bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between blood amyloid A and resting magnetic resonance functional brain connections in patients with obstructive sleep apnea–hypopnea syndrome
Authors: Wang Xiang , Bai Zhiyu , He Yaqing , Wu Qiaozhen
Published: May 2022

Objective

The aim of this study was to analyze the relationship between serum amyloid A (SAA) concentrations in patients with obstructive sleep apnea–hypopnea syndrome (OSAHS) and their magnetic resonance imaging (MRI) of resting brain function.

Methods

Male patients with OSAHS were enrolled from January to June 2019 in Suzhou Ninth People’s Hospital Affiliated to Soochow University, and nineteen healthy male volunteers were selected as the normal control group. The patients with OSAHS were divided into mild, moderate, and severe groups according to their apnea-hypopnea index (AHI). Early in the morning after the polysomnography (PSG), blood samples were collected and serum levels of serum amyloid A (SAA) were measured by enzyme-linked immunosorbent assay. All subjects were scored by the Auditory Verbal Learning Test (AVLT) scale. Resting brain function images of healthy male volunteers and patients in the severe group were collected by 3.0 T magnetic resonance scanner. SPSS25.0 software was used for statistical analysis.

Results

The SAA of the OSAHS group (n = 43) were higher than those of control group (n = 19). The scores of AVLT-immediate and AVLT-delay in the severe OSAHS group were lower than those in the control group (P < 0.05), and it was negatively correlated with SAA. In the severe OSAHS group, the rest state Function Connection (rsFC) in temporal lobe, marginal lobe, and frontal lobe was lower than that in the control group (P < 0.05) and was significantly negatively correlated with SAA. The rsFC in bilateral parietal lobes was higher than that in the control group (P < 0.05), was significantly positively correlated with SAA, and was negatively correlated with AVLT-delay.

Conclusions

The significant increase in SAA concentration in patients with OSAHS correlated with brain rsFC intensity, providing a reference role for the diagnosis, treatment, and prognosis of cognitive dysfunction in patients with OSAHS.
A Latent Variable Mixed-Effects Location Scale Model with an Application to Daily Diary Data
Authors: Blozis Shelley A.
Published: May 2022

A mixed-effects location scale model allows researchers to study within- and between-person variation in repeated measures. Key components of the model include separate variance models to study predictors of the within-person variance, as well as predictors of the between-person variance of a random effect, such as a random intercept. In this paper, a latent variable mixed-effects location scale model is developed that combines a longitudinal common factor model and a mixed-effects location scale model to characterize within- and between-person variation in a common factor. The model is illustrated using daily reports of positive affect and daily stressors for a large sample of adult women.
Learning intraoperative organ manipulation with context-based reinforcement learning
Authors: D’Ettorre Claudia , Zirino Silvia , Dei Neri Niccolò , Stilli Agostino , De Momi Elena , Stoyanov Danail
Published: May 2022

Purpose

Automation of sub-tasks during robotic surgery is challenging due to the high variability of the surgical scenes intra- and inter-patients. For example, the pick and place task can be executed different times during the same operation and for distinct purposes. Hence, designing automation solutions that can generalise a skill over different contexts becomes hard. All the experiments are conducted using the Pneumatic Attachable Flexible (PAF) rail, a novel surgical tool designed for robotic-assisted intraoperative organ manipulation.

Methods

We build upon previous open-source surgical Reinforcement Learning (RL) training environment to develop a new RL framework for manipulation skills, rlman. In rlman, contextual RL agents are trained to solve different aspects of the pick and place task using the PAF rail system. rlman is implemented to support both low- and high-dimensional state information to solve surgical sub-tasks in a simulation environment.

Results

We use rlman to train state of the art RL agents to solve four different surgical sub-tasks involving manipulation skills using the PAF rail. We compare the results with state-of-the-art benchmarks found in the literature. We evaluate the ability of the agent to be able to generalise over different aspects of the targeted surgical environment.

Conclusion

We have shown that the rlman framework can support the training of different RL algorithms for solving surgical sub-task, analysing the importance of context information for generalisation capabilities. We are aiming to deploy the trained policy on the real da Vinci using the dVRK and show that the generalisation of the trained policy can be transferred to the real world.
A Study of the Effect of Alloying Elements and Temperature on Nitrogen Solubility in Industrial Stainless Steelmaking
Authors: Pitkälä Jyrki , Holappa Lauri , Jokilaakso Ari
Published: May 2022

