bluuebunny/crossref_metadata_2025 huggingface dataset:
The unusual French policy mix towards labour market inequalities
Authors: Bozio Antoine
Published: June 2023

This short paper presents an overview of the French policy mix towards labour market inequalities, consisting of a high minimum wage together with targeted payroll tax cuts around the minimum wage. It reviews the recent literature documenting the impact of that policy mix on employment and wage inequality. The main takeaways are that pre‐tax wage inequality has been increasing in France rather like it has in the UK and the US, while net wage inequality has decreased and then remained stable. The employment experience for the middle age group is also very close in France to the one in the UK and the US, while it differs markedly at young and older ages. The paper offers two more general thoughts on how to make progress in comparing policy options. First, most studies tend to give too much weight to tax and benefit reforms in being able to reduce inequality as they disregard incidence mechanisms, and fail to incorporate properly longer‐term effects of other policies on pre‐tax inequality. Second, the design of effective policy should always incorporate simplicity and salience. Failure to do so is likely to lead to little expected impact of such policies.
Double vision due to lateral rectus injury after cosmetic botulinum toxin injections
Authors: Khan Samavia , Pathak Gaurav , Milgraum David , Tamhankar Madhura , Milgraum Sandy
Published: June 2023

Facial intramuscular injections of Botulinum toxin (BoNT) injections are among the most common cosmetic procedures in dermatology. Rarely, serious adverse reactions such as blepharoptosis, diplopia and periorbital hematoma may occur with improper administration technique. Here we report a case of painless diplopia 5 weeks post‐BoNT injection for ‘crow's feet’ likely due to inadvertent BoNT diffusion into the lateral rectus muscle causing a temporary palsy. This case aims to raise awareness of proper cosmetic BoNT injection techniques in the periorbital area to avoid ophthalmic complications.
Notes from winter storm Uri, a.k.a. Snowmageddon. Austin, Texas. February 2021
Authors: Campbell Craig
Published: June 2023

This piece is part of a special section of “hundreds” for Kathleen Stewart.
The voice of persons with intellectual disability: Why does autonomy support make them feel better?
Authors: Estreder Yolanda , Martínez‐Tur Vicente , Moliner Carolina , Gracia Esther , Lira Eva
Published: June 2023

Our study focused on the role of inclusive environments characterized by the support that supervisors provide to individuals with intellectual disability working in sheltered workshops. We propose that autonomy support is positively related to the satisfaction of individuals with intellectual disability with their autonomy in this organizational context. Satisfaction, in turn, is expected to be positively related to well‐being. A total of 394 individuals with intellectual disability working in 59 sheltered workshops located in Spain participated in the study. The research team used a pictorial questionnaire designed in cooperation with experts on measures for individuals with intellectual disability and tested in a pilot study. Using a cross‐lagged design, participants answered the questionnaire by reporting how much support they received from non‐disabled supervisors, their satisfaction with their level of autonomy, and their general well‐being (T1). Four weeks after T1, they reported their satisfaction (T2), and 8 weeks after T1, they reported their well‐being (T3). Using structural equation modeling methods with robust maximum likelihood estimation via Mplus, our results confirmed the mediation of satisfaction, not only in T1 but also over time. This study contributes to the knowledge about how supportive organizational environments help individuals with intellectual disability.
Detection of changes in regional colonic fermentation in response to supplementing a low FODMAP diet with dietary fibres by hydrogen concentrations, but not by luminal pH
Authors: So Daniel , Yao Chu K. , Gill Paul A. , Thwaites Phoebe A. , Ardalan Zaid S. , McSweeney Chris S. , Denman Stuart E. , Chrimes Adam F. , Muir Jane G. , Berean Kyle J. , Kalantar‐Zadeh Kourosh , Gibson Peter R.
Published: June 2023

Background

Carbohydrate fermentation plays a pivotal role in maintaining colonic health with excessive proximal and deficient distal fermentation being detrimental.

Aims

To utilise telemetric gas‐ and pH‐sensing capsule technologies for defining patterns of regional fermentation following dietary manipulations, alongside conventional techniques of measuring fermentation.

Methods

In a double‐blind crossover trial, 20 patients with irritable bowel syndrome were fed low FODMAP diets that included no extra fibre (total fibre content 24 g/day), or additional poorly fermented fibre, alone (33 g/day) or with fermentable fibre (45 g/day) for 2 weeks. Plasma and faecal biochemistry, luminal profiles defined by tandem gas‐ and pH‐sensing capsules, and faecal microbiota were assessed.

Results

Plasma short‐chain fatty acid (SCFA) concentrations (μmol/L) were median (IQR) 121 (100–222) with fibre combination compared with 66 (44–120) with poorly fermented fibre alone (p = 0.028) and 74 (55–125) control (p = 0.069), but no differences in faecal content were observed. Luminal hydrogen concentrations (%), but not pH, were higher in distal colon (mean 4.9 [95% CI: 2.2–7.5]) with fibre combination compared with 1.8 (0.8–2.8) with poorly fermented fibre alone (p = 0.003) and 1.9 (0.7–3.1) control (p = 0.003). Relative abundances of saccharolytic fermentative bacteria were generally higher in association with supplementation with the fibre combination.

Conclusions

A modest increase in fermentable plus poorly fermented fibres had minor effects on faecal measures of fermentation, despite increases in plasma SCFA and abundance of fermentative bacteria, but the gas‐sensing capsule, not pH‐sensing capsule, detected the anticipated propagation of fermentation distally in the colon. The gas‐sensing capsule technology provides unique insights into localisation of colonic fermentation.

