bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient decision aids for patients with differentiated thyroid carcinoma: development process and alpha and beta testing
Authors: Koot Anna , Hermens Rosella , Ottevanger Petronella , Netea-Maier Romana , Stalmeier Peep ,   the COMBO study group
Published: May 2023

Background

Patient decision aids (PtDAs) are structured clinical tools that facilitate shared decision-making. Two important treatment decisions for patients with differentiated thyroid cancer (DTC), which could benefit from PtDAs, are as follows (1): the extent of surgery decision in patients with low-risk DTC and (2) the decision to start or delay starting the treatment with tyrosine kinase inhibitors (TKIs) in patients with advanced tumors.

Material and methods

PtDAs for these two decisions were developed using the International Patient Decision Aids Standards (IPDAS) quality criteria in an iterative process of prototype development via alpha and beta testing by patients and physicians. The information content of the PtDAs was based on the available literature, current guidelines, and patient’s needs, preferences, and values.

Results

The web-based PtDAs underwent two rounds of alpha testing, revisions, and beta testing. The PtDAs have the same structure, consisting of six steps: a general introduction, information about the treatment options, comparing the treatment options, knowledge questions, a values clarification exercise, and saving the information. The alpha testing (n = 8 patients, n = 10 physicians) showed that the PtDAs were highly acceptable and usable for decision-making. Results of the beta testing in 20 patients showed that two patients did not use the PtDA; the other 18 patients found that the PtDAs were readable (n = 17) and helpful (n = 14) for decision-making. All patients recommend using the PtDAs.

Conclusions

Evidence-based PtDAs were created for patients with DTC for two different treatment decisions. Our final version was judged to be clear, balanced, and helpful in decision-making.
Flexible torque control for wind turbines considering frequency response under wind speed crossing region
Authors: Wang Yingwei , Guo Yufeng , Du Yilin , Xu Weimao
Published: May 2023

The operational range of a wind turbine is typically divided into two regions based on wind speed: below and above the rated wind speed. The turbine switches between these two regions depending on the prevailing wind speed; however, during the transition, the generator may undergo transient shocks in torque, which can negatively impact both the mechanical load of the turbine and the reliability of the power system. This article presents a flexible torque control method for wind turbines, specifically designed to handle the transition between wind speed regions when the turbine is participating in frequency regulation. First, the anomalies in generator torque caused by traditional torque control methods during frequency response scenarios are analyzed. Next, two methods—dynamic deloading and flexible torque control—are developed to address these issues. The developed methods set transition regions based on generator speed, which helps to reduce the impact of transient changes in generator torque. Importantly, the addition of transition regions does not require additional feedback, making the controller easy to implement. The response characteristics of the proposed methods are then analyzed under different deloading factors and wind speeds using model linearization. Simulation studies are presented to verify the effectiveness of the proposed methods. Overall, this study demonstrates the potential value of flexible torque control methods for wind turbines, which can help to mitigate the negative impact of torque shocks and improve the reliability and efficiency of wind power systems.
COVID-19 pandemic and the social determinants of health
Authors: Meador John E. , James Wesley , Branson Joseph , Bennett Jonathan , Matthews Karen
Published: May 2023

Hesitancy to receive a COVID-19 vaccination across sub-groups within the US population contributed to higher illness rates and deaths. Specifically, minority groups and those living in rural and remote areas are more vaccine-hesitant populations known to suffer from higher disparities in health. Identifying successful and replicable approaches to promoting vaccination within these subpopulations is critical to ensuring vaccination rates can be maximized in these vulnerable groups. In this paper, we present findings from the Mississippi Recognizing Important Vaccine & Education Resources (RIVERs) project, a multi-state effort to spread accurate information related to COVID-19 vaccinations using a variety of community and media-based methods as well as provide vaccinations. Vaccination rates for Black people in Mississippi exceeded those of White people, likely due to the concerted effort of regional health and community organizations. Propensity score matching is performed to test intervention styles using spatial and temporal data related to approximately 7,000 events across Mississippi and parts of Tennessee and publicly available data on vaccination rates and socio-economic data. We demonstrate that vaccination rates within the vulnerable groups may be closely related to misinformation being spread through local social networks and that interventions carried out by local leaders with high levels of local social capital are best at quashing misinformation at the local level. We recommend that policymakers consider the importance of local efforts as an effective tool in increasing vaccination rates in future pandemics.
Leveraging T-cell receptor – epitope recognition models to disentangle unique and cross-reactive T-cell response to SARS-CoV-2 during COVID-19 progression/resolution
Authors: Postovskaya Anna , Vujkovic Alexandra , de Block Tessa , van Petersen Lida , van Frankenhuijsen Maartje , Brosius Isabel , Bottieau Emmanuel , Van Dijck Christophe , Theunissen Caroline , van Ierssel Sabrina H. , Vlieghe Erika , Bartholomeus Esther , Mullan Kerry , Adriaensen Wim , Vanham Guido , Ogunjimi Benson , Laukens Kris , Vercauteren Koen , Meysman Pieter
Published: May 2023