The role of nitrogen varies in different stainless steels from a harmful impurity to a valuable alloying element. Therefore, the strict control of nitrogen content is a very important issue in the steel making process. Better understanding about the thermodynamics of nitrogen solubility is the basis for this control. The aim of this study was to determine whether the nitrogen solubility at atmospheric pressure at any given composition and temperature in an Argon Oxygen Decarburization (AOD) converter could be reliably predicted. This was done by comparing different equations for nitrogen solubility to industrial measurements of several different steel grades with a wide range of compositions and temperatures. The test set consisted of 100 heats to ensure reproducibility and sufficient variability. The focus was on examining the effect of the main alloying elements (Cr, Ni, Mo, Mn) and temperature on nitrogen solubility. Nitrogen solubility is increased most by the chromium content, followed by manganese and molybdenum, whereas nickel decreases the solubility. The interaction effect of an alloying element on nitrogen declines at increasing temperatures, resulting in a negative temperature dependence, i.e., the maximum nitrogen solubility is obtained near the liquidus temperature. The study showed that most of the examined thermodynamic equations predicted the nitrogen solubility quite well in common stainless steels and even in high alloyed steels. On the other hand, clear discrepancies were observed for steels with a high manganese content as well as with strongly deviating temperatures. Therefore, based on the present measurements and the literature data, a new equation was developed for predicting the solubility of nitrogen in a wide range of stainless steels. This equation can be coupled with the existing process models to control the AOD process.
Research Progress of Catalysts and Initiators for Promoting the Cracking of Endothermic Hydrocarbon Fuels
Authors: Liu Yiyao , Chen Ran , Liu Jie , Zhang Xiangwen
Published: May 2022

Catalytic/initiated cracking of endothermic hydrocarbon fuels is an effective technology for cooling a hypersonic aircraft with a high Mach number (over 5). Catalysts and initiators can promote fuel cracking at low temperatures, increase fuel conversion and the heat sink capacity, and suppress coke deposition, thereby reducing waste heat. Catalysts mainly include metal oxide catalysts, noble metal catalysts and metal nanoparticles, zeolite catalysts, nanozeolite catalysts, and coating catalysts. Moreover, initiators roughly include nitrogenous compounds, oxygenated compounds, and hyperbranched polymer initiators. In this review, we aim to summarize the catalysts and initiators for cracking endothermic hydrocarbon fuels and their mechanisms for promoting cracking. This review will facilitate the development of the synthesis and exploration of catalysts and initiators.
Efficacy and Dosage Pattern of Sacubitril/Valsartan in Chinese Heart Failure with Reduced Ejection Fraction Patients
Authors: Cheang Iokfai , Shi Shi , Lu Xinyi , Liao Shengen , Zhu Xu , Su Xi , Lu Qi , Yuan Jing , Xu Dachun , Zhang Min , Dai Cuilian , Wang Jingfeng , Yuan Fang , Zhao Yan , Zhou Jingmin , Li Xinli
Published: May 2022

This study aims to investigate the dosage pattern, efficacy, and safety of sacubitril/valsartan (Sac/Val) in Chinese heart failure with reduced ejection fraction (HFrEF) patients regarding real-world settings. Patients from 27 centers with a confirmed diagnosis of HFrEF and initiated Sac/Val treatment were enrolled. The primary objective was to evaluate the dosage pattern and change of heart failure status. In a final cohort of 983 patients, outpatient Sac/Val treatment demonstrated a similar beneficial effect in NT-proBNP and cardiac function. After initiating the treatment, overall and sub-population showed similar safety and efficacy. Patients who received a higher dose of Sac/Val (> 200 mg/d) demonstrated better improvement in LV function and reduction of NT-proBNP regardless of adjustment. Among Chinese HFrEF patients, Sac/Val showed a comparable reduction in NT-proBNP and improvement in cardiac function. Data further support guideline recommendations of Sac/Val in Chinese population. Optimal up-titration might provide further benefits. Further long-term and prognostic studies are needed.

Graphical abstract
Near-Peer Teaching in Radiation Oncology: a Proof of Principle Study for Learning Treatment Planning
Authors: Walls Gerard M. , Ellis Rachel , Lynch Sophie , Flynn Margaret A. , McCann Gemma , Jellett Lucy J. , Harrison Claire
Published: May 2022

Radiotherapy techniques are expanding in range and complexity; therefore, protecting learning environments where residents nurture treatment planning skills is critical. The evidence base for ‘near-peer’ teaching (NPT), where professionals at a similar career stage assist in each other’s learning, is growing in hospital-based disciplines, but has not been reported in radiation oncology. The feasibility of a resident-led teaching programme for developing treatment planning skills was investigated herein with quality improvement (QI) methodology. Following consultation with attendings (n = 10) and all residents (n = 17) at the two cancer centres in the region, a regular NPT session focused on planning skills was initiated at the largest centre, with video-linking to the second centre. Tutorials were case-based and pitched at the level of qualifying examinations. Plan–Do–Study–Act (PDSA) cycles were designed based on primary and secondary improvement drivers derived by group consensus among residents, with tutorials adopted accordingly. Participation, content, and satisfaction were monitored for 20 months. Six PDSA cycles reformed the tutorial format, leading to logistical and pedagogical benefits including interprofessional contributions and enhanced interactivity. Tutorials occurred on 85% prescribed occasions (n = 45) during the subsequent 18-month follow-up, with 25 distinct tumour sites featured. Resident participation and satisfaction increased, independent of resident seniority. Tutorials were paused for the first 2 months of the SARS-CoV-2 pandemic only. A high-quality and cost-effective regional, trainee-led teaching programme on treatment planning was feasible and cost-effective in this study.
Experimental study on CO2 capture by using n-butylamine to plug the gas channeling to enhanced oil recovery
Authors: Wang Chengjun , Ma Bin , Zhang Lei
Published: May 2022

