bluuebunny/crossref_metadata_2025 huggingface dataset:
A Topical Review of Conjunctive Heart Rate Variability Biofeedback and Acceptance and Commitment Therapy for Pediatric Disorders of Gut–Brain Interaction
Authors: Freeman Baez Katelyn , Lackey Nicholas S. , Ferdousian Vanoosheh , Fathi Moe , Clarke Dennis F. , Mathias Marisa S. , Wynveen Rachel , Weiss Lizabeth , Gevirtz Richard N.
Published: December 2023

Objective:

Disorders of gut–brain interaction (DGBI) affect a large segment of the pediatric population, significantly impacting quality of life and functioning. Recent findings indicate emerging psychological therapies targeting autonomic mechanisms may be effective treatment approaches. This article reviews utilization of conjunctive heart rate variability biofeedback (HRVB) alongside acceptance and commitment therapy (ACT) in the treatment of DGBI.

Method:

This study includes a topical review of HRVB as an adjunct to ACT in the context of autonomic regulation in DGBI intervention. An overview of our treatment model at the Center for Applied Biobehavioral Sciences (CABS) and procedures for future replication is provided. Clinic referrals, administrative processes, patient intake, education and measures, and treatment protocol are outlined. A review of previous studies at CABS and their outcomes are detailed.

Results:

Previous data suggests that utilization of HRVB as an adjunctive approach to psychological therapies which target autonomic regulation, such as ACT, alongside standard medical treatment should be considered in pediatric DGBI management. CABS outcomes support the inclusion of HRVB to target autonomic dysregulation in DGBI to improve symptomatology and functioning in this population.

Conclusion:

HRVB and ACT appear to be promising treatments for pediatric DGBI to be included in psychological and multidisciplinary clinical settings. Given the correlates of autonomic nervous system dysregulation in adults and preliminary findings in pediatric DGBI, these may be useful approaches for targeting the autonomic mechanisms of DGBI symptomatology. We address future directions for research to replicate and extend the findings for use in clinical settings.

Implications for Impact Statement

Heart rate variability biofeedback and acceptance and commitment therapy may be effective and promising treatments to be included in psychological and multidisciplinary clinical settings for pediatric disorders of gut–brain interaction (DGBI). These interventions may work by targeting the autonomic nervous system, potentially improving DGBI symptoms and functioning in the pediatric population. These treatments require further research and validation, which this article aims to demonstrate.
Toward Promotion of Health Equity in Pediatric Disorders of Gut–Brain Interaction: A Call to Action
Authors: Low Kapalu Christina , Wilkes Caroline D.
Published: December 2023

Objectives:

There has been increased attention to health equity, or the opportunity to obtain one’s health potential without disadvantage caused by discriminatory social systems, in recent years. The social determinants of health (SDoH), including economic stability, educational access and quality, healthcare access and quality, neighborhood and built environment, and social and community context, are the social, political, and systems-level factors that contribute to health inequities.

Method:

In this commentary, the authors will review the ways in which structural and systemic racism impact health, discuss what is known about SDoH in pediatric DGBIs and propose a call to action for pediatric psychologists to promote health equity via research, clinical work, teaching, and advocacy.

Results:

Unfortunately, very limited research on SDoH in pediatric disorders of gut–brain interaction (DGBIs) has been conducted to date. What we do know is that exposure to early life stressors influences DGBI prevalence and symptoms in both childhood and adulthood ( Chitkara et al., 2008 ). Thus, addressing SDoHs in pediatric gastroenterology has the potential to improve population health and reduce functional disability.

Conclusion:

Upstream, systems-level interventions are needed in order to make measurable change in health outcomes in pediatric DGBIs.

Implications for Impact Statement

Social determinants of health have been linked with health care disparities within pediatric disorders of gut–brain interaction. Pediatric psychologists are embedded members of medical teams, who possess the knowledge and skills needed to create upstream interventions to directly address social and systemic root causes of disparities.
Pyrotinib and chrysin synergistically potentiate autophagy in HER2-positive breast cancer
Authors: Liu Xiaoxiao , Zhang Xing , Shao Zhiying , Zhong Xiaorong , Ding Xin , Wu Liang , Chen Jie , He Ping , Cheng Yan , Zhu Kunrui , Zheng Dan , Jing Jing , Luo Ting
Published: December 2023

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been the most challenging subtype of BC, consisting of 20% of BC with an apparent correlation with poor prognosis. Despite that pyrotinib, a new HER2 inhibitor, has led to dramatic improvements in prognosis, the efficacy of pyrotinib monotherapy remains largely restricted due to its acquired resistance. Therefore, identifying a new potential antitumor drug in combination with pyrotinib to amplify therapeutic efficacy is a pressing necessity. Here, we reported a novel combination of pyrotinib with chrysin and explored its antitumor efficacy and the underlying mechanism in HER2-positive BC. We determined that pyrotinib combined with chrysin yielded a potent synergistic effect to induce more evident cell cycle arrest, inhibit the proliferation of BT-474 and SK-BR-3 BC cells, and repress in vivo tumor growth in xenograft mice models. This may be attributed to enhanced autophagy induced by endoplasmic reticulum stress. Furthermore, the combined treatment of pyrotinib and chrysin induced ubiquitination and glucose-6-phosphate dehydrogenase (G6PD) degradation by upregulating zinc finger and BTB/POZ domain-containing family protein 16 (ZBTB16) in tumorigenesis of BC. Mechanistically, we identified that miR-16-5p was a potential upstream regulator of ZBTB16, and it showed a significant inverse correlation with ZBTB16. Inhibition of miR-16-5p overexpression by restoring ZBTB16 significantly potentiated the overall antitumor efficacy of pyrotinib combined with chrysin against HER2-positive BC. Together, these findings demonstrate that the combined treatment of pyrotinib and chrysin enhances autophagy in HER2-positive BC through an unrecognized miR-16-5p/ZBTB16/G6PD axis.
Evidence for a shared genetic contribution to loneliness and borderline personality disorder
Authors: Schulze Anna , Streit Fabian , Zillich Lea , Awasthi Swapnil , Hall Alisha S. M. , Jungkunz Martin , Kleindienst Nikolaus , Frank Josef , Schwarze Cornelia E. , Dahmen Norbert , Schott Björn H. , Nöthen Markus , Mobascher Arian , Rujescu Dan , Lieb Klaus , Roepke Stefan , Herpertz Sabine C. , Schmahl Christian , Bohus Martin , Ripke Stephan , Rietschel Marcella , Lis Stefanie , Witt Stephanie
Published: December 2023

