphene and boron nitride (BN@GNs) with good mechanical properties and wear resistance. To ensure good dispersion of the nanoparticles in the polypropylene (PP) matrix, they were functionalized and preparation of masterbatch using polypropylene maleic anhydride (PPMA) was adopted, while the polymer nanocomposites for this study were developed via melt compounding. The addition of the nanoparticles in the PP matrix promoted its wear resistance as all the developed nanocomposites showed a low coefficient of friction (CoF). The wear rate of the nanocomposites was dramatically reduced to a minimum of 2.05 × 10−4 mm3/Nm for the PP/3wt%BN@GNs nanocomposite from around 24.9 × 10−4 mm3/Nm for the pure PP. The nanoindentation test results of the nanocomposites also revealed improvement in their nanomechanical characteristics. For instance, PP/3wt%BN@GNs nanocomposite showed an ideal increase of about 124% nano-hardness and 65.7% nano-elastic modulus when compared to pure PP. In comparison to pure PP, all of the developed nanocomposites displayed lower nano-percentage creep and nanoindenter’s tip penetration depth, which suggest greater plastic deformation resistance.
Fivefold‐Coordinated Silicon in MgSiO3 Melt Accommodates Viscous Flow up to Transition Zone Pressures
Authors: Schulze Maximilian , Spiekermann Georg
Published: November 2023

Fivefold‐coordinated silicon is assumed to be the transitional species that accommodates the structural relaxation needed for viscous flow of silicate melts, but so far robust insight at the atomic scale is missing. Furthermore, the role of fivefold‐coordinated silicon in melts at Earth's mantle pressures is unknown. Here we discuss the relative dynamic stabilities of four‐, five‐ and sixfold Si–O coordination polyhedra in MgSiO3 melt at pressures up to 40 GPa, obtained from ab initio molecular dynamics simulations and a novel concept based on a coordination auto‐correlation function. Successfully benchmarked against the relaxation time predicted by Maxwell's relation, our results show that fivefold‐coordinated silicon accommodates structural relaxation not only at ambient pressure, but at least up to the pressures of the mantle transition zone. These results shed new light on the interplay between structure and viscosity of silicate melts.
Radio Occultation Measurements of Europa's Ionosphere From Juno's Close Flyby
Authors: Parisi M. , Caruso A. , Buccino D. R. , Gramigna E. , Withers P. , Gomez‐Casajus L. , Coffin D. A. , Park R. S. , Steffes P. , Tortora P. , Zannoni M. , Levin S. , Bolton S.
Published: November 2023

On 29 September 2022 the Juno spacecraft flew within 354 km of Europa's surface while several instruments probed the moon's surroundings. During the close flyby, radio occultations were performed by collecting single‐frequency Doppler measurements. These investigations are essential to the study of Europa's ionosphere and represent the first repeat sampling of any set of conditions since the Galileo era. Ingress measurements resulted in a marginal detection with a peak ionospheric density of 4,000 ± 3,700 cm−3 (3σ) at 22 km altitude. A more significant detection emerged on egress, with a peak density of 6,000 ± 3,000 cm−3 (3σ) at 320 km altitude. Comparison with Galileo measurements reveals a consistent picture of Europa's ionosphere, and confirms its dependence on illumination conditions and position within Jupiter's magnetosphere. However, the overall lower densities measured by Juno suggest a dependence on time of observation, with implications for the structure of the neutral atmosphere.
Observations on the Variations of the Field‐Aligned Irregularities in the Plasma Bubbles at Low‐Latitudes of China
Authors: Jia Wei , Chen Gang , Xu Jiyao , Yan Chunxiao , Wu Kun , Zhang Shaodong , Zhang Min , Yuan Wei , Li Yaxian , Gong Wanlin , Hu Pengfei
Published: November 2023

