bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient and error-free correction of sickle mutation in human erythroid cells using prime editor-2
Authors: George Anila , Ravi Nithin Sam , Prasad Kirti , Panigrahi Lokesh , Koikkara Sanya , Rajendiran Vignesh , Devaraju Nivedhitha , Paul Joshua , Pai Aswin Anand , Nakamura Yukio , Kurita Ryo , Balasubramanian Poonkuzhali , Thangavel Saravanabhavan , Marepally Srujan , Velayudhan Shaji R. , Srivastava Alok , Mohankumar Kumarasamypet M.
Published: December 2022

Sickle cell anaemia (SCA) is one of the common autosomal recessive monogenic disorders, caused by a transverse point mutation (GAG > GTG) at the sixth codon of the beta-globin gene, which results in haemolytic anaemia due to the fragile RBCs. Recent progress in genome editing has gained attention for the therapeutic cure for SCA. Direct correction of SCA mutation by homology-directed repair relies on a double-strand break (DSB) at the target site and carries the risk of generating beta-thalassaemic mutations if the editing is not error-free. On the other hand, base editors cannot correct the pathogenic SCA mutation resulting from A > T base transversion. Prime editor (PE), the recently described CRISPR/Cas 9 based gene editing tool that enables precise gene manipulations without DSB and unintended nucleotide changes, is a viable approach for the treatment of SCA. However, the major limitation with the use of prime editing is the lower efficiency especially in human erythroid cell lines and primary cells. To overcome these limitations, we developed a modular lenti-viral based prime editor system and demonstrated its use for the precise modelling of SCA mutation and its subsequent correction in human erythroid cell lines. We achieved highly efficient installation of SCA mutation (up to 72%) and its subsequent correction in human erythroid cells. For the first time, we demonstrated the functional restoration of adult haemoglobin without any unintended nucleotide changes or indel formations using the PE2 system. We also validated that the off-target effects mediated by the PE2 system is very minimal even with very efficient on-target conversion, making it a safe therapeutic option. Taken together, the modular lenti-viral prime editor system developed in this study not only expands the range of cell lines targetable by prime editor but also improves the efficiency considerably, enabling the use of prime editor for myriad molecular, genetic, and translational studies.
Cancer risks in rheumatoid arthritis patients who received immunosuppressive therapies: Will immunosuppressants work?
Authors: Zhang Yuzhuo , Lin Jiangpeng , You Zhixuan , Tu Hengjia , He Peng , Li Jiarong , Gao Rui , Liu Ziyu , Xi Zhiyuan , Li Zekun , Lu Yi , Hu Qiyuan , Li Chenhui , Ge Fan , Huo Zhenyu , Qiao Guibin
Published: December 2022

Background

Exploring the cancer risks of rheumatoid arthritis (RA) patients with disease-modifying anti-rheumatic drugs (DMARDs) can help detect, evaluate, and treat malignancies at an early stage for these patients. Thus, a comprehensive analysis was conducted to determine the cancer risk of RA patients using different types of DMARDs and analyze their relationship with tumor mutational burdens (TMBs) reflecting immunogenicity.

Methods

A thorough search of PubMed, EMBASE, Web of Science, and Medline was conducted up to 20 August 2022. Standardized incidence ratios (SIRs) were constructed with a random-effect model to determine risks for different types of malignancies in comparison with the general population. We also analyzed the correlation between SIRs and TMBs using linear regression (LR).

Results

From a total of 22 studies, data on 371,311 RA patients receiving different types of DMARDs, 36 kinds of malignancies, and four regions were available. Overall cancer risks were 1.15 (SIR 1.15; 1.09–1.22; p < 0.001) and 0.91 (SIR 0.91; 0.72–1.14; p = 0.402) in RA populations using conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs), respectively. RA patients taking csDMARDs displayed a 1.77-fold lung cancer risk (SIR 1.77; 1.50–2.09; p < 0.001), a 2.15-fold lymphoma risk (SIR 2.15; 1.78–2.59; p < 0.001), and a 1.72-fold melanoma risk (SIR 1.72; 1.26–2.36; p = 0.001). Correlation coefficients between TMBs and SIRs were 0.22 and 0.29 from those taking csDMARDs and bDMARDs, respectively.

Conclusion

We demonstrated a cancer risk spectrum of RA populations using DMARDs. Additionally, TMBs were not associated with elevated cancer risks in RA patients following immunosuppressive therapy, which confirmed that iatrogenic immunosuppression might not increase cancer risks in patients with RA.