Despite the general agreement on the significance of T cells during SARS-CoV-2 infection, the clinical impact of specific and cross-reactive T-cell responses remains uncertain. Understanding this aspect could provide insights for adjusting vaccines and maintaining robust long-term protection against continuously emerging variants. To characterize CD8+ T-cell response to SARS-CoV-2 epitopes unique to the virus (SC2-unique) or shared with other coronaviruses (CoV-common), we trained a large number of T-cell receptor (TCR) – epitope recognition models for MHC-I-presented SARS-CoV-2 epitopes from publicly available data. These models were then applied to longitudinal CD8+ TCR repertoires from critical and non-critical COVID-19 patients. In spite of comparable initial CoV-common TCR repertoire depth and CD8+ T-cell depletion, the temporal dynamics of SC2-unique TCRs differed depending on the disease severity. Specifically, while non-critical patients demonstrated a large and diverse SC2-unique TCR repertoire by the second week of the disease, critical patients did not. Furthermore, only non-critical patients exhibited redundancy in the CD8+ T-cell response to both groups of epitopes, SC2-unique and CoV-common. These findings indicate a valuable contribution of the SC2-unique CD8+ TCR repertoires. Therefore, a combination of specific and cross-reactive CD8+ T-cell responses may offer a stronger clinical advantage. Besides tracking the specific and cross-reactive SARS-CoV-2 CD8+ T cells in any TCR repertoire, our analytical framework can be expanded to more epitopes and assist in the assessment and monitoring of CD8+ T-cell response to other infections.
Keratinocytes use FPR2 to detect Staphylococcus aureus and initiate antimicrobial skin defense
Authors: Lebtig Marco , Scheurer Jasmin , Muenkel Marie , Becker Janna , Bastounis Effie , Peschel Andreas , Kretschmer Dorothee
Published: May 2023

Introduction

Keratinocytes form a multilayer barrier that protects the skin from invaders or injuries. The barrier function of keratinocytes is in part mediated by the production of inflammatory modulators that promote immune responses and wound healing. Skin commensals and pathogens such as Staphylococcus aureus secrete high amounts of phenol-soluble modulin (PSM) peptides, agonists of formyl-peptide receptor 2 (FPR2). FPR2 is crucial for the recruitment of neutrophils to the sites of infection, and it can influence inflammation. FPR1 and FPR2 are also expressed by keratinocytes but the consequences of FPR activation in skin cells have remained unknown.

Methods

Since an inflammatory environment influences S. aureus colonization, e. g. in patients with atopic dermatitis (AD), we hypothesized that interference with FPRs may alter keratinocyte-induced inflammation, proliferation, and bacterial colonization of the skin. To assess this hypothesis, we investigated the effects of FPR activation and inhibition in keratinocytes with respect to chemokine and cytokine release as well as proliferation and skin wound gap closure.

Results

We observed that FPR activation induces the release of IL-8, IL-1α and promotes keratinocyte proliferation in a FPR-dependent manner. To elucidate the consequence of FPR modulation on skin colonization, we used an AD-simulating S. aureus skin colonization mouse model using wild-type (WT) or Fpr2-/- mice and demonstrate that inflammation enhances the eradication of S. aureus from the skin in a FPR2-dependent way. Consistently, inhibition of FPR2 in the mouse model or in human keratinocytes as well as human skin explants promoted S. aureus colonization.

Discussion

Our data indicate that FPR2 ligands promote inflammation and keratinocyte proliferation in a FPR2-dependent manner, which is necessary for eliminating S. aureus during skin colonization.
New insights into inflammatory memory of epidermal stem cells
Authors: Cheng Dapeng , Zhu Xiaochen , Yan Shaochen , Shi Linli , Liu Zhi , Zhou Xin , Bi Xinling
Published: May 2023

Inflammatory memory, as one form of innate immune memory, has a wide range of manifestations, and its occurrence is related to cell epigenetic modification or metabolic transformation. When re-encountering similar stimuli, executing cells with inflammatory memory function show enhanced or tolerated inflammatory response. Studies have identified that not only hematopoietic stem cells and fibroblasts have immune memory effects, but also stem cells from various barrier epithelial tissues generate and maintain inflammatory memory. Epidermal stem cells, especially hair follicle stem cells, play an essential role in wound healing, immune-related skin diseases, and skin cancer development. In recent years, it has been found that epidermal stem cells from hair follicle can remember the inflammatory response and implement a more rapid response to subsequent stimuli. This review updates the advances of inflammatory memory and focuses on its mechanisms in epidermal stem cells. We are finally looking forward to further research on inflammatory memory, which will allow for the development of precise strategies to manipulate host responses to infection, injury, and inflammatory skin disease.
Aberrant inflammasome activation as a driving force of human autoimmune skin disease
Authors: Fetter Tanja , de Graaf Dennis Marinus , Claus Isabelle , Wenzel Joerg
Published: May 2023

