bluuebunny/crossref_metadata_2025 huggingface dataset:
Time counts? A two-wave panel study investigating the effects of WeChat affordances on social capital and well-being
Authors: Zhang Lianshan , Jung Eun Hwa
Published: November 2022

Drawing from the social capital framework and socioemotional selectivity theory, this study examines how individuals’ future time perspective (FTP) alters their social capital processes, which further influences their well-being. A two-wave survey was conducted across WeChat users possessing different FTPs. The findings showed that bonding and bridging social capital accumulation were attributed to differential WeChat affordances, which in turn exerted disparate influences on individuals’ positive affect and psychological well-being. Importantly, multigroup analyses revealed that future-oriented users were more fulfilled from the broadcasting affordance, whereas present-oriented users derived more emotional gains from the association affordance. Notably, frequent engagement with the reviewability affordance was found to diminish WeChat bonding social capital only for those who possessed open-ended FTP. The findings contribute to theoretical knowledge of social media affordances and provide practical implications for social media developers in harnessing social media to improve users’ well-being across lifespans by considering their priority of social goals.
Association of intermittency with electron heating in the near-Sun solar wind
Authors: Phillips C , Bandyopadhyay R , McComas D J , Bale S D
Published: November 2022

Several studies in the near-Earth environment show that intermittent structures are important sites of energy dissipation and particle energization. Recent Parker Solar Probe (PSP) data, sampled in the near-Sun environment, have shown that proton heating is concentrated near coherent structures, suggesting local heating of protons by turbulent cascade in this region. However, whether electrons exhibit similar behaviour in the near-Sun environment is not clear. Here, we address this question using PSP data collected near the Sun during the first seven orbits. We use the partial variance of increments (PVI) technique to identify coherent structures. We find that electron temperature is preferentially enhanced near strong discontinuities. Our results provide strong support for the inhomogeneous heating of electrons in the ‘young’ solar wind associated with the dissipation of turbulent fluctuations near intermittent structures.
Potential abiotic stress targets for modern genetic manipulation
Authors: Bowerman Andrew F , Byrt Caitlin S , Roy Stuart John , Whitney Spencer M , Mortimer Jenny C , Ankeny Rachel A , Gilliham Matthew , Zhang Dabing , Millar Anthony A , Rebetzke Greg J , Pogson Barry J
Published: November 2022

Research into crop yield and resilience has underpinned global food security, evident in yields tripling in the past 5 decades. The challenges that global agriculture now faces are not just to feed 10+ billion people within a generation, but to do so under a harsher, more variable, and less predictable climate, and in many cases with less water, more expensive inputs, and declining soil quality. The challenges of climate change are not simply to breed for a “hotter drier climate,” but to enable resilience to floods and droughts and frosts and heat waves, possibly even within a single growing season. How well we prepare for the coming decades of climate variability will depend on our ability to modify current practices, innovate with novel breeding methods, and communicate and work with farming communities to ensure viability and profitability. Here we define how future climates will impact farming systems and growing seasons, thereby identifying the traits and practices needed and including exemplars being implemented and developed. Critically, this review will also consider societal perspectives and public engagement about emerging technologies for climate resilience, with participatory approaches presented as the best approach.
Predicting future publishing success among sociologists at time of hire in the US Higher education system
Authors: Hermanowicz Joseph C , Scheitle Christopher P
Published: November 2022

This article assesses the characteristics of faculty members’ publishing records at the start of a first assistant professor position in order to predict their continued publication productivity. Using data from nearly 500 US-based sociologists, we examine how indicators, such as number of published articles, the extent of sole authorship, journal placement, and doctoral pedigree, predict success in publishing. After accounting for year of PhD, primary research methodology, and demographic characteristics, the analysis finds that the total number of articles published at the time of hire is not a significant predictor of future productivity. But the number of sole-authored articles published at the time of hire is positively associated with subsequent publication. The analysis also finds that doctoral pedigree is negatively associated with the total number of articles published post-hire but positively associated with publishing in top sociology journals. The authors suggest that faculty with different doctoral origins pursue varied publishing ‘scripts’ in their careers. Sole authorship operates as a potent trigger at career onset for cumulative advantage. In the context of the reward system of science, a moral community identifies early solo work as a sign of work prowess, which begets further publishing success.
Discussion on the entrepreneurial university in Spain: The case of the Madrid Region
Authors: Quintero Natalia Dévora , Serrano Gonzalo León
Published: November 2022

A central theme in the literature has been the identification of the factors that drive the creation of entrepreneurial universities. The application of these factors and university institutional commitment become essential to overcome the institutional barriers that may exist. Moreover, some authors have warned that in some university systems, transformation becomes a challenge due to high dependence on the State. In this paper, we have examined whether the dependence of Spanish universities on the State can be interpreted as an inhibitor of the transformation process, as well as the institutional commitment of several universities to become entrepreneurial entities, in a national framework that—considering the literature—would not seem the most optimal to achieve it. We note that the State is not an inhibitor, but not all universities show the same internal commitment. When universities are committed to change, the process is accelerated by the sum of two impulses.
Biological Control of Grapevine Crown Gall Disease, Caused by Allorhizobium vitis, Using Paraburkholderia phytofirmans PsJN
Authors: Trong Nguyen-Huu , Doré Jeanne , Gaucher Matthieu , Jacquard Cédric , Richet Nicolas , Leclère Vincent , Aït Barka Essaïd , Brisset Marie Noëlle , Kerzaon Isabelle , Lavire Céline , Clément Christophe , Vial Ludovic , Sanchez Lisa
Published: November 2022

