bluuebunny/crossref_metadata_2025 huggingface dataset:
Visual Event-Related Potentials under External Emotional Stimuli in Bipolar I Disorder with and without Hypersexuality
Authors: Wang Chu , Rimol Lars M. , Wang Wei
Published: March 2022

Hypersexuality is related to functions of personality and emotion and is a salient symptom of bipolar I disorder especially during manic episode. However, it is uncertain whether bipolar I disorder with (BW) and without (BO) hypersexuality exhibits different cerebral activations under external emotion stimuli. In 54 healthy volunteers, 27 BW and 26 BO patients, we administered the visual oddball event-related potentials (ERPs) under external emotions of Disgust, Erotica, Fear, Happiness, Neutral, and Sadness. Participants’ concurrent states of mania, hypomania, and depression were also evaluated. The N1 latencies under Erotica and Happiness were prolonged, and the P3b amplitudes under Fear and Sadness were decreased in BW; the P3b amplitudes under Fear were increased in BO. The parietal, frontal, and occipital activations were found in BW, and the frontal and temporal activations in BO under different external emotional stimuli, respectively. Some ERP components were correlated with the concurrent affective states in three groups of participants. The primary perception under Erotica and Happiness, and voluntary attention under Fear and Sadness, were impaired in BW, while the voluntary attention under Fear was impaired in BO. Our study indicates different patterns of visual attentional deficits under different external emotions in BW and BO.
Personality as a Possible Intervention Target to Prevent Traumatic Events in Adolescence
Authors: Grummitt Lucinda , Barrett Emma , Kelly Erin , Stapinski Lexine , Newton Nicola
Published: March 2022

Traumatic events (severe injury, violence, threatened death) are commonly experienced by children. Such events are associated with a dose-response increasing risk of subsequent substance use, mental illness, chronic disease, and premature mortality. Preventing the accumulation of traumatic events is thus an urgent public health priority. Substance use risk personality profiles (impulsivity, sensation seeking, hopelessness, and anxiety sensitivity) may be an important target for preventing trauma exposure, given associations between these personality traits and risky behaviour, substance misuse, and injuries across adolescence. The current study aimed to investigate associations between personality at age 13 and the number of traumatic events experienced by age 18. It also examined associations between traumas before age 13 and personality at age 13. Participants were the control group of a cluster-randomised controlled trial examining prevention of adolescent alcohol misuse. Baseline data were collected at ages 12–13 (2012). Participants were followed-up at ages 18–19 (2017–2018). Personality profiles of hopelessness, anxiety sensitivity, impulsivity, and sensation seeking were measured at baseline using the Substance Use Risk Profile Scale. Traumatic events and age of exposure were measured at age 18–19 using the Life Events Checklist for DSM-5. Mixed-effect regression was conducted on 287 participants in Stata 17, controlling for sex. High scores on hopelessness, impulsivity, and sensation seeking at age 13 were associated with a greater number of traumatic events by age 18. Impulsivity and sensation seeking predicted the number of new traumatic events from age 13 to 18. Prior trauma exposure was associated with high hopelessness at age 13. Adolescents exhibiting high impulsivity or sensation seeking may be at greater risk of experiencing traumatic events. Additionally, early trauma exposure may contribute to the development of a hopelessness personality trait.
Taxonomy of Defects in Auxiliary Elements of Facades and Its Relation with Lawsuits Filed by Property Owners
Authors: Carretero-Ayuso Manuel J. , Rodríguez-Jiménez Carlos E. , Pinheiro-Alves Maria Teresa , Fernández-Tapia Enrique
Published: March 2022

While at first it can be thought that the auxiliary elements of facades are merely ornamental with little practical function, this study shows that these components of the building envelope have a high impact on the envelope’s functioning and performance. This is carried out through the analysis of all relevant lawsuits filed in Spain over a 10 year period, a data set in which a surprisingly high number of 1033 cases of defects was found to affect external windowsills, exterior wainscots or cornices (the three auxiliary elements considered) was found. Considering the total number of lawsuits, this is an objectively unprecedented study. An analysis is carried out regarding the interrelations between elements, defects, causes, and types of buildings, with the aim of obtaining a sorted classification of the data. This constitutes a useful tool to prevent future problems arising from either the design, execution, or maintenance of facades. These include various issues resulting from humidities, one of the most frequent envelope defects, which are found to significantly affect the auxiliary elements of facades.
Prediction of Incontinence after Robot-Assisted Radical Prostatectomy: Development and Validation of a 24-Month Incontinence Nomogram
Authors: Pinkhasov Ruben M. , Lee Timothy , Huang Rogerio , Berkley Bonnie , Pinkhasov Alexandr M. , Dodge Nicole , Loecher Matthew S. , James Gaybrielle , Pop Elena , Attwood Kristopher , Mohler James L.
Published: March 2022