Autoimmune skin diseases are understood as conditions in which the adaptive immune system with autoantigen-specific T cells and autoantibody-producing B cells reacting against self-tissues plays a crucial pathogenic role. However, there is increasing evidence that inflammasomes, which are large multiprotein complexes that were first described 20 years ago, contribute to autoimmune disease progression. The inflammasome and its contribution to the bioactivation of interleukins IL-1β and IL-18 play an essential role in combating foreign pathogens or tissue damage, but may also act as a pathogenic driver of myriad chronic inflammatory diseases when dysfunctionally regulated. Inflammasomes containing the NOD-like receptor family members NLRP1 and NLRP3 as well as the AIM2-like receptor family member AIM2 have been increasingly investigated in inflammatory skin conditions. In addition to autoinflammatory diseases, which are often associated with skin involvement, the aberrant activation of the inflammasome has also been implied in autoimmune diseases that can either affect the skin besides other organs such as systemic lupus erythematosus and systemic sclerosis or are isolated to the skin in humans. The latter include, among others, the T-cell mediated disorders vitiligo, alopecia areata, lichen planus and cutaneous lupus erythematosus as well as the autoantibody-driven blistering skin disease bullous pemphigoid. Some diseases are characterized by both autoinflammatory and autoimmune responses such as the chronic inflammatory skin disease psoriasis. Further insights into inflammasome dysregulation and associated pathways as well as their role in forming adaptive immune responses in human autoimmune skin pathology could potentially offer a new field of therapeutic options in the future.
Sintilimab as maintenance treatment for local/regional recurrent esophageal squamous carcinoma after concurrent chemoradiotherapy: a single-arm Ib/II phase study
Authors: Liu Chengxin , Sun Hongfu , Huang Wei , Wang Zhongtang , Fu Chengrui , Han Dan , Zhao Qian , Wu Xue , Li Baosheng
Published: May 2023

Background

Esophageal cancer (EC) is an aggressive neoplasm of the gastrointestinal tract that is usually treated with a combination of chemotherapy, radiotherapy (RT), and/or surgery, according to disease status. Despite the availability of multimodal therapeutic strategies, local recurrence is frequently observed. However, there is no standard treatment or promising therapeutic approach for local recurrence or metastatic esophageal carcinoma after the RT. This study tended to investigate the efficacy and safety of sintilimab maintenance after concurrent chemoradiotherapy (CCRT) for local/regional recurrent esophageal squamous carcinoma.

Methods

This study was a single-arm, phase Ib/II trial conducted in a single site in China. Patients previously radically treated (surgery or CCRT), histologically confirmed, local or regional recurrence esophageal squamous carcinoma, qualified for the study design, were treated with 25–28 times radiotherapy plus raltitrexed once every 3 weeks for up to two cycles. Patients who have not progressed after CCRT received sintilimab as maintenance once every 3 weeks up to 1 year. Primary endpoints were overall survival (OS) and safety. Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR).

Results

Between September 2019 and March 2022, in a total of 36 enrolled patients, 34 pts completed CCRT. Three patients excluded due to violation of the exclusion criteria (1 pt) and consent withdrawal (2 pts). Finally, 33 pts were included in the final analysis, in which 3 pts had disease progression, and the remaining 30 entered maintenance therapy with sintilimab. The median follow-up time was 12.3 months. Median OS was 20.6 months (95%CI 10.5–NA) and the 1-year OS rate was 64%. Median PFS was 11.5 months (95%CI 5.29–21.3) and the 1-year PFS rate was 43.6%. The ORR was 63.6% (95%CI 44.6–77.8), including 2 cases of CR and 19 cases of PR. The DCR was 19.9%, the median DOR was 19.5 months, and the median TTR was 2.4 months. The rate of any grade TRAEs was 96.7%; ≥Grade 3 TRAE was 23.4%. The incidence of immune-related AE was 60%, most of which were grade 1–2, and only one case of thyroid-stimulating hormone increased was irAE with grade 3 or above.

Conclusion

Sintilimab has shown promising clinical efficacy and a manageable safety profile as maintenance therapy after CCRT for local/regional recurrent esophageal squamous carcinoma. In addition, further confirmation from a large-scale real-world study is still needed.
A plasmatic score using a miRNA signature and CXCL-10 for accurate prediction and diagnosis of liver allograft rejection
Authors: Millán Olga , Ruiz Pablo , Julian Judit , Lizana Ana , Fundora Yiliam , Crespo Gonzalo , Colmenero Jordi , Navasa Miquel , Brunet Mercè
Published: May 2023

Introduction

The use of noninvasive biomarkers may avoid the need for liver biopsy (LB) and could guide immunosuppression adjustment in liver transplantation (LT). The aims of this study were: to confirm the predictive and diagnostic capacity of plasmatic expression of miR-155-5p, miR-181a-5p, miR-122-5p and CXCL-10 for assessing T-cell mediated rejection (TCMR) risk; to develop a score based on a panel of noninvasive biomarkers to predict graft rejection risk and to validate this score in a separate cohort.

Methods

A prospective, observational study was conducted with a cohort of 79 patients followed during the first year after LT. Plasma samples were collected at predetermined time points for the analysis of miRNAs and the CXCL-10. Patients with LFTs abnormalities were submitted to a LB to rule out rejection, assessing previous and concurrent expression of the biomarkers to evaluate their predictive and diagnostic ability. Information from 86 patients included in a previous study was collected and used as a validation cohort.

Results

Twenty-four rejection episodes were diagnosed in 22 patients. Plasmatic CXCL-10 concentration and the expression of the three miRNAs were significantly elevated prior to and at the moment of the diagnosis of rejection. We developed a logistic model for rejection prediction and diagnosis, which included CXCL-10, miR-155-5p and miR-181a-5p. The area under the ROC curve (AUROC) for rejection prediction was 0.975 (79.6% sensitivity, 99.1% specificity, 90,7% PPV; 97.7% NPV; 97.1% correctly classified) and 0.99 for diagnosis (87.5% sensitivity, 99.5% specificity, 91.3% PPV; 99.3% NPV; 98.9% correctly classified). In the validation cohort (n=86; 14 rejections), the same cut-off points were used obtaining AUROCs for rejection prediction and diagnosis of 0.89 and 0.92 respectively. In patients with graft dysfunction in both cohorts the score could discriminate those with rejection regarding other causes with an AUROC of 0.98 (97.3% sensitivity, 94.1%specificity).