Controlling crown gall in grapevine ( Vitis vinifera L.) caused by the pathogenic bacterium Allorhizobium vitis is a major challenge for global viticulture, as this pathogen is highly persistent in vineyards once infected. The bacteria can enter the plant through open wounds during pruning and then systemically colonize the plant. This study aimed at evaluating the potential of Paraburkholderia phytofirmans PsJN, a beneficial endophytic bacterium able to colonize the xylem of grapevine, the same ecological niche as A. vitis, to control grapevine crown gall disease. P. phytofirmans PsJN was root-inoculated on grapevine plantlets before infection by A. vitis S4 on shoots. A. vitis S4 level in planta, vitopine production, accumulation of lignin in tumors, and symptoms of crown gall were investigated on grapevine prebacterized or not with PsJN. The expression of 28 grapevine genes involved in defense mechanisms was also simultaneously determined by quantitative real-time PCR. Despite a direct antibacterial effect against AvS4, PsJN has no significant impact on the incidence of crown gall or disease severity. However, PsJN leads to a stronger accumulation of vitopine in tumors and significantly reduced the population level of the pathogen in planta.

[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Breaking the Silence: A Mental Health Initiative to Reduce Stigma Among Medical Students
Authors: Brenner Louisa Dru , Wei Helen , Sakthivel Meera , Farley Brianna , Blythe Kate , Woodruff James N. , Lee Wei Wei
Published: November 2022

Problem

Mental health conditions are common among medical students. While stigma contributes to low rates of help seeking, little programming exists to address stigma.

Approach

In 2015, the authors developed a mental health initiative (MHI) to combat stigma at the Pritzker School of Medicine featuring 3 elements: (1) Mental Health Panel, an annual first-year event where faculty/peers share mental health stories; (2) Pritzker, I Screwed Up, an annual all-school event where faculty/peers share experiences with failure; and (3) Humans of Pritzker, a social media initiative featuring students’ mental health posts. Postevent surveys and the 2021–2022 MHI survey assessed student satisfaction and impact on stigma and help-seeking behaviors. Student Counseling Services utilization rates for medical and nonmedical students were compared for academic years 2014–2015 vs 2018–2019 and 2020–2021 to account for the pandemic’s impact on mental health care utilization.

Outcomes

The MHI survey response rate was 61% (261/430). Respondents were distributed across class-years. Most were female (57%, 150/261). The majority agreed they could speak about mental health without judgment from peers (78%, 203/259) and faculty (57%, 149/260). Most (62%, 161/260) utilized mental health services during medical school. Of these, 41% (66/161) agreed that MHI programming contributed to their decision to seek care. On the 2021–2022 Mental Health Panel and Pritzker, I Screwed Up evaluations, almost all agreed that faculty/peers sharing experiences destigmatized mental illness (99%, 78/79) and making mistakes (96%, 152/159). Student Counseling Services utilization increased from 8% (32/389) for 2014–2015 to 19% (75/394) for 2018–2019 and 33% (136/406) for 2020–2021 for medical students, compared with 19% (2,248/12,138) to 21% (3,024/14,293) and 22% (3,285/15,004) for nonmedical students.

Next Steps

Faculty and peers sharing mental health stories may help reduce stigma and increase help seeking in medical students. Future work should explore the longitudinal impact of programming and disseminating similar initiatives at other institutions.
Risk Factors for Reoperation to Promote Union in 1111 Distal Femur Fractures
Authors: Lee Christopher , Brodke Dane , O'Hara Nathan , Devana Sai , Hernandez Adolfo , Burke Cynthia , Gupta Jayesh , McKibben Natasha , O'Toole Robert , Morellato John , Gillon Hunter , Walters Murphy , Barber Colby , Perdue Paul , Dekeyser Graham , Steffenson Lillia , Marchand Lucas , Fairres Marshall James , Black Loren , Working Zachary , Roddy Erika , El Naga Ashraf , Hogue Matthew , Gulbrandsen Trevor , Atassi Omar , Mitchell Thomas , Shymon Stephen
Published: November 2022

Objectives:

To identify modifiable and nonmodifiable risk factors for reoperation to promote union after distal femur fracture.

Design:

Multicenter retrospective cohort study.

Setting:

Ten Level-I trauma centers.

Patients/Participants:

Patients with OTA/AO 33A or C distal femur fractures (n = 1111).

Intervention:

Surgical fixation of distal femur fracture. Fixation constructs were classified as lateral plate, dual plate, nail, or nail plate combination.

Main Outcome Measurements:

The outcome of interest was unplanned reoperation to promote union.

Results:

There was an 11% (121/1111) rate of unplanned reoperation to promote union. In the multivariate analysis, predictive factors included body mass index [odds ratio (OR) = 1.18; 95% confidence interval (CI), 1.06–1.32; P < 0.01], intra-articular fracture (OR = 1.57; 95% CI, 1.01–2.45; P = 0.04), type III open injury (OR = 2.29; 95% CI, 1.41–3.72; P < 0.01), the presence of medial comminution (OR = 1.85; 95% CI, 1.14–3.06; P = 0.01), and medial translation on postoperative radiographs (OR = 1.23 per one 10th of condylar width; 95% CI, 1.01–1.48; P = 0.03). Construct type was not significantly predictive.