Loneliness, influenced by genetic and environmental factors such as childhood maltreatment, is one aspect of interpersonal dysfunction in Borderline Personality Disorder (BPD). Numerous studies link loneliness and BPD and twin studies indicate a genetic contribution to this association. The aim of our study was to investigate whether genetic predisposition for loneliness and BPD risk overlap and whether genetic risk for loneliness contributes to higher loneliness reported by BPD patients, using genome-wide genotype data. We assessed the genetic correlation of genome-wide association studies (GWAS) of loneliness and BPD using linkage disequilibrium score regression and tested whether a polygenic score for loneliness (loneliness-PGS) was associated with case-control status in two independent genotyped samples of BPD patients and healthy controls (HC; Witt2017-sample: 998 BPD, 1545 HC; KFO-sample: 187 BPD, 261 HC). In the KFO-sample, we examined associations of loneliness-PGS with reported loneliness, and whether the loneliness-PGS influenced the association between childhood maltreatment and loneliness. We found a genetic correlation between the GWAS of loneliness and BPD in the Witt2017-sample (rg = 0.23, p = 0.015), a positive association of loneliness-PGS with BPD case-control status (Witt2017-sample: NkR² = 2.3%, p = 2.7*10–12; KFO-sample: NkR² = 6.6%, p = 4.4*10–6), and a positive association between loneliness-PGS and loneliness across patient and control groups in the KFO-sample (β = 0.186, p = 0.002). The loneliness-PGS did not moderate the association between childhood maltreatment and loneliness in BPD. Our study is the first to use genome-wide genotype data to show that the genetic factors underlying variation in loneliness in the general population and the risk for BPD overlap. The loneliness-PGS was associated with reported loneliness. Further research is needed to investigate which genetic mechanisms and pathways are involved in this association and whether a genetic predisposition for loneliness contributes to BPD risk.
Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination
Authors: Sun Xiangfei , Zhang Qiang , Lin Xiaohan , Shu Ping , Gao Xiaodong , Shen Kuntang
Published: December 2023

Imatinib (IM) has significantly improved the prognosis of gastrointestinal stromal tumor (GIST) patients, but some patients still have primary resistance to IM, and approximately half of patients develop acquired drug resistance within 2 years of treatment, necessitating exploration of new treatment strategies. Targeting ferroptosis as a novel approach to tumor treatment has gained attention. Yet, there is limited research on ferroptosis in GIST, and the underlying mechanism remains unclear. In this study, we revealed that IM increased lipid reactive oxygen species and intracellular Fe2+ levels, and decreased glutathione levels in GIST. This effect could be partially inhibited by Ferrostatin-1. Additionally, knocking down STUB1 and overexpressing GPX4 reversed the IM-induced ferroptosis effect. Moreover, STUB1 was identified as a novel E3 ubiquitin ligase of GPX4, promoting the ubiquitination at site K191 of GPX4. The combination of the GPX4 inhibitor RSL3 and IM synergistically induces ferroptosis, inhibiting GIST proliferation both in vivo and in vitro. Furthermore, STUB1 and GPX4 expression serve as independent prognostic factors for GIST. In conclusion, This study is the first to demonstrate that IM induces ferroptosis by promoting STUB1-mediated GPX4 ubiquitination in GIST, and the combination of RSL3 and IM emerges as a promising therapeutic strategy for GIST.
Respiration modulates sleep oscillations and memory reactivation in humans
Authors: Schreiner Thomas , Petzka Marit , Staudigl Tobias , Staresina Bernhard P.
Published: December 2023

The beneficial effect of sleep on memory consolidation relies on the precise interplay of slow oscillations and spindles. However, whether these rhythms are orchestrated by an underlying pacemaker has remained elusive. Here, we tested the relationship between respiration, which has been shown to impact brain rhythms and cognition during wake, sleep-related oscillations and memory reactivation in humans. We re-analysed an existing dataset, where scalp electroencephalography and respiration were recorded throughout an experiment in which participants (N = 20) acquired associative memories before taking a nap. Our results reveal that respiration modulates the emergence of sleep oscillations. Specifically, slow oscillations, spindles as well as their interplay (i.e., slow-oscillation_spindle complexes) systematically increase towards inhalation peaks. Moreover, the strength of respiration - slow-oscillation_spindle coupling is linked to the extent of memory reactivation (i.e., classifier evidence in favour of the previously learned stimulus category) during slow-oscillation_spindles. Our results identify a clear association between respiration and memory consolidation in humans and highlight the role of brain-body interactions during sleep.
Capturing critical gem-diol intermediates and hydride transfer for anodic hydrogen production from 5-hydroxymethylfurfural
Authors: Fu Guodong , Kang Xiaomin , Zhang Yan , Guo Ying , Li Zhiwei , Liu Jianwen , Wang Lei , Zhang Jiujun , Fu Xian-Zhu , Luo Jing-Li
Published: December 2023