Trial registration: ACTRN12619000691145.
Understanding the co‐construction of safety in the paediatric intensive care unit: A meta‐ethnography of parents' experiences
Authors: Seaton Sarah E. , Manning Joseph C. , Draper Elizabeth S. , Davis Peter J. , Mackintosh Nicola
Published: June 2023

Background

Children experiencing critical illness or injury may require admission to a paediatric intensive care unit (PICU) to receive life‐sustaining or life‐saving treatment. Studies have explored the experience of parents with a child in PICU but tend to focus on subgroups of children or specific healthcare systems. Therefore, we aimed to undertake a meta‐ethnography to draw together the published research.

Methods

A systematic search strategy was developed to identify qualitative studies, which had explored the experiences of parents with a critically ill child treated in a PICU. A meta‐ethnography was undertaken following the structured steps of identifying the topic; undertaking a systematic search; reading the research; determining how the studies relate and translate into each other; and synthesising and expressing the results.

Results

We identified 2989 articles from our search and after a systematic series of exclusions, 15 papers remaining for inclusion. We explored the original parent voices (first order) and the interpretation of the study authors (second order) to identify three third‐order concepts (our interpretation of the findings), which related to technical, relational and temporal factors. These factors influenced parents' experiences, providing both barriers and facilitators to how parents and caregivers experienced the time their child was in the PICU. The dynamic and co‐constructed nature of safety provided an analytical overarching frame of reference.

Conclusion

This synthesis demonstrates novel ways in which parents and caregivers can contribute to the vital role of ensuring a co‐created safe healthcare environment for their child when receiving life‐saving care within the PICU.
Unraveling the effectiveness of antibiotics for peri‐implantitis treatment: A scoping review
Authors: Feres Magda , Martins Rodrigo , Souza João Gabriel S. , Bertolini Martinna , Barão Valentim A. R. , Shibli Jamil A.
Published: June 2023

Background

Antibiotics are the most effective adjuncts in the treatment of periodontitis. However, the benefits of these agents in treating peri‐implantitis are still debatable and demand further analysis.

Purpose

The aim of this review was to critically appraise the literature on the use of antibiotics to treat peri‐implantitis, with the ultimate goal of supporting evidence‐based clinical recommendations, defining gaps in knowledge and guiding future studies on this topic.

Methods

A systematized literature search was conducted in MEDLINE/PubMed and Cochrane Library databases for randomized clinical trials (RCTs) on patients with peri‐implantitis treated by mechanical debridement‐only or with adjunctive use of local or systemic antibiotics. Clinical and microbiological data were extracted from the RCTs included. The findings were critically reviewed, interpreted, and discussed. An overview of antibiotic‐loaded dental implant materials in peri‐implantitis treatment was also provided.

Results

Twelve RCTs testing local/systemic antibiotics were included. Although not always statistically significant, all antibiotic‐treated groups had greater reductions in mean PD than those treated by mechanical debridement‐only. The only clinically relevant antibiotic protocol supported by one RCT with low risk of bias and long‐lasting benefits was systemic metronidazole (MTZ). Studies using ultrasonic debridement reported better outcomes. No RCTs to date have tested MTZ‐only or with amoxicillin (AMX) as adjuncts to open‐flap implant debridement. In vitro/animal studies suggested that biomaterials with antimicrobial properties are promising to treat peri‐implantitis.

Conclusion

There are insufficient data to support a particular evidence‐based antibiotic protocol to treat peri‐implantitis using surgical or nonsurgical therapy, but some conclusions may be drawn. Systemic MTZ adjunct to ultrasonic debridement is an effective protocol to improve the outcomes of nonsurgical treatment. Future studies should assess the clinical and microbiological effects of MTZ and MTZ + AMX as adjuncts to optimal nonsurgical implant decontamination protocols or open‐flap debridement. In addition, new locally delivered drugs and antibiotic‐loaded surfaces should be assessed by RCTs.
Development of acoustic source localization with adaptive neural network using distance mating‐based red deer algorithm
Authors: Bharat Babu E. , Krishna D. Hari , Hussain S. Munavvar , Veeramalla Santhosh Kumar
Published: June 2023

Multichannel, audio processing approaches are widely examined in human–computer interaction, autonomous robots, audio surveillance, and teleconferencing systems. The numerous applications are linked to the speech technology and acoustic analysis area. Much attention is received to the active speakers and spatial localization of acoustic sources on the acoustic sensor arrays. Baseline approaches provide negotiable performance in a real‐world comprised of far‐field/near‐field monitoring, reverberant and noisy environments, and also the outdoor/indoor scenarios. A practical system to detect defects in complex structures is the time difference mapping (TDM) technique. The significant scope of the research is to search the location using the minimum distance point in the time difference database to be apart from the verification point. In the case of the improved “time difference mapping (I‐TDM)” technique and traditional “time difference mapping (T‐TDM)” technique, the denser grids and vast database permit increased accuracy. In the database, if the location points are not present, then the accurate localization of the I‐TDM and T‐TDM techniques is damaged. Hence, to handle these problems, this article plans to develop acoustic source localization according to the deep learning strategy. The audio dataset is gathered from the benchmark source called the SSLR dataset and is initially subjected to preprocessing, which involves artifact removal and smoothing for effective processing. Further, the adaptive convolutional neural network (CNN)‐based feature set creation is performed. Here, the adaptive CNN is accomplished by the improved optimization algorithm called distance mating‐based red deer algorithm (DM‐RDA). With this trained feature set, the acoustic source localization is done by the weight updated deep neural network, in which the same DM‐RDA is used for optimizing the training weight. The simulation outcome proves that the designed model produced enhanced performance compared to other traditional source localization estimators.
Disability and narrative medicine: Challenges and opportunities
Authors: Guthrie Elisabeth , Charon Rita
Published: June 2023