Interpretation

Changes were similar in cancer risk after different immunosuppressive treatments, and there was a lack of correlation between SIRs and TMBs. These suggest that we should look for causes of increased risks from the RA disease itself, rather than using different types of DMARDs.
Immune suppression of vaccine-induced CD8+ T-cell responses by gamma retrovirus envelope is mediated by interleukin-10-producing CD4+ T cells
Authors: Podschwadt Philip , Malyshkina Anna , Windmann Sonja , Papadamakis Athanasios , Kerkmann Leonie , Lapuente Dennis , Tenbusch Matthias , Lu Mengji , Schindler Michael , Lang Karl Sebastian , Hansen Wiebke , Bayer Wibke
Published: December 2022

Retroviral envelope (Env) proteins have long been recognized to exhibit immunosuppressive properties, which affect the CD8+ T-cell response to an infection but also to immunization. Interestingly, we previously showed in the Friend murine leukemia virus (F-MuLV) model that the surface Env protein gp70 also plays a role in immunosuppression, in addition to the immunosuppressive function attributed to the transmembrane Env protein. We now demonstrate that immunization with F-MuLV Env leads to a significant increase in interleukin-10 (IL-10)-producing CD4+ T cells and that the induction of CD8+ T-cell responses in the presence of Env is rescued if the capacity of CD4+ T cells to produce IL-10 is abrogated, indicating a mechanistic role of IL-10-producing CD4+ T cells in mediating the Env-induced suppression of CD8+ T-cell responses in Env co-immunization. We found that CD8+ T-cell responses against different immunogens are not all equally affected. On the other hand, suppression of immunity was observed not only in co-immunization experiments but also for immune control of subcutaneous tumor growth after an Env immunization. Finally, we show that suppression of CD8+ T cells by the surface Env protein is observed not only for Friend MuLV Env but also for the Env proteins of other gamma retroviruses. Taken together, our results show that IL-10-producing CD4+ T cells mechanistically underlie the Env-mediated suppression of CD8+ T-cell responses and suggest the presence of an immunosuppressive motif in the surface Env protein of gamma retroviruses.
Immune checkpoint inhibitor induced nephrotoxicity: An ongoing challenge
Authors: Catalano Martina , Roviello Giandomenico , Galli Ilaria Camilla , Santi Raffaella , Nesi Gabriella
Published: December 2022

Although immune checkpoint inhibitors (ICIs) have dramatically revolutionized the field of oncology over the last decade, severe immune-related adverse events (irAEs) are potentially life-threatening. In comparison with toxicities involving the skin, gastrointestinal tract and endocrine system, nephrotoxicity is less common but often underestimated due to difficult diagnosis. Management usually consists of treatment discontinuation and/or corticosteroid use. In this review, we summarize current knowledge of ICI-induced nephrotoxicity, evaluating drawbacks and future perspectives.
Does 18F-FDG PET/CT add value to conventional imaging in clinical assessment of chronic disseminated candidiasis?
Authors: Rammaert Blandine , Maunoury Christophe , Rabeony Tioka , Correas Jean-Michel , Elie Caroline , Alfandari Serge , Berger Pierre , Rubio Marie-Thérèse , Braun Thorsten , Bakouboula Prissile , Candon Sophie , Montravers Françoise , Lortholary Olivier
Published: December 2022

Background

Chronic disseminated candidiasis (CDC) classically occurs after profound and prolonged neutropenia. The aim of the CANHPARI study was to assess the clinical value of adding 18F-fluorodeoxyglucose PET/CT to conventional radiology for initial and subsequent evaluations of CDC.

Materials and methods

A pilot prospective study was conducted in 23 French onco-hematological centers from 2013 to 2017 (NCT01916057). Patients ≥ 18 y.o. suspected for CDC on abdominal conventional imaging (CT or MRI) were included. PET/CT and conventional imaging were performed at baseline and month 3 (M3). Follow-up was assessed until M12. The primary outcome measure was the global response at M3, i.e., apyrexia and complete response to PET/CT. The secondary outcome measure consists in comparison between responses to PET/CT and conventional imaging at diagnosis and M3.

Results

Among 52 included patients, 44 were evaluable (20 probable and 24 possible CDC); 86% had acute leukemia, 55% were male (median age 47 years). At diagnosis, 34% had fever and conventional imaging was always abnormal with microabscesses on liver and spleen in 66%, liver in 25%, spleen in 9%. Baseline PET/CT showed metabolic uptake on liver and/or spleen in 84% but did not match with lesion localizations on conventional imaging in 32%. M3 PET/CT showed no metabolic uptake in 13 (34%) patients, 11 still having pathological conventional imaging. Global response at M3 was observed in eight patients.