The non-classical anodic H2 production from 5-hydroxymethylfurfural (HMF) is very appealing for energy-saving H2 production with value-added chemical conversion due to the low working potential (~0.1 V vs RHE). However, the reaction mechanism is still not clear due to the lack of direct evidence for the critical intermediates. Herein, the detailed mechanisms are explored in-depth using in situ Raman and Infrared spectroscopy, isotope tracking, and density functional theory calculations. The HMF is observed to form two unique inter-convertible gem-diol intermediates in an alkaline medium: 5-(Dihydroxymethyl)furan-2-methanol anion (DHMFM−) and dianion (DHMFM2−). The DHMFM2− is easily oxidized to produce H2 via H− transfer, whereas the DHMFM− is readily oxidized to produce H2O via H+ transfer. The increases in potential considerably facilitate the DHMFM− oxidation rate, shifting the DHMFM− ↔ DHMFM2− equilibrium towards DHMFM− and therefore diminishing anodic H2 production until it terminates. This work captures the critical intermediate DHMFM2− leading to hydrogen production from aldehyde, unraveling a key point for designing higher performing systems.
Personalized functional brain network topography is associated with individual differences in youth cognition
Authors: Keller Arielle S. , Pines Adam R. , Shanmugan Sheila , Sydnor Valerie J. , Cui Zaixu , Bertolero Maxwell A. , Barzilay Ran , Alexander-Bloch Aaron F. , Byington Nora , Chen Andrew , Conan Gregory M. , Davatzikos Christos , Feczko Eric , Hendrickson Timothy J. , Houghton Audrey , Larsen Bart , Li Hongming , Miranda-Dominguez Oscar , Roalf David R. , Perrone Anders , Shetty Alisha , Shinohara Russell T. , Fan Yong , Fair Damien A. , Satterthwaite Theodore D.
Published: December 2023

Individual differences in cognition during childhood are associated with important social, physical, and mental health outcomes in adolescence and adulthood. Given that cortical surface arealization during development reflects the brain’s functional prioritization, quantifying variation in the topography of functional brain networks across the developing cortex may provide insight regarding individual differences in cognition. We test this idea by defining personalized functional networks (PFNs) that account for interindividual heterogeneity in functional brain network topography in 9–10 year olds from the Adolescent Brain Cognitive Development℠ Study. Across matched discovery (n = 3525) and replication (n = 3447) samples, the total cortical representation of fronto-parietal PFNs positively correlates with general cognition. Cross-validated ridge regressions trained on PFN topography predict cognition in unseen data across domains, with prediction accuracy increasing along the cortex’s sensorimotor-association organizational axis. These results establish that functional network topography heterogeneity is associated with individual differences in cognition before the critical transition into adolescence.
A DARPin promotes faster onset of botulinum neurotoxin A1 action
Authors: Leka Oneda , Wu Yufan , Zanetti Giulia , Furler Sven , Reinberg Thomas , Marinho Joana , Schaefer Jonas V. , Plückthun Andreas , Li Xiaodan , Pirazzini Marco , Kammerer Richard A.
Published: December 2023

In this study, we characterize Designed Ankyrin Repeat Proteins (DARPins) as investigative tools to probe botulinum neurotoxin A1 (BoNT/A1) structure and function. We identify DARPin-F5 that completely blocks SNAP25 substrate cleavage by BoNT/A1 in vitro. X-ray crystallography reveals that DARPin-F5 inhibits BoNT/A1 activity by interacting with a substrate-binding region between the α- and β-exosite. This DARPin does not block substrate cleavage of BoNT/A3, indicating that DARPin-F5 is a subtype-specific inhibitor. BoNT/A1 Glu-171 plays a critical role in the interaction with DARPin-F5 and its mutation to Asp, the residue found in BoNT/A3, results in a loss of inhibition of substrate cleavage. In contrast to the in vitro results, DARPin-F5 promotes faster substrate cleavage of BoNT/A1 in primary neurons and muscle tissue by increasing toxin translocation. Our findings could have important implications for the application of BoNT/A1 in therapeutic areas requiring faster onset of toxin action combined with long persistence.
Intranasal mask for protecting the respiratory tract against viral aerosols
Authors: Hu Xiaoming , Wang Shuang , Fu Shaotong , Qin Meng , Lyu Chengliang , Ding Zhaowen , Wang Yan , Wang Yishu , Wang Dongshu , Zhu Li , Jiang Tao , Sun Jing , Ding Hui , Wu Jie , Chang Lingqian , Cui Yimin , Pang Xiaocong , Wang Youchun , Huang Weijin , Yang Peidong , Wang Limin , Ma Guanghui , Wei Wei
Published: December 2023