Despite decades of international entreaties for improvement, education about and provision of healthcare for people with disabilities remains harmfully inferior to that of the non‐disabled population. Many obstacles confound efforts to ameliorate this inequity, perhaps the most pernicious of which is negative bias on the part of providers. Narrative medicine offers a means to address healthcare attitudes towards people with disabilities, in particular negative attitudes based on ‘ableism’. Through absorbing, writing, and sharing of diverse perspectives, narrative medicine kindles imagination and empathy, promoting self‐reflection. This approach enriches the students' capacity to absorb what their patients are trying to say, and to appreciate, respect, and hopefully meet the healthcare needs of people with disability.

What this paper adds

Narrative medicine is a pedagogical tool to help providers listen and reflect on patients with disabilities.
Trade‐offs in non‐native plant herbivore defences enhance performance
Authors: Sun Xiao , Sun Yumei , Cao Xueyao , Zhai Xincong , Callaway Ragan M. , Wan Jinlong , Flory S. Luke , Huang Wei , Ding Jianqing
Published: June 2023

Non‐native plants are typically released from specialist enemies but continue to be attacked by generalists, albeit at lower intensities. This reduced herbivory may lead to less investment in constitutive defences and greater investment in induced defences, potentially reducing defence costs. We compared herbivory on 27 non‐native and 59 native species in the field and conducted bioassays and chemical analyses on 12 pairs of non‐native and native congeners. Non‐natives suffered less damage and had weaker constitutive defences, but stronger induced defences than natives. For non‐natives, the strength of constitutive defences was correlated with the intensity of herbivory experienced, whereas induced defences showed the reverse. Investment in induced defences correlated positively with growth, suggesting a novel mechanism for the evolution of increased competitive ability. To our knowledge, these are the first linkages reported among trade‐offs in plant defences related to the intensity of herbivory, allocation to constitutive versus induced defences, and growth.
The collaborative study on the genetics of alcoholism: Genetics
Authors: Johnson Emma C. , Salvatore Jessica E. , Lai Dongbing , Merikangas Alison K. , Nurnberger John I. , Tischfield Jay A. , Xuei Xiaoling , Kamarajan Chella , Wetherill Leah ,   COGA Collaborators, Rice John P. , Kramer John R. , Kuperman Samuel , Foroud Tatiana , Slesinger Paul A. , Goate Alison M. , Porjesz Bernice , Dick Danielle M. , Edenberg Howard J. , Agrawal Arpana
Published: June 2023

This review describes the genetic approaches and results from the family‐based Collaborative Study on the Genetics of Alcoholism (COGA). COGA was designed during the linkage era to identify genes affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD‐focused studies to subsequently adopt a genome‐wide association (GWAS) approach. COGA's family‐based structure, multimodal assessment with gold‐standard clinical and neurophysiological data, and the availability of prospective longitudinal phenotyping continues to provide insights into the etiology of AUD and related disorders. These include investigations of genetic risk and trajectories of substance use and use disorders, phenome‐wide association studies of loci of interest, and investigations of pleiotropy, social genomics, genetic nurture, and within‐family comparisons. COGA is one of the few AUD genetics projects that includes a substantial number of participants of African ancestry. The sharing of data and biospecimens has been a cornerstone of the COGA project, and COGA is a key contributor to large‐scale GWAS consortia. COGA's wealth of publicly available genetic and extensive phenotyping data continues to provide a unique and adaptable resource for our understanding of the genetic etiology of AUD and related traits.
Estimating co‐extinction threats in terrestrial ecosystems
Authors: Doherty Seamus , Saltré Frédérik , Llewelyn John , Strona Giovanni , Williams Stephen E. , Bradshaw Corey J. A.
Published: June 2023

The biosphere is changing rapidly due to human endeavour. Because ecological communities underlie networks of interacting species, changes that directly affect some species can have indirect effects on others. Accurate tools to predict these direct and indirect effects are therefore required to guide conservation strategies. However, most extinction‐risk studies only consider the direct effects of global change—such as predicting which species will breach their thermal limits under different warming scenarios—with predictions of trophic cascades and co‐extinction risks remaining mostly speculative. To predict the potential indirect effects of primary extinctions, data describing community interactions and network modelling can estimate how extinctions cascade through communities. While theoretical studies have demonstrated the usefulness of models in predicting how communities react to threats like climate change, few have applied such methods to real‐world communities. This gap partly reflects challenges in constructing trophic network models of real‐world food webs, highlighting the need to develop approaches for quantifying co‐extinction risk more accurately. We propose a framework for constructing ecological network models representing real‐world food webs in terrestrial ecosystems and subjecting these models to co‐extinction scenarios triggered by probable future environmental perturbations. Adopting our framework will improve estimates of how environmental perturbations affect whole ecological communities. Identifying species at risk of co‐extinction (or those that might trigger co‐extinctions) will also guide conservation interventions aiming to reduce the probability of co‐extinction cascades and additional species losses.
Hybrid SV‐GARCH, t‐GARCH and Markov‐switching covariance structures in VEC models—Which is better from a predictive perspective?
Authors: Pajor Anna , Wróblewska Justyna , Kwiatkowski Łukasz , Osiewalski Jacek
Published: June 2023