Conclusion

Baseline PET/CT does not replace conventional imaging for initial staging of CDC lesions but should be performed after 3 months of antifungal therapy.

Clinical trial registration

[www.clinicaltrials.gov], identifier [NCT01916057].
Renin-angiotensin blocker use is associated with improved cardiovascular mortality in Indian patients with mild-moderate chronic kidney disease—findings from the ICKD study
Authors: Prasad Narayan , Yadav Ashok Kumar , Kundu Monica , Jaryal Ajay , Sircar Dipankar , Modi Gopesh , Sahay Manisha , Gopalakrishnan Natarajan , Vikrant Sanjay , Varughese Santosh , Baid-Agrawal Seema , Singh Shivendra , Gang Sishir , Parameswaran Sreejith , Ghosh Arpita , Kumar Vivek , Jha Vivekanand
Published: December 2022

Introduction

Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are the antihypertensive drug class of choice in patients with chronic kidney disease (CKD). Head-to-head comparisons of the renal or non-renal outcomes between ACEI/ARB users and nonusers have not been conducted in all population groups. We examined the renal and cardiovascular outcomes in users and nonusers enrolled in the Indian Chronic Kidney Disease (ICKD) Study.

Methods

A total of 4,056 patients with mild-moderate CKD were studied. Patients were categorized as ACEI/ARB users or nonusers. Major adverse kidney events [ESKD (end stage kidney disease), ≥50% decline in eGFR and kidney death], all-cause mortality, and cardiovascular mortality were analyzed over a median follow-up period of 2.64 (1.40, 3.89) years between the two groups.

Results

Out of a total of 4,056 patients, 3,487 (87%) were hypertensive. The adjusted sub-hazard ratio (SHR) and 95 % CI for ACEI /ARB users was 0.85 (0.71, 1.02) for MAKE, 0.80 (0.64, 0.99) for a 50% decline in eGFR, and 0.72 (0.58, 0.90) for ESKD. For cardiovascular mortality, ACEI/ARB users were at lower risk (SHR = 0.55, 95% CI: 0.34, 0.88). Diuretic users were at increased risk of all-cause mortality (HR = 1.95, 95% CI: 1.50, 2.53) and cardiovascular mortality (adjusted SHR = 1.73, 95% CI: 1.09, 2.73). There was non-significant association between the use of other antihypertensives and any of the end points.

Discussion

ACEI/ARB use is associated with slower rate of decline in eGFR in those with CKD stage 1-3. ACEI/ARB users had a significantly lower risk of renal outcomes, and cardiovascular mortality.
Long-term peritoneal dialysate exposure modulates expression of membrane complement regulators in human peritoneal mesothelial cells
Authors: Kobayashi Kazuma , Ozeki Toshikazu , Kim Hangsoo , Imai Masaki , Kojima Hiroshi , Iguchi Daiki , Fukui Sosuke , Suzuki Masafumi , Suzuki Yasuhiro , Maruyama Shoichi , Ito Yasuhiko , Mizuno Masashi
Published: December 2022

The membrane complement regulators (CRegs) CD46, CD55, and CD59 are highly expressed on human peritoneal mesothelial cells. However, how mesothelial CRegs change according to the peritoneal dialysis (PD) history of patients has remained unclear. We therefore examined longitudinal changes in CRegs in primary cultured mesothelial cells from PD patients (human peritoneal mesothelial cells; HPMCs) and examined which components of PD fluid (PDF) affect CRegsin vitro. We measured levels of soluble C5b-9 in overnight-dwelling PDF in PD patients and also evaluated changes in CRegs expression on HPMCs collected from PDF using flow cytometry and polymerase chain reaction at a 1-year interval of PD therapy. We also evaluated changes in CReg expressions with stimulation by each component of PDF (glucose, lactic acid and pH) using the Met5A human mesothelial cell line. Levels of sC5b-9 in PDF decreased significantly during 1 year, while expressions of CD46 and CD59 proteins and mRNAs increased significantly in HPMCs during 1 year. Analyzing Met-5A cells, we observed that expressions of the three CRegs were increased by glucose and lactic acid in a concentration-dependent manner, but conversely that expressions of CRegs were decreased by lower pH stimulation. History of PD might influence expression of CRegs by HPMCs through properties of PDF such as glucose, lactic acid, and pH. These results suggest that mesothelial cells may alter expression of CRegs for the purpose of protecting the peritoneum and the presence of PDF might affect peritoneal homeostasis associated with the complement system.
The bacteria of Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) are site-specific and distinct from freshwater environment
Authors: Zhang Xizhao , Ying Congping , Jiang Min , Lin Danqing , You Lei , Yin Denghua , Zhang Jialu , Liu Kai , Xu Pao
Published: December 2022