The concurrent observation of the Hainan COherent Scatter Phased Array Radar (HCOPAR) and the 630 nm all‐sky airglow imager was carried out on the night of 13 April 2015 in low‐latitudes of China. The plasma bubble recorded by the airglow imager and the Field‐Aligned Irregularities (FAIs) observed by the HCOPAR kept a good consistency. At the beginning, the FAIs were found to fill the entire plasma bubble, and they were drifting eastward together. During the dissipation process, the plasma bubble became wider and wider in zonal direction, while the airglow gray gradient on the eastern and western walls of the bubble had no much changes. Simultaneously, the echo Signal‐to‐Noise Ratio (SNR) of the irregularities in the bubble became lower and lower. The SNR at the depletion center decreased fastest, and the SNR of the FAIs on the western wall of the bubble fell more slowly than those in other parts. Polarization electric field in the bubble is suggested to have influence on the distribution of the FAIs. Gradient drift instability on the western wall supported the FAIs to live longer, and the FAIs on the eastern wall, namely on the front edge of the bubble, dissipated more rapidly.
Sensitivity of African Easterly Waves to Dust Forcing
Authors: Bangalath Hamza Kunhu , Raj Jerry , Stenchikov Georgiy
Published: November 2023

There is a lack of consensus regarding the sign and magnitude of the effect of dust‐radiative forcing on African easterly waves (AEWs) among past studies. The uncertainty in the dust‐radiative forcing associated with the estimation of shortwave absorption is a leading cause of disagreement in the literature. The inability of models to represent various dust‐AEW interaction pathways also leads to uncertainty among modeling studies. The present study investigates the sensitivity of AEWs to the observed variability in dust shortwave absorption using a high‐resolution atmospheric general circulation model. Global simulations are conducted at a spatial resolution of about 25 km to simulate AEWs and associated circulation features adequately well. The results reveal that AEWs are highly sensitive to dust shortwave absorption. In addition, the AEW activity intensifies and broadens the wave track with a southward shift in response to dust shortwave absorption. Eddy kinetic energy (EKE) associated with AEWs changes by approximately ±25% for the range of dust shortwave absorption used. The 6–9 days waves are more sensitive to dust shortwave absorption than the 3–5 days waves, with the response in the former exhibiting a stark land‐sea contrast. The sensitivity of AEWs to dust heating stems from a combination of the responses from various energy conversions. Although baroclinic energy conversion is the dominant term in the energy cycle, the responses to dust shortwave heating in barotropic and generation terms are comparable to those in baroclinic conversion.
Characteristics and Variability of Precipitation Across Different Sectors of an Extra‐Tropical Cyclone: A Case Study Over the High‐Latitudes of the Southern Ocean
Authors: Truong S. C. H. , Siems S. T. , May P. T. , Huang Y. , Vignon É. , Gevorgyan A.
Published: November 2023

Shipborne observations from the CAPRICORN‐2018 field campaign were used to investigate the characteristics and variability of precipitation across different sectors of an extra‐tropical cyclone on 16 February 2018, over the Southern Ocean (SO). Three distinct time periods—frontal, post‐frontal, and cyclone—were identified during the day. The frontal passage recorded a total accumulation of 1.9 mm, where the precipitation phases were primarily composed of rain (96%), while the cyclone period recorded the largest precipitation (4.0 mm), where the precipitation phases varied with snow (10%), mixed‐phase (40%), and rain (50%). The BASTA radar suggests the freezing level was shallow (∼500 m) with snow present above. The cloud top heights, observed by a C‐band radar, were shallower in the cyclone period, although deeper cloud depths of ∼6 km were sporadically recorded. Increased surface fluxes and a southerly wind direction indicate that cold air advection, was likely the main cause of high precipitation during the cyclone period. A non‐precipitating multi‐layer cloud structure with a geometrically thin (200 m) homogeneous layer of supercooled liquid water (SLW) overlaying shallow boundary layer convection was seen during the post‐frontal period. The ship‐borne observations were used to evaluate Weather Research & Forecasting (WRF) simulations with different microphysics settings. We found the frontal precipitation intensity is well reproduced, but it is underestimated during the cyclone period. This study represents a unique set of observations and highlights the need for understanding how ice processes and potentially horizontal advection contribute to the development of precipitation and convection over the SO.
Modeling the Air Pollution and Aerosol‐PBL Interactions Over China Using a Variable‐Resolution Global Model
Authors: Yue Man , Dong Xinyi , Wang Minghuai , Emmons Louisa K. , Liang Yuan , Tong Dan , Liu Yawen , Liu Yaman
Published: November 2023