The spread of many infectious diseases relies on aerosol transmission to the respiratory tract. Here we design an intranasal mask comprising a positively-charged thermosensitive hydrogel and cell-derived micro-sized vesicles with a specific viral receptor. We show that the positively charged hydrogel intercepts negatively charged viral aerosols, while the viral receptor on vesicles mediates the entrapment of viruses for inactivation. We demonstrate that when displaying matched viral receptors, the intranasal masks protect the nasal cavity and lung of mice from either severe acute respiratory syndrome coronavirus 2 or influenza A virus. With computerized tomography images of human nasal cavity, we further conduct computational fluid dynamics simulation and three-dimensional printing of an anatomically accurate human nasal cavity, which is connected to human lung organoids to generate a human respiratory tract model. Both simulative and experimental results support the suitability of intranasal masks in humans, as the likelihood of viral respiratory infections induced by different variant strains is dramatically reduced.
Dissecting the genetic landscape of GPCR signaling through phenotypic profiling in C. elegans
Authors: Pu Longjun , Wang Jing , Lu Qiongxuan , Nilsson Lars , Philbrook Alison , Pandey Anjali , Zhao Lina , Schendel Robin van , Koh Alan , Peres Tanara V. , Hashi Weheliye H. , Myint Si Lhyam , Williams Chloe , Gilthorpe Jonathan D. , Wai Sun Nyunt , Brown Andre , Tijsterman Marcel , Sengupta Piali , Henriksson Johan , Chen Changchun
Published: December 2023

G protein-coupled receptors (GPCRs) mediate responses to various extracellular and intracellular cues. However, the large number of GPCR genes and their substantial functional redundancy make it challenging to systematically dissect GPCR functions in vivo. Here, we employ a CRISPR/Cas9-based approach, disrupting 1654 GPCR-encoding genes in 284 strains and mutating 152 neuropeptide-encoding genes in 38 strains in C. elegans. These two mutant libraries enable effective deorphanization of chemoreceptors, and characterization of receptors for neuropeptides in various cellular processes. Mutating a set of closely related GPCRs in a single strain permits the assignment of functions to GPCRs with functional redundancy. Our analyses identify a neuropeptide that interacts with three receptors in hypoxia-evoked locomotory responses, unveil a collection of regulators in pathogen-induced immune responses, and define receptors for the volatile food-related odorants. These results establish our GPCR and neuropeptide mutant libraries as valuable resources for the C. elegans community to expedite studies of GPCR signaling in multiple contexts.
Pathway centric analysis for single-cell RNA-seq and spatial transcriptomics data with GSDensity
Authors: Liang Qingnan , Huang Yuefan , He Shan , Chen Ken
Published: December 2023

Advances in single-cell technology have enabled molecular dissection of heterogeneous biospecimens at unprecedented scales and resolutions. Cluster-centric approaches are widely applied in analyzing single-cell data, however they have limited power in dissecting and interpreting highly heterogenous, dynamically evolving data. Here, we present GSDensity, a graph-modeling approach that allows users to obtain pathway-centric interpretation and dissection of single-cell and spatial transcriptomics (ST) data without performing clustering. Using pathway gene sets, we show that GSDensity can accurately detect biologically distinct cells and reveal novel cell-pathway associations ignored by existing methods. Moreover, GSDensity, combined with trajectory analysis can identify curated pathways that are active at various stages of mouse brain development. Finally, GSDensity can identify spatially relevant pathways in mouse brains and human tumors including those following high-order organizational patterns in the ST data. Particularly, we create a pan-cancer ST map revealing spatially relevant and recurrently active pathways across six different tumor types.
Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD
Authors: Chen Zhefan Stephen , Ou Mingxi , Taylor Stephanie , Dafinca Ruxandra , Peng Shaohong Isaac , Talbot Kevin , Chan Ho Yin Edwin
Published: December 2023

The GGGGCC hexanucleotide repeat expansion mutation in the chromosome 9 open reading frame 72 (C9orf72) gene is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). In this study, we demonstrate that the zinc finger (ZF) transcriptional regulator Yin Yang 1 (YY1) binds to the promoter region of the planar cell polarity gene Fuzzy to regulate its transcription. We show that YY1 interacts with GGGGCC repeat RNA via its ZF and that this interaction compromises the binding of YY1 to the FuzzyYY1 promoter sites, resulting in the downregulation of Fuzzy transcription. The decrease in Fuzzy protein expression in turn activates the canonical Wnt/β-catenin pathway and induces synaptic deficits in C9ALS/FTD neurons. Our findings demonstrate a C9orf72 GGGGCC RNA-initiated perturbation of YY1–Fuzzy transcriptional control that implicates aberrant Wnt/β-catenin signalling in C9ALS/FTD-associated neurodegeneration. This pathogenic cascade provides a potential new target for disease-modifying therapy.
Cdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice
Authors: Chen Min , Zhu Jie-Ying , Mu Wang-Jing , Luo Hong-Yang , Li Yang , Li Shan , Yan Lin-Jing , Li Ruo-Ying , Guo Liang
Published: December 2023

Exercise is an effective non-pharmacological strategy for ameliorating nonalcoholic fatty liver disease (NAFLD), but the underlying mechanism needs further investigation. Cysteine dioxygenase type 1 (Cdo1) is a key enzyme for cysteine catabolism that is enriched in liver, whose role in NAFLD remains poorly understood. Here, we show that exercise induces the expression of hepatic Cdo1 via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific knockout of Cdo1 (Cdo1LKO) decreases basal metabolic rate of the mice and impairs the effect of exercise against NAFLD, whereas hepatocyte-specific overexpression of Cdo1 (Cdo1LTG) increases basal metabolic rate of the mice and synergizes with exercise to ameliorate NAFLD. Mechanistically, Cdo1 tethers Camkk2 to AMPK by interacting with both of them, thereby activating AMPK signaling. This promotes fatty acid oxidation and mitochondrial biogenesis in hepatocytes to attenuate hepatosteatosis. Therefore, by promoting hepatic Camkk2-AMPK signaling pathway, Cdo1 acts as an important downstream effector of exercise to combat against NAFLD.
Extending the toolbox for RNA biology with SegModTeX: a polymerase-driven method for site-specific and segmental labeling of RNA
Authors: Haslecker Raphael , Pham Vincent V. , Glänzer David , Kreutz Christoph , Dayie Theodore Kwaku , D’Souza Victoria M.
Published: December 2023