Bacteria play an essential role in the health of marine mammals, and the bacteria of marine mammals are widely concerned, but less is known about freshwater mammals. In this study, we investigated the bacteria of various body sites of Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) and analyzed their association with freshwater environmental bacteria. The bacterial community and function of Yangtze finless porpoise showed apparent site-specificity. Various body sites have distinct differences in bacteria and have their dominant bacteria. Romboutsia, Plesiomonas, Actinobacillus, Candidatus Arthromitus dominated in the intestine (fecal and rectal samples). Fusobacterium, Streptococcus, and Acinetobacter dominated in the oral. The dominant genera in the blowhole include Suttonella, Psychrobacter, and two uncultured genera. Psychrobacter, Flavobacterium, and Acinetobacter were dominant in the skin. The alpha diversity of intestinal (fecal and rectal) bacteria was the lowest, while that of skin was the highest. The oral and skin bacteria of Yangtze finless porpoise significantly differed between the natural and semi-natural conditions, but no sex difference was observed. A clear boundary was found between the animal and the freshwater environmental bacteria. Even the skin bacteria, which are more affected by the environment, are significantly different from the environmental bacteria and harbor indigenous bacteria. Our results provide a comprehensive preliminary exploration of the bacteria of Yangtze finless porpoise and its association with bacteria in the freshwater environment.
Population dynamics and antimicrobial resistance of Salmonella Derby ST40 from Shenzhen, China
Authors: Luo Miaomiao , She Yiying , Jiang Yixiang , Xie Li , Yang Chao , Qiu Yaqun , Cai Rui , Li Yinghui , Xu Liangcai , Hu Lulu , Wang Lei , Wu Shuang , Chen Qiongcheng , Shi Xiaolu , Jiang Min , Hu Qinghua
Published: December 2022

Salmonella enterica subsp. enterica serovar Derby (S. Derby) is one of the most common serotypes responsible for salmonellosis in humans and animals. The two main sequence types (ST) observed in China are ST40 and ST71, with ST40 presently being the most common in Shenzhen. Recent years have seen an increasing number of cases of salmonella caused by ST40 S. Derby, but the epidemiology is not clear. We gathered 314 ST40 S. Derby isolates from food and patient samples for 11 years in Shenzhen; 76 globally prevalent representative strains were also collected. Whole-genome sequencing (WGS) combined with drug resistance phenotyping was used to examine population structural changes, inter-host associations, drug resistance characteristics, and the food-transmission risks of ST40 S. Derby in Shenzhen over this period. The S. enterica evolutionary tree is divided into five clades, and the strains isolated in Shenzhen were primarily concentrated in Clades 2, 4, and 5, and thus more closely related to strains from Asian (Thailand and Vietnam) than European countries. Our 11-year surveillance of S. Derby in Shenzhen showed that Clades 2, 4, and 5 are now the dominant epidemic branches, and branches 2 and 5 are heavily multi-drug resistant. The main resistance pattern is ampicillin-tetracycline-ciprofloxacin-chloramphenicol-nalidixic acid-streptomycin-sulfamethoxazole/trimethoprim. This may lead to a trend of increasing resistance to ST40 S. Derby in Shenzhen. Using a segmentation of ≤3 SNP among clone clusters, we discovered that Clades 2 and 4 contained multiple clonal clusters of both human- and food-derived strains. The food-derived strains were mainly isolated from pig liver, suggesting this food has a high risk of causing disease outbreaks in Shenzhen.
Construction of a compound microbial agent for biocontrol against Fusarium wilt of banana
Authors: Du Chanjuan , Yang Di , Ye Yunfeng , Pan Lianfu , Zhang Jin , Jiang Shangbo , Fu Gang
Published: December 2022