Incontinence after robot-assisted radical prostatectomy (RARP) is feared by most patients with prostate cancer. Many risk factors for incontinence after RARP are known, but a paucity of data integrates them. Prospectively acquired data from 680 men who underwent RARP January 2008–December 2015 and met inclusion/exclusion criteria were queried retrospectively and then divided into model development (80%) and validation (20%) cohorts. The UCLA-PCI-Short Form-v2 Urinary Function questionnaire was used to categorize perfect continence (0 pads), social continence (1–2 pads), or incontinence (≥3 pads). The observed incontinence rates were 26% at 6 months, 7% at 12 months, and 3% at 24 months. Logistic regression was used for model development, with variables identified using a backward selection process. Variables found predictive included age, race, body mass index, and preoperative erectile function. Internal validation and calibration were performed using standard bootstrap methodology. Calibration plots and receiver operating curves were used to evaluate model performance. The initial model had 6-, 12-, and 24-month areas under the curves (AUCs) of 0.64, 0.66, and 0.80, respectively. The recalibrated model had 6-, 12-, and 24-month AUCs of 0.52, 0.52, and 0.76, respectively. The final model was superior to any single clinical variable for predicting the risk of incontinence after RARP.
Germline Variants in Cancer Genes from Young Breast Cancer Mexican Patients
Authors: Gómez-Flores-Ramos Liliana , Barraza-Arellano Angélica Leticia , Mohar Alejandro , Trujillo-Martínez Miguel , Grimaldo Lizbeth , Ortiz-Lopez Rocío , Treviño Víctor
Published: March 2022

Breast cancer (BC) is one of the most frequent cancer types in women worldwide. About 7% is diagnosed in young women (YBC) less than 40 years old. In Mexico, however, YBC reaches 15% suggesting a higher genetic susceptibility. There have been some reports of germline variants in YBC across the world. However, there is only one report from a Mexican population, which is not restricted by age and limited to a panel of 143 genes resulting in 15% of patients carrying putatively pathogenic variants. Nevertheless, expanding the analysis to whole exome involves using more complex tools to determine which genes and variants could be pathogenic. We used germline whole exome sequencing combined with the PeCanPie tool to analyze exome variants in 115 YBC patients. Our results showed that we were able to identify 49 high likely pathogenic variants involving 40 genes on 34% of patients. We noted many genes already reported in BC and YBC worldwide, such as BRCA1, BRCA2, ATM, CHEK2, PALB2, and POLQ, but also others not commonly reported in YBC in Latin America, such as CLTCL1, DDX3X, ERCC6, FANCE, and NFKBIE. We show further supporting and controversial evidence for some of these genes. We conclude that exome sequencing combined with robust annotation tools and further analysis, can identify more genes and more patients affected by germline mutations in cancer.
Anaplastic Large Cell Lymphoma: Molecular Pathogenesis and Treatment
Authors: Zhang Xin-Rui , Chien Pham-Ngoc , Nam Sun-Young , Heo Chan-Yeong
Published: March 2022

Anaplastic large cell lymphoma (ALCL) is an uncommon type of non-Hodgkin’s lymphoma (NHL), as well as one of the subtypes of T cell lymphoma, accounting for 1 to 3% of non-Hodgkin’s lymphomas and around 15% of T cell lymphomas. In 2016, the World Health Organization (WHO) classified anaplastic large cell lymphoma into four categories: ALK-positive ALCL (ALK+ALCL), ALK-negative ALCL (ALK−ALCL), primary cutaneous ALCL (pcALCL), and breast-implant-associated ALCL (BIA-ALCL), respectively. Clinical symptoms, gene changes, prognoses, and therapy differ among the four types. Large lymphoid cells with copious cytoplasm and pleomorphic characteristics with horseshoe-shaped or reniform nuclei, for example, are found in both ALK+ and ALK−ALCL. However, their epidemiology and pathogenetic origins are distinct. BIA-ALCL is currently recognized as a new provisional entity, which is a noninvasive disease with favorable results. In this review, we focus on molecular pathogenesis and management of anaplastic large cell lymphoma.
Sphingosine 1-Phosphate Receptor 5 (S1P5) Deficiency Promotes Proliferation and Immortalization of Mouse Embryonic Fibroblasts
Authors: Talmont Franck , Mitri Elodie , Dozier Christine , Besson Arnaud , Cuvillier Olivier , Hatzoglou Anastassia
Published: March 2022

Sphingosine 1-phosphate (S1P), a bioactive lipid, interacts with five widely expressed G protein-coupled receptors (S1P1-5), regulating a variety of downstream signaling pathways with overlapping but also opposing functions. To date, data regarding the role of S1P5 in cell proliferation are ambiguous, and its role in controlling the growth of untransformed cells remains to be fully elucidated. In this study, we examined the effects of S1P5 deficiency on mouse embryonic fibroblasts (MEFs). Our results indicate that lack of S1P5 expression profoundly affects cell morphology and proliferation. First, S1P5 deficiency reduces cellular senescence and promotes MEF immortalization. Second, it decreases cell size and leads to cell elongation, which is accompanied by decreased cell spreading and migration. Third, it increases proliferation rate, a phenotype rescued by the reintroduction of exogenous S1P5. Mechanistically, S1P5 promotes the activation of FAK, controlling cell spreading and adhesion while the anti-proliferative function of the S1P/S1P5 signaling is associated with reduced nuclear accumulation of activated ERK. Our results suggest that S1P5 opposes the growth-promoting function of S1P1-3 through spatial control of ERK activation and provides new insights into the anti-proliferative function of S1P5.
Advancements in Ultrasound and Ultrasound-Based Risk Stratification Systems for the Assessment of Thyroid Nodule
Authors: Trimboli Pierpaolo
Published: March 2022

Ultrasound (US) is an essential in-office imaging procedure used for evaluating thyroid nodules [...]
Harnessing Liquid Biopsies to Guide Immune Checkpoint Inhibitor Therapy
Authors: Fatima Shadma , Ma Yafeng , Safrachi Azadeh , Haider Sana , Spring Kevin J. , Vafaee Fatemeh , Scott Kieran F. , Roberts Tara L. , Becker Therese M. , de Souza Paul
Published: March 2022