The national policy of peak carbon dioxide emission and carbon neutrality has pointed out the technological direction for the development of the petroleum industry in China. In order to efficiently utilize CO2 gas source to enhance oil recovery, n-butylamine is taken as the plugging channeling agent for experiment study to plug the produced channeling-path during the process of CO2 flooding in ultra-low permeability reservoir. The contents of the experiment included three parts: reaction mechanism of n-butylamine with CO2, evaluation of the injection performance of n-butylamine, and the extent of enhanced oil recovery after plugging the gas channeling by using n-butylamine. Reaction product of n-butylamine and CO2 is white solid, which is a type of organic urea so that it can be used to plug the gas channeling. N-butylamine has a good injection performance after adding protecting slug on the condition of high temperature. 80% of the whole volume of core can be spread after injecting 0.3 PV of n-butylamine. During plugging and displacement experiment of heterogeneous cores, oil recovery can be greatly enhanced by 25–30% after injecting n-butylamine. Experimental results show that it can provide a new train of thought for the gas injection development of fractured, heterogeneous and ultra-low permeability reservoirs by using n-butylamine to plug the high permeability area.
Integrating blue: How do we make nationally determined contributions work for both blue carbon and local coastal communities?
Authors: Dencer-Brown Amrit Melissa , Shilland Robyn , Friess Daniel , Herr Dorothée , Benson Lisa , Berry Nicholas J. , Cifuentes-Jara Miguel , Colas Patrick , Damayanti Ellyn , García Elisa López , Gavaldão Marina , Grimsditch Gabriel , Hejnowicz Adam P. , Howard Jennifer , Islam Sheikh Tawhidul , Kennedy Hilary , Kivugo Rahma Rashid , Lang’at Joseph K. S. , Lovelock Catherine , Malleson Ruth , Macreadie Peter I. , Andrade-Medina Rosalía , Mohamed Ahmed , Pidgeon Emily , Ramos Jorge , Rosette Minerva , Salim Mwanarusi Mwafrica , Schoof Eva , Talukder Byomkesh , Thomas Tamara , Vanderklift Mathew A. , Huxham Mark
Published: May 2022

Blue Carbon Ecosystems (BCEs) help mitigate and adapt to climate change but their integration into policy, such as Nationally Determined Contributions (NDCs), remains underdeveloped. Most BCE conservation requires community engagement, hence community-scale projects must be nested within the implementation of NDCs without compromising livelihoods or social justice. Thirty-three experts, drawn from academia, project development and policy, each developed ten key questions for consideration on how to achieve this. These questions were distilled into ten themes, ranked in order of importance, giving three broad categories of people, policy & finance, and science & technology. Critical considerations for success include the need for genuine participation by communities, inclusive project governance, integration of local work into national policies and practices, sustaining livelihoods and income (for example through the voluntary carbon market and/or national Payment for Ecosystem Services and other types of financial compensation schemes) and simplification of carbon accounting and verification methodologies to lower barriers to entry.
Quintessential effects on quasiperiodic oscillations in 4D Einstein–Gauss–Bonnet gravity
Authors: Rayimbaev Javlon , Tadjimuratov Pulat , Ahmedov Bobomurat , Palvanov Satimbay
Published: May 2022

Dynamics of test particles in the space-time of a quintessential black hole (BH) in a novel four-dimensional Einstein–Gauss–Bonnet (EGB) theory is studied. First, we analyse the properties of the space-time of the BH and possible values of the coupling $$\alpha $$
α
and quintessential parameters q that allows the existence of the event horizon. The scalar invariants of the space-time and effects of the parameters on innermost stable circular orbits (ISCOs) radius are also studied. Moreover, fundamental frequencies such as Keplerian and harmonic oscillations are investigated together with applications to quasi-periodic oscillations (QPOs) where the powerful way to test gravity theories using astrophysical observations of twin-peak QPOs is discussed.
New bag-of-feature for histopathology image classification using reinforced cat swarm algorithm and weighted Gaussian mixture modelling
Authors: Vijh Surbhi , Kumar Sumit , Saraswat Mukesh
Published: May 2022

The progress in digital histopathology for computer-aided diagnosis leads to advancement in automated histopathological image classification system. However, heterogeneity and complexity in structural background make it a challenging process. Therefore, this paper introduces robust and reliable new bag-of-feature framework. The optimal visual words are obtained by applying proposed reinforcement cat swarm optimization algorithm. Moreover, the frequency of occurrence of each visual words is depicted through histogram using new weighted Gaussian mixture modelling method. Reinforcement cat swarm optimization algorithm is evaluated on the IEEE CEC 2017 benchmark function problems and compared with other state-of-the-art algorithms. Moreover, statistical test analysis is done on acquired mean and the best fitness values from benchmark functions. The proposed classification model effectively identifies and classifies the different categories of histopathological images. Furthermore, the comparative experimental result analysis of proposed reinforcement cat swarm optimization-based bag-of-feature is performed on standard quality metrics measures. The observation states that reinforcement cat swarm optimization-based bag-of-feature outperforms the other methods and provides promising results.
End-to-end human inspired learning based system for dynamic obstacle avoidance
Authors: Jafri S. M. Haider , Kala Rahul
Published: May 2022