Modeling air quality has always been a challenge in global models constrained by coarse grids. Here, the variable‐resolution Community Atmosphere Model with full chemistry based on the scalable spectral element (SE) dynamical core (MUSICAv0) is applied in simulating air pollution with a finer grid resolution of ∼0.25° over East Asia (SE_VR), in contrast to the same model with a uniform resolution of ∼1.0° (SE_UR). Two nudging experiments and four free‐running experiments are conducted to investigate the capabilities of SE_VR in modeling the air pollution and aerosol‐planetary boundary layer (PBL) interactions over China. Results show the regional refinement in SE_VR is essential for simulating haze events over complex terrain areas attributed to its better performance in representing the local vertical and horizontal dispersion conditions. SE_VR shows prominent advantages over SE_UR in simulating surface ozone because of better resolving spatial segregation of NOx and volatile organic compounds (VOC) chemical regimes and subsequently representing more detailed chemical processes related to ozone formation, although the model generally overestimates surface ozone over China. Further analysis of SE_VR shows the daytime radiative effect of black carbon (BC) aerosols lowers PBL height by 12.0% (17.9%), and leads to an increase of PM2.5 by 14.5% (10.8%) under the moderate (severe) air pollution conditions over Sichuan Basin. However, SE_UR has deficiencies in simulating BC‐PBL interactions due to its inability to reproduce the strong inverse temperature structure caused by BC aerosols in the lower atmosphere layer. Our results highlight the value of variable‐resolution global models for simulating air pollution and its interactions with climate.
Toward an Interpretable CNN Model for the Classification of Lightning‐Produced VLF/LF Signals
Authors: Xiao Lilang , Chen Weijiang , Wang Yu , Bian Kai , Fu Zhong , Xiang Nianwen , He Hengxin , Cheng Yang
Published: November 2023

An interpretable convolutional neural network model is proposed for the classification of very low frequency and low frequency lightning electric field waveforms. This model adopts multi‐scale convolutional kernels and shortcut connections to enhance the ability of lightning waveform classification. Based on the data recorded from five provinces in China, the proposed model achieves an accuracy of 98.56% for a four‐type classification task including return strokes, the intra‐cloud lightning, preliminary breakdown, and narrow bipolar events. The proposed model is validated with another open‐source data set from Argentina with an accuracy of 98.45%, which shows good robustness. To ensure the classification, the features learned by the model are visualized. The class activation mapping (CAM) method is adopted to visualize the class‐specific contribution of different waveform parts by using the feature maps of the final convolutional layer. It is highlighted by the CAM method that the proposed model focuses on waveform parts that align with those areas of interests identified by human experts. The high‐contribution waveform parts are furtherly analyzed, which indicate that the proposed model possesses the capability to associate waveform features with the corresponding lightning discharge processes.
The effects of bariatric surgery on cardiac function: a systematic review and meta-analysis
Authors: Sargsyan Narek , Chen Jun Yu , Aggarwal Ravi , Fadel Michael G. , Fehervari Matyas , Ashrafian Hutan
Published: November 2023

Introduction

Obesity is associated with alterations in cardiac structure and haemodynamics leading to cardiovascular mortality and morbidity. Culminating evidence suggests improvement of cardiac structure and function following bariatric surgery.

Objective

To evaluate the effect of bariatric surgery on cardiac structure and function in patients before and after bariatric surgery.

Methods

Systematic review and meta-analysis of studies reporting pre- and postoperative cardiac structure and function parameters on cardiac imaging in patients undergoing bariatric surgery.

Results

Eighty studies of 3332 patients were included. Bariatric surgery is associated with a statistically significant improvement in cardiac geometry and function including a decrease of 12.2% (95% CI 0.096–0.149; p < 0.001) in left ventricular (LV) mass index, an increase of 0.155 (95% CI 0.106–0.205; p < 0.001) in E/A ratio, a decrease of 2.012 mm (95% CI 1.356–2.699; p < 0.001) in left atrial diameter, a decrease of 1.16 mm (95% CI 0.62–1.69; p < 0.001) in LV diastolic dimension, and an increase of 1.636% (95% CI 0.706–2.566; p < 0.001) in LV ejection fraction after surgery.