Immunotherapy (IO), involving the use of immune checkpoint inhibition, achieves improved response-rates and significant disease-free survival for some cancer patients. Despite these beneficial effects, there is poor predictability of response and substantial rates of innate or acquired resistance, resulting in heterogeneous responses among patients. In addition, patients can develop life-threatening adverse events, and while these generally occur in patients that also show a tumor response, these outcomes are not always congruent. Therefore, predicting a response to IO is of paramount importance. Traditionally, tumor tissue analysis has been used for this purpose. However, minimally invasive liquid biopsies that monitor changes in blood or other bodily fluid markers are emerging as a promising cost-effective alternative. Traditional biomarkers have limitations mainly due to difficulty in repeatedly obtaining tumor tissue confounded also by the spatial and temporal heterogeneity of tumours. Liquid biopsy has the potential to circumvent tumor heterogeneity and to help identifying patients who may respond to IO, to monitor the treatment dynamically, as well as to unravel the mechanisms of relapse. We present here a review of the current status of molecular markers for the prediction and monitoring of IO response, focusing on the detection of these markers in liquid biopsies. With the emerging improvements in the field of liquid biopsy, this approach has the capacity to identify IO-eligible patients and provide clinically relevant information to assist with their ongoing disease management.
Validation of CD98hc as a Therapeutic Target for a Combination of Radiation and Immunotherapies in Head and Neck Squamous Cell Carcinoma
Authors: Köseer Ayşe Sedef , Loureiro Liliana R. , Jureczek Justyna , Mitwasi Nicola , González Soto Karla Elizabeth , Aepler Julia , Bartsch Tabea , Feldmann Anja , Kunz-Schughart Leoni A. , Linge Annett , Krause Mechthild , Bachmann Michael , Arndt Claudia , Dubrovska Anna
Published: March 2022

Most patients with head and neck squamous cell carcinomas (HNSCC) are diagnosed at a locally advanced stage and show heterogeneous treatment responses. Low SLC3A2 (solute carrier family 3 member 2) mRNA and protein (CD98hc) expression levels are associated with higher locoregional control in HNSCC patients treated with primary radiochemotherapy or postoperative radiochemotherapy, suggesting that CD98hc could be a target for HNSCC radiosensitization. One of the targeted strategies for tumor radiosensitization is precision immunotherapy, e.g., the use of chimeric antigen receptor (CAR) T cells. This study aimed to define the potential clinical value of new treatment approaches combining conventional radiotherapy with CD98hc-targeted immunotherapy. To address this question, we analyzed the antitumor activity of the combination of fractionated irradiation and switchable universal CAR (UniCAR) system against radioresistant HNSCC cells in 3D culture. CD98hc-redirected UniCAR T cells showed the ability to destroy radioresistant HNSCC spheroids. Also, the infiltration rate of the UniCAR T cells was enhanced in the presence of the CD98hc target module. Furthermore, sequential treatment with fractionated irradiation followed by CD98hc-redirected UniCAR T treatment showed a synergistic effect. Taken together, our obtained data underline the improved antitumor effect of the combination of radiotherapy with CD98hc-targeted immunotherapy. Such a combination presents an attractive approach for the treatment of high-risk HNSCC patients.
Metastatic Renal Medullary and Collecting Duct Carcinoma in the Era of Antiangiogenic and Immune Checkpoint Inhibitors: A Multicentric Retrospective Study
Authors: Guillaume Zoé , Colomba Emeline , Thouvenin Jonathan , Saldana Carolina , Campedel Luca , Dumont Clément , Laguerre Brigitte , Maillet Denis , Vicier Cécile , Rolland Frédéric , Borchiellini Delphine , Barthelemy Philippe , Albiges Laurence , Auclin Edouard , Roulleaux Dugage Matthieu , Oudard Stéphane , Thibault Constance
Published: March 2022

Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are two rare subtypes of kidney cancer with a poor prognosis in the metastatic setting. Beyond first-line treatment, there are no standard-of-care therapies. This retrospective study assessed the efficacy of treatments after first-line chemotherapy in 57 patients with metastatic (m) CDC (n = 35) or RMC (n = 22) treated between 2010 and 2019 at 11 French centers. The median age was 53 years; overall, 60% (n = 34) of patients were metastatic at diagnosis. After a median follow-up of 13 months, the median overall survival was 12 (95% CI, 11–16) months. All patients received first-line platinum chemotherapy ± bevacizumab, with a median time to progression of 7.27 (95% CI, 7–100 months and an objective response rate (ORR) of 39% (95% CI, 26–52%). Patients received a median of two (1–5) treatment lines. Subsequent treatments included tyrosine kinase inhibitors (n = 12), chemotherapy (n = 34), and checkpoint inhibitors (n = 20), with ORR ranging 10–15% and disease control rates ranging 24–50%. The duration of response for all treatments was ~2 months. Notably, nine patients with CDC were still alive > two years after metastatic diagnosis. Beyond first-line therapy, treatments showed very low antitumor activity in mCDC/RMC. A better understanding of the biology of those rare tumors is urgently needed in order to identify potential targets.
Value of c-MET and Associated Signaling Elements for Predicting Outcomes and Targeted Therapy in Penile Cancer
Authors: Thomas Anita , Slade Kimberly Sue , Blaheta Roman A. , Markowitsch Sascha D. , Stenzel Philipp , Tagscherer Katrin E. , Roth Wilfried , Schindeldecker Mario , Michaelis Martin , Rothweiler Florian , Cinatl Jaroslav , Dotzauer Robert , Vakhrusheva Olesya , Albersen Maarten , Haferkamp Axel , Juengel Eva , Cinatl Jindrich , Tsaur Igor
Published: March 2022