As a first, the paper proposes modelling and learning of specific behaviors for dynamic obstacle avoidance in end-to-end motion planning. In the literature many end-to-end methods have been used in simulators to drive a car and to apply the learnt strategies to avoid the obstacles using the lane changing, following the vehicle as per the traffic rules, driving in-between the lane boundaries, and many more behaviors. The proposed method is designed to avoid obstacles in the scenarios where a dynamic obstacle is headed directly towards the robot from different directions. To avoid the critical encounter of the dynamic obstacles, we trained a novel deep neural network (DNN) with two specific behavioral obstacle avoidance strategies, namely“head-on collision avoidance”and“stop and move”. These two strategies of obstacle avoidance come from the human behavior of obstacle avoidance. Looking at the current frame only, for a very similar visual display of the scenario, the two strategies have contrasting outputs and overall outcomes that makes learning very difficult. A random data recording over general simulations is unlikely to record the corner cases of both behaviors that rarely occur, and a behavior-specific training used in this paper intensifies the same cases for a better learning of the robot in such corner cases. We calculate the intention of the obstacle, whether it will move or not. This proposed method is compared with three state-of-the-art methods of motion planning, namely Timed-Elastic Band, Dynamic Window Approach and Nonlinear Probabilistic Velocity Obstacle. The proposed method beats all the state-of-the-art methods used for comparisons.
Bioinspired MXene-Based User-Interactive Electronic Skin for Digital and Visual Dual-Channel Sensing
Authors: Cao Wentao , Wang Zheng , Liu Xiaohao , Zhou Zhi , Zhang Yue , He Shisheng , Cui Daxiang , Chen Feng
Published: May 2022

User-interactive electronic skin (e-skin) that could convert mechanical stimuli into distinguishable outputs displays tremendous potential for wearable devices and health care applications. However, the existing devices have the disadvantages such as complex integration procedure and lack of the intuitive signal display function. Here, we present a bioinspired user-interactive e-skin, which is simple in structure and can synchronously achieve digital electrical response and optical visualization upon external mechanical stimulus. The e-skin comprises a conductive layer with a carbon nanotubes/cellulose nanofibers/MXene nanohybrid network featuring remarkable electromechanical behaviors, and a stretchable elastomer layer, which is composed of silicone rubber and thermochromic pigments. Furthermore, the conductive nanohybrid network with outstanding Joule heating performance can generate controllable thermal energy under voltage input and then achieve the dynamic coloration of silicone-based elastomer. Especially, such an innovative fusion strategy of digital data and visual images enables the e-skin to monitor human activities with evermore intuition and accuracy. The simple design philosophy and reliable operation of the demonstrated e-skin are expected to provide an ideal platform for next-generation flexible electronics.
Impacting Change in Classroom Literacy Instruction: A Further Investigation of the Better Start Literacy Approach
Authors: Scott Amy , Gillon Gail , McNeill Brigid , Gath Megan
Published: May 2022

A controlled intervention study supported the effectiveness of teachers implementing an integrated intervention (Better Start Literacy Approach; BSLA) to accelerate foundational literacy skills for children in Year 1 with low levels of oral language ability in a community with significant challenges to effective teaching and learning (Gillon et al., 2019). As part of an implementation approach, the current study aimed to investigate whether teachers from less challenging contexts can successfully implement the Better Start Literacy Approach with reduced support from researchers. Two schools with a total of 93 Year 0/1 children participated in the teacher-led classroom literacy intervention, with 20% of sample classified as linguistically diverse. A series of research questions explored the impact of the intervention on children’s foundational literacy skills. Repeated measures general linear models demonstrated a positive impact of the intervention for the research group compared to the control group. Further analysis demonstrated the intervention was equally effective for linguistically diverse learners. The findings have important implications for better understanding the effectiveness of the BSLA in differing contexts and for linguistically diverse learners, further adding to the research for this literacy intervention.
Dissecting Human Gonadal Cell Lineage Specification and Sex Determination Using a Single-Cell RNA-Seq Approach
Authors: Wang Rui , Liu Xixi , Li Li , Yang Ming , Yong Jun , Zhai Fan , Wen Lu , Yan Liying , Qiao Jie , Tang Fuchou
Published: May 2022

Gonadal somatic cells are the main players in gonad development and are important for sex determination and germ cell development. Here, using a time-series single-cell RNA sequencing (scRNA-seq) strategy, we analyzed fetal germ cells (FGCs) and gonadal somatic cells in human embryos and fetuses. Clustering analysis of testes and ovaries revealed several novel cell subsets, including POU5F1+SPARC+ FGCs and KRT19+ somatic cells. Furthermore, our data indicated that the bone morphogenetic protein (BMP) signaling pathway plays cell type-specific and developmental stage-specific roles in testis development and promotes the gonocyte-to-spermatogonium transition (GST) in late-stage testicular mitotic arrest FGCs. Intriguingly, testosterone synthesis function transitioned from fetal Sertoli cells to adult Leydig cells in a stepwise manner. In our study, potential interactions between gonadal somatic cells were systematically explored and we identified cell type-specific developmental defects in both FGCs and gonadal somatic cells in a Turner syndrome embryo (45, XO). Our work provides a blueprint of the complex yet highly ordered development of and the interactions among human FGCs and gonadal somatic cells.
Survival Analysis
Authors: Quiroz Flores Alejandro
Published: May 2022