Banana wilt caused by Fusarium oxysporum f. sp. cubense has devastated a large number of banana plantations worldwide. Biological control is a possible method to conquer this disease. However, the control effect was often low and unstable while a single biocontrol strain had been applied in the field. Therefore, this study aimed to construct an effective compound microbial agent to control Fusarium wilt of banana (FWB) in the field. In addition to it, the compounding strategy of combining single strains for improving the control effect was investigated. Based on the compatibility test, five representative biocontrol strains were selected for the combination of all possible permutations. The pot experiment indicated that every biocontrol strain and their 26 combinations could control FWB to varying degrees. The control effect of combinations on FWB was higher than that of a single strain. In terms of the number of combinatorial biocontrol strains, the control effect of the four-strain combinations was the highest. According to the taxonomic differences of the five biocontrol strains, 26 biocontrol strain combinations could be divided into four groups. Among the strains in the combination, the larger the taxonomic differences the more easily it was to obtain a higher control effect. To obtain stable and efficient combinations, eight combinations were selected out and evaluated for their effectiveness in controlling FWB in different type soil. Compared with the other seven combinations, the four-strain combination T28 (Pt05 + Bc11 + Ba62 + gz-2) got the highest and stablest control effect in the four types of soil in greenhouse. And then the control effect of combination T28 was evaluated in field conditions, compared with commercially agents Bacillus subtilis, Trichoderma harzianum, and carbendazim. After four consecutive applications in the field, the control effect of T28 against FWB was the highest, reaching 57.14%. The results showed that combination T28 had a good application prospect, and the finding provided a reference for the construction of compound microbial agents.
Acute flaccid myelitis a review of the literature
Authors: Dinov Darina , Donowitz Jeffrey R.
Published: December 2022

Acute flaccid myelitis (AFM) is a rare neurological disorder that first rose to national attention in 2014. This neurological disorder has a biennial presentation with every other even year being a peak year. Most patients present in childhood 5 days after a prodromal infection. Patients usually present with muscle weakness and hypo or areflexia in the summer or fall months. Clinical outcomes are variable however most patients do not improve. Currently there are no definitive prognostic factors or etiologies found. However, it is thought that enterovirus-D68 (EV-D68) could be a potential component in the pathobiology of AFM. Treatment options are limited with variable options and no consensus. Supportive therapy has been shown to be the most effective thus far. With our review of the literature, we highlight the recent growing evidence of a possible relationship between EV-D68 and AFM. Additionally, we identify the knowledge gaps in AFM with treatment and prognostic factors.
Heterogeneity evaluation of multi-high b-value apparent diffusion coefficient on cerebral ischemia in MCAO rat
Authors: Shi Liwei , Yu Bo , Chen Qiuyan , Zheng Tianxiu , Xing Peiqiu , Wei Dingtai
Published: December 2022

Purpose

To assess brain damage in a rat model of cerebral ischemia based on apparent diffusion coefficient (ADC) data obtained from multi-high b-values and evaluate the relationship between Aquaporin 4 (AQP4) expression and ADC.

Methods

Thirty eight male Sprague–Dawley rats were randomized into two groups: (1) sham controls (n = 6) and (2) cerebral ischemia (successful model, n = 19). All rats underwent diffusion-weighted imaging (DWI) with both standard b-values and multi-high b-values (2,500–4,500 s/mm2) using a 3.0-T device. Standard ADC (ADCst) maps and multi-high b-value ADCs (ADCmh) were calculated, respectively. Aquaporin 4 expression was quantified using Western blot. Relative values of ADCst and ADCmh, AQP4 expression were compared between the sham group and the ischemia group. Correlations between ADC values and AQP4 expression were evaluated.

Results

At 0.5 h after suture insertion, the value of ADCmh on the lesion was obviously decreased, and there was no difference in lesion volume when compared with ADCst. After reperfusion, besides similar regions where ADCst values decreased, we also found additional large values on ADCmh within the cortex of the ipsilateral side or surrounding the lesion. The lesion evolution of the large value on ADCmh was quite different from other indicators. But the total ADCmh values were still significantly associated with ADCst. The AQP4 protein expression level was appreciably increased after middle cerebral artery occlusion (MCAO), but there was no correlation between AQP4 expression either with ADCmh or ADCst.

Conclusion

We found the large values on ADCmh during the progression of cerebral infarction is varied, but there was no correlation between ADCmh values and AQP4 expression. ADCmh may indicate the heterogeneity of ischemia lesions, but the underlying pathological basis should be further explored.
Applying muscle synergy analysis to forearm high-density electromyography of healthy people
Authors: Geng Yanjuan , Chen Ziyin , Zhao Yang , Cheung Vincent C. K. , Li Guanglin
Published: December 2022

Introduction

Muscle synergy is regarded as a motor control strategy deployed by the central nervous system (CNS). Clarifying the modulation of muscle synergies under different strength training modes is important for the rehabilitation of motor-impaired patients.