We compare predictive performance of a multitude of alternative Bayesian vector autoregression (VAR) models allowing for cointegration and time‐varying conditional covariances, described by different multivariate stochastic volatility (MSV) models, including their hybrids with multivariate GARCH processes (MSV‐MGARCH), as well as t‐GARCH and Markov‐switching structures. The forecast accuracy is evaluated mainly through predictive Bayes factors, but energy scores and the probability integral transform are also used. Two empirical studies, for the US and Polish economies, are based on a small model of monetary policy comprising inflation, unemployment and interest rate. The results indicate that capturing conditional heteroskedasticity by some MSV‐MGARCH specifications contributes the most to the forecasting power of the VAR/VEC model.
Integrated analysis identifies RAC3 as an immune‐related prognostic biomarker associated with chemotherapy sensitivity in endometrial cancer
Authors: Huang Pu , Qian Yiyu , Xia Yu , Wang Siyuan , Xu Cheng , Zhu Xueqiong , Gao Qinglei
Published: June 2023

Endometrial cancer (EC) is one of the most common gynaecological malignant tumours with a high incidence, leading to urgent demands for exploring novel carcinogenic mechanisms and developing rational therapeutic strategies. The rac family of small GTPase 3 (RAC3) functions as an oncogene in various human malignant tumours and plays an important role in tumour development. However, the critical roles of RAC3 in the progression of EC need further investigation. Based on TCGA, single‐cell RNA‐Seq, CCLE and clinical specimens, we revealed that the RAC3 was specifically distributed in EC tumour cells compared to normal tissues and functioned as an independent diagnostic marker with a high area under curve (AUC) score. Meanwhile, the RAC3 expression in EC tissues was also correlated with a poor prognosis. In detail, the high levels of RAC3 in EC tissues were reversely associated with CD8+T cell infiltration and orchestrated an immunosuppressive microenvironment. Furthermore, RAC3 accelerated tumour cell proliferation and inhibited its apoptosis, without impacting cell cycle stages. Importantly, silencing RAC3 improved the sensitivity of EC cells to chemotherapeutic drugs. In this paper, we revealed that RAC3 was predominantly expressed in EC and significantly correlated with the progression of EC via inducing immunosuppression and regulating tumour cell viability, providing a novel diagnostic biomarker and a promising strategy for sensitizing chemotherapy to EC.
A Study of Physical Resilience and Aging (SPRING): Conceptual framework, rationale, and study design
Authors: Walston Jeremy , Varadhan Ravi , Xue Qian‐Li , Buta Brian , Sieber Frederick , Oni Julius , Imus Phil , Crews Deidra C. , Artz Andrew , Schrack Jennifer , Kalyani Rita R. , Abadir Peter , Carlson Michelle , Hladek Melissa , McAdams‐DeMarco Mara , Jones Rick , Johnson Aaron , Shafi Tariq , Newman Anne B. , Bandeen‐Roche Karen
Published: June 2023

Understanding the physiological basis of physical resilience to clinical stressors is crucial for the well‐being of older adults. This article presents a novel framework to discover the biological underpinnings of physical resilience in older adults as part of the “Characterizing Resiliencies to Physical Stressors in Older Adults: A Dynamical Physiological Systems Approach” study, also known as The Study of Physical Resilience and Aging (SPRING). Physical resilience, defined as the capacity of a person to withstand clinical stressors and quickly recover or improve upon a baseline functional level, is examined in adults aged 55 years and older by studying the dynamics of stress response systems. The hypothesis is that well‐regulated stress response systems promote physical resilience. The study employs dynamic stimulation tests to assess energy metabolism, the hypothalamic–pituitary–adrenal axis, the autonomic nervous system, and the innate immune system. Baseline characteristics influencing resilience outcomes are identified through deep phenotyping of physical and cognitive function, as well as of biological, environmental, and psychosocial characteristics. SPRING aims to study participants undergoing knee replacement surgery (n = 100), bone and marrow transplantation (n = 100), or anticipating dialysis initiation (n = 60). Phenotypic and functional measures are collected pre‐stressor and at multiple times after stressor for up to 12 months to examine resilience trajectories. By improving our understanding of physical resilience in older adults, SPRING has the potential to enhance resilient outcomes to major clinical stressors. The article provides an overview of the study's background, rationale, design, pilot phase, implementation, and implications for improving the health and well‐being of older adults.
Academic Accommodations for Middle and High School Students Following a Concussion: Perspectives of Teachers and School Administrators
Authors: Shepherd Heather A. , Yeates Keith O. , Reed Nick , Caron Jeffrey G. , Schneider Kathryn J. , Emery Carolyn A. , Black Amanda M.
Published: June 2023

BACKGROUND

An estimated 1 in 5 adolescents have sustained a concussion in North America. Teachers and school administrators are responsible for implementing academic accommodations and other supports for optimal return to learn following a concussion. The primary objective of this study was to describe the prevalence and feasibility of providing academic accommodations to students following concussion from the perspectives of middle and high school teachers and school administrators.