RNA performs a wide range of functions regulated by its structure, dynamics, and often post-transcriptional modifications. While NMR is the leading method for understanding RNA structure and dynamics, it is currently limited by the inability to reduce spectral crowding by efficient segmental labeling. Furthermore, because of the challenging nature of RNA chemistry, the tools being developed to introduce site-specific modifications are increasingly complex and laborious. Here we use a previously designed Tgo DNA polymerase mutant to present SegModTeX — a versatile, one-pot, copy-and-paste approach to address these challenges. By precise, stepwise construction of a diverse set of RNA molecules, we demonstrate the technique to be superior to RNA polymerase driven and ligation methods owing to its substantially high yield, fidelity, and selectivity. We also show the technique to be useful for incorporating some fluorescent- and a wide range of other probes, which significantly extends the toolbox of RNA biology in general.
Proteomics-driven noninvasive screening of circulating serum protein panels for the early diagnosis of hepatocellular carcinoma
Authors: Xing Xiaohua , Cai Linsheng , Ouyang Jiahe , Wang Fei , Li Zongman , Liu Mingxin , Wang Yingchao , Zhou Yang , Hu En , Huang Changli , Wu Liming , Liu Jingfeng , Liu Xiaolong
Published: December 2023

Early diagnosis of hepatocellular carcinoma (HCC) lacks highly sensitive and specific protein biomarkers. Here, we describe a staged mass spectrometry (MS)-based discovery-verification-validation proteomics workflow to explore serum proteomic biomarkers for HCC early diagnosis in 1002 individuals. Machine learning model determined as P4 panel (HABP2, CD163, AFP and PIVKA-II) clearly distinguish HCC from liver cirrhosis (LC, AUC 0.979, sensitivity 0.925, specificity 0.915) and healthy individuals (HC, AUC 0.992, sensitivity 0.975, specificity 1.000) in an independent validation cohort, outperforming existing clinical prediction strategies. Furthermore, the P4 panel can accurately predict LC to HCC conversion (AUC 0.890, sensitivity 0.909, specificity 0.877) with predicting HCC at a median of 11.4 months prior to imaging in prospective external validation cohorts (No.: Keshen 2018_005_02 and NCT03588442). These results suggest that proteomics-driven serum biomarker discovery provides a valuable reference for the liquid biopsy, and has great potential to improve early diagnosis of HCC.
Customizing cellular signal processing by synthetic multi-level regulatory circuits
Authors: Gao Yuanli , Wang Lei , Wang Baojun
Published: December 2023

As synthetic biology permeates society, the signal processing circuits in engineered living systems must be customized to meet practical demands. Towards this mission, novel regulatory mechanisms and genetic circuits with unprecedented complexity have been implemented over the past decade. These regulatory mechanisms, such as transcription and translation control, could be integrated into hybrid circuits termed “multi-level circuits”. The multi-level circuit design will tremendously benefit the current genetic circuit design paradigm, from modifying basic circuit dynamics to facilitating real-world applications, unleashing our capabilities to customize cellular signal processing and address global challenges through synthetic biology.
MarrowCellDLD: a microfluidic method for label-free retrieval of fragile bone marrow-derived cells
Authors: Porro Gloria , Sarkis Rita , Obergozo Clara , Godot Lucie , Amato Francesco , Humbert Magali , Naveiras Olaia , Guiducci Carlotta
Published: December 2023

Functional bone marrow studies have focused primarily on hematopoietic progenitors, leaving limited knowledge about other fragile populations, such as bone marrow adipocytes (BMAds) and megakaryocytes. The isolation of these cells is challenging due to rupture susceptibility and large size. We introduce here a label-free cytometry microsystem, MarrowCellDLD, based on deterministic lateral displacement. MarrowCellDLD enables the isolation of large, fragile BM-derived cells based on intrinsic size properties while preserving their viability and functionality. Bone marrow adipocytes, obtained from mouse and human stromal line differentiation, as well as megakaryocytes, from primary human CD34+ hematopoietic stem and progenitor cells, were used for validation. Precise micrometer-range separation cutoffs were adapted for each cell type. Cells were sorted directly in culture media, without pre-labeling steps, and with real-time imaging for quality control. At least 106 cells were retrieved intact per sorting round. Our method outperformed two FACS instruments in purity and yield, particularly for large cell size fractions. MarrowCellDLD represents a non-destructive sorting tool for large, fragile BM-derived cells, facilitating the separation of pure populations of BMAds and megakaryocytes to further investigate their physiological and pathological roles.
Relationship between mental health and stressors among fathers of children with chronic illnesses and cognitive structure of fathers’ stress experiences
Authors: Haraguchi Masahiro
Published: December 2023