Quantitative social scientists use survival analysis to understand the forces that determine the duration of events. This Element provides a guideline to new techniques and models in survival analysis, particularly in three areas: non-proportional covariate effects, competing risks, and multi-state models. It also revisits models for repeated events. The Element promotes multi-state models as a unified framework for survival analysis and highlights the role of general transition probabilities as key quantities of interest that complement traditional hazard analysis. These quantities focus on the long term probabilities that units will occupy particular states conditional on their current state, and they are central in the design and implementation of policy interventions.
La Maison des esclaves de Gorée : à l’intersection entre histoire, mémoires et émotions – ADDENDUM
Authors: Sene Cheikh
Published: May 2022

A ilha de Gorée é um símbolo e um lugar de memória do tráfico atlântico de escravos e da escravatura na Senegâmbia. A 27 de dezembro de 1996, o jornalista francês Emmanuel de Roux publicou, no jornal diário Le Monde, um artigo intitulado “Le mythe de la maison des esclaves résiste à la réalité” (“O mito da casa dos escravos resiste à realidade”). Este artigo punha em causa a Casa dos Escravos de Gorée, a qual, de acordo com o autor, nunca tinha albergado escravos do tráfico negreiro. O artigo deu origem a um debate público envolvendo história, memória e emoções. Em 1997, os investigadores e as autoridades políticas senegalesas organizaram um encontro científico destinado a contrariar todas as “tentativas de anestesiar a memória coletiva”.
War as Work: Labor and Soldiering in History
Authors: Daly Samuel Fury Childs
Published: May 2022

In the decade since International Labor and Working-Class History (ILWCH) published its special issue on “Labor and the Military,” treating military service as a problem of labor has grown from a provocation into a major debate. By surveying five recent books on soldiering as a form of labor, this essay poses a set of questions about warfare and work. Is military service best understood as a form of labor, and what might that perspective reveal, or occlude? How do militaries draw the line between those who work and those who fight? Where does that line become blurry? How do soldiers themselves understand the peculiar forms of “work” that war demands? War and work are not separate domains of experience, as these books show. But in some respects, they still demand different tools of analysis.
Safewards-Modell: Was bringt es?
Authors: Fangmeyer Martin , Günthör Edeltraud
Published: May 2022

Was ist zu diesem Thema bereits bekannt?

Patient_innen im psychiatrischen Setting können gefährliche Verhaltensweisen entwickeln. Eine Möglichkeit derartiges Verhalten zu reduzieren, stellen die Maßnahmen des Safewards-Modells dar.

Wie wird eine neue Perspektive eingebracht?

Auf Basis einer systematischen Literaturrecherche wurden die Studienergebnisse in einer Evidenzsynthese zusammengefasst.

Was sind die Auswirkungen für die Praxis?

Auf Basis der vorliegenden Daten zu den Endpunkten, Konflikten sowie Eindämmungs- und Zwangsmaßnahmen können Entscheidungen bezüglich einer Implementierung des Modells unterstützt werden.
Decline in the Nutrient Inventories of the Upper Subtropical Northwest Pacific Ocean
Authors: Kim JiHyun , Kim Guebuem , Cho Hyung‐Mi , Nam SungHyun , Hwang Jeomshik , Park Sojin , Lee KyungJae , DeVries Tim
Published: May 2022

The surface nutrient concentrations of the Northwest Pacific Ocean have shown distinct changes over the past four decades, which have been variably attributed to changes in anthropogenic nitrogen inputs or stratification. Here, we present a new data compilation that demonstrates a long‐term decline in the surface nutrient concentrations caused by a significant decrease (∼25%) in the nutrient inventories of the permanent thermocline (100–850 m) rather than by enhanced stratification. This subsurface nutrient decrease is likely due to the northward expansion of high‐temperature, low‐nutrient subtropical gyre waters associated with climate change and a regional physical regime shift. Furthermore, a declining trend in the N:P ratio pointing toward greater N‐limitation is observed in this research, in contrast to current assumptions inferring P‐limitation by anthropogenic nitrogen inputs. Our results imply that these shifts may influence new production as well as carbon sequestration in this region.
Neutrophils and polymorphonuclear myeloid-derived suppressor cells: an emerging battleground in cancer therapy
Authors: Raskov Hans , Orhan Adile , Gaggar Shruti , Gögenur Ismail
Published: May 2022

Neutrophils are central mediators of innate and adaptive immunity and first responders to tissue damage. Although vital to our health, their activation, function, and resolution are critical to preventing chronic inflammation that may contribute to carcinogenesis. Cancers are associated with the expansion of the neutrophil compartment with an escalation in the number of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in the peripheral circulation and tumor microenvironment. Although phenotypically similar to classically activated neutrophils, PMN-MDSC is pathologically activated and immunosuppressive in nature. They dynamically interact with other cell populations and tissue components and convey resistance to anticancer therapies while accelerating disease progression and metastatic spread. Cancer-associated neutrophilia and tumor infiltration of neutrophils are significant markers of poor outcomes in many cancers. Recently, there has been significant progress in the identification of molecular markers of PMN-MDSC providing insights into the central role of PMN-MDSC in the local tumor microenvironment as well as the systemic immune response in cancer. Further advances in sequencing and proteomics techniques will improve our understanding of their diverse functionalities and the complex molecular mechanisms at play. Targeting PMN-MDSC is currently one of the major focus areas in cancer research and several signaling pathways representing possible treatment targets have been identified. Positive results from preclinical studies clearly justify the current investigation in drug development and thus novel therapeutic strategies are being evaluated in clinical trials. In this review, we discuss the involvement of PMN-MDSC in cancer initiation and progression and their potential as therapeutic targets and clinical biomarkers in different cancers.
Severe intraventricular hemorrhage causes long-lasting structural damage in a preterm rabbit pup model
Authors: Romantsik Olga , Ross-Munro Emily , Grönlund Susanne , Holmqvist Bo , Brinte Anders , Gerdtsson Erik , Vallius Suvi , Bruschettini Matteo , Wang Xiaoyang , Fleiss Bobbi , Ley David
Published: May 2022