METHODS

A cross‐sectional survey was administered to teachers and school administrators (grades 7‐12) across Canada online via REDCap. Participants were recruited via word‐of‐mouth and social media sampling. Survey responses were analyzed descriptively using proportions.

RESULTS

The survey was completed by 180 educators (138 teachers and 41 school administrators), of whom 86% had previously provided academic accommodations to students following concussion, and 96% agreed that students should have access to accommodations following concussion. Some accommodations (eg, breaks, extra time) were provided more often and were more feasible to provide than others (eg, no new learning, reduced bright light). Educators reported limited preparation time and limited school personnel support to assist students following concussion.

IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY

The most feasible accommodations should be prioritized, ensuring students are supported within the school environment.

CONCLUSIONS

Teachers and school administrators confirmed the importance of providing accommodations to students following concussion.
Veterans with blood cancers: Clinical trial navigation and the challenge of rurality
Authors: Friedman Daphne R. , Rodgers Thomas D. , Kovalick Courtney , Yellapragada Sarvari , Szumita Leah , Weiss Elisa S.
Published: June 2023

Purpose

The proportion of cancer patients who participate in clinical trials (CTs) remains low, despite an understanding of barriers to enrollment. The barrier of rural residence is relevant to Veterans, who more commonly live in rural areas than non‐Veterans. In this exploratory study, we aimed to examine geographic factors that could impede CT enrollment and to improve access to CTs for Veterans.

Methods

To assess the influence of rurality on the availability of CTs, we performed simulated searches using The Leukemia & Lymphoma Society's Clinical Trial Support Center (LLS CTSC) database. The LLS CTSC provides free CT education and navigation. In the second part of this study, we offered Veterans with blood cancers who received care at the Durham, Salem, Clarksburg, Sioux Falls, and Houston Veterans Administration (VA) Medical Centers referral to the LLS CTSC.

Findings

In simulated searches, we found significantly lower numbers of CTs open to enrollment in rural areas, compared to urban areas. In actual referrals, 33 Veterans were referred to the LLS CTSC, of which 15 (45%) lived in rural areas. Three Veterans enrolled in CTs. Patients declined referral or did not enroll in CTs for various reasons, including a desire to maintain care within the VA and/or to initiate therapy quickly.

Conclusions

We identified “clinical trial deserts,” which might hinder access and reduce CT participation for rural Veterans. Referral to the LLS CTSC promoted CT education and enrollment among a highly rural cohort of Veterans receiving care in the VA system.
Comrades in the family? Soviet communism and demand for family insurance
Authors: Costa‐Font Joan , Nicińska Anna
Published: June 2023

We study how exposure to (Soviet) communism (EC), a political‐economic regime based on collectivist state planning, affected the preferences for family support, which we refer to as informal family insurance. Against the backdrop that ‘communism gave rise to the abolition of the family’, we document that it actually strengthened the preference (the demand) for informal family insurance without depressing individuals' preferences for social insurance. We exploit cross‐country and cohort variation in EC on more than 314,000 individuals living in 33 Central and Eastern European countries, among which 14 had been subject to communist regimes. We estimate that EC gave rise to 9.6 percentage point (pp) increase in the preference for family care for older parent and 4.3 pp increase in the support (both financial and nonfinancial) for children. These effects are explained by the strengthening of social and family networks that resulted from the erosion of generalized, interpersonal and institutional trust, rather than by ‘indoctrination effects’ during Soviet communism times.
MdNAC104 positively regulates apple cold tolerance via CBF‐dependent and CBF‐independent pathways
Authors: Mei Chuang , Yang Jie , Mei Quanlin , Jia Dongfeng , Yan Peng , Feng Beibei , Mamat Aisajan , Gong Xiaoqing , Guan Qingmei , Mao Ke , Wang Jixun , Ma Fengwang
Published: June 2023

Low temperature is the main environmental factor affecting the yield, quality and geographical distribution of crops, which significantly restricts development of the fruit industry. The NAC (NAM, ATAF1/2 and CUC2) transcription factor (TF) family is involved in regulating plant cold tolerance, but the mechanisms underlying these regulatory processes remain unclear. Here, the NAC TF MdNAC104 played a positive role in modulating apple cold tolerance. Under cold stress, MdNAC104‐overexpressing transgenic plants exhibited less ion leakage and lower ROS (reactive oxygen species) accumulation, but higher contents of osmoregulatory substances and activities of antioxidant enzymes. Transcriptional regulation analysis showed that MdNAC104 directly bound to the MdCBF1 and MdCBF3 promoters to promote expression. In addition, based on combined transcriptomic and metabolomic analyses, as well as promoter binding and transcriptional regulation analyses, we found that MdNAC104 stimulated the accumulation of anthocyanin under cold conditions by upregulating the expression of anthocyanin synthesis‐related genes, including MdCHS‐b, MdCHI‐a, MdF3H‐a and MdANS‐b, and increased the activities of the antioxidant enzymes by promoting the expression of the antioxidant enzyme‐encoding genes MdFSD2 and MdPRXR1.1. In conclusion, this study revealed the MdNAC104 regulatory mechanism of cold tolerance in apple via CBF‐dependent and CBF‐independent pathways.
On the Electromechanical Instability of Polar Elastomers
Authors: Jiang Yanhui , Nayeb-Hashemi Hamid , Su Yan
Published: June 2023