To clarify the relationship between stressor and mental health of the fathers with children with chronic illnesses and to examine the cognitive structure of fathers’ stress experiences. This study employs a cross-sectional research design. A self-reported questionnaire survey was conducted on 137 respondents. The dependent variables were the stressors of the fathers and depression. Focusing on the data of 51 fathers of children with chronic illness, for 21 items related to the stressful experiences had been identified in a previous study, an exploratory factor analysis using the principal factor method was performed. Logistic regression analysis results showed that the items “There are children with chronic illness” and “The large number of medical treatments required for the children” were significantly associated with the fathers’ poor mental health. In the factor analysis, the following three factors were extracted as a recognition of the fathers’ stress experiences. The fathers positively recognized their role as a father and a husband, perceiving it in a positive light despite their negative feelings. The results also suggested that it should be essential for nurses to re-evaluate those fathers who are exposed to daily stressors as care subjects, as well as to positively include them in the support activities.
Non-myopic multipoint multifidelity Bayesian framework for multidisciplinary design
Authors: Di Fiore Francesco , Mainini Laura
Published: December 2023

The adoption of high-fidelity models in multidisciplinary design optimization (MDO) permits to enhance the identification of superior design configurations, but would prohibitively rise the demand for computational resources and time. Multifidelity Bayesian Optimization (MFBO) efficiently combines information from multiple models at different levels of fidelity to accelerate the MDO procedure. State-of-the-art MFBO methods currently meet two major limitations: (i) the sequential adaptive sampling precludes parallel computations of high-fidelity models, and (ii) the search scheme measures the utility of new design evaluations only at the immediate next iteration. This paper proposes a Non-Myopic Multipoint Multifidelity Bayesian Optimization (NM3-BO) algorithm to sensitively accelerate MDO overcoming the limitations of standard methods. NM3-BO selects a batch of promising design configurations to be evaluated in parallel, and quantifies the expected long-term improvement of these designs at future steps of the optimization. Our learning scheme leverages an original acquisition function based on the combination of a two-step lookahead policy and a local penalization strategy to measure the future utility achieved evaluating multiple design configurations simultaneously. We observe that the proposed framework permits to sensitively accelerate the MDO of a space vehicle and outperforms popular algorithms.
A comprehensive study on criteria of sustainable urban waste management system: using content analysis
Authors: Khosravani Farhad , Abbasi Enayat , Choobchian Shahla , Jalili Ghazizade Mahdi
Published: December 2023

The present study was developed to comprehensively analyze experts' views and content of documents focusing on goals and criteria of sustainable waste management system in Tehran, Iran. To this end, the suitable goals for sustainable waste management system in Tehran city were adopted from domestic, national and international documents. For this purpose, 27 national and international documents and 2 domestic documents related to waste management were selected and analyzed by using content analysis according to Gall, 1994. Further, in order to formulate goals in case of bottlenecks and challenges of waste management in Tehran, the focus group technique was used based on Stewart and Shamdasani, 2014. At this stage, 24 key experts in the field of waste management were interviewed in the form of 4 focus groups. Data collection were performed via audio recording and word-for-word implementation of conversations, taking notes and writing field notes. The data collection continued until reaching theoretical saturation. Next, content analysis and coding methods were used to analyze the data. Finally, the goals of waste management were divided into five general categories including: institutional (with emphasis on the integration and inclusion of the key elements of the urban waste management system), technical and infrastructural (with emphasis on the optimization of existing processes in the use of urban waste management technologies), environmental (with emphasis on minimizing the adverse health and environmental effects of the urban waste management system, economic (with emphasis on the economic and financial sustainability of the urban waste management system), and cultural-social (with emphasis on attracting the maximum participation of citizens and service recipients). The results clearly showed that sustainable waste management measures in Tehran should follow these five components in order to reduce the problems caused by unrealistic waste management and make sustainable use of basic, natural, financial and human resources.
Blocking MyD88 signaling with MyD88 inhibitor prevents colitis-associated colorectal cancer development by maintaining colonic microbiota homeostasis
Authors: Xie Bin , Wang Bo , Shang Runshi , Wang Lu , Huang Xia , Xie Lin
Published: December 2023

Certain intestinal microbiota alterations appear to positively correlate with tumorigenesis of CAC due to the disruption of the balance between the host and microorganisms. It is proven that blocking MyD88 signaling can prevent colitis-associated colorectal cancer (CAC) development in mice. We are aim to reveal the role of MyD88 signaling of maintaining colonic microbiota homeostasis for preventing CAC development. We here analyzed the landscape of gut microbiome in the mice model of AOM/DSS-induced CAC with MyD88 inhibitor treatment. PCoA revealed significant reduction in Lactobacillus load and increase in Escherichia load in the mucosal microbial composition of mice with CAC, compared with normal controls (NCs). Inhibitor-treatment led to almost undetectable Proteobacteria (Escherichia) and the retention of the dominance of Firmicutes and Bacteroidota (Muribaculaceae) in the mucosa. RNA sequencing analysis identified genes were up-regulated (Hp, SAA3 and IL-1F9) and down-regulated (CYP3A44, SLC30A10, GPNMB and OTC) in Inhibitor-treated mice (vs. CAC). Meanwhile, Inhibitor-treated mice had higher percentage of MUC2-positive area in colon sections (vs. CAC, which was less than NCs) by IF staining and decreased Escherichia in the mucus layer (vs. CAC) by FISH. And intestinal microbiota from mice with MyD88 inhibitor treatment could lessen the outcome of CAC by fecal microbiota transplantation. The development of CAC was involved in the increasing and ectopic Escherichia in the decreasing colonic mucus layer. MyD88 signaling blockade may maintain the host-microbiota homeostasis by up-regulating MUC2 production, increasing probiotics and their protective effects, and inhibiting the reproduction of Escherichia.
Mathematical model predicts tumor control patterns induced by fast and slow cytotoxic T lymphocyte killing mechanisms
Authors: Wang Yixuan , Bergman Daniel R , Trujillo Erica , Pearson Alexander T. , Sweis Randy F. , Jackson Trachette L.
Published: December 2023