Conclusion

Bariatric surgery led to reverse remodelling and improvement in cardiac geometry and function driven by metabolic and haemodynamic factors.
METTL3 promotes colorectal cancer progression through activating JAK1/STAT3 signaling pathway
Authors: Sun Yuechao , Gong Weipeng , Zhang Song
Published: November 2023

The role of METTL3-mediated N6-methyladenosine (m6A) modification has been elucidated in several cancers, but the concrete mechanism underlying its function in colorectal cancer is still obscure. Here, we revealed that upregulated methyltransferase-like 3 (METTL3) in colorectal cancer exerted both methyltransferase activity-dependent and -independent functions in gene regulation. METTL3 deposited m6A on the 3’ untranslated region of the JAK1 transcript to promote JAK1 translation relying on YTHDF1 recognition. Besides, METTL3 was redistributed to the STAT3 promoter and worked in concert with NF-κB to facilitate STAT3 transcription, which was achieved independently on METTL3 methyltransferase activity. The increased JAK1 and STAT3 corporately contributed to the activation of the p-STAT3 signaling pathway and further upregulated downstream effectors expressions, including VEGFA and CCND1, which finally resulted in enhanced cancer cell proliferation and metastasis in vitro and in vivo. Collectively, our study revealed the unappreciated dual role of METTL3 as an m6A writer and a transcription regulator, which worked together in the same signaling pathway to drive colorectal cancer malignancy.
Mechanisms of ferroptosis and targeted therapeutic approaches in lymphoma
Authors: Yu Tiantian , Xu-Monette Zijun Y. , Yu Li , Li Yong , Young Ken H.
Published: November 2023

Lymphoma is the sixth most common type of cancer worldwide. Under the current treatment standards, patients with lymphoma often fail to respond to treatment or relapse early and require further therapy. Hence, novel therapeutic strategies need to be explored and our understanding of the molecular underpinnings of lymphomas should be expanded. Ferroptosis, a non-apoptotic regulated cell death, is characterized by increased reactive oxygen species and lipid peroxidation due to metabolic dysfunction. Excessive or lack of ferroptosis has been implicated in tumor development. Current preclinical evidences suggest that ferroptosis participates in tumorigenesis, progression, and drug resistance of lymphoma, identifying a potential biomarker and an attractive molecular target. Our review summarizes the core mechanisms and regulatory networks of ferroptosis and discusses existing evidences of ferroptosis induction for the treatment of lymphoma, with intent to provide a framework for understanding the role of ferroptosis in lymphomagenesis and a new perspective of lymphoma treatment.
Caspase-8 activation by cigarette smoke induces pro-inflammatory cell death of human macrophages exposed to lipopolysaccharide
Authors: Cristaldi Marta , Buscetta Marco , Cimino Maura , La Mensa Agnese , Giuffrè Maria Rita , Fiore Luigi , Carcione Claudia , Bucchieri Fabio , Rappa Francesca , Coronnello Claudia , Sciaraffa Nicolina , Amato Santina , Aronica Tommaso Silvano , Lo Iacono Giovanna , Bertani Alessandro , Pace Elisabetta , Cipollina Chiara
Published: November 2023