Conclusion

These results suggest that the clinical implementation of the monitoring of this noninvasive plasmatic score may allow the prediction and diagnosis of rejection and identify patients with graft dysfunction due to rejection, helping with a more efficient guide for immunosuppressive therapy adjustment. This finding warrants the development of prospective biomarker-guided clinical trials.
A novel signature predicts prognosis and immunotherapy in lung adenocarcinoma based on cancer-associated fibroblasts
Authors: Ren Qianhe , Zhang Pengpeng , Lin Haoran , Feng Yanlong , Chi Hao , Zhang Xiao , Xia Zhijia , Cai Huabao , Yu Yue
Published: May 2023

Background

Extensive research has established the significant correlations between cancer-associated fibroblasts (CAFs) and various stages of cancer development, including initiation, angiogenesis, progression, and resistance to therapy. In this study, we aimed to investigate the characteristics of CAFs in lung adenocarcinoma (LUAD) and develop a risk signature to predict the prognosis of patients with LUAD.

Methods

We obtained single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from the public database. The Seurat R package was used to process the scRNA-seq data and identify CAF clusters based on several biomarkers. CAF-related prognostic genes were further identified using univariate Cox regression analysis. To reduce the number of genes, Lasso regression was performed, and a risk signature was established. A novel nomogram that incorporated the risk signature and clinicopathological features was developed to predict the clinical applicability of the model. Additionally, we conducted immune landscape and immunotherapy responsiveness analyses. Finally, we performed in vitro experiments to verify the functions of EXO1 in LUAD.

Results

We identified 5 CAF clusters in LUAD using scRNA-seq data, of which 3 clusters were significantly associated with prognosis in LUAD. A total of 492 genes were found to be significantly linked to CAF clusters from 1731 DEGs and were used to construct a risk signature. Moreover, our immune landscape exploration revealed that the risk signature was significantly related to immune scores, and its ability to predict responsiveness to immunotherapy was confirmed. Furthermore, a novel nomogram incorporating the risk signature and clinicopathological features showed excellent clinical applicability. Finally, we verified the functions of EXP1 in LUAD through in vitro experiments.

Conclusions

The risk signature has proven to be an excellent predictor of LUAD prognosis, stratifying patients more appropriately and precisely predicting immunotherapy responsiveness. The comprehensive characterization of LUAD based on the CAF signature can predict the response of LUAD to immunotherapy, thus offering fresh perspectives into the management of LUAD patients. Our study ultimately confirms the role of EXP1 in facilitating the invasion and growth of tumor cells in LUAD. Nevertheless, further validation can be achieved by conducting in vivo experiments.
Gaining a (tube) foothold – trends and status following two decades of the long-spined echinoid Diadema setosum (Leske, 1778) invasion to the Mediterranean Sea
Authors: Zirler Rotem , Leck Lynn Angele , Farkash Tamar Feldstein , Holzknecht Martina , Kroh Andreas , Gerovasileiou Vasilis , Huseyinoglu Mehmet Fatih , Jimenez Carlos , Resaikos Vasilis , Yokeş Mehmet Baki , Bronstein Omri
Published: May 2023

The Eastern Mediterranean Sea is an exceptional habitat. Its relative isolation and distinct characteristics create a unique ecosystem recognized as a marine biodiversity hot spot, where one-fifth of the species are endemic. Yet, native Mediterranean biodiversity is under increasing threat, mainly due to massive alien species invasions of Indo-Pacific origin. To date, more than 800 non-indigenous species have been reported in the Eastern Mediterranean Sea, justifying its reputation as one of the most severely affected habitats in the world in terms of marine biological invasions. Here we summarized the Mediterranean invasion dynamics of the long-spined echinoid Diadema setosum (Leske, 1778), one of the most ubiquitous Indo-Pacific sea urchin species. We show an alarming exponential population growth of D. setosum throughout the Eastern Mediterranean since 2018, following more than a decade of ‘invasion lag’ since its first detection in 2006. Molecular analyses illustrate the presence of a single genetic D. setosum clade in the Mediterranean Sea – corresponding to the Arabian Peninsula clade of this species, reinforcing the notion of a Red Sea origin. Our data support the current working hypothesis that the initial introduction of D. setosum occurred in the Northern Levantine Basin from which it gradually expanded in both north-west and south-east trajectories – in contrast to a stepping-stone hypothesis of gradual advancement from the opening of the Suez Canal. Demographic data of D. setosum along the Israeli Mediterranean coastline reveals a well-established population of broad size distributions, from juveniles to adult individuals of remarkably large size. Additionally, we provide evidence of the reproductive capacity of D. setosum in its new environment. Due to the magnitude of Diadema’s ecological footprint, it poses a severe threat to the entire Eastern Mediterranean Sea, including the Levantine Basin and South Aegean Sea, calling for rapid and coordinated action at both national and regional scales.
Prediction of molten pool temperature in laser solid forming based on PSO-LSTM
Authors: Wang Junhua , Xu Junfei , Lu Yan , Xie Tancheng , Peng Jianjun , Yang Fang , Ma Xiqiang
Published: May 2023