Based on a continuum theory that accounts for the underlying molecular physics of polar elastomers (PEs), a typical boundary value problem (BVP) is developed to analyze the electromechanical instability (EMI) of PEs with randomly distributed dielectric particles. Through extensive numerical simulations, the effects of various parameters such as particle volume fraction, particle size, and enhancement factor related to polar groups on the critical voltage leading to EMI of PEs are investigated. The results are presented in 3D phase diagrams, which may better help researchers to understand EMI of PEs and guide them in synthesis, design, and application of PEs in the fields of chemistry, physics, bio-engineering, etc.
The p23 co-chaperone is a succinate-activated COX-2 transcription factor in lung adenocarcinoma tumorigenesis
Authors: Yu Zhenlong , Peng Yulin , Gao Jian , Zhou Meirong , Shi Lei , Zhao Feng , Wang Chao , Tian Xiangge , Feng Lei , Huo Xiaokui , Zhang Baojing , Liu Min , Fang Deyu , Ma Xiaochi
Published: June 2023

P23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it translocates into the nucleus. The molecular nature underlying how this HSP90-independent p23 function is achieved remains as a biological mystery. Here, we found that p23 is a previously unidentified transcription factor of COX-2, and its nuclear localization predicts the poor clinical outcomes. Intratumor succinate promotes p23 succinylation at K7, K33, and K79, which drives its nuclear translocation for COX-2 transcription and consequently fascinates tumor growth. We then identified M16 as a potent p23 succinylation inhibitor from 1.6 million compounds through a combined virtual and biological screening. M16 inhibited p23 succinylation and nuclear translocation, attenuated COX-2 transcription in a p23-dependent manner, and markedly suppressed tumor growth. Therefore, our study defines p23 as a succinate-activated transcription factor in tumor progression and provides a rationale for inhibiting p23 succinylation as an anticancer chemotherapy.
Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness
Authors: Oropeza Elena , Seker Sinem , Carrel Sabrina , Mazumder Aloran , Lozano Daniel , Jimenez Athena , VandenHeuvel Sabrina N. , Noltensmeyer Dillon A. , Punturi Nindo B. , Lei Jonathan T. , Lim Bora , Waltz Susan E. , Raghavan Shreya A. , Bainbridge Matthew N. , Haricharan Svasti
Published: June 2023

Cell cycle dysregulation is prerequisite for cancer formation. However, it is unknown whether the mode of dysregulation affects disease characteristics. Here, we conduct comprehensive analyses of cell cycle checkpoint dysregulation using patient data and experimental investigations. We find that
ATM
mutation predisposes the diagnosis of primary estrogen receptor (ER)
+
/human epidermal growth factor (HER)2
−
cancer in older women. Conversely, CHK2 dysregulation induces formation of metastatic, premenopausal ER
+
/HER2
−
breast cancer (
P
= 0.001) that is treatment-resistant (HR = 6.15,
P
= 0.01). Lastly, while mutations in
ATR
alone are rare,
ATR
/
TP53
co-mutation is 12-fold enriched over expected in ER
+
/HER2
−
disease (
P
= 0.002) and associates with metastatic progression (HR = 2.01,
P
= 0.006). Concordantly, ATR dysregulation induces metastatic phenotypes in
TP53
mutant, not wild-type, cells. Overall, we identify mode of cell cycle dysregulation as a distinct event that determines subtype, metastatic potential, and treatment responsiveness, providing rationale for reconsidering diagnostic classification through the lens of the mode of cell cycle dysregulation.

.
A transcriptome-informed QSP model of metastatic triple-negative breast cancer identifies predictive biomarkers for PD-1 inhibition
Authors: Arulraj Theinmozhi , Wang Hanwen , Emens Leisha A. , Santa-Maria Cesar A. , Popel Aleksander S.
Published: June 2023

Triple-negative breast cancer (TNBC), a highly metastatic breast cancer subtype, has limited treatment options. While a small number of patients attain clinical benefit with single-agent checkpoint inhibitors, identifying these patients before the therapy remains challenging. Here, we developed a transcriptome-informed quantitative systems pharmacology model of metastatic TNBC by integrating heterogenous metastatic tumors. In silico clinical trial with an anti–PD-1 drug, pembrolizumab, predicted that several features, such as the density of antigen-presenting cells, the fraction of cytotoxic T cells in lymph nodes, and the richness of cancer clones in tumors, could serve individually as biomarkers but had a higher predictive power as combinations of two biomarkers. We showed that PD-1 inhibition neither consistently enhanced all antitumorigenic factors nor suppressed all protumorigenic factors but ultimately reduced the tumor carrying capacity. Collectively, our predictions suggest several candidate biomarkers that might effectively predict the response to pembrolizumab monotherapy and potential therapeutic targets to develop treatment strategies for metastatic TNBC.
Three-dimensional histological electrophoresis enables fast automatic distinguishment of cancer margins and lymph node metastases
Authors: Zhang Feiran , Xu Jiajun , Yue Ying , Wang Yajun , Sun Jianing , Song Dong , Zhang Chengbin , Qu Limei , Zhu Shoujun , Zhang Junhu , Yang Bai
Published: June 2023