Cigarette smoking impairs the lung innate immune response making smokers more susceptible to infections and severe symptoms. Dysregulation of cell death is emerging as a key player in chronic inflammatory conditions. We have recently reported that short exposure of human monocyte-derived macrophages (hMDMs) to cigarette smoke extract (CSE) altered the TLR4-dependent response to lipopolysaccharide (LPS). CSE caused inhibition of the MyD88-dependent inflammatory response and activation of TRIF/caspase-8/caspase-1 pathway leading to Gasdermin D (GSDMD) cleavage and increased cell permeability. Herein, we tested the hypothesis that activation of caspase-8 by CSE increased pro-inflammatory cell death of LPS-stimulated macrophages. To this purpose, we measured apoptotic and pyroptotic markers as well as the expression/release of pro-inflammatory mediators in hMDMs exposed to LPS and CSE, alone or in combination, for 6 and 24 h. We show that LPS/CSE-treated hMDMs, but not cells treated with CSE or LPS alone, underwent lytic cell death (LDH release) and displayed apoptotic features (activation of caspase-8 and -3/7, nuclear condensation, and mitochondrial membrane depolarization). Moreover, the negative regulator of caspase-8, coded by CFLAR gene, was downregulated by CSE. Activation of caspase-3 led to Gasdermin E (GSDME) cleavage. Notably, lytic cell death caused the release of the damage-associated molecular patterns (DAMPs) heat shock protein-60 (HSP60) and S100A8/A9. This was accompanied by an impaired inflammatory response resulting in inhibited and delayed release of IL6 and TNF. Of note, increased cleaved caspase-3, higher levels of GSDME and altered expression of cell death-associated genes were found in alveolar macrophages of smoker subjects compared to non-smoking controls. Overall, our findings show that CSE sensitizes human macrophages to cell death by promoting pyroptotic and apoptotic pathways upon encountering LPS. We propose that while the delayed inflammatory response may result in ineffective defenses against infections, the observed cell death associated with DAMP release may contribute to establish chronic inflammation.
RMI1 facilitates repair of ionizing radiation–induced DNA damage and maintenance of genomic stability
Authors: Fang Lianying , Sun Yuxiao , Dong Mingxin , Yang Mengmeng , Hao Jianxiu , Li Jiale , Zhang Huanteng , He Ningning , Du Liqing , Xu Chang
Published: November 2023

Ionizing radiation (IR) causes a wide variety of DNA lesions, of which DNA double-stranded breaks (DSBs) are the most deleterious. Homologous recombination (HR) is a crucial route responsible for repairing DSBs. RecQ-mediated genome instability protein 1 (RMI1) is a member of an evolutionarily conserved Bloom syndrome complex, which prevents and resolves aberrant recombination products during HR, thereby promoting genome stability. However, little is known about the role of RMI1 in regulating the cellular response to IR. This study aimed to understand the cellular functions and molecular mechanisms by which RMI1 maintains genomic stability after IR exposure. Here, we showed IR upregulated the RMI1 protein level and induced RMI1 relocation to the DNA damage sites. We also demonstrated that the loss of RMI1 in cells resulted in enhanced levels of DNA damage, sustained cell cycle arrest, and impaired HR repair after IR, leading to reduced cell viability and elevated genome instability. Taken together, our results highlighted the direct roles of RMI1 in response to DNA damage induced by IR and implied that RMI1 might be a new genome safeguard molecule to radiation-induced damage.
Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis
Authors: Fang Zijian , Corbizi Fattori Giuditta , McKerrell Thomas , Boucher Rebecca H. , Jackson Aimee , Fletcher Rachel S. , Forte Dorian , Martin Jose-Ezequiel , Fox Sonia , Roberts James , Glover Rachel , Harris Erica , Bridges Hannah R. , Grassi Luigi , Rodriguez-Meira Alba , Mead Adam J. , Knapper Steven , Ewing Joanne , Butt Nauman M. , Jain Manish , Francis Sebastian , Clark Fiona J. , Coppell Jason , McMullin Mary F. , Wadelin Frances , Narayanan Srinivasan , Milojkovic Dragana , Drummond Mark W. , Sekhar Mallika , ElDaly Hesham , Hirst Judy , Paramor Maike , Baxter E. Joanna , Godfrey Anna L. , Harrison Claire N. , Méndez-Ferrer Simón
Published: November 2023

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen’s safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study’s A’herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.
The rate of epigenetic drift scales with maximum lifespan across mammals
Authors: Bertucci-Richter Emily M. , Parrott Benjamin B.
Published: November 2023