Whereas the lack of biomarkers in penile cancer (PeCa) impedes the development of efficacious treatment protocols, preliminary evidence suggests that c-MET and associated signaling elements may be dysregulated in this disorder. In the following study, we investigated whether c-MET and associated key molecular elements may have prognostic and therapeutic utility in PeCa. Formalin-fixed, paraffin-embedded tumor tissue from therapy-naïve patients with invasive PeCa was used for tissue microarray (TMA) analysis. Immunohistochemical staining was performed to determine the expression of the proteins c-MET, PPARg, β-catenin, snail, survivin, and n-MYC. In total, 94 PeCa patients with available tumor tissue were included. The median age was 64.9 years. High-grade tumors were present in 23.4%, and high-risk HPV was detected in 25.5%. The median follow-up was 32.5 months. High expression of snail was associated with HPV-positive tumors. Expression of β-catenin was inversely associated with grading. In both univariate COX regression analysis and the log-rank test, an increased expression of PPARg and c-MET was predictive of inferior disease-specific survival (DSS). Moreover, in multivariate analysis, a higher expression of c-MET was independently associated with worse DSS. Blocking c-MET with cabozantinib and tivantinib induced a significant decrease in viability in the primary PeCa cell line UKF-PeC3 isolated from the tumor tissue as well as in cisplatin- and osimertinib-resistant sublines. Strikingly, a higher sensitivity to tivantinib could be detected in the latter, pointing to the promising option of utilizing this agent in the second-line treatment setting.
Senescence-Associated Cell Transition and Interaction (SACTAI): A Proposed Mechanism for Tissue Aging, Repair, and Degeneration
Authors: Liu Yajun , Schwam Jonah , Chen Qian
Published: March 2022

Aging is a broad process that occurs as a time-dependent functional decline and tissue degeneration in living organisms. On a smaller scale, aging also exists within organs, tissues, and cells. As the smallest functional unit in living organisms, cells “age” by reaching senescence where proliferation stops. Such cellular senescence is achieved through replicative stress, telomere erosion and stem cell exhaustion. It has been shown that cellular senescence is key to tissue degradation and cell death in aging-related diseases (ARD). However, senescent cells constitute only a small percentage of total cells in the body, and they are resistant to death during aging. This suggests that ARD may involve interaction of senescent cells with non-senescent cells, resulting in senescence-triggered death of non-senescent somatic cells and tissue degeneration in aging organs. Here, based on recent research evidence from our laboratory and others, we propose a mechanism—Senescence-Associated Cell Transition and Interaction (SACTAI)—to explain how cell heterogeneity arises during aging and how the interaction between somatic cells and senescent cells, some of which are derived from aging somatic cells, results in cell death and tissue degeneration.
Integrative Computational Modeling of Cardiomyocyte Calcium Handling and Cardiac Arrhythmias: Current Status and Future Challenges
Authors: Sutanto Henry , Heijman Jordi
Published: March 2022

Cardiomyocyte calcium-handling is the key mediator of cardiac excitation-contraction coupling. In the healthy heart, calcium controls both electrical impulse propagation and myofilament cross-bridge cycling, providing synchronous and adequate contraction of cardiac muscles. However, calcium-handling abnormalities are increasingly implicated as a cause of cardiac arrhythmias. Due to the complex, dynamic and localized interactions between calcium and other molecules within a cardiomyocyte, it remains experimentally challenging to study the exact contributions of calcium-handling abnormalities to arrhythmogenesis. Therefore, multiscale computational modeling is increasingly being used together with laboratory experiments to unravel the exact mechanisms of calcium-mediated arrhythmogenesis. This article describes various examples of how integrative computational modeling makes it possible to unravel the arrhythmogenic consequences of alterations to cardiac calcium handling at subcellular, cellular and tissue levels, and discusses the future challenges on the integration and interpretation of such computational data.
The Landscape of Novel Expressed Chimeric RNAs in Rheumatoid Arthritis
Authors: Detroja Rajesh , Mukherjee Sumit , Frenkel-Morgenstern Milana
Published: March 2022

In cancers and other complex diseases, the fusion of two genes can lead to the production of chimeric RNAs, which are associated with disease development. Several recurrent chimeric RNAs are expressed in different cancers and are thus used for clinical cancer diagnosis. Rheumatoid arthritis (RA) is an immune-mediated joint disorder resulting in synovial inflammation and joint destruction. Despite advances in therapy, many patients do not respond to treatment and present persistent inflammation. Understanding the landscape of chimeric RNA expression in RA patients could provide a better insight into RA pathogenesis, which might provide better treatment strategies and tailored therapies. Accordingly, we analyzed the publicly available RNA-seq data of synovium tissue from 151 RA patients and 28 healthy controls and were able to identify 37 recurrent chimeric RNAs found to be expressed in at least 3 RA samples. Furthermore, the parental genes of these 37 recurrent chimeric RNAs were found to be differentially expressed and enriched in immune-related processes, such as adaptive immune response and the positive regulation of B-cell activation. Interestingly, the appearance of 5 coding and 23 non-coding chimeric RNAs might be associated with regulating their parental gene expression, leading to the generation of dysfunctional immune responses, such as inflammation and bone destruction. Therefore, in this paper, we present the first study to demonstrate the novel chimeric RNAs that are highly expressed and functional in RA.
Sevoflurane Dampens Acute Pulmonary Inflammation via the Adenosine Receptor A2B and Heme Oxygenase-1
Authors: Ngamsri Kristian-Christos , Fuhr Anika , Schindler Katharina , Simelitidis Mariana , Hagen Michelle , Zhang Yi , Gamper-Tsigaras Jutta , Konrad Franziska M.
Published: March 2022