Conclusions:

Eleven percent of distal femur fractures underwent unplanned reoperation to promote union. Body mass index, intra-articular fracture, type III open injury, medial comminution, and medial translation on postoperative radiographs were predictive factors. Construct type was not associated with unplanned reoperation; however, this conclusion was limited by small numbers in the dual plate and nail plate groups.

Level of Evidence:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Pediatric distal third tibial shaft fractures: a comparison of surgical fixation methods and incidence of concomitant physeal fractures
Authors: McGraw-Heinrich Jessica A. , Ezeokoli Ekene U. , Mitchell Parker , Silverstein Rachel S. , Smith Brian G.
Published: November 2022

The purposeof this study was to compare outcomes of operatively treated pediatric distal third tibial shaft fractures fixed with elastic nailing or plate fixation and to evaluate the incidence of concurrent distal tibia physeal fractures. Retrospective review identified skeletally immature patients that underwent operative fixation of distal third tibia fractures at a level 1 children’s hospital from 2010 to 2020. Patient and fracture characteristics were recorded. Analysis of treatment outcomes was performed and rates of concurrent distal tibia physeal fractures were evaluated. Of the 214 surgically treated tibial shaft fractures, 43 were distal third fractures. A concurrent distal tibia physeal fracture was present in 32.6% of patients. These were significantly associated with spiral distal third tibial shaft fractures. The presence of concurrent physeal fractures did not affect patient treatment outcomes. Comparing elastic nailing versus open reduction and plating revealed no difference with time to fracture union, time of postoperative immobilization, or time to full weight-bearing. While elastic nailing was associated with increased coronal angulation, translation, and shortening of fractures on initial postoperative imaging, there was no difference in rates of malunion at final follow-up. In our series, there were no differences in treatment outcomes based on fixation method. Our operatively treated distal third tibial shaft fractures had a higher rate of associated distal tibial physeal fractures than previously published in the pediatric orthopedic literature. We recommend careful evaluation of the ankle for concurrent physeal injuries in patients with distal third tibial shaft fractures indicated for operative treatment. Level of evidence: level III therapeutic study – retrospective comparative study.
Potential mechanism of pyrotinib-induced diarrhea was explored by gut microbiome and ileum metabolomics
Authors: Lai Jingjiang , Zhuo Xiaoli , Yin Ke , Jiang Fengxian , Liu Lei , Xu Xiaoying , Liu Hongjing , Wang Jingliang , Zhao Jing , Xu Wei , Yang Shuping , Guo Honglin , Yuan Xiaotian , Lin Xiaoyan , Qi Fanghua , Fu Guobin
Published: November 2022

Background

Pyrotinib is a novel epidermal growth factor receptor/human epidermal growth factor receptor-2 (HER2) tyrosine kinase inhibitor that exhibited clinical efficacy in patients with HER2-positive breast cancer and HER2-mutant/amplified lung cancer. However, severe diarrhea adverse responses preclude its practical use. At present, the mechanism of pyrotinib-induced diarrhea is unknown and needs further study.

Methods

First, to develop a suitable and reproducible animal model, we compared the effects of different doses of pyrotinib (20, 40, 60 and 80 mg/kg) in Wistar rats. Second, we used this model to examine the intestinal toxicity of pyrotinib. Finally, the mechanism underlying pyrotinib-induced diarrhea was fully studied using gut microbiome and host intestinal tissue metabolomics profiling.

Results

Reproducible diarrhea occurred in rats when they were given an 80 mg/kg daily dose of pyrotinib. Using the pyrotinib-induced model, we observed that Lachnospiraceae and Acidaminococcaceae decreased in the pyrotinib groups, whereas Enterobacteriaceae, Helicobacteraceae and Clostridiaceae increased at the family level by 16S rRNA gene sequence. Multiple bioinformatics methods revealed that glycocholic acid, ursodeoxycholic acid and cyclic AMP increased in the pyrotinib groups, whereas kynurenic acid decreased, which may be related to the pathogenesis of pyrotinib-induced diarrhea. Additionally, pyrotinib-induced diarrhea may be associated with a number of metabolic changes mediated by the gut microbiome, such as Primary bile acid biosynthesis.

Conclusion

We reported the establishment of a reproducible pyrotinib-induced animal model for the first time. Furthermore, we concluded from this experiment that gut microbiome imbalance and changes in related metabolites are significant contributors to pyrotinib-induced diarrhea.
External Validation of Mortality Prediction Models for Critical Illness Reveals Preserved Discrimination but Poor Calibration
Authors: Cox Eline G. M. , Wiersema Renske , Eck Ruben J. , Kaufmann Thomas , Granholm Anders , Vaara Suvi T. , Møller Morten Hylander , van Bussel Bas C. T. , Snieder Harold , Pleijhuis Rick G. , van der Horst Iwan C. C. , Keus Frederik
Published: November 2022

OBJECTIVES:

In a recent scoping review, we identified 43 mortality prediction models for critically ill patients. We aimed to assess the performances of these models through external validation.

DESIGN:

Multicenter study.

SETTING:

External validation of models was performed in the Simple Intensive Care Studies-I (SICS-I) and the Finnish Acute Kidney Injury (FINNAKI) study.