Background

Intraventricular hemorrhage causes significant lifelong mortality and morbidity, especially in preterm born infants. Progress in finding an effective therapy is stymied by a lack of preterm animal models with long-term follow-up. This study addresses this unmet need, using an established model of preterm rabbit IVH and analyzing outcomes out to 1 month of age.

Methods

Rabbit pups were delivered preterm and administered intraperitoneal injection of glycerol at 3 h of life and approximately 58% developed IVH. Neurobehavioral assessment was performed at 1 month of age followed by immunohistochemical labeling of epitopes for neurons, synapses, myelination, and interneurons, analyzed by means of digital quantitation and assessed via two-way ANOVA or Student’s t test.

Results

IVH pups had globally reduced myelin content, an aberrant cortical myelination microstructure, and thinner upper cortical layers (I–III). We also observed a lower number of parvalbumin (PV)-positive interneurons in deeper cortical layers (IV–VI) in IVH animals and reduced numbers of neurons, synapses, and microglia. However, there were no discernable changes in behaviors.

Conclusions

We have established in this preterm pup model that long-term changes after IVH include significant wide-ranging alterations to cortical organization and microstructure. Further work to improve the sensitivity of neurocognitive testing in this species at this age may be required.

Impact

This study uses an established animal model of preterm birth, in which the rabbit pups are truly born preterm, with reduced organ maturation and deprivation of maternally supplied trophic factors.

This is the first study in preterm rabbits that explores the impacts of severe intraventricular hemorrhage beyond 14 days, out to 1 month of age.

Our finding of persisting but subtle global changes including brain white and gray matter will have impact on our understanding of the best path for therapy design and interventions.
Probiotic supplementation for neonates with congenital gastrointestinal surgical conditions: guidelines for future research
Authors: Rao Shripada , Esvaran Meera , Chen Liwei , Kok Chooi , Keil Anthony D. , Gollow Ian , Simmer Karen , Wemheuer Bernd , Conway Patricia , Patole Sanjay
Published: May 2022

Our pilot RCT found that probiotic supplementation with the three-strain bifidobacterial product (B. breve M-16V, B. longum subsp. infantis M-63 and B. longum subsp. longum BB536) attenuates gut dysbiosis, increases stool short-chain fatty acid (SCFA) levels and improves the growth of head circumference in neonates with congenital gastrointestinal surgical conditions (CGISC). In this article, we have provided guidelines for designing future multicentre RCTs based on the experience gained from our pilot RCT. The recommendations include advice about sample size, potential confounders, outcomes of interest, probiotic strain selection, storage, dose, duration and microbial quality assurance, collection of stool samples, storage and analysis and reporting. Following these guidelines will increase the validity of future RCTs in this area and hence confidence in their results.

Impact

Probiotic supplementation attenuates gut dysbiosis, increases stool short-chain fatty acid (SCFA) levels and improves the growth of head circumference in neonates with congenital gastrointestinal surgical conditions.

The current review provides evidence-based guidelines to conduct adequately powered RCTs in this field.
PET2 response associated with survival in newly diagnosed diffuse large B-cell lymphoma: results of two independent prospective cohorts
Authors: Desai Sanjal H. , Pederson Levi , LaPlant Betsy , Mwangi Raphael , Maurer Matthew , Young Jason R. , Macon William R. , King Rebecca L. , Wang Yucai , Cerhan James R. , Feldman Andrew , Inwards David J. , Micallef Ivana , Johnston Patrick , Porrata Luis F. , Ansell Stephen M. , Habermann Thomas M. , Witzig Thomas E. , Nowakowski Grzegorz S.
Published: May 2022