Acute respiratory distress syndrome is a life-threatening disease associated with high mortality. The adenosine receptor A2B (Adora2b) provides anti-inflammatory effects, which are also associated with the intracellular enzyme heme oxygenase-1 (HO-1). Our study determined the mechanism of sevoflurane’s protective properties and investigated the link between sevoflurane and the impact of a functional Adora2b via HO-1 modulation during lipopolysaccharide (LPS)-induced lung injury. We examined the LPS-induced infiltration of polymorphonuclear neutrophils (PMNs) into the lung tissue and protein extravasation in wild-type and Adora2b−/− animals. We generated chimeric animals, to identify the impact of sevoflurane on Adora2b of hematopoietic and non-hematopoietic cells. Sevoflurane decreased the LPS-induced PMN-infiltration and diminished the edema formation in wild-type mice. Reduced PMN counts after sevoflurane treatment were detected only in chimeric mice, which expressed Adora2b exclusively on leukocytes. The Adora2b on hematopoietic and non-hematopoietic cells was required to improve the permeability after sevoflurane inhalation. Further, sevoflurane increased the protective effects of HO-1 modulation on PMN migration and microvascular permeability. These protective effects were abrogated by specific HO-1 inhibition. In conclusion, our data revealed new insights into the protective mechanisms of sevoflurane application during acute pulmonary inflammation and the link between sevoflurane and Adora2b, and HO-1 signaling, respectively.
Comprehensive Gene Expression Analysis to Identify Differences and Similarities between Sex- and Stage-Stratified Melanoma Samples
Authors: Chrysanthou Eirini , Sehovic Emir , Ostano Paola , Chiorino Giovanna
Published: March 2022

Overall lower incidence and better prognosis are observed in female melanoma patients compared to males. As sex and stage differences in the context of melanoma gene expression are understudied, we aim to highlight them through statistical analysis of melanoma gene expression datasets. Data from seven online datasets, including normal skin, commonly acquired nevi, and melanomas, were collected and analyzed. Sex/stage-related differences were assessed using statistical analyses on survival, gene expression, and its variability. Significantly better overall survival in females was observed in stage I, II but not in stage III. Gene expression variability was significantly different between stages and sexes. Specifically, we observed a significantly lower variability in genes expressed in normal skin and nevi in females compared to males, as well as in female stage I, II melanomas. However, in stage III, variability was lower in males. Similarly, class comparison showed that the gene expression differences between sexes are most notable in non-melanoma followed by early-stage-melanoma samples. Sexual dimorphism is an important aspect to consider for a holistic understanding of early-stage melanomas, not only from the tumor characteristics but also from the gene expression points of view.
WRKY Gene Family Drives Dormancy Release in Onion Bulbs
Authors: Puccio Guglielmo , Crucitti Antonino , Tiberini Antonio , Mauceri Antonio , Taglienti Anna , Palumbo Piccionello Antonio , Carimi Francesco , van Kaauwen Martijn , Scholten Olga , Sunseri Francesco , Vosman Ben , Mercati Francesco
Published: March 2022

Onion (Allium cepa L.) is an important bulb crop grown worldwide. Dormancy in bulbous plants is an important physiological state mainly regulated by a complex gene network that determines a stop of vegetative growth during unfavorable seasons. Limited knowledge on the molecular mechanisms that regulate dormancy in onion were available until now. Here, a comparison between uninfected and onion yellow dwarf virus (OYDV)-infected onion bulbs highlighted an altered dormancy in the virus-infected plants, causing several symptoms, such as leaf striping, growth reduction, early bulb sprouting and rooting, as well as a lower abscisic acid (ABA) level at the start of dormancy. Furthermore, by comparing three dormancy stages, almost five thousand four hundred (5390) differentially expressed genes (DEGs) were found in uninfected bulbs, while the number of DEGs was significantly reduced (1322) in OYDV-infected bulbs. Genes involved in cell wall modification, proteolysis, and hormone signaling, such as ABA, gibberellins (GAs), indole-3-acetic acid (IAA), and brassinosteroids (BRs), that have already been reported as key dormancy-related pathways, were the most enriched ones in the healthy plants. Interestingly, several transcription factors (TFs) were up-regulated in the uninfected bulbs, among them three genes belonging to the WRKY family, for the first time characterized in onion, were identified during dormancy release. The involvement of specific WRKY genes in breaking dormancy in onion was confirmed by GO enrichment and network analysis, highlighting a correlation between AcWRKY32 and genes driving plant development, cell wall modification, and division via gibberellin and auxin homeostasis, two key processes in dormancy release. Overall, we present, for the first time, a detailed molecular analysis of the dormancy process, a description of the WRKY-TF family in onion, providing a better understanding of the role played by AcWRKY32 in the bulb dormancy release. The TF co-expressed genes may represent targets for controlling the early sprouting in onion, laying the foundations for novel breeding programs to improve shelf life and reduce postharvest.
Neutrophil Extracellular Traps in Severe SARS-CoV-2 Infection: A Possible Impact of LPS and (1→3)-β-D-glucan in Blood from Gut Translocation
Authors: Saithong Supichcha , Worasilchai Navaporn , Saisorn Wilasinee , Udompornpitak Kanyarat , Bhunyakarnjanarat Thansita , Chindamporn Ariya , Tovichayathamrong Punyot , Torvorapanit Pattama , Chiewchengchol Direkrit , Chancharoenthana Wiwat , Leelahavanichkul Asada
Published: March 2022