PATIENTS:

The SICS-I study consisted of 1,075 patients, and the FINNAKI study consisted of 2,901 critically ill patients.

MEASUREMENTS AND MAIN RESULTS:

For each model, we assessed: 1) the original publications for the data needed for model reconstruction, 2) availability of the variables, 3) model performance in two independent cohorts, and 4) the effects of recalibration on model performance. The models were recalibrated using data of the SICS-I and subsequently validated using data of the FINNAKI study. We evaluated overall model performance using various indexes, including the (scaled) Brier score, discrimination (area under the curve of the receiver operating characteristics), calibration (intercepts and slopes), and decision curves. Eleven models (26%) could be externally validated. The Acute Physiology And Chronic Health Evaluation (APACHE) II, APACHE IV, Simplified Acute Physiology Score (SAPS)-Reduced (SAPS-R)‚ and Simplified Mortality Score for the ICU models showed the best scaled Brier scores of 0.11‚ 0.10‚ 0.10‚ and 0.06‚ respectively. SAPS II, APACHE II, and APACHE IV discriminated best; overall discrimination of models ranged from area under the curve of the receiver operating characteristics of 0.63 (0.61–0.66) to 0.83 (0.81–0.85). We observed poor calibration in most models, which improved to at least moderate after recalibration of intercepts and slopes. The decision curve showed a positive net benefit in the 0–60% threshold probability range for APACHE IV and SAPS-R.

CONCLUSIONS:

In only 11 out of 43 available mortality prediction models, the performance could be studied using two cohorts of critically ill patients. External validation showed that the discriminative ability of APACHE II, APACHE IV, and SAPS II was acceptable to excellent, whereas calibration was poor.
Peri-operative management of neuromuscular blockade
Authors: Fuchs-Buder Thomas , Romero Carolina S. , Lewald Heidrun , Lamperti Massimo , Afshari Arash , Hristovska Ana-Marjia , Schmartz Denis , Hinkelbein Jochen , Longrois Dan , Popp Maria , de Boer Hans D. , Sorbello Massimiliano , Jankovic Radmilo , Kranke Peter
Published: November 2022

Recent data indicated a high incidence of inappropriate management of neuromuscular block, with a high rate of residual paralysis and relaxant-associated postoperative complications. These data are alarming in that the available neuromuscular monitoring, as well as myorelaxants and their antagonists basically allow well tolerated management of neuromuscular blockade. In this first European Society of Anaesthesiology and Intensive Care (ESAIC) guideline on peri-operative management of neuromuscular block, we aim to present aggregated and evidence-based recommendations to assist clinicians provide best medical care and ensure patient safety. We identified three main clinical questions: Are myorelaxants necessary to facilitate tracheal intubation in adults? Does the intensity of neuromuscular blockade influence a patient's outcome in abdominal surgery? What are the strategies for the diagnosis and treatment of residual paralysis? On the basis of this, PICO (patient, intervention, comparator, outcome) questions were derived that guided a structured literature search. A stepwise approach was used to reduce the number of trials of the initial research (n = 24 000) to the finally relevant clinical studies (n = 88). GRADE methodology (Grading of Recommendations, Assessment, Development and Evaluation) was used for formulating the recommendations based on the findings of the included studies in conjunction with their methodological quality. A two-step Delphi process was used to determine the agreement of the panel members with the recommendations: R1 We recommend using a muscle relaxant to facilitate tracheal intubation (1A). R2 We recommend the use of muscle relaxants to reduce pharyngeal and/or laryngeal injury following endotracheal intubation (1C). R3 We recommend the use of a fast-acting muscle relaxant for rapid sequence induction intubation (RSII) such as succinylcholine 1 mg kg−1 or rocuronium 0.9 to 1.2 mg kg−1 (1B). R4 We recommend deepening neuromuscular blockade if surgical conditions need to be improved (1B). R5 There is insufficient evidence to recommend deep neuromuscular blockade in general to reduce postoperative pain or decrease the incidence of peri-operative complications. (2C). R6 We recommend the use of ulnar nerve stimulation and quantitative neuromuscular monitoring at the adductor pollicis muscle to exclude residual paralysis (1B). R7 We recommend using sugammadex to antagonise deep, moderate and shallow neuromuscular blockade induced by aminosteroidal agents (rocuronium, vecuronium) (1A). R8 We recommend advanced spontaneous recovery (i.e. TOF ratio >0.2) before starting neostigmine-based reversal and to continue quantitative monitoring of neuromuscular blockade until a TOF ratio of more than 0.9 has been attained. (1C)
Novel proresolving lipid mediator mimetic 3-oxa-PD1n-3 docosapentaenoic acid reduces acute and chronic itch by modulating excitatory and inhibitory synaptic transmission and astroglial secretion of lipocalin-2 in mice
Authors: Furutani Kenta , Chen Ouyang , McGinnis Aidan , Wang Yuqing , Serhan Charles N. , Hansen Trond Vidar , Ji Ru-Rong
Published: November 2022