Methods

To represent the subtle variation of neuromuscular activities from the smaller forearm muscles during wrist motion, we proposed to apply muscle synergy analysis to preprocessed high-density electromyographic data (HDEMG). Here, modulation of muscle synergies within and across the isometric and isotonic training modes for strengthening muscles across the wrist were investigated. Surface HDEMGs were recorded from healthy subjects (N = 10). Three different HDEMG electrode configurations were used for comparison and validation of the extracted muscle synergies. The cosine of principal angles (CPA) and the Euclidian distance (ED) between synergy vectors were used to evaluate the intra- and inter-mode similarity of muscle synergies. Then, how the activation coefficients modulate the excitation of specific synergy under each mode was examined by pattern recognition. Next, for a closer look at the mode-specific synergies and the synergies shared by the two training modes, k-means clustering was applied.

Results

We observed high similarity of muscle synergies across different tasks within each training mode, but decreased similarity of muscle synergies across different training modes. Both intra- and intermode similarity of muscle synergies were consistently robust to electrode configurations regardless of the similarity metric used.

Discussion

Overall, our findings suggest that applying muscle synergy analysis to HDEMG is feasible, and that the traditional muscle synergies defined by whole-muscle components may be broadened to include sub-muscle components represented by the HDEMG channels. This work may lead to an appropriate neuromuscular analysis method for motor function evaluation in clinical settings and provide valuable insights for the prescription of rehabilitation training therapies.
The adverse impact of a gain in chromosome 1q on the prognosis of multiple myeloma treated with bortezomib-based regimens: A retrospective single-center study in China
Authors: Chen Qingxiao , Han Xiaoyan , Zheng Gaofeng , Yang Yang , Li Yi , Zhang Enfan , Yang Li , Dong Mengmeng , He Donghua , He Jingsong , Cai Zhen
Published: December 2022

Background

Multiple myeloma is genetically heterogeneous, and chromosome abnormalities play a pivotal role in prognosis. A gain in chromosome 1q (+1q) is among the most common cytogenetic abnormalities; however, its relationship with overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma is still unclear. We aim to clarify the impact of +1q on the clinical characteristics and survival outcomes of patients treated with bortezomib-based combination regimes.

Materials and methods

We retrospectively analyzed 258 patients first diagnosed with myeloma who underwent bortezomib-based therapy at the bone marrow transplantation department of a multiple myeloma treatment center in the first affiliated hospital of Zhejiang University, China.

Results

We identified 258 newly diagnosed patients with multiple myeloma in our department from July 2013 to September 2018. We observed that 127 (49.2%) of the patients acquired +1q at diagnosis, and +1q strongly correlated with the occurrence of del(13q) and IgH rearrangement (P < 0.001). In the patients with +1q, the PFS was 22.2 months (95% CI 15.8–28.5 months), and the three-year and five-year PFS was 35.1% and 15.3%, respectively. Univariate analysis revealed that albumin, lactate dehydrogenase (LDH), and the percentage of plasma cells significantly affected PFS. Multivariate analysis showed that LDH and the percentage of plasma cells significantly affected PFS in the +1q patients. In terms of OS, the median OS for the +1q patients was 47.4 months (95% CI 34.7–59.5), while the OS of the non-+1q patients was not reached (P = 0.048). The univariate and multivariate analyses revealed that age, platelet count, and extramedullary lesions were significant adverse factors for OS in the +1q patients. There were no statistical differences between PFS and OS when there were other chromosomal abnormalities, but there was a decreased tendency in PFS. LDH and +1q also had a synergistic adverse effect on survival.

Conclusion

+1q is associated with a higher tumor burden and correlated with the occurrence of del(13q) and IgH rearrangement at diagnosis. In the era of novel agents, +1q still significantly affects PFS and OS.
Classification and challenges in the histopathological diagnosis of peripheral T-cell lymphomas, emphasis on the WHO-HAEM5 updates
Authors: Murga-Zamalloa Carlos , Inamdar Kedar
Published: December 2022

Mature T-cell lymphomas represent neoplastic expansions of T-cell lymphocytes with a post-thymic derivation. Most of these tumors feature aggressive clinical behavior and challenging histopathological diagnosis and classification. Novel findings in the genomic landscape of T-cell lymphomas are helping to improve the understanding of the biology and the molecular mechanisms that underly its clinical behavior. The most recent WHO-HAEM5 classification of hematolymphoid tumors introduced novel molecular and histopathological findings that will aid in the diagnostic classification of this group of neoplasms. The current review article summarizes the most relevant diagnostic features of peripheral T-cell lymphomas with an emphasis on the updates that are incorporated at the WHO-HAEM5.
Single-cell profiling reveals that SAA1+ epithelial cells promote distant metastasis of esophageal squamous cell carcinoma
Authors: Shu Zhao , Guo Junfeng , Xue Qian , Tang Qi , Zhang Bingqiang
Published: December 2022

Introduction

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers globally, with significant cell heterogeneity and poor prognosis. Distant metastasis in ESCC is one of the key factors that affects the prognosis of patients.