Due to limited data on the link between gut barrier defects (leaky gut) and neutrophil extracellular traps (NETs) in coronavirus disease 2019 (COVID-19), blood samples of COVID-19 cases—mild (upper respiratory tract symptoms without pneumonia; n = 27), moderate (pneumonia without hypoxia; n = 28), and severe (pneumonia with hypoxia; n = 20)—versus healthy control (n = 15) were evaluated, together with in vitro experiments. Accordingly, neutrophil counts, serum cytokines (IL-6 and IL-8), lipopolysaccharide (LPS), bacteria-free DNA, and NETs parameters (fluorescent-stained nuclear morphology, dsDNA, neutrophil elastase, histone–DNA complex, and myeloperoxidase–DNA complex) were found to differentiate COVID-19 severity, whereas serum (1→3)-β-D-glucan (BG) was different between the control and COVID-19 cases. Despite non-detectable bacteria-free DNA in the blood of healthy volunteers, using blood bacteriome analysis, proteobacterial DNA was similarly predominant in both control and COVID-19 cases (all severities). In parallel, only COVID-19 samples from moderate and severe cases, but not mild cases, were activated in vitro NETs, as determined by supernatant dsDNA, Peptidyl Arginine Deiminase 4, and nuclear morphology. With neutrophil experiments, LPS plus BG (LPS + BG) more prominently induced NETs, cytokines, NFκB, and reactive oxygen species, when compared with the activation by each molecule alone. In conclusion, pathogen molecules (LPS and BG) from gut translocation along with neutrophilia and cytokinemia in COVID-19-activated, NETs-induced hyperinflammation.
The Role of Airway Epithelial Cell Alarmins in Asthma
Authors: Whetstone Christiane E. , Ranjbar Maral , Omer Hafsa , Cusack Ruth P. , Gauvreau Gail M.
Published: March 2022

The airway epithelium is the first line of defense for the lungs, detecting inhaled environmental threats through pattern recognition receptors expressed transmembrane or intracellularly. Activation of pattern recognition receptors triggers the release of alarmin cytokines IL-25, IL-33, and TSLP. These alarmins are important mediators of inflammation, with receptors widely expressed in structural cells as well as innate and adaptive immune cells. Many of the key effector cells in the allergic cascade also produce alarmins, thereby contributing to the airways disease by driving downstream type 2 inflammatory processes. Randomized controlled clinical trials have demonstrated benefit when blockade of TSLP and IL-33 were added to standard of care medications, suggesting these are important new targets for treatment of asthma. With genome-wide association studies demonstrating associations between single-nucleotide polymorphisms of the TSLP and IL-33 gene and risk of asthma, it will be important to understand which subsets of asthma patients will benefit most from anti-alarmin therapy.
In Vitro Characterization of Doxorubicin-Mediated Stress-Induced Premature Senescence in Human Chondrocytes
Authors: Kirsch Valeria , Ramge Jan-Moritz , Schoppa Astrid , Ignatius Anita , Riegger Jana
Published: March 2022

Accumulation of senescent chondrocytes is thought to drive inflammatory processes and subsequent cartilage degeneration in age-related as well as posttraumatic osteoarthritis (OA). However, the underlying mechanisms of senescence and consequences on cartilage homeostasis are not completely understood so far. Therefore, suitable in vitro models are needed to study chondrocyte senescence. In this study, we established and evaluated a doxorubicin (Doxo)-based model of stress-induced premature senescence (SIPS) in human articular chondrocytes (hAC). Cellular senescence was determined by the investigation of various senescence associated (SA) hallmarks including β-galactosidase activity, expression of p16, p21, and SA secretory phenotype (SASP) markers (IL-6, IL-8, MMP-13), the presence of urokinase-type plasminogen activator receptor (uPAR), and cell cycle arrest. After seven days, Doxo-treated hAC displayed a SIPS-like phenotype, characterized by excessive secretion of SASP factors, enhanced uPAR-positivity, decreased proliferation rate, and increased β-galactosidase activity. This phenotype was proven to be stable seven days after the removal of Doxo. Moreover, Doxo-treated hAC exhibited increased granularity and flattened or fibroblast-like morphology. Further analysis implies that Doxo-mediated SIPS was driven by oxidative stress as demonstrated by increased ROS levels and NO release. Overall, we provide novel insights into chondrocyte senescence and present a suitable in vitro model for further studies.
Newborn Screening: Review of its Impact for Cystinosis
Authors: Hohenfellner Katharina , Elenberg Ewa , Ariceta Gema , Nesterova Galina , Soliman Neveen A. , Topaloglu Rezan
Published: March 2022