Specialized proresolving mediators (SPMs) have demonstrated potent analgesic actions in animal models of pathological pain. The actions of SPMs in acute and chronic itch are currently unknown. Recently, n-3 docosapentaenoic acid (DPA) was found to be a substrate for the biosynthesis of several novel families of SPMs and 3-oxa-PD1n-3 DPA (3-oxa-PD1) is an oxidation-resistant metabolic stable analogue of the n-3 DPA-derived protectin D1 (PD1). In this article, we demonstrate that 3-oxa-PD1 effectively reduces both acute and chronic itch in mouse models. Intrathecal injection of 3-oxa-PD1 (100 ng) reduced acute itch induced by histamine, chloroquine, or morphine. Furthermore, intrathecal 3-oxa-PD1 effectively reduced chronic itch, induced by cutaneous T-cell lymphoma (CTCL), allergic contact dermatitis with dinitrofluorobenzene, and psoriasis by imiquimod. Intratumoral injection of 3-oxa-PD1 also suppressed CTCL-induced chronic itch. Strikingly, the antipruritic effect lasted for several weeks after 1-week intrathecal 3-oxa-PD1 treatment. Whole-cell recordings revealed significant increase in excitatory postsynaptic currents in spinal dorsal horn (SDH) neurons of CTCL mice, but this increase was blocked by 3-oxa-PD1. 3-oxa-PD1 further increased inhibitory postsynaptic currents in SDH neurons of CTCL mice. Cutaneous T-cell lymphoma increased the spinal levels of lipocalin-2 (LCN2), an itch mediator produced by astrocytes. 3-oxa-PD1 suppressed LCN2 production in CTCL mice and LCN2 secretion in astrocytes. Finally, CTCL-induced anxiety was alleviated by intrathecal 3-oxa-PD1. Our findings suggest that 3-oxa-PD1 potently inhibits acute and chronic itch through the regulation of excitatory or inhibitory synaptic transmission and astroglial LCN2 production. Therefore, stable SPM analogs such as 3-oxa-PD1 could be useful to treat pruritus associated with different skin injuries.
Mapping glioma heterogeneity using multiparametric 18F-choline PET/MRI in childhood and teenage-young adults
Authors: Ferrazzoli Valentina , Shankar Ananth , Cockle Julia V. , Tang Christine , Al-Khayfawee Ahmed , Bomanji Jamshed , Fraioli Francesco , Hyare Harpreet
Published: November 2022

Objective

The heterogeneity of post-treatment imaging remains a significant challenge in children and teenagers/young adults (TYA) diagnosed with glioma. The aim of this study was to evaluate the utility of 18F-choline PET/MRI in determining intratumoural heterogeneity in paediatric and TYA gliomas.

Methods

Twenty-six patients (mean age 16 years, range 8–22 years) with suspected glioma disease progression were evaluated with 18F-choline PET/MRI. Relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC) and maximum standardised uptake values (SUVmax) in enhancing (enh) and non-enhancing (ne) tumour volumes and normal-appearing white matter (wm) were calculated (rCBVenh, rCBVne, rCBVwm, ADCenh, ADCne, ADCwm, SUVenh, SUVne and SUVwm).

Results

Significantly higher SUVenh and SUVne compared with SUVwm were observed [SUVenh 0.89 (0.23–1.90), SUVne 0.36 (0.16–0.78) versus SUVwm 0.15 (0.04–1.19); P < 0.001 and P = 0.004, respectively]. Equivalent results were observed for ADV and rCBV (ADCenh, ADCne: P < 0.001 versus ADCwm; rCBVenh, rCBVne: P < 0.001 versus rCBVwm). The highest values for mean SUVmax [0.89 (0.23–1.90)] and mean rCBV [2.1 (0.74–5.08)] were in the enhancing component, while the highest values for ADC [1780 mm2/s (863–2811)] were in the necrotic component.

Conclusion

18F-choline PET/MRI is able map imaging heterogeneity in paediatric and TYA gliomas, detecting post-treatment enhancing, non-enhancing, and necrotic tumour components equivalent to ADC and DSC-derived rCBV. This offers potential in the response assessment of diffuse non-enhancing gliomas and in selected cases such as posterior fossa tumours where quantitative MRI is technically difficult.
Strategies for Mitigating Antibody-Drug Conjugate Related Adverse Events for Precision Therapy
Authors: Gouda Mohamed A. , Subbiah Vivek
Published: November 2022

Antibody-drug conjugates (ADCs) have been revolutionary in improving personalized therapy of cancer. Through combining monoclonal antibodies, which are targeted to tumor-specific antigens, and cytotoxic agents, ADCs lead to selective delivery of active components, also called payloads, to cancerous cells while sparing healthy body cells from possible collateral damage. Adverse events, however, can still develop because of early release of the payload or cross-expression of targets by normal cells leading to collateral damage. In this review, we elaborate on the common and serious adverse events for the currently US Food and Drug Administration–approved ADCs in solid tumors and discuss mitigating strategies and dose modification guidance for optimizing efficacy and toxicity.
Antibody-Drug Conjugates in Breast Cancer: What Is Beyond HER2?
Authors: Nicolò Eleonora , Repetto Matteo , Boscolo Bielo Luca , Tarantino Paolo , Curigliano Giuseppe
Published: November 2022