The temperature of the molten pool in Laser Solid Forming has a direct effect on the dimensional accuracy and mechanical properties of the parts. Accurate prediction of the melt pool temperature is important to ensure the stability of the melt pool temperature and to improve the forming accuracy and quality of the part. In order to accurately predict the melt pool temperature, this study proposes a melt pool temperature prediction method based on particle swarm optimization (PSO) optimised long short-term memory neural network (LSTM). Using IR camera to obtain melt pool temperature data and establish long short-term memory neural network melt pool temperature prediction model based on experimental data. Optimization of the initial learning rate and the number of hidden layer units of the long short-term memory neural network model using the particle swarm optimization algorithm to build a PSO-LSTM model for prediction of melt pool temperature. The results show that the PSO-LSTM prediction model outperforms the long short-term memory neural network and Ridge Regression models in all evaluation indicators and can achieve accurate prediction of melt pool temperature.
Minimally invasive surgery vs. open thoracotomy for non-small-cell lung cancer with N2 disease: a systematic review and meta-analysis
Authors: Liu Songlin , Li Shaopeng , Tang Yong , Chen Rixin , Qiao Guibin
Published: May 2023

Background

This meta-analysis aimed to investigate the effectiveness and safety of minimally invasive surgery [MIS, including robotic-assisted thoracoscopic surgery (RATS) and video-assisted thoracoscopic surgery (VATS)] and open thoracotomy (OT) for non-small cell lung cancer (NSCLC) patients with N2 disease.

Methods

We searched online databases and studies from the creation of the database to August 2022, comparing the MIS group to the OT group for NSCLC with N2 disease. Study endpoints included intraoperative outcomes [e.g., conversion, estimated blood loss (EBL), surgery time (ST), total lymph nodes (TLN), and R0 resection], postoperative outcomes [e.g., length of stay (LOS) and complication], and survival outcomes [e.g., 30-day mortality, overall survival (OS), and disease-free survival (DFS)]. We estimated outcomes using random effects meta-analysis to account for studies with high heterogeneity (I2 > 50 or p < 0.05). Otherwise, we used a fixed-effect model. We calculated odds ratios (ORs) for binary outcomes and standard mean differences (SMDs) for continuous outcomes. Treatment effects on OS and DFS were described by hazard ratio (HR).

Results

This systematic review and meta-analysis of 15 studies on MIS vs. OT for NSCLC with N2 disease included 8,374 patients. Compared to OT, patients that underwent MIS had less estimated blood loss (EBL) (SMD = – 64.82, p < 0.01), shorter length of stay (LOS) (SMD = −0.15, p < 0.01), higher R0 resection rate (OR = 1.22, p = 0.049), lower 30-day mortality (OR = 0.67, p = 0.03), and longer overall survival (OS) (HR = 0.61, P < 0.01). The results showed no statistically significant differences in surgical time (ST), total lymph nodes (TLN), complications, and disease-free survival (DFS) between the two groups.

Conclusion

Current data suggest that minimally invasive surgery may provide satisfying outcomes, a higher R0 resection rate, and better short-term and long-term survival than open thoracotomy.

Systematic review registration

https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022355712.
High-quality genome assembly of Verticillium dahliae VD991 allows for screening and validation of pathogenic genes
Authors: Yang Jiaxiang , Liu Lisen , Yang Lan , Liu Renju , Gao Chenxu , Hu Wei , Yan Qingdi , Yang Zhaoen , Fan Liqiang
Published: May 2023

Verticillium dahliae (V. dahliae) is a notorious soil-borne pathogen causing Verticillium wilt in more than 400 dicotyledonous plants, including a wide range of economically important crops, such as cotton, tomato, lettuce, potato, and romaine lettuce, which can result in extensive economic losses. In the last decade, several studies have been conducted on the physiological and molecular mechanisms of plant resistance to V. dahliae. However, the lack of a complete genome sequence with a high-quality assembly and complete genomic annotations for V. dahliae has limited these studies. In this study, we produced a full genomic assembly for V. dahliae VD991 using Nanopore sequencing technology, consisting of 35.77 Mb across eight pseudochromosomes and with a GC content of 53.41%. Analysis of the genome completeness assessment (BUSCO alignment: 98.62%; Illumina reads alignment: 99.17%) indicated that our efforts resulted in a nearly complete and high-quality genomic assembly. We selected 25 species closely related to V. dahliae for evolutionary analysis, confirming the evolutionary relationship between V. dahliae and related species, and the identification of a possible whole genome duplication event in V. dahliae. The interaction between cotton and V. dahliae was investigated by transcriptome sequencing resulting in the identification of many genes and pathways associated with cotton disease resistance and V. dahliae pathogenesis. These results will provide new insights into the pathogenic mechanisms of V. dahliae and contribute to the cultivation of cotton varieties resistant to Verticillium wilt.
Functional diversity of nanohaloarchaea within xylan-degrading consortia
Authors: Reva Oleg , Messina Enzo , La Cono Violetta , Crisafi Francesca , Smedile Francesco , La Spada Gina , Marturano Laura , Selivanova Elena A. , Rohde Manfred , Krupovic Mart , Yakimov Michail M.
Published: May 2023