Methods and results

Starting with the analysis of ESCC single-cell sequencing data, we constructed a single-cell atlas of ESCC in detail and clarified the cell heterogeneity within tumor tissues. Through analysis of epithelial-mesenchymal transition (EMT) levels, gene expression, and pathway activation, we revealed the existence of a novel subpopulation of SAA1+ malignant cells in ESCC that are highly aggressive and closely associated with distant metastasis of ESCC. In vitro wound healing and transwell assays confirmed a strong invasion capacity of ESCC tumor cells with high expression of SAA1. Then, we constructed an effective and reliable prediction model based on the gene expression pattern of SAA1+ malignant cell subpopulations and confirmed that patients in the high-risk group had significantly worse prognosis than those in the low-risk group in the training cohort, internal verification cohort and external verification cohort.

Discussion

This manuscript contributes to exploration of the heterogeneity of ESCC tumor tissues and the search for new ESCC subpopulations with special biological functions. These results contribute to our understanding of the underlying mechanisms of distant metastasis of ESCC and thus provide a theoretical basis for improved therapies.
Risk factors to identify the indication for regional nodal irradiation in T1-2N1M0 breast cancer: A joint analysis of 4,243 real-world cases from two institutions
Authors: Sun Guang-Yi , Wen Ge , Zhang Yu-Jing , Tang Yu , Jing Hao , Fang Hui , Wang Jian-Yang , Zhang Jiang-Hu , Zhao Xu-Ran , Chen Si-Ye , Song Yong-Wen , Jin Jing , Liu Yue-Ping , Tang Yuan , Qi Shu-Nan , Li Ning , Chen Bo , Lu Ning-Ning , Li Ye-Xiong , Wang Shu-Lian
Published: December 2022

Purpose

The aim of this study is to evaluate the role of regional nodal irradiation (RNI) in patients with T1-2N1M0 breast cancer and to identify the subgroup that could benefit from RNI.

Methods and materials

A total of 4,243 women with pT1-2N1M0 breast cancer treated at two institutions in China were retrospectively reviewed. Survival rates were calculated by the Kaplan–Meier method and compared by the log-rank test. The association of risk factors with survival outcomes was evaluated using multivariable proportional hazards regression.

Results

A total of 932 patients (22.0%) received RNI. At a median follow-up of 5.9 years, the 5-year locoregional recurrence (LRR), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS) rates were 4.0% and 7.2% (P = 0.001), 13.2% and 10.6% (P = 0.465), 85.0% and 84.7% (P = 0.131), and 93.9% and 92.8% (P = 0.004) in the RNI and non-RNI groups, respectively. Multivariate analysis revealed that RNI was an independent prognostic factor for lower LRR (P = 0.001) and longer DFS (P = 0.013). Patients were stratified into low-, intermediate-, and high-risk groups based on the eight non-therapeutic risk factors. RNI significantly decreased the 5-year LRR (2.2% vs. 7.0%, P = 0.001) and improved the 5-year DFS (88.8% vs. 84.9%, P = 0.015) and OS (95.8% vs. 93.9%, P = 0.010) in the intermediate-risk group. However, neither the low-risk group nor the high-risk group had survival benefit from RNI.

Conclusion

T1-2N1M0 breast cancer is a heterogeneous disease. We found that RNI only improved survival in the intermediate-risk group. It might be omitted in low-risk patients, and the role of RNI in high-risk patients needs further study.
The effects of football practice on children's fundamental movement skills: A systematic review and meta-analysis
Authors: Mao Xiaojin , Zhang Jingyue , Li Yulian , Cao Yuang , Ding Meng , Li Weidong , Fan Lixia
Published: December 2022