Newborn screening (NBS) programmes are considered to be one of the most successful secondary prevention measures in childhood to prevent or reduce morbidity and/or mortality via early disease identification and subsequent initiation of therapy. However, while many rare diseases can now be detected at an early stage using appropriate diagnostics, the introduction of a new target disease requires a detailed analysis of the entire screening process, including a robust scientific background, analytics, information technology, and logistics. In addition, ethics, financing, and the required medical measures need to be considered to allow the benefits of screening to be evaluated at a higher level than its potential harm. Infantile nephropathic cystinosis (INC) is a very rare lysosomal metabolic disorder. With the introduction of cysteamine therapy in the early 1980s and the possibility of renal replacement therapy in infancy, patients with cystinosis can now reach adulthood. Early diagnosis of cystinosis remains important as this enables initiation of cysteamine at the earliest opportunity to support renal and patient survival. Using molecular technologies, the feasibility of screening for cystinosis has been demonstrated in a pilot project. This review aims to provide insight into NBS and discuss its importance for nephropathic cystinosis using molecular technologies.
The DREADDful Hurdles and Opportunities of the Chronic Chemogenetic Toolbox
Authors: Claes Marie , De Groef Lies , Moons Lieve
Published: March 2022

The chronic character of chemogenetics has been put forward as one of the assets of the technique, particularly in comparison to optogenetics. Yet, the vast majority of chemogenetic studies have focused on acute applications, while repeated, long-term neuromodulation has only been booming in the past few years. Unfortunately, together with the rising number of studies, various hurdles have also been uncovered, especially in relation to its chronic application. It becomes increasingly clear that chronic neuromodulation warrants caution and that the effects of acute neuromodulation cannot be extrapolated towards chronic experiments. Deciphering the underlying cellular and molecular causes of these discrepancies could truly unlock the chronic chemogenetic toolbox and possibly even pave the way for chemogenetics towards clinical application. Indeed, we are only scratching the surface of what is possible with chemogenetic research. For example, most investigations are concentrated on behavioral read-outs, whereas dissecting the underlying molecular signature after (chronic) neuromodulation could reveal novel insights in terms of basic neuroscience and deregulated neural circuits. In this review, we highlight the hurdles associated with the use of chemogenetic experiments, as well as the unexplored research questions for which chemogenetics offers the ideal research platform, with a particular focus on its long-term application.
Development of a Vitrification Preservation Process for Bioengineered Epithelial Constructs
Authors: Campbell Lia H. , Brockbank Kelvin G. M.
Published: March 2022

The demand for human bioengineered tissue constructs is growing in response to the worldwide movement away from the use of animals for testing of new chemicals, drug screening and household products. Presently, constructs are manufactured and delivered just in time, resulting in delays and high costs of manufacturing. Cryopreservation and banking would speed up delivery times and permit cost reduction due to larger scale manufacturing. Our objective in these studies was development of ice-free vitrification formulations and protocols using human bioengineered epithelial constructs that could be scaled up from individual constructs to 24-well plates. Initial experiments using single EpiDerm constructs in vials demonstrated viability >80% of untreated control, significantly higher than our best freezing strategy. Further studies focused on optimization and evaluation of ice-free vitrification strategies. Vitrification experiments with 55% (VS55) and 70% (VS70) cryoprotectant (CPA) formulations produced constructs with good viability shortly after rewarming, but viability decreased in the next days, post-rewarming in vitro. Protocol changes contributed to improved outcomes over time in vitro. We then transitioned from using glass vials with 1 construct to deep-well plates holding up to 24 individual constructs. Construct viability was maintained at >80% post-warming viability and >70% viability on days 1–3 in vitro. Similar viability was demonstrated for other related tissue constructs. Furthermore, we demonstrated maintenance of viability after 2–7 months of storage below −135 °C.
Identification and Validation of Autophagy-Related Genes in Vitiligo
Authors: Yang Yiwen , Wu Xiuyi , Lu Xiaoli , Wang Chen , Xiang Leihong , Zhang Chengfeng
Published: March 2022

Vitiligo is a common depigmented disease with unclear pathogenesis. Autophagy is crucial for maintaining cellular homeostasis and has been linked to a variety of autoimmune disorders; however, there have been no reports exploring the involvement of autophagy-related genes (ARGs) in vitiligo using bioinformatics methodologies. In this study, RNA-sequencing technology was used to identify the differentially expressed genes (DEGs) and the Human Autophagy Database (HADb) was overlapped to identify differentially expressed autophagy-related genes (DEARGs) in stable non-segmental vitiligo (NSV). Bioinformatics analyses were conducted with R packages and Ingenuity Pathways Analysis (IPA). DEARGs were further confirmed with qRT-PCR. Critical autophagy markers were detected with Western blotting analysis. We identified a total of 39 DEARGs in vitiligo lesions. DEARGs-enriched canonical pathways, diseases and bio functions, upstream regulators, and networks were discovered. qRT-PCR confirmed the significant increases in FOS and RGS19 in vitiligo lesions. Lower microtubule-associated protein 1 light chain (LC3) II/LC3I ratio and higher sequestosome 1 (SQSTM1, p62) expression were found in vitiligo lesions. In conclusion, this study provided a new insight that autophagy dysregulation appeared in stable vitiligo lesions and might be involved in the etiology of vitiligo by taking part in multiple pathways and bio functions.
Activin A Causes Muscle Atrophy through MEF2C-Dependent Impaired Myogenesis
Authors: Loumaye Audrey , Lause Pascale , Zhong Xiaoling , Zimmers Teresa A. , Bindels Laure B. , Thissen Jean-Paul
Published: March 2022