The therapeutic landscape of patients with breast cancer has changed significantly with the introduction of antibody-drug conjugates (ADCs). Although human epidermal growth factor receptor 2 (HER2) has been the centerpiece of ADC development, potentially any surface antigen with differential expression between tumor and normal cells may be suitable for targeting with ADCs. Exploration of new targets is critical to expand the fraction of patients who can benefit from ADCs. Sacituzumab govitecan, an anti–trophoblast cell surface antigen 2 ADC, is the only non–anti-HER2 ADC approved for breast cancer to date, with several novel ADCs directed against novel targets (e.g., HER3, LIV-1) at various stages of preclinical and clinical development. The aim of this review is to provide an overview of clinical trials investigating ADCs targeting novel antigens. We discuss the optimal characteristics of the target to be exploited in ADCs' design and potential future challenges in the evolving field of ADCs such as biomarker assessment, patient selection, and sequencing of ADCs.
Highly Realistic Whole Transcriptome Synthesis through Generative Adversarial Networks
Authors: Fu Suneng
Published: November 2022

The transcriptome is the most extensive and standardized among all biological data, but its lack of inherent structure impedes the application of deep learning tools. This study resolves the neighborhood relationship of protein-coding genes through uniform manifold approximation and projection (UMAP) of high-quality gene expression data. The resultant transcriptome image is conducive to classification tasks and generative learning. Convolutional neural networks (CNNs) trained with full or partial transcriptome images differentiate normal versus lung squamous cell carcinoma (LUSC) and LUSC versus lung adenocarcinoma (LUAD) with over 96% accuracy, comparable to XGBoost. Meanwhile, the generative adversarial network (GAN) model trained with 93 TcgaTargetGtex transcriptome classes synthesizes highly realistic and diverse tissue/cancer-specific transcriptome images. Comparative analysis of GAN-synthesized LUSC and LUAD transcriptome images show selective retention and enhancement of epithelial identity gene expression in the LUSC transcriptome. Further analyses of synthetic LUSC transcriptomes identify a novel role for mitochondria electron transport complex I expression in LUSC stratification and prognosis. In summary, this study provides an intuitive transcriptome embedding compatible with generative deep learning and realistic transcriptome synthesis.

Significance Statement

Deep learning is most successful when the subject is structured. This study provides a novel way of converting unstructured gene expression lists to 2D-structured transcriptome portraits that are intuitive and compatible with a generative adversarial network (GAN)-based deep learning. The StyleGAN generator trained with transcriptome portrait libraries synthesizes tissue- and disease-specific transcriptomes with significant diversity. Detailed analyses of the synthetic transcriptomes reveal selective enhancement of clinically significant features not apparent in the original transcriptome. Therefore, transcriptome-image-based generative learning may become a significant source of de novo insight generation.
Selective brain cooling monitored by CT perfusion as adjuvant therapy in a porcine model of severe ischemic stroke
Authors: Tong Olivia L.H. , Chung Kevin J. , Hadway Jennifer , Morrison Laura , Desjardins Lise , Tyler Susan , Flamminio Marcus , Keenliside Lynn , Lee Ting-Yim
Published: November 2022

Despite the advances in ischemic stroke treatment, not all patients are eligible for or fully recovered after recanalization therapies. Therapeutic hypothermia could be adjuvant therapy that optimizes the beneficial effect of reperfusion. While conventional whole-body cooling has severe adverse effects, selective brain cooling has emerged as an attractive alternative. However, clinical application is limited by the lack of optimal delivery methods and unknown treatment parameters. Optimal parameters may depend on injury levels and monitoring cerebral perfusion may provide valuable information. Here, we show that selective brain cooling via our in-house developed Vortex tube IntraNasal Cooling Instrument (VINCI), even with a clinically relevant delay in treatment, can attenuate subacute injuries in animals with severe ischemic stroke. The treatment responses of selective brain cooling were characterized by CT Perfusion (CTP). The predicted lesion volume by CTP matched the true infarct volume by histology when the brain temperature was decreased by 5°C from normothermia. More importantly, we found that global hyperemia (high cerebral blood flow) before rewarming could be an early manifestation of poor treatment outcomes. Altogether, our study shows that VINCI-enabled brain cooling could be guided by CTP imaging as adjuvant therapy for severe ischemic stroke. This work lays the groundwork toward individualized selective brain cooling.

Significance Statement

Not all patients suffering from ischemic stroke are eligible or fully recovered after recanalization therapies. Therapeutic hypothermia could be an adjuvant therapy, but the clinical application is hindered by the delivery methods. The optimum treatment depth and duration are also unknown, and they may depend on the injury level. We developed a non-invasive selective brain cooling device, Vortex tube IntraNasal Cooling Instrument (VINCI). The treatment responses were characterized by CT Perfusion (CTP). Global hyperemia (high cerebral blood flow) was identified and could be an early manifestation of poor treatment outcomes. Our work shows that VINCI-enabled brain cooling could be guided by CTP imaging as adjuvant therapy for ischemic stroke. This work also lays the groundwork toward individualized selective brain cooling.
Systematic identification and characterization of novel genes in the regulation and biogenesis of photosynthetic machinery
Authors: Kafri Moshe , Patena Weronika , Martin Lance , Wang Lianyong , Gomer Gillian , Sirkejyan Arthur K , Goh Audrey , Wilson Alexandra T. , Gavrilenko Sophia E , Breker Michal , Roichman Asael , McWhite Claire D. , Rabinowitz Joshua D. , Cross Frederick R , Wühr Martin , Jonikas Martin C.
Published: November 2022

Photosynthesis is central to food production and the Earth’s biogeochemistry, yet the molecular basis for its regulation remains poorly understood. Here, using high-throughput genetics in the model eukaryotic algaChlamydomonas reinhardtii, we identify with high confidence (FDR<0.11) 70 previously-uncharacterized genes required for photosynthesis. We then provide a resource of mutant proteomes that enables functional characterization of these novel genes by revealing their relationship to known genes. The data allow assignment of 34 novel genes to the biogenesis or regulation of one or more specific photosynthetic complexes. Additional analysis uncovers at least seven novel critical regulatory proteins, including five Photosystem I mRNA maturation factors and two master regulators: MTF1, which impacts chloroplast gene expression directly; and PMR1, which impacts expression via nuclear-expressed factors. Our work provides a rich resource identifying novel regulatory and functional genes and placing them into pathways, thereby opening the door to a system-level understanding of photosynthesis.