Epigenetic drift or “disorder” increases across the mouse lifespan and is suggested to underlie epigenetic clock signals. While the role of epigenetic drift in determining maximum lifespan across species has been debated, robust tests of this hypothesis are lacking. Here, we test if epigenetic disorder at various levels of genomic resolution explains maximum lifespan across four mammal species. We show that epigenetic disorder increases with age in all species and at all levels of genomic resolution tested. The rate of disorder accumulation occurs faster in shorter lived species and corresponds to species adjusted maximum lifespan. While the density of cytosine-phosphate-guanine dinucleotides (“CpGs”) is negatively associated with the rate of age-associated disorder accumulation, it does not fully explain differences across species. Our findings support the hypothesis that the rate of epigenetic drift explains maximum lifespan and provide partial support for the hypothesis that CpG density buffers against epigenetic drift.
Gene duplication and deletion caused by over-replication at a fork barrier
Authors: Oehler Judith , Morrow Carl A. , Whitby Matthew C.
Published: November 2023

Replication fork stalling can provoke fork reversal to form a four-way DNA junction. This remodelling of the replication fork can facilitate repair, aid bypass of DNA lesions, and enable replication restart, but may also pose a risk of over-replication during fork convergence. We show that replication fork stalling at a site-specific barrier in fission yeast can induce gene duplication-deletion rearrangements that are independent of replication restart-associated template switching and Rad51-dependent multi-invasion. Instead, they resemble targeted gene replacements (TGRs), requiring the DNA annealing activity of Rad52, the 3’-flap nuclease Rad16-Swi10, and mismatch repair protein Msh2. We propose that excess DNA, generated during the merging of a canonical fork with a reversed fork, can be liberated by a nuclease and integrated at an ectopic site via a TGR-like mechanism. This highlights how over-replication at replication termination sites can threaten genome stability in eukaryotes.
Diversity of cortical activity changes beyond depression during Spreading Depolarizations
Authors: Nasretdinov Azat , Vinokurova Daria , Lemale Coline L. , Burkhanova-Zakirova Gulshat , Chernova Ksenia , Makarova Julia , Herreras Oscar , Dreier Jens P. , Khazipov Roustem
Published: November 2023

Spreading depolarizations (SDs) are classically thought to be associated with spreading depression of cortical activity. Here, we found that SDs in patients with subarachnoid hemorrhage produce variable, ranging from depression to booming, changes in electrocorticographic activity, especially in the delta frequency band. In rats, depression of activity was characteristic of high-potassium-induced full SDs, whereas partial superficial SDs caused either little change or a boom of activity at the cortical vertex, supported by volume conduction of signals from spared delta generators in the deep cortical layers. Partial SDs also caused moderate neuronal depolarization and sustained excitation, organized in gamma oscillations in a narrow sub-SD zone. Thus, our study challenges the concept of homology between spreading depolarization and spreading depression by showing that SDs produce variable, from depression to booming, changes in activity at the cortical surface and in different cortical layers depending on the depth of SD penetration.
Acetyl-CoA is a key molecule for nephron progenitor cell pool maintenance
Authors: Diniz Fabiola , Ngo Nguyen Yen Nhi , Colon-Leyva Mariel , Edgington-Giordano Francesca , Hilliard Sylvia , Zwezdaryk Kevin , Liu Jiao , El-Dahr Samir S. , Tortelote Giovane G.
Published: November 2023

Nephron endowment at birth impacts long-term renal and cardiovascular health, and it is contingent on the nephron progenitor cell (NPC) pool. Glycolysis modulation is essential for determining NPC fate, but the underlying mechanism is unclear. Combining RNA sequencing and quantitative proteomics we identify 267 genes commonly targeted by Wnt activation or glycolysis inhibition in NPCs. Several of the impacted pathways converge at Acetyl-CoA, a co-product of glucose metabolism. Notably, glycolysis inhibition downregulates key genes of the Mevalonate/cholesterol pathway and stimulates NPC differentiation. Sodium acetate supplementation rescues glycolysis inhibition effects and favors NPC maintenance without hindering nephrogenesis. Six2Cre-mediated removal of ATP-citrate lyase (Acly), an enzyme that converts citrate to acetyl-CoA, leads to NPC pool depletion, glomeruli count reduction, and increases Wnt4 expression at birth. Sodium acetate supplementation counters the effects of Acly deletion on cap-mesenchyme. Our findings show a pivotal role of acetyl-CoA metabolism in kidney development and uncover new avenues for manipulating nephrogenesis and preventing adult kidney disease.
Cryogenic multiplexing using selective area grown nanowires
Authors: Olšteins Dāgs , Nagda Gunjan , Carrad Damon J. , Beznasyuk Daria V. , Petersen Christian E. N. , Martí-Sánchez Sara , Arbiol Jordi , Jespersen Thomas S.
Published: November 2023