Extremely halophilic representatives of the phylum Candidatus Nanohaloarchaeota (members of the DPANN superphyla) are obligately associated with extremely halophilic archaea of the phylum Halobacteriota (according to the GTDB taxonomy). Using culture-independent molecular techniques, their presence in various hypersaline ecosystems around the world has been confirmed over the past decade. However, the vast majority of nanohaloarchaea remain uncultivated, and thus their metabolic capabilities and ecophysiology are currently poorly understood. Using the (meta)genomic, transcriptomic, and DNA methylome platforms, the metabolism and functional prediction of the ecophysiology of two novel extremely halophilic symbiotic nanohaloarchaea (Ca. Nanohalococcus occultus and Ca. Nanohalovita haloferacivicina) stably cultivated in the laboratory as members of a xylose-degrading binary culture with a haloarchaeal host, Haloferax lucentense, was determined. Like all known DPANN superphylum nanoorganisms, these new sugar-fermenting nanohaloarchaea lack many fundamental biosynthetic repertoires, making them exclusively dependent on their respective host for survival. In addition, given the cultivability of the new nanohaloarchaea, we managed to discover many unique features in these new organisms that have never been observed in nano-sized archaea both within the phylum Ca. Nanohaloarchaeota and the entire superphylum DPANN. This includes the analysis of the expression of organism-specific non-coding regulatory (nc)RNAs (with an elucidation of their 2D-secondary structures) as well as profiling of DNA methylation. While some ncRNA molecules have been predicted with high confidence as RNAs of an archaeal signal recognition particle involved in delaying protein translation, others resemble the structure of ribosome-associated ncRNAs, although none belong to any known family. Moreover, the new nanohaloarchaea have very complex cellular defense mechanisms. In addition to the defense mechanism provided by the type II restriction-modification system, consisting of Dcm-like DNA methyltransferase and Mrr restriction endonuclease, Ca. Nanohalococcus encodes an active type I-D CRISPR/Cas system, containing 77 spacers divided into two loci. Despite their diminutive genomes and as part of their host interaction mechanism, the genomes of new nanohaloarchaea do encode giant surface proteins, and one of them (9,409 amino acids long) is the largest protein of any sequenced nanohaloarchaea and the largest protein ever discovered in cultivated archaea.
Information theoretic measures of causal influences during transient neural events
Authors: Shao Kaidi , Logothetis Nikos K. , Besserve Michel
Published: May 2023

Introduction: Transient phenomena play a key role in coordinating brain activity at multiple scales, however their underlying mechanisms remain largely unknown. A key challenge for neural data science is thus to characterize the network interactions at play during these events.

Methods: Using the formalism of Structural Causal Models and their graphical representation, we investigate the theoretical and empirical properties of Information Theory based causal strength measures in the context of recurring spontaneous transient events.

Results: After showing the limitations of Transfer Entropy and Dynamic Causal Strength in this setting, we introduce a novel measure, relative Dynamic Causal Strength, and provide theoretical and empirical support for its benefits.

Discussion: These methods are applied to simulated and experimentally recorded neural time series and provide results in agreement with our current understanding of the underlying brain circuits.
Identification of miRNAs regulating MAPT expression and their analysis in plasma of patients with dementia
Authors: Piscopo Paola , Grasso Margherita , Manzini Valeria , Zeni Andrea , Castelluzzo Michele , Fontana Francesca , Talarico Giuseppina , Castellano Anna Elisa , Rivabene Roberto , Crestini Alessio , Bruno Giuseppe , Ricci Leonardo , Denti Michela A.
Published: May 2023

Background

Dementia is one of the most common diseases in elderly people and hundreds of thousand new cases per year of Alzheimer’s disease (AD) are estimated. While the recent decade has seen significant advances in the development of novel biomarkers to identify dementias at their early stage, a great effort has been recently made to identify biomarkers able to improve differential diagnosis. However, only few potential candidates, mainly detectable in cerebrospinal fluid (CSF), have been described so far.

Methods

We searched for miRNAs regulating MAPT translation. We employed a capture technology able to find the miRNAs directly bound to the MAPT transcript in cell lines. Afterwards, we evaluated the levels of these miRNAs in plasma samples from FTD (n = 42) and AD patients (n = 33) and relative healthy controls (HCs) (n = 42) by using qRT-PCR.

Results

Firstly, we found all miRNAs that interact with the MAPT transcript. Ten miRNAs have been selected to verify their effect on Tau levels increasing or reducing miRNA levels by using cell transfections with plasmids expressing the miRNAs genes or LNA antagomiRs. Following the results obtained, miR-92a-3p, miR-320a and miR-320b were selected to analyse their levels in plasma samples of patients with FTD and AD respect to HCs. The analysis showed that the miR-92a-1-3p was under-expressed in both AD and FTD compared to HCs. Moreover, miR-320a was upregulated in FTD vs. AD patients, particularly in men when we stratified by sex. Respect to HC, the only difference is showed in men with AD who have reduced levels of this miRNA. Instead, miR-320b is up-regulated in both dementias, but only patients with FTD maintain this trend in both genders.

Conclusions

Our results seem to identify miR-92a-3p and miR-320a as possible good biomarkers to discriminate AD from HC, while miR-320b to discriminate FTD from HC, particularly in males. Combining three miRNAs improves the accuracy only in females, particularly for differential diagnosis (FTD vs. AD) and to distinguish FTD from HC.
An updated catalog of CTCF variants associated with neurodevelopmental disorder phenotypes
Authors: Price Emma , Fedida Liron M. , Pugacheva Elena M. , Ji Yon J. , Loukinov Dmitri , Lobanenkov Victor V.
Published: May 2023

Introduction

CTCF-related disorder (CRD) is a neurodevelopmental disorder (NDD) caused by monoallelic pathogenic variants in CTCF. The first CTCF variants in CRD cases were documented in 2013. To date, 76 CTCF variants have been further described in the literature. In recent years, due to the increased application of next-generation sequencing (NGS), growing numbers of CTCF variants are being identified, and multiple genotype-phenotype databases cataloging such variants are emerging.