Tissue diagnosis is important during surgical excision of solid tumors for margin evaluation. Conventional histopathologic methods rely heavily on image-based visual diagnosis by specialized pathologists, which can be time-consuming and subjective. We report a three-dimensional (3D) histological electrophoresis system for rapid labeling and separation of the proteins within tissue sections, providing a more precise assessment of tumor-positive margin in surgically resected tissues. The 3D histological electrophoresis system uses a tumor-seeking dye labeling strategy to visualize the distribution of tumor-specific proteins within sections and a tumor finder that automatically predicts the tumor contour. We successfully demonstrated the system’s capability to predict the tumor contours from five murine xenograft models and distinguish the tumor-invaded region of sentinel lymph nodes. Specifically, we used the system to accurately assess tumor-positive margins from 14 patients with cancer. Our 3D histological electrophoresis system serves as an intraoperative tissue assessment technology for more accurate and automatic pathologic diagnosis.
Primary infection with Zika virus provides one-way heterologous protection against Spondweni virus infection in rhesus macaques
Authors: Jaeger Anna S. , Crooks Chelsea M. , Weiler Andrea M. , Bliss Mason I. , Rybarczyk Sierra , Richardson Alex , Einwalter Morgan , Peterson Eric , Capuano Saverio , Barkhymer Alison , Becker Jordan T. , Greene Joseph T. , Freedman Tanya S. , Langlois Ryan A. , Friedrich Thomas C. , Aliota Matthew T.
Published: June 2023

Spondweni virus (SPONV) is the closest known relative of Zika virus (ZIKV). SPONV pathogenesis resembles that of ZIKV in pregnant mice, and both viruses are transmitted by
Aedes aegypti
mosquitoes. We aimed to develop a translational model to further understand SPONV transmission and pathogenesis. We found that cynomolgus macaques (
Macaca fascicularis
) inoculated with ZIKV or SPONV were susceptible to ZIKV but resistant to SPONV infection. In contrast, rhesus macaques (
Macaca mulatta
) supported productive infection with both ZIKV and SPONV and developed robust neutralizing antibody responses. Crossover serial challenge in rhesus macaques revealed that SPONV immunity did not protect against ZIKV infection, whereas ZIKV immunity was fully protective against SPONV infection. These findings establish a viable model for future investigation into SPONV pathogenesis and suggest that the risk of SPONV emergence is low in areas with high ZIKV seroprevalence due to one-way cross-protection between ZIKV and SPONV.
Monocytic MDSCs exhibit superior immune suppression via adenosine and depletion of adenosine improves efficacy of immunotherapy
Authors: Sarkar Omar S. , Donninger Howard , Al Rayyan Numan , Chew Lewis C. , Stamp Bryce , Zhang Xiang , Whitt Aaron , Li Chi , Hall Melissa , Mitchell Robert A. , Zippelius Alfred , Eaton John , Chesney Jason A. , Yaddanapudi Kavitha
Published: June 2023

Immune checkpoint inhibitor (ICI) therapy is effective against many cancers for a subset of patients; a large percentage of patients remain unresponsive to this therapy. One contributing factor to ICI resistance is accumulation of monocytic myeloid-derived suppressor cells (M-MDSCs), a subset of innate immune cells with potent immunosuppressive activity against T lymphocytes. Here, using lung, melanoma, and breast cancer mouse models, we show that CD73-expressing M-MDSCs in the tumor microenvironment (TME) exhibit superior T cell suppressor function. Tumor-derived PGE
2
, a prostaglandin, directly induces CD73 expression in M-MDSCs via both Stat3 and CREB. The resulting CD73 overexpression induces elevated levels of adenosine, a nucleoside with T cell–suppressive activity, culminating in suppression of antitumor CD8
+
T cell activity. Depletion of adenosine in the TME by the repurposed drug PEGylated adenosine deaminase (PEG-ADA) increases CD8
+
T cell activity and enhances response to ICI therapy. Use of PEG-ADA can therefore be a therapeutic option to overcome resistance to ICIs in cancer patients.
Transcription activator WCC recruits deacetylase HDA3 to control transcription dynamics and bursting in
Neurospora
Authors: Oehler Michael , Geisser Leonie , Diernfellner Axel C. R. , Brunner Michael
Published: June 2023

RNA polymerase II initiates transcription either randomly or in bursts. We examined the light-dependent transcriptional activator White Collar Complex (WCC) of
Neurospora
to characterize the transcriptional dynamics of the strong
vivid
(
vvd
) promoter and the weaker
frequency
(
frq
) promoter. We show that WCC is not only an activator but also represses transcription by recruiting histone deacetylase 3 (HDA3). Our data suggest that bursts of
frq
transcription are governed by a long-lived refractory state established and maintained by WCC and HDA3 at the core promoter, whereas transcription of
vvd
is determined by WCC binding dynamics at an upstream activating sequence. Thus, in addition to stochastic binding of transcription factors, transcription factor–mediated repression may also influence transcriptional bursting.
Biomimetic thermoresponsive superstructures by colloidal soft-and-hard co-assembly
Authors: Lyu Dengping , Xu Wei , Zhou Nansen , Duan Wendi , Wang Zhisheng , Mu Yijiang , Zhou Renjie , Wang Yufeng
Published: June 2023