Immunotherapy has dramatically transformed the cancer treatment landscape largely due to the efficacy of immune checkpoint inhibitors (ICIs). Although ICIs have shown promising results for many patients, the low response rates in many cancers highlight the ongoing challenges in cancer treatment. Cytotoxic T lymphocytes (CTLs) execute their cell-killing function via two distinct mechanisms: a fast-acting, perforin-mediated process and a slower, Fas ligand (FasL)-driven pathway. Evidence also suggests that the preferred killing mechanism of CTLs depends on the antigenicity of tumor cells. To determine the critical factors affecting responses to ICIs, we construct an ordinary differential equation model describing in vivo tumor-immune dynamics in the presence of active or blocked PD-1/PD-L1 immune checkpoint. Specifically, we identify important aspects of the tumor-immune landscape that affect tumor size and composition in the short and long term. We also generate a virtual cohort of mice with diverse tumor and immune attributes to simulate the outcomes of immune checkpoint blockade in a heterogeneous population. By identifying key tumor and immune characteristics associated with tumor elimination, dormancy, and escape, we predict which fraction of a population potentially responds well to ICIs and ways to enhance therapeutic outcomes with combination therapy.
Implementation of inclusion and exclusion criteria in clinical studies in OHDSI ATLAS software
Authors: Blasini Romina , Buchowicz Kornelia Marta , Schneider Henning , Samans Birgit , Sohrabi Keywan
Published: December 2023

Clinical trials are essential parts of a medical study process, but studies are often cancelled due to a lack of participants. Clinical Trial Recruitment Support Systems are systems that help to increase the number of participants by seeking more suitable subjects. The software ATLAS (developed by Observational Health Data Sciences and Informatics) can support the launch of a clinical trial by building cohorts of patients who fulfill certain criteria. The correct use of medical classification systems aiming at clearly defined inclusion and exclusion criteria in the studies is an important pillar of this software. The aim of this investigation was to determine whether ATLAS can be used in a Clinical Trial Recruitment Support System to portray the eligibility criteria of clinical studies. Our analysis considered the number of criteria feasible for integration with ATLAS and identified its strengths and weaknesses. Additionally, we investigated whether nonrepresentable criteria were associated with the utilized terminology systems. We analyzed ATLAS using 223 objective eligibility criteria from 30 randomly selected trials conducted in the last 10 years. In the next step, we selected appropriate ICD, OPS, LOINC, or ATC codes to feed the software. We classified each criterion and study based on its implementation capability in the software, ensuring a clear and logical progression of information. Based on our observations, 51% of the analyzed inclusion criteria were fully implemented in ATLAS. Within our selected example set, 10% of the studies were classified as fully portrayable, and 73% were portrayed to some extent. Additionally, we conducted an evaluation of the software regarding its technical limitations and interaction with medical classification systems. To improve and expand the scope of criteria within a cohort definition in a practical setting, it is recommended to work closely with personnel involved in the study to define the criteria precisely and to carefully select terminology systems. The chosen criteria should be combined according to the specific setting. Additional work is needed to specify the significance and amount of the extracted criteria.
Genomic hypomethylation in cell-free DNA predicts responses to checkpoint blockade in lung and breast cancer
Authors: Kim Kyeonghui , Kim Hyemin , Shin Inkyung , Noh Seung-Jae , Kim Jeong Yeon , Suh Koung Jin , Kim Yoo-Na , Lee Jung-Yun , Cho Dae-Yeon , Kim Se Hyun , Kim Jee Hyun , Lee Se-Hoon , Choi Jung Kyoon
Published: December 2023

Genomic hypomethylation has recently been identified as a determinant of therapeutic responses to immune checkpoint blockade (ICB). However, it remains unclear whether this approach can be applied to cell-free DNA (cfDNA) and whether it can address the issue of low tumor purity encountered in tissue-based methylation profiling. In this study, we developed an assay named iMethyl, designed to estimate the genomic hypomethylation status from cfDNA. This was achieved through deep targeted sequencing of young LINE-1 elements with > 400,000 reads per sample. iMethyl was applied to a total of 653 ICB samples encompassing lung cancer (cfDNA n = 167; tissue n = 137; cfDNA early during treatment n = 40), breast cancer (cfDNA n = 91; tissue n = 50; PBMC n = 50; cfDNA at progression n = 44), and ovarian cancer (tissue n = 74). iMethyl-liquid predicted ICB responses accurately regardless of the tumor purity of tissue samples. iMethyl-liquid was also able to monitor therapeutic responses early during treatment (3 or 6 weeks after initiation of ICB) and detect progressive hypomethylation accompanying tumor progression. iMethyl-tissue had better predictive power than tumor mutation burden and PD-L1 expression. In conclusion, our iMethyl-liquid method allows for reliable noninvasive prediction, early evaluation, and monitoring of clinical responses to ICB therapy.
Diversity and pathogenic characteristics of the Fusarium species isolated from minor legumes in Korea
Authors: Ha Min Sun , Ryu Hyunjoo , Ju Ho Jong , Choi Hyo-Won
Published: December 2023