Methods

In this study, we aimed to expand the genotypic spectrum of CRD, by cataloging NDD phenotypes associated with reported CTCF variants. Here, we systematically reviewed all known CTCF variants reported in case studies and large-scale exome sequencing cohorts. We also conducted a meta-analysis using public variant data from genotype-phenotype databases to identify additional CTCF variants, which we then curated and annotated.

Results

From this combined approach, we report an additional 86 CTCF variants associated with NDD phenotypes that have not yet been described in the literature. Furthermore, we describe and explain inconsistencies in the quality of reported variants, which impairs the reuse of data for research of NDDs and other pathologies.

Discussion

From this integrated analysis, we provide a comprehensive and annotated catalog of all currently known CTCF mutations associated with NDD phenotypes, to aid diagnostic applications, as well as translational and basic research.
GluN2B-containing NMDARs in the mammalian brain: pharmacology, physiology, and pathology
Authors: Ge Yang , Wang Yu Tian
Published: May 2023

Glutamate N-methyl-D-aspartate receptor (NMDAR) is critical for promoting physiological synaptic plasticity and neuronal viability. As a major subpopulation of the NMDAR, the GluN2B subunit-containing NMDARs have distinct pharmacological properties, physiological functions, and pathological relevance to neurological diseases compared with other NMDAR subtypes. In mature neurons, GluN2B-containing NMDARs are likely expressed as both diheteromeric and triheteromeric receptors, though the functional importance of each subpopulation has yet to be disentangled. Moreover, the C-terminal region of the GluN2B subunit forms structural complexes with multiple intracellular signaling proteins. These protein complexes play critical roles in both activity-dependent synaptic plasticity and neuronal survival and death signaling, thus serving as the molecular substrates underlying multiple physiological functions. Accordingly, dysregulation of GluN2B-containing NMDARs and/or their downstream signaling pathways has been implicated in neurological diseases, and various strategies to reverse these deficits have been investigated. In this article, we provide an overview of GluN2B-containing NMDAR pharmacology and its key physiological functions, highlighting the importance of this receptor subtype during both health and disease states.
Flavonoids improve type 2 diabetes mellitus and its complications: a review
Authors: Yi Xinrui , Dong Mosi , Guo Naifei , Tian Jinlong , Lei Ping , Wang Song , Yang Yufeng , Shi Yan
Published: May 2023

The prevalence of type 2 diabetes mellitus (T2DM) is increasing every year. Medications are currently the most common therapy for T2DM. However, these medications have certain adverse effects. In order to find safe and effective ways to improve this disease, researchers have discovered that some natural products can decrease blood sugar. Flavonoids are one of the most essential low molecular weight phenolic chemicals in the plant world, which widely exist in plant roots, stems, leaves, flowers, and fruits. They possess a variety of biological activities, including organ protection, hypoglycemic, lipid-lowering, anti-oxidative and anti-inflammatory effects. Some natural flavonoids ameliorate T2DM and its complications through anti-oxidation, anti-inflammatory action, glucose and lipid metabolism regulation, insulin resistance management, etc. Hence, this review aims at demonstrating the potential benefits of flavonoids in T2DM and its complications. This laid the foundation for the development of novel hypoglycemic medications from flavonoids.
Low body mass index is associated with diminished plasma cytokines and chemokines in both active and latent tuberculosis
Authors: Kumar Nathella Pavan , Nancy Arul P. , Moideen Kadar , Menon Pradeep A. , Banurekha Vaithilingam V. , Nair Dina , Nott Sujatha , Babu Subash
Published: May 2023

Introduction

Low body mass index (BMI) is a major risk factor for tuberculosis (PTB). Low BMI can impair the immune system and thus might affect TB incidence.

Methods

We examined the plasma levels of Type 1, Type 17, pro-inflammatory, Type 2 and regulatory cytokines and CC and CXC chemokines in PTB and latent TB (LTB) individuals with low BMI (LBMI) or normal BMI (NBMI).

Results

Our data show that PTB is associated with significantly lower levels of IFNγ, TNFα, IL-2, IL-17A, IL-6, IL-12, IL-4 and IL-5 cytokines but significantly higher levels of IL-10, TGFβ and GM-CSF in LBMI compared to NBMI. Similarly, PTB is also associated with significantly lower levels of CCL2, CCL3, CCL11, CXCL1, CXCL9 and CXCL10 chemokines in LBMI compared to NBMI. Our data reveals that LTB is associated with significantly lower levels of IFNγ, TNFα, IL-2, IL1β, IL-12, IL-13 cytokines but significantly higher levels of IL-10, TGFβ, IL-4 and IL-22 in LBMI compared to NBMI. Similarly, LTB is also associated with significantly lower levels of CCL2, CXCL1, CXCL9 and CXCL10 and significantly higher levels of CCL1, CCL3, and CCL4 in LBMI compared to NBMI.