Activin A (ActA) is considered to play a major role in cancer-induced cachexia (CC). Indeed, circulating ActA levels are elevated and predict survival in patients with CC. However, the mechanisms by which ActA mediates CC development and in particular skeletal muscle (SM) atrophy in humans are not yet fully understood. In this work, we aimed to investigate the effects of ActA on human SM and in mouse models of CC. We used a model of human muscle cells in culture to explore how ActA acts towards human SM. In this model, recombinant ActA induced myotube atrophy associated with the decline of MyHC-β/slow, the main myosin isoform in human muscle cells studied. Moreover, ActA inhibited the expression and activity of MEF2C, the transcription factor regulating MYH7, the gene which codes for MyHC-β/slow. This decrease in MEF2C was involved in the decline of MyHC-β/slow expression, since inhibition of MEF2C by a siRNA leads to the decrease in MyHC-β/slow expression. The relevance of this ActA/MEF2C pathway in vivo was supported by the parallel decline of MEF2C expression and SM mass, which are both blunted by ActA inhibition, in animal models of CC. In this work, we showed that ActA is a potent negative regulator of SM mass by inhibiting MyHC-β/slow synthesis through downregulation of MEF2C. This observation highlights a novel interaction between ActA signaling and MEF2C transcriptional activity which contributes to SM atrophy in CC models.
Effect of Massage with Oil Balanced in Essential Fatty Acids on Development and Lipid Parameters in Very Premature Neonates: A Randomized, Controlled Study
Authors: Garbi Aurélie , Armand Martine , Beltran-Anzola Any-Alejandra , Sarté Catherine , Brévaut-Malaty Véronique , Tosello Barthélémy , Gire Catherine
Published: March 2022

Background: Oil massage versus only massage can increase preterm newborn development, especially weight gain, via a supposed percutaneous absorption of oil lipids, but data are contradictory. Aims: Investigating whether massage with a vegetable oil balanced in essential fatty acids improves neonatal weight gain, and digestive autonomy as proxy for neuro-development outcomes. Methods: A prospective monocentric randomized study was conducted in very premature newborns who received massage with oil (isio4 10 mL/kg/day, n = 18) versus with no oil (n = 18) for five consecutive days (10-min session twice daily) at a corrected gestational age of 34–35 weeks. Anthropometrics and clinical characteristics were recorded. Plasma triglyceride and total cholesterol concentrations were analyzed with an enzymatic kit. The fatty acid composition (weight%, mg/mL) of total plasma lipids and of red blood cell (RBC) membrane was analyzed by gas chromatography. Results: Weight gain velocity at the end of massage period was 12.3 ± 1.4 g/kg/day with oil vs. 9.8 ± 1.4 g/kg/day with no oil (p = 0.1). Digestive autonomy, plasma lipid parameters, polyunsaturated fatty acids in plasma total lipids or in RBC were comparable. The no oil group displayed a higher RBC level in nervonic acid at discharge (4.3 ± 0.2 vs. 3.4 ± 0.2%; p = 0.025) and in C18:1n-9 plasmalogen species at the end of the massage period and at discharge (0.73 ± 0.06 vs. 0.48 ± 0.06; 0.92 ± 0.06 vs. 0.69 ± 0.06%; p < 0.01), two molecules that are involved in neurodevelopment. Conclusions: The use of isio4 oil did not provide additional benefits for the development of very premature newborns, neither changed lipid metabolism nor polyunsaturated fatty acid biological status, which did not corroborate the existence of a percutaneous route for oil lipid absorption. The reason for different levels of nervonic acid and plasmalogen in RBC remains to be explored.
GCEN: An Easy-to-Use Toolkit for Gene Co-Expression Network Analysis and lncRNAs Annotation
Authors: Chen Wen , Li Jing , Huang Shulan , Li Xiaodeng , Zhang Xuan , Hu Xiang , Xiang Shuanglin , Liu Changning
Published: March 2022

Gene co-expression network analysis has been widely used in gene function annotation, especially for long noncoding RNAs (lncRNAs). However, there is a lack of effective cross-platform analysis tools. For biologists to easily build a gene co-expression network and to predict gene function, we developed GCEN, a cross-platform command-line toolkit developed with C++. It is an efficient and easy-to-use solution that will allow everyone to perform gene co-expression network analysis without the requirement of sophisticated programming skills, especially in cases of RNA-Seq research and lncRNAs function annotation. Because of its modular design, GCEN can be easily integrated into other pipelines.
Parameterization-Driven Uncertainties in Single-Forcing, Single-Model Wave Climate Projections from a CMIP6-Derived Dynamic Ensemble
Authors: Kumar Rajesh , Lemos Gil , Semedo Alvaro , Alsaaq Faisal
Published: March 2022

This study is focused on the impact of different parameterizations in the state-of-the art wave model WAVEWATCH3 (WW3) in describing the present climate and future wave climate projections. We have used a Coupled Model Intercomparison Project Phase 6 (CMIP6)-derived single-wind forcing (from EC-EARTH) to produce a dynamic wind-wave climate ensemble for its historic (1995–2014) and future (2081–2100) periods. We discuss the uncertainty due to the wave model (intra-model uncertainty) in simulating the present and future wave climate. The historical wave climate runs were compared against the ERA5 reanalysis and found to be in good agreement for the significant wave height. This gives a good degree of confidence to investigate the intra-model uncertainty in WW3 using the available physics packages such as ST2, ST3, ST4, and ST6. In general, for the historic period, ST3 and ST4 physics packages perform better in the tropics whereas ST6 performs better in the extratropics, based on M-Score performance assessment. The study also reveals that the extratropical South Indian Ocean and tropical eastern South Pacific areas exhibit a larger amount of uncertainty, mainly induced by the ST2 physics package. The results of this study shed new light on the impacts associated with the use of multiple physics parameterizations in wave climate ensembles, an issue that has not received the necessary attention in scientific literature.