Bottom-up grown nanomaterials play an integral role in the development of quantum technologies but are often challenging to characterise on large scales. Here, we harness selective area growth of semiconductor nanowires to demonstrate large-scale integrated circuits and characterisation of large numbers of quantum devices. The circuit consisted of 512 quantum devices embedded within multiplexer/demultiplexer pairs, incorporating thousands of interconnected selective area growth nanowires operating under deep cryogenic conditions. Multiplexers enable a range of new strategies in quantum device research and scaling by increasing the device count while limiting the number of connections between room-temperature control electronics and the cryogenic samples. As an example of this potential we perform a statistical characterization of large arrays of identical quantum dots thus establishing the feasibility of applying cross-bar gating strategies for efficient scaling of future selective area growth quantum circuits. More broadly, the ability to systematically characterise large numbers of devices provides new levels of statistical certainty to materials/device development.
Modulation of insulin secretion by RBFOX2-mediated alternative splicing
Authors: Moss Nicole D. , Wells Kristen L. , Theis Alexandra , Kim Yong-Kyung , Spigelman Aliya F. , Liu Xiong , MacDonald Patrick E. , Sussel Lori
Published: November 2023

Insulin secretion is a tightly regulated process that is vital for maintaining blood glucose homeostasis. Although the molecular components of insulin granule trafficking and secretion are well established, how they are regulated to rapidly fine-tune secretion in response to changing environmental conditions is not well characterized. Recent studies have determined that dysregulation of RNA-binding proteins (RBPs) and aberrant mRNA splicing occurs at the onset of diabetes. We demonstrate that the RBP, RBFOX2, is a critical regulator of insulin secretion through the alternative splicing of genes required for insulin granule docking and exocytosis. Conditional mutation of Rbfox2 in the mouse pancreas results in decreased insulin secretion and impaired blood glucose homeostasis. Consistent with defects in secretion, we observe reduced insulin granule docking and corresponding splicing defects in the SNARE complex components. These findings identify an additional mechanism for modulating insulin secretion in both healthy and dysfunctional pancreatic β cells.
Multi-client distributed blind quantum computation with the Qline architecture
Authors: Polacchi Beatrice , Leichtle Dominik , Limongi Leonardo , Carvacho Gonzalo , Milani Giorgio , Spagnolo Nicolò , Kaplan Marc , Sciarrino Fabio , Kashefi Elham
Published: November 2023

Universal blind quantum computing allows users with minimal quantum resources to delegate a quantum computation to a remote quantum server, while keeping intrinsically hidden input, algorithm, and outcome. State-of-art experimental demonstrations of such a protocol have only involved one client. However, an increasing number of multi-party algorithms, e.g. federated machine learning, require the collaboration of multiple clients to carry out a given joint computation. In this work, we propose and experimentally demonstrate a lightweight multi-client blind quantum computation protocol based on a recently proposed linear quantum network configuration (Qline). Our protocol originality resides in three main strengths: scalability, since we eliminate the need for each client to have its own trusted source or measurement device, low-loss, by optimizing the orchestration of classical communication between each client and server through fast classical electronic control, and compatibility with distributed architectures while remaining intact even against correlated attacks of server nodes and malicious clients.
Local probe-induced structural isomerization in a one-dimensional molecular array
Authors: Kawai Shigeki , Silveira Orlando J. , Kurki Lauri , Yuan Zhangyu , Nishiuchi Tomohiko , Kodama Takuya , Sun Kewei , Custance Oscar , Lado Jose L. , Kubo Takashi , Foster Adam S.
Published: November 2023