Legumes are primarily grown agriculturally for human consumption, livestock forage, silage, and as green manure. However, production has declined primarily due to fungal pathogens. Among them, this study focused on Fusarium spp. that cause Fusarium wilt in minor legumes in Korea. Diseased legume plants were collected from 2020 to 2021, and diverse fungal genera were isolated from the internal tissues of the plant roots and stems. Fusarium spp. were the most dominant, accounting for 71% of the isolates. They were identified via morphological characteristics and molecular identification. In the pathogenicity test, Fusarium oxysporum and Fusarium fujikuroi generally exhibited high virulence. The host range investigation revealed that the NC20-738, NC20-739, and NC21-950 isolates infected all nine crops, demonstrating the widest host range. In previous studies, the focus was solely on Fusarium wilt disease in soybeans. Therefore, in this study, we aimed to investigate Fusarium wilt occurred in minor legumes, which are consumed as extensively as soybeans, due to the scarcity of data on the diversity and characteristics of Fusarium spp. existing in Korea. The diverse information obtained in this study will serve as a foundation for implementing effective management strategies against Fusarium-induced plant diseases.
LncRNA SNHG8 regulates the migration and angiogenesis of pHUVECs induced by high glucose via the TRPM7/ERK1/2 signaling axis
Authors: Fan Zongcheng , Chen Xin , Wang Laicheng , Yu Jianjian , Zhang Shunpeng , Xu Changsheng , Lin Jinxiu , Lin Yunchai , Peng Feng
Published: December 2023

This study aimed to evaluate the regulatory effect and molecular mechanism of long noncoding RNA small nucleolus RNA host gene 8 (LncRNA SNHG8) in the migration and angiogenesis of primary human umbilical vein endothelial cells (pHUVECs) under high-glucose (HG) conditions. The HG-induced endothelial injury model was established in vitro.The cell model of silencing SNHG8, overexpressing SNHG8, and silencing TRPM7 was established by transfecting SNHG8-siRNA, SNHG8 plasmid and TRPM7-siRNA into cells with liposomes.The SNHG8 level was determined through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression levels of transient receptor potential melastatin 7 (TRPM7), endothelial nitric oxide synthase (eNOS), p-eNOS, extracellular signal-regulated kinase 1/2(ERK1/2), and p-ERK1/2 were assessed through western blot. Nitric oxide (NO) levels were measured with DAF-FM. pHUVEC migration was examined through wound healing and Transwell assay, and pHUVEC angiogenesis was observed through a tube formation assay. Results showed that HG promoted the expression of lncRNA SNHG8 and TRPM7 and decreased the ratio of p-eNOS/eNOS and p-ERK1/2/ERK1/2 in pHUVECs . NO production, migration , and angiogenesis were inhibited in pHUVECs under HG conditions. Silencing lncRNA SNHG8 and TRPM7 could significantly reverse the HG-induced decrease in eNOS activation, NO production , migration, and angiogenesis . SNHG8 and U0126 (ERK pathway inhibitor) overexpression enhanced the HG effects, whereas using U0126 did not affect the TRPM7 expression. In conclusion, lncRNA SNHG8 participates in HG-induced endothelial cell injury and likely regulates NO production, migration, and angiogenesis of pHUVECs via the TRPM7/ERK1/2 signaling axis.
Lymphocyte subsets and inflammatory factors as predictors of immunotherapy efficacy in patients with hepatocellular carcinoma
Authors: Shuyue Gao , Jiamin Cheng , Niansong Qian
Published: December 2023

We aimed to investigate the correlation between lymphocyte subpopulations expressing inhibitor receptors, IL-6 levels, and the efficacy of immunotherapy in patients with hepatocellular carcinoma. Blood samples were prospectively collected before and after immunotherapy from patients with intermediate and advanced hepatocellular carcinoma who were treated with immunotherapy at the Fifth Medical Center of the PLA General Hospital from August 2022 to October 2023. According to the efficacy of the patients, patients were divided into effective and ineffective groups, with 40 in the effective group and 44 in the ineffective group. We compared changes in lymphocyte subsets and IL-6 levels between the two groups. Optimal cut-off value was determined using ROC curves. Then, patients were categorized into high and low groups based on cut-off value, and the disease control rates and progression free survival were compared. Before immunotherapy, there were no significant differences in the baseline levels of lymphocyte subsets (PD1 + TIM3 + T/T, TIGIT + T/T, TIM3 + T/T, CTLA4 + T/T, LAG3 + T/T, PD1 + T/T) and IL-6 between the two groups (P > 0.05). After immunotherapy, the levels of PD1 + TIM3 + T/T, TIGIT + T/T, and IL-6 in the effective group were lower than those in the ineffective group and these differences were statistically significant (P = 0.001, P = 0.008, P = 0.000). However, the levels of other lymphocyte subsets showed no significant difference. Using the ROC curve to assess efficacy prediction, PD1 + TIM3 + T/T, TIGIT + T/T and IL-6 demonstrated high predictive ability (AUC = 0.79, AUC = 0.81, AUC = 0.78). The predictive value of efficacy was further improved when all three factors were combined (AUC = 0.92, P = 0.000). Based on the ROC curve, we identified optimal cut-off value for three factors. Notably, patients with values below the optimal cut-off value had higher disease control rate and progression free survival. The levels of PD1 + TIM3 + T/T, TIGIT + T/T, and IL-6 after 2 cycles of immunotherapy may serve as predictors of treatment efficacy in patients with hepatocellular carcinoma.