Studies evaluating Positron Emission Tomography scan after 2 cycles of chemotherapy (PET2) in newly diagnosed diffuse large B cell lymphoma (DLBCL) are heterogeneous in patient characteristics, treatments and have conflicting results. Here we report association of PET2 with outcomes in two large independent prospective cohorts of newly diagnosed DLBCL pts treated with two RCHOP-based regimens. The discovery cohort consisted of pts enrolled in single arm phase 2 MC078E study of lenalidomide with RCHOP (R2CHOP). The validation cohort consisted of RCHOP-treated pts from the Molecular Epidemiology Resource (MER) cohort. Pts who received 3-6 cycles of therapy and had PET2 were included in the study. Patients who progressed on PET2 were excluded. Revised response criteria 2007 were used to define PET2 response PET2 positive (PET2 + ) pts had inferior EFS [24-month EFS 45.5% vs 87.9%, HR 4.0, CI95 (2.1–7.9), p < 0.0001) with a trend towards lower OS [24-months OS 77% vs 94.8%, HR 2.0, CI95 (0.9–4.8), P = 0.1] than PET2 negative (PET2−) pts in MC078E cohort. PET2 + pts had an inferior EFS (24 month EFS 48.7% vs 81.6%, HR 2.9, CI95 2.0–4.2, p < 0.0001) and OS (24-month OS 68.6% vs 88.1%, HR 2.3, CI95: 1.5–3.5, p < 0.0001) in the MER cohort. These results were consistent regardless of age, sex and in the subgroup of advanced stage and high-risk international prognostic index (IPI). For MER, PET2 + pts also had higher odds of positive end of treatment PET (OR: 17.3 (CI95 7.9–37.7), p < 0.001). PET2 is an early predictor DLBCL pts at high risk of progression and death in two independent prospective cohorts. PET2-guided risk-adapted strategies may improve outcomes, and should be explored in clinical trials.
Mitochondria supply sub-lethal signals for cytokine secretion and DNA-damage in H. pylori infection
Authors: Dörflinger Benedikt , Badr Mohamed Tarek , Haimovici Aladin , Fischer Lena , Vier Juliane , Metz Arlena , Eisele Bianca , Bronsert Peter , Aumann Konrad , Höppner Jens , Waguia Kontchou Collins , Parui Ishita , Weber Arnim , Kirschnek Susanne , Häcker Georg
Published: May 2022

The bacterium Helicobacter pylori induces gastric inflammation and predisposes to cancer. H. pylori-infected epithelial cells secrete cytokines and chemokines and undergo DNA-damage. We show that the host cell’s mitochondrial apoptosis system contributes to cytokine secretion and DNA-damage in the absence of cell death. H. pylori induced secretion of cytokines/chemokines from epithelial cells, dependent on the mitochondrial apoptosis machinery. A signalling step was identified in the release of mitochondrial Smac/DIABLO, which was required for alternative NF-κB-activation and contributed to chemokine secretion. The bacterial cag-pathogenicity island and bacterial muropeptide triggered mitochondrial host cell signals through the pattern recognition receptor NOD1. H. pylori-induced DNA-damage depended on mitochondrial apoptosis signals and the caspase-activated DNAse. In biopsies from H. pylori-positive patients, we observed a correlation of Smac-levels and inflammation. Non-apoptotic cells in these samples showed evidence of caspase-3-activation, correlating with phosphorylation of the DNA-damage response kinase ATM. Thus, H. pylori activates the mitochondrial apoptosis pathway to a sub-lethal level. During infection, Smac has a cytosolic, pro-inflammatory role in the absence of apoptosis. Further, DNA-damage through sub-lethal mitochondrial signals is likely to contribute to mutagenesis and cancer development.
HMGA1 positively regulates the microtubule-destabilizing protein stathmin promoting motility in TNBC cells and decreasing tumour sensitivity to paclitaxel
Authors: Sgubin Michela , Pegoraro Silvia , Pellarin Ilenia , Ros Gloria , Sgarra Riccardo , Piazza Silvano , Baldassarre Gustavo , Belletti Barbara , Manfioletti Guidalberto
Published: May 2022

High Mobility Group A1 (HMGA1) is an architectural chromatin factor involved in the regulation of gene expression and a master regulator in Triple Negative Breast Cancer (TNBC). In TNBC, HMGA1 is overexpressed and coordinates a gene network that controls cellular processes involved in tumour development, progression, and metastasis formation. Here, we find that the expression of HMGA1 and of the microtubule-destabilizing protein stathmin correlates in breast cancer (BC) patients. We demonstrate that HMGA1 depletion leads to a downregulation of stathmin expression and activity on microtubules resulting in decreased TNBC cell motility. We show that this pathway is mediated by the cyclin-dependent kinase inhibitor p27kip1 (p27). Indeed, the silencing of HMGA1 expression in TNBC cells results both in an increased p27 protein stability and p27-stathmin binding. When the expression of both HMGA1 and p27 is silenced, we observe a significant rescue in cell motility. These data, obtained in cellular models, were validated in BC patients. In fact, we find that patients with high levels of both HMGA1 and stathmin and low levels of p27 have a statistically significant lower survival probability in terms of relapse-free survival (RFS) and distant metastasis-free survival (DMFS) with respect to the patient group with low HMGA1, low stathmin, and high p27 expression levels. Finally, we show in an in vivo xenograft model that depletion of HMGA1 chemo-sensitizes tumour cells to paclitaxel, a drug that is commonly used in TNBC treatments. This study unveils a new interaction among HMGA1, p27, and stathmin that is critical in BC cell migration. Moreover, our data suggest that taxol-based treatments may be more effective in reducing the tumour burden when tumour cells express low levels of HMGA1.
Somatic FOXC1 insertion mutation remodels the immune microenvironment and promotes the progression of childhood acute lymphoblastic leukemia
Authors: Wang Yaping , Ma Xiaopeng , Huang Jie , Yang Xiaoyun , Kang Meiyun , Sun Xiaoyan , Li Huimin , Wu Yijun , Zhang Heng , Zhu Yuting , Xue Yao , Fang Yongjun
Published: May 2022