Highlights

High-confidence identification of 70 previously-uncharacterized genes required for photosynthesis

Proteomic analysis of mutants allows assignment of function to novel genes

Characterization of 5 novel Photosystem I mRNA maturation factors validates this resource

MTF1 and PMR1 identified as master regulators of photosynthesis
Neisseria meningitidissibling small regulatory RNAs connect metabolism with colonization by controlling propionate use
Authors: Man-Bovenkerk Sandra , Schipper Kim , van Sorge Nina M. , Speijer Dave , van der Ende Arie , Pannekoek Yvonne
Published: November 2022

Neisseria meningitidis(the meningococcus) colonizes the human nasopharynx, primarily as a commensal, but sporadically causing septicemia and meningitis. During colonization and invasion, it encounters different niches with specific nutrient compositions. Small non-coding RNAs (sRNAs) are used to fine-tune expression of genes allowing adaptation to their physiological differences. We have previously characterized sRNAs (Neisseria metabolic switch regulators [NmsRs]) controlling switches between cataplerotic and anaplerotic metabolism. Here we extend the NmsRs regulon by studying methylcitrate lyase (PrpF) and propionate kinase (AckA-1) involved in the methylcitrate cycle, and serine hydroxymethyltransferase (GlyA) and 3-hydroxyacid dehydrogenase (MmsB) involved in protein degradation. These proteins were previously shown to be dysregulated in a ΔnmsRsstrain. Levels of transcription of target genes and NmsRs were assessed by RT-qPCR. We also used a novel gene-reporter system, in which the 5’UTR of the target gene is fused to mcherry to study NmsRs-target gene interaction in the meningococcus.

Under nutrient-rich conditions, NmsRs downregulate expression of PrpF and AckA-1, by direct interaction with the 5’ UTR of their mRNA. Overexpression of NmsRs impaired growth under nutrient-limiting growth conditions with pyruvate and propionic acid as the only carbon sources. Our data strongly suggest that NmsRs downregulate propionate metabolism by lowering methylcitrate enzyme activity under nutrient-rich conditions. Under nutrient-poor conditions, NmsRs are downregulated, increasing propionate metabolism, resulting in higher tricarboxylic acid (TCA) activities. This allows metabolism to support nasopharynx colonization with breakdown products of amino acids functioning as anaplerotic substrates, as highlighted by NmsRs regulation of GlyA and MmsB.

SIGNIFICANCE

Neisseria meningitidiscolonizes the human adult nasopharynx, forming a reservoir for the sporadic occurrence of epidemic invasive meningococcal disease like septicemia and meningitis. Propionic acid generated by other bacteria that co-inhabit the human adolescent/adult nasopharynx can be utilized by meningococci for replication in this environment. Here we showed that the sibling small RNAs designated NmsRs (Neisseria metabolic switch regulators) riboregulate propionic acid utilization by meningococci, and thus, colonization. Under conditions mimicking the nasopharyngeal environment, NmsRs upregulated expression of enzymes of the methylcitrate cycle. This leads to the conversion of propionic acid to pyruvate and succinate, resulting in higher tricarboxylic acid cycle activity, allowing colonization of the nasopharynx. NmsRs link metabolic state with colonization, which is a crucial step on the trajectory to invasive meningococcal disease.
De novodesign of modular peptide binding proteins by superhelical matching
Authors: Wu Kejia , Bai Hua , Chang Ya-Ting , Redler Rachel , McNally Kerrie E. , Sheffler William , Brunette TJ , Hicks Derrick R. , Morgan Tomos E , Stevens Tim J , Broerman Adam , Goreshnik Inna , DeWitt Michelle , Chow Cameron M. , Shen Yihang , Stewart Lance , Derivery Emmanuel , Silva Daniel Adriano , Bhabha Gira , Ekiert Damian , Baker David
Published: November 2022