Synthesis of one-dimensional molecular arrays with tailored stereoisomers is challenging yet has great potential for application in molecular opto-, electronic- and magnetic-devices, where the local array structure plays a decisive role in the functional properties. Here, we demonstrate the construction and characterization of dehydroazulene isomer and diradical units in three-dimensional organometallic compounds on Ag(111) with a combination of low-temperature scanning tunneling microscopy and density functional theory calculations. Tip-induced voltage pulses firstly result in the formation of a diradical species via successive homolytic fission of two C-Br bonds in the naphthyl groups, which are subsequently transformed into chiral dehydroazulene moieties. The delicate balance of the reaction rates among the diradical and two stereoisomers, arising from an in-line configuration of tip and molecular unit, allows directional azulene-to-azulene and azulene-to-diradical local probe structural isomerization in a controlled manner. Furthermore, our theoretical calculations suggest that the diradical moiety hosts an open-shell singlet with antiferromagnetic coupling between the unpaired electrons, which can undergo an inelastic spin transition of 91 meV to the ferromagnetically coupled triplet state.
Multi-omics analysis of hospital-acquired diarrhoeal patients reveals biomarkers of enterococcal proliferation and Clostridioides difficile infection
Authors: Bosnjak Marijana , Karpe Avinash V. , Van Thi Thu Hao , Kotsanas Despina , Jenkin Grant A. , Costello Samuel P. , Johanesen Priscilla , Moore Robert J. , Beale David J. , Srikhanta Yogitha N. , Palombo Enzo A. , Larcombe Sarah , Lyras Dena
Published: November 2023

Hospital-acquired diarrhoea (HAD) is common, and often associated with gut microbiota and metabolome dysbiosis following antibiotic administration. Clostridioides difficile is the most significant antibiotic-associated diarrhoeal (AAD) pathogen, but less is known about the microbiota and metabolome associated with AAD and C. difficile infection (CDI) with contrasting antibiotic treatment. We characterised faecal microbiota and metabolome for 169 HAD patients (33 with CDI and 133 non-CDI) to determine dysbiosis biomarkers and gain insights into metabolic strategies C. difficile might use for gut colonisation. The specimen microbial community was analysed using 16 S rRNA gene amplicon sequencing, coupled with untargeted metabolite profiling using gas chromatography-mass spectrometry (GC-MS), and short-chain fatty acid (SCFA) profiling using GC-MS. AAD and CDI patients were associated with a spectrum of dysbiosis reflecting non-antibiotic, short-term, and extended-antibiotic treatment. Notably, extended antibiotic treatment was associated with enterococcal proliferation (mostly vancomycin-resistant Enterococcus faecium) coupled with putative biomarkers of enterococcal tyrosine decarboxylation. We also uncovered unrecognised metabolome dynamics associated with concomitant enterococcal proliferation and CDI, including biomarkers of Stickland fermentation and amino acid competition that could distinguish CDI from non–CDI patients. Here we show, candidate metabolic biomarkers for diagnostic development with possible implications for CDI and vancomycin-resistant enterococci (VRE) treatment.
Overlapping speckle correlation algorithm for high-resolution imaging and tracking of objects in unknown scattering media
Authors: Shi Yaoyao , Sheng Wei , Fu Yangyang , Liu Youwen
Published: November 2023

Optical imaging in scattering media is important to many fields but remains challenging. Recent methods have focused on imaging through thin scattering layers or thicker scattering media with prior knowledge of the sample, but this still limits practical applications. Here, we report an imaging method named ‘speckle kinetography’ that enables high-resolution imaging in unknown scattering media with thicknesses up to about 6 transport mean free paths. Speckle kinetography non-invasively records a series of incoherent speckle images accompanied by object motion and the inherently retained object information is extracted through an overlapping speckle correlation algorithm to construct the object’s autocorrelation for imaging. Under single-colour light-emitting diode, white light, and fluorescence illumination, we experimentally demonstrate 1 μm resolution imaging and tracking of objects moving in scattering samples, while reducing the requirements for prior knowledge. We anticipate this method will enable imaging in currently inaccessible scenarios.