Acute lymphoblastic leukemia (ALL) is the most common malignant hematological diseases in children. An immunosuppressive microenvironment, particularly regulatory T cell (Treg) infiltration, has been documented to be highly associated with childhood ALL. This present study, based on genetic factors, was aimed at investigating the mutations potentially involved in the immunosuppressive microenvironment in childhood ALL. After whole-exome sequencing was used on DNA extracted from the T cells of ALL bone marrow samples, we found the FOXC1 H446HG induced a increased Treg while decreased cytotoxic T lymphocyte (CTL) in bone marrow. The mutation of FOXC1 in T cell promoted the proliferation of leukemia cells in vitro and in vivo. CpG islands formed by insertion mutation led to an abnormal increase in exon methylation and were associated with the suppression of FOXC1. Decreased FOXC1 attenuated the transcription of HDAC1, thus resulting in the activation of KLF10 through increasing H3K27 acetylation in the promoter region. In conclusion, the de novo insertion mutation in FOXC1 induced suppression of FOXC1, thereby promoting a Treg/CTL shift in the ALL immune microenvironment. The FOXC1 H446HG mutation might be a potential therapeutic target for ALL in the future.
Bacteriophage treatment of disseminated cutaneous Mycobacterium chelonae infection
Authors: Little Jessica S. , Dedrick Rebekah M. , Freeman Krista G. , Cristinziano Madison , Smith Bailey E. , Benson Constance A. , Jhaveri Tulip A. , Baden Lindsey R. , Solomon Daniel A. , Hatfull Graham F.
Published: May 2022

Mycobacterium chelonae is a rare cause of chronic disseminated cutaneous infections in immunocompromised patients. Multidrug-resistant M. chelonae infections present a challenge for treatment, and prolonged antimicrobial courses lead to significant toxicities and further antimicrobial resistance. We report a case of refractory cutaneous disseminated M. chelonae infection in a patient with seronegative arthritis on immunotherapy with tofacitinib that was treated with combination antimicrobial, surgical, and single bacteriophage therapy with excellent clinical response. The patient developed neutralizing antibodies against the bacteriophage but continues to have stable improvement of disease with negative biopsies and no evidence of bacterial resistance to the phage.
Multivalent interactions essential for lentiviral integrase function
Authors: Ballandras-Colas Allison , Chivukula Vidya , Gruszka Dominika T. , Shan Zelin , Singh Parmit K. , Pye Valerie E. , McLean Rebecca K. , Bedwell Gregory J. , Li Wen , Nans Andrea , Cook Nicola J. , Fadel Hind J. , Poeschla Eric M. , Griffiths David J. , Vargas Javier , Taylor Ian A. , Lyumkis Dmitry , Yardimci Hasan , Engelman Alan N. , Cherepanov Peter
Published: May 2022

A multimer of retroviral integrase (IN) synapses viral DNA ends within a stable intasome nucleoprotein complex for integration into a host cell genome. Reconstitution of the intasome from the maedi-visna virus (MVV), an ovine lentivirus, revealed a large assembly containing sixteen IN subunits1. Herein, we report cryo-EM structures of the lentiviral intasome prior to engagement of target DNA and following strand transfer, refined at 3.4 and 3.5 Å resolution, respectively. The structures elucidate details of the protein-protein and protein-DNA interfaces involved in lentiviral intasome formation. We show that the homomeric interfaces involved in IN hexadecamer formation and the α-helical configuration of the linker connecting the C-terminal and catalytic core domains are critical for MVV IN strand transfer activity in vitro and for virus infectivity. Single-molecule microscopy in conjunction with photobleaching reveals that the MVV intasome can bind a variable number, up to sixteen molecules, of the lentivirus-specific host factor LEDGF/p75. Concordantly, ablation of endogenous LEDGF/p75 results in gross redistribution of MVV integration sites in human and ovine cells. Our data confirm the importance of the expanded architecture observed in cryo-EM studies of lentiviral intasomes and suggest that this organization underlies multivalent interactions with chromatin for integration targeting to active genes.
Inverse design enables large-scale high-performance meta-optics reshaping virtual reality
Authors: Li Zhaoyi , Pestourie Raphaël , Park Joon-Suh , Huang Yao-Wei , Johnson Steven G. , Capasso Federico
Published: May 2022

Meta-optics has achieved major breakthroughs in the past decade; however, conventional forward design faces challenges as functionality complexity and device size scale up. Inverse design aims at optimizing meta-optics design but has been currently limited by expensive brute-force numerical solvers to small devices, which are also difficult to realize experimentally. Here, we present a general inverse-design framework for aperiodic large-scale (20k × 20k λ2) complex meta-optics in three dimensions, which alleviates computational cost for both simulation and optimization via a fast approximate solver and an adjoint method, respectively. Our framework naturally accounts for fabrication constraints via a surrogate model. In experiments, we demonstrate aberration-corrected metalenses working in the visible with high numerical aperture, poly-chromatic focusing, and large diameter up to the centimeter scale. Such large-scale meta-optics opens a new paradigm for applications, and we demonstrate its potential for future virtual-reality platforms by using a meta-eyepiece and a laser back-illuminated micro-Liquid Crystal Display.