Conclusion

Thus, LBMI has a major impact on the cytokine and chemokine milieu of both PTB and LTB and might predispose to the increased risk of tuberculosis by this immunomodulatory effect.
Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes
Authors: Doddato Gabriella , Valentino Floriana , Giliberti Annarita , Papa Filomena Tiziana , Tita Rossella , Bruno Lucia Pia , Resciniti Sara , Fallerini Chiara , Benetti Elisa , Palmieri Maria , Mencarelli Maria Antonietta , Fabbiani Alessandra , Bruttini Mirella , Orrico Alfredo , Baldassarri Margherita , Fava Francesca , Lopergolo Diego , Lo Rizzo Caterina , Lamacchia Vittoria , Mannucci Sara , Pinto Anna Maria , Currò Aurora , Mancini Virginia ,   Oncologic Multidisciplinary Team, Azienda Ospedaliera Universitaria Senese,   Oncologic Multidisciplinary Team, Azienda Usl Toscana Sud Est, Mari Francesca , Renieri Alessandra , Ariani Francesca
Published: May 2023

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast and ovarian cancer is higher than in the general population. The prevalent pathogenesis is attributable to inactivating variants of the BRCA1-2 highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Exome Sequencing (ES) we analyzed a series of 200 individuals selected for genetic testing in BRCA1-2 genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large BRCA1-2 deletions/duplications. Focusing on BRCA1-2 genes, data analysis identified 11 cases with pathogenic variants (4 in BRCA1 and 7 in BRCA1-2) and 12 with uncertain variants (7 in BRCA1 and 5 in BRCA2). Only one case was found with a large BRCA1 deletion. Exome analysis allowed to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer (ATM, BRIP1, CDH1, PALB2, PTEN, RAD51C, and TP53) (5% diagnostic yield) and 11 in candidate cancer susceptibility genes (DPYD, ERBB3, ERCC2, MUTYH, NQO2, NTHL1, PARK2, RAD54L, and RNASEL). In conclusion, this study allowed a personalized risk assessment and clinical surveillance in an increased number of HBOC families and to broaden the spectrum of causative variants also to candidate “non-canonical” genes.
Clinical utility of geriatric assessment tools in older patients with gastrointestinal cancer
Authors: Doi Ayako , Mizukami Takuro , Takeda Hiroyuki , Umemoto Kumiko , Arai Hiroyuki , Horie Yoshiki , Izawa Naoki , Ogura Takashi , Sunakawa Yu
Published: May 2023

Background

Geriatric 8 (G8) and instrumental activities of daily living (IADL) are recommended to predict overall survival (OS) or risk of serious adverse events (SAEs) in older cancer patients. However, the clinical utility is relatively unknown in older patients suffering malnutrition with gastrointestinal (GI) cancer, including gastric cancer (GC) and pancreatic cancer (PC).

Materials and methods

We retrospectively included patients aged ≥65 years with GC, PC, and colorectal cancer (CRC) who received a G8 questionnaire at first visit from April 2018 to March 2020. The associations between G8/IADL and safety or OS were assessed in patients with advanced/unresectable tumors.

Results

Of 207 patients (median age: 75 years), the median G8 score was 10.5 and normal G8 score rate was 6.8%. Both the median G8 score and normal G8 (>14) score rate numerically increased in the order of GC < PC < CRC. There was no clear association between the G8 standard cutoff value of 14 and SAEs or OS. However, OS was significantly longer in patients with G8 >11 than in those with G8 ≤11 (19.3 vs. 10.5 months, p = 0.0017). Furthermore, OS was significantly better in patients with normal IADL than in those with abnormal IADL (17.6 vs. 11.4 months, p = 0.049).

Conclusion

The G8 cutoff value of 14 would not be clinically useful in patients with GI cancer for predicting OS or SAEs; however, the cutoff value of 11 and IADL may be useful to predict OS for older patients with GI cancers including GC and PC.
Gasless submental-transoral combined approach endoscopic thyroidectomy: a new surgical technique
Authors: Jiang Jinxi , He Gaofei , Chu Junjie , Li Jianbo , Lu Xiaoxiao , Jiang Xianfeng , Xie Lei , Gao Li , Zhang Deguang
Published: May 2023

Background

The development of transoral endoscopic vestibular approach thyroidectomy (TOETVA) has been limited by inherent defects, such as mental nerve injury and carbon dioxide (CO2)-related complications. Herein, we proposed a new technique without CO2 called gasless submental-transoral combined approach endoscopic thyroidectomy (STET) to solve the problems in TOETVA.

Methods

We reviewed 75 patients who successfully underwent gasless STET using novel instruments at our institution from November 2020 to November 2021. A main incision of approximately 2 cm was made in the natural submental crease line and then combined with two vestibule incisions to complete the procedure. Demographic data, surgical technique and perioperative outcomes were retrospectively recorded.

Results

Thirteen male and sixty-two female patients with a mean age of 34.0 ± 8.1 years were enrolled in this study. Sixty-eight patients had papillary thyroid carcinomas and seven had benign nodules. We successfully performed all gasless STET without conversion to open surgery. The average postoperative hospital stay was 4.2 ± 1.8 days. One transient recurrent laryngeal nerve injury and two transient hypoparathyroidisms were observed. Three patients complained of slight lower lip numbness on the first postoperative day. One case of lymphatic fistula, subcutaneous effusion, and incision swelling occurred each, all of which were conservatively cured. One patient developed a recurrence six months after surgery.

Conclusions

Gasless STET using our own designed suspension system is technically safe and feasible with reasonable operative and oncologic results.