General approaches for designing sequence-specific peptide binding proteins would have wide utility in proteomics and synthetic biology. Although considerable progress has been made in designing proteins which bind to other proteins, the general peptide binding problem is more challenging as most peptides do not have defined structures in isolation, and to offset the loss in solvation upon binding the protein binding interface has to provide specific hydrogen bonds that complement the majority of the buried peptide’s backbone polar groups (1–3). Inspired by natural repeat protein-peptide complexes, and engineering efforts to alter their specificity (4–11), we describe a general approach forde novodesign of proteins made out of repeating units that bind peptides with repeating sequences such that there is a one to one correspondence between repeat units on the protein and peptide. We develop a rapid docking plus geometric hashing method to identify protein backbones and protein-peptide rigid body arrangements that are compatible with bidentate hydrogen bonds between side chains on the protein and the backbone of the peptide (12); the remainder of the protein sequence is then designed using Rosetta to incorporate additional interactions with the peptide and drive folding to the desired structure. We use this approach to design, from scratch, alpha helical repeat proteins that bind six different tripeptide repeat sequences--PLP, LRP, PEW, IYP, PRM and PKW--in near polyproline 2 helical conformations. The proteins are expressed at high levels in E. coli, are hyperstable, and bind peptides with 4-6 copies of the target tripeptide sequences with nanomolar to picomolar affinities both in vitro and in living cells. Crystal structures reveal repeating interactions between protein and peptide interactions as designed, including a ladder of protein sidechain to peptide backbone hydrogen bonds. By redesigning the binding interfaces of individual repeat units, specificity can be achieved for non-repeating sequences, and for naturally occuring proteins containing disordered regions. Our approach provides a general route to designing specific binding proteins for a broad range of repeating and non-repetitive peptide sequences.
Firing rate adaptation affords place cell theta sweeps, phase precession and procession
Authors: Chu Tianhao , Ji Zilong , Zuo Junfeng , Mi Yuanyuan , Zhang Wen-hao , Huang Tiejun , Bush Daniel , Burgess Neil , Wu Si
Published: November 2022

Hippocampal place cells in freely moving rodents display both theta phase precession and procession, which is thought to play important roles in cognition, but the neural mechanism for producing theta phase shift remains largely unknown. Here we show that firing rate adaptation within a continuous attractor neural network causes the neural activity bump to oscillate around the external input, resembling theta sweeps of decoded position during locomotion. These forward and backward sweeps naturally account for theta phase precession and procession of individual neurons, respectively. By tuning the adaptation strength, our model explains the difference between “bimodal cells” showing interleaved phase precession and procession, and “unimodal cells” in which phase precession predominates. Our model also explains the constant cycling of theta sweeps along different arms in a T-maze environment, the speed modulation of place cells’ firing frequency, and the continued phase shift after transient silencing of the hippocampus. We hope that this study will aid an understanding of the neural mechanism supporting theta phase coding in the brain.
Effects of transformational leadership and work engagement on managers’ creative performance
Authors: Juyumaya Jesus , Torres Juan Pablo
Published: November 2022

Purpose

The purpose of the study is to investigate the effect of transformational leadership on creative performance in managers and the mediation effect of work engagement. The study also explores whether manager autonomy is a moderator of the model.

Design/methodology/approach

The authors captured information about transformational leadership, work engagement, creative performance and autonomy, using an experimental design and surveys among a sample of managers. They modeled the first-stage moderated mediation effect using Hayes' PROCESS macro.

Findings

The results confirm that transformational leadership is positively related to creative performance in managers. This mediation effect is partially explained by work engagement. Interestingly, autonomy was a significant moderator of the mediation effect.

Practical implications

The findings suggest that learning to practice transformational leadership will positively move companies to increase managers' work engagement and creative performance. These outcomes have been associated with higher productivity and long-term satisfaction, which are predictors of an organization's effectiveness.

Originality/value

This paper closes a gap between transformational leadership and job demands-resources (JD-R) theory by providing evidence on the effects of transformational leadership, work engagement and autonomy on managers' creative performance. The authors supplement existing empirical tests by adopting an experimental design to eliminate potential alternative explanations.
Blood-based hybrid nanofluid flow through converging/diverging channel with multiple slips effect: a development of Jeffery-Hamel problem
Authors: Dinarvand Saeed , Berrehal Hamza , Pop Ioan , Chamkha Ali. J.
Published: November 2022

Purpose

The purpose of this paper is to study and analyze the converging/diverging channel flow and heat transfer with the multiple slips effect, which is a development of the Jeffery–Hamel problem using the mass-based hybrid nanofluid algorithm. Whereas transferring biological liquid by arteries is a vital issue, mathematical modeling of hybrid nanofluid flow containing titanium dioxide and silver as nanoparticles and blood as base liquid through a converging/diverging duct, which can be a useful analysis for the fields of drug delivery, has been investigated.

Design/methodology/approach

The present approach is based on the Tiwari–Das nanofluid method. In this modeling, the volume fraction of nanoparticles is replaced with nanoparticles masses. The partial differential equations of the mass, momentum and energy conservations are changed to the system of ordinary differential equations through the similarity solution method. The final governing equations are solved by Runge–Kutta–Fehlberg procedure and shooting method.

Findings

The effect of emerging parameters on the temperature, the velocity, the Nusselt number and the skin friction have been analyzed by graphical and tabular reports. It is observed that the opposition to hybrid nanofluid flow in the attendance of particles of nonspherical shapes is more enhanced than those in the attendance of particles of spherical shapes. This issue demonstrates that the rheology of a hybrid nanofluid is dependent on the shape of particles. Besides, backflow regimes form in the divergent channel for high values of Reynolds number, m2 and a. Indeed, this modeling for the hybrid nanofluid can be useful in different technologies and industries such as biological ones. It is worth mentioning that the excellent achievement of the mass-based algorithm for heat transfer and hybrid nanofluid flow is the most important success of this study.

Originality/value

The main originality is related to the development of the Jeffery–Hamel problem using the mass-based hybrid nanofluid algorithm. This new mass-based method is a single-phase hybrid nanofluid approach that the inputs are masses of nanoparticles and base liquid. Besides, considering the multiple slips effect and also pure blood as base fluid in this problem are also new.