Soft-and-hard hybrid structures are ubiquitous in biological systems and have inspired the design of man-made mechanical devices, actuators, and robots. The realization of these structures, however, has been challenging at microscale, where material integration and actuation become exceedingly less practical. Here, through simple colloidal assembly, we create microscale superstructures consisting of soft and hard materials, which, serving as microactuators, have thermoresponsive shape-transforming properties. In this case, anisotropic metal-organic framework (MOF) particles as the hard components are integrated with liquid droplets, forming spine-mimicking colloidal chains via valence-limited assembly. The chains, with alternating soft and hard segments, are referred to as MicroSpine and can reversibly change shape, switching between straight and curved states through a thermoresponsive swelling/deswelling mechanism. By solidification of the liquid parts within a chain with prescribed patterns, we design various chain morphologies, such as “colloidal arms,” with controlled actuating behaviors. The chains are further used to build colloidal capsules, which encapsulate and release guests by the temperature-programmed actuation.
HLA-E–restricted SARS-CoV-2–specific T cells from convalescent COVID-19 patients suppress virus replication despite HLA class Ia down-regulation
Authors: Yang Hongbing , Sun Hong , Brackenridge Simon , Zhuang Xiaodong , Wing Peter A C , Quastel Max , Walters Lucy , Garner Lee , Wang Beibei , Yao Xuan , Felce Suet Ling , Peng Yanchun , Moore Shona , Peeters Bas W.A. , Rei Margarida , Canto Gomes Joao , Tomas Ana , Davidson Andrew , Semple Malcolm G. , Turtle Lance C.W. , Openshaw Peter J.M. , Baillie J. Kenneth , Mentzer Alexander J. , Klenerman Paul ,   ISARIC4C Investigators, Borrow Persephone , Dong Tao , McKeating Jane A , Gillespie Geraldine M , McMichael Andrew J
Published: June 2023

Pathogen-specific CD8
+
T cell responses restricted by the nonpolymorphic nonclassical class Ib molecule human leukocyte antigen E (HLA-E) are rarely reported in viral infections. The natural HLA-E ligand is a signal peptide derived from classical class Ia HLA molecules that interact with the NKG2/CD94 receptors to regulate natural killer cell functions, but pathogen-derived peptides can also be presented by HLA-E. Here, we describe five peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that elicited HLA-E–restricted CD8
+
T cell responses in convalescent patients with coronavirus disease 2019. These T cell responses were identified in the blood at frequencies similar to those reported for classical HLA-Ia–restricted anti–SARS-CoV-2 CD8
+
T cells. HLA-E peptide–specific CD8
+
T cell clones, which expressed diverse T cell receptors, suppressed SARS-CoV-2 replication in Calu-3 human lung epithelial cells. SARS-CoV-2 infection markedly down-regulated classical HLA class I expression in Calu-3 cells and primary reconstituted human airway epithelial cells, whereas HLA-E expression was not affected, enabling T cell recognition. Thus, HLA-E–restricted T cells could contribute to the control of SARS-CoV-2 infection alongside classical T cells.
Petrology and geochronology of Cretaceous−Eocene plutonic rocks in northeastern Washington, USA: Crustal thickening, slab rollback, and origin of the Challis episode
Authors: Tepper Jeffrey H. , Loewen Matthew W. , Caulfield Liam M. , Davidson Peter C. , Ruthenberg Kaitlin L. , Blakely Samuel W.F. , Knudsen Duncan F.J.F. , Black Devin F. , Nelson Bruce K. , Asmerom Yemane
Published: June 2023

Cretaceous through Eocene plutonic rocks in northeastern Washington, USA, document a 60 m.y. history of crustal thickening and subsequent collapse and extension in response to two terrane-accretion events. Rocks emplaced 113−53 Ma have increasing La/Yb ratios reflecting orogenic plateau development after arrival of the Insular terrane by 100 Ma. Plutons emplaced 52−45 Ma (the Challis episode) document collapse of this plateau and define a SW-younging age progression attributed to breakoff and rollback of the Farallon slab following accretion of the Siletzia terrane at ca. 50 Ma. All of the rocks have chemical traits of arc magmas, likely inherited from their lower-crustal sources, but low B/Be ratios and the lack of evidence for amphibole fractionation indicate the Eocene magmas formed under drier conditions than are typical of active subduction settings. These magmas also originated at greater depth (eclogitic vs. gabbroic source) and were emplaced more shallowly than the earlier ones. All rocks have overlapping Sr-Nd and O isotopic data, indicating significant contributions from older continental crust, and depleted mantle Nd model ages become older toward the east, defining three regions that correspond with previously inferred lower-crustal domains. Farallon slab rollback also drove extension (core complex formation, dike swarms) and crustal uplift, which, along with voluminous magmatism, define the Challis episode. This tectonic model is further supported by seismic tomography, which has identified remnants of a detached slab in the upper mantle beneath the region.
Acute pneumolabyrinth: a rare complication after cochlear implantation in a patient with obstructive sleep apnoea on CPAP therapy
Authors: Immordino Angelo , Lorusso Francesco , Sireci Federico , Dispenza Francesco
Published: June 2023

Pneumolabyrinth is a condition characterised by the presence of air within the inner ear and is a rare complication after cochlear implant surgery. One of the causes of pneumolabyrinth may be the increase in pressure in the middle ear. The use of continuous positive airway pressure (CPAP) is an effective treatment strategy for obstructive sleep apnoea. According to a recent study, the use of CPAP should be delayed by 1 or 2 weeks in subjects undergoing middle ear surgery; however, there is currently no indication to delay the CPAP in subjects undergoing cochlear implant surgery. We report the case of a patient on CPAP who underwent left cochlear implantation and, in the early postoperative period, reported severe vertigo and tinnitus. Cone-beam CT of the temporal bone revealed the presence of pneumolabyrynth. We believe that the use of CPAP should be delayed in subjects undergoing cochlear implantation to avoid the development of acute pneumolabyrinth.