The purpose of this systematic review and meta-analysis was to explore the effects of different soccer practices on fundamental movement skills (FMS) of children of different ages and genders, in order to help children to improve their fundamental movement skills through soccer practice more effectively. The databases of CNKI, Wanfang database, Pubmed, Web of science and Cochrane library were searched to collect relevant studies on the effects of soccer practices on FMS, and the quality of the included studies was evaluated by using the Cochrane Risk of Bias Tool, and Meta-analysis was conducted by Review Manager 5.4 software. 16 studies were finally included, with a total of 3,121 subjects were included. The results showed that soccer had a positive effect on linear sprint ability [SMD 95% CI = −0.37 (−0.61, −0.14), P = 0.002], horizontal jump [SMD 95% CI = 0.22 (−0.34, 0.77), P = 0.003], object control [SMD 95% CI = 1.32 (0.8, 1.85), P = 0.0003], Closed-eye single-leg test [SMD 95% CI = 0.87(0.48,1.25), P < 0.0001],while countermovement jump [SMD 95% CI = 0.50(−0.35,1.35), P = 0.25] and flamingo balance [SMD 95% CI = −0.16(−0.31,−0.02), P = 0.03] had a less significant effect. Meanwhile, the effect of the practice was mainly influenced by the total duration of the intervention, age and gender of the intervention subjects, in which the total intervention time longer than 1,800 min promoted linear sprint ability, horizontal jump and flamingo balance test better than those below 1,800 min; the promotion effect of linear sprint ability and horizontal jump was better in children aged 7–9 years than 10–13 years, while Children aged 10–13 years showed better improvement in Closed-eye single-leg test after the intervention than 7–9 years; Girls were better promoted in linear sprint ability and Closed-eye single-leg test, but the horizontal jump is better for boys to improve the effect. It is recommended that the effects of different soccer practice contents on fundamental movement skills can be further explored in the future to improve the relevance and efficiency of fundamental movement skill development for children.
Mechanisms of manganese-induced neurotoxicity and the pursuit of neurotherapeutic strategies
Authors: Pajarillo Edward , Nyarko-Danquah Ivan , Digman Alexis , Multani Harpreet Kaur , Kim Sanghoon , Gaspard Patric , Aschner Michael , Lee Eunsook
Published: December 2022

Chronic exposure to elevated levels of manganese via occupational or environmental settings causes a neurological disorder known as manganism, resembling the symptoms of Parkinson’s disease, such as motor deficits and cognitive impairment. Numerous studies have been conducted to characterize manganese’s neurotoxicity mechanisms in search of effective therapeutics, including natural and synthetic compounds to treat manganese toxicity. Several potential molecular targets of manganese toxicity at the epigenetic and transcriptional levels have been identified recently, which may contribute to develop more precise and effective gene therapies. This review updates findings on manganese-induced neurotoxicity mechanisms on intracellular insults such as oxidative stress, inflammation, excitotoxicity, and mitophagy, as well as transcriptional dysregulations involving Yin Yang 1, RE1-silencing transcription factor, transcription factor EB, and nuclear factor erythroid 2-related factor 2 that could be targets of manganese neurotoxicity therapies. This review also features intracellular proteins such as PTEN-inducible kinase 1, parkin, sirtuins, leucine-rich repeat kinase 2, and α-synuclein, which are associated with manganese-induced dysregulation of autophagy/mitophagy. In addition, newer therapeutic approaches to treat manganese’s neurotoxicity including natural and synthetic compounds modulating excitotoxicity, autophagy, and mitophagy, were reviewed. Taken together, in-depth mechanistic knowledge accompanied by advances in gene and drug delivery strategies will make significant progress in the development of reliable therapeutic interventions against manganese-induced neurotoxicity.
WSVAS: A YOLOv4 -based phenotyping platform for automatically detecting the salt tolerance of wheat based on seed germination vigour
Authors: Fu Xiuqing , Han Bing , Liu Shouyang , Zhou Jiayi , Zhang Hongwen , Wang Hongbiao , Zhang Hui , Ouyang Zhiqian
Published: December 2022

Salt stress is one of the major environmental stress factors that affect and limit wheat production worldwide. Therefore, properly evaluating wheat genotypes during the germination stage could be one of the effective ways to improve yield. Currently, phenotypic identification platforms are widely used in the seed breeding process, which can improve the speed of detection compared with traditional methods. We developed the Wheat Seed Vigour Assessment System (WSVAS), which enables rapid and accurate detection of wheat seed germination using the lightweight convolutional neural network YOLOv4. The WSVAS system can automatically acquire, process and analyse image data of wheat varieties to evaluate the response of wheat seeds to salt stress under controlled environments. The WSVAS image acquisition system was set up to continuously acquire images of seeds of four wheat varieties under three types of salt stress. In this paper, we verified the accuracy of WSVAS by comparing manual scoring. The cumulative germination curves of wheat seeds of four genotypes under three salt stresses were also investigated. In this study, we compared three models, VGG16 + Faster R-CNN, ResNet50 + Faster R-CNN and YOLOv4. We found that YOLOv4 was the best model for wheat seed germination target detection, and the results showed that the model achieved an average detection accuracy (mAP) of 97.59%, a recall rate (Recall) of 97.35% and the detection speed was up to 6.82 FPS. This proved that the model could effectively detect the number of germinating seeds in wheat. In addition, the germination rate and germination index of the two indicators were highly correlated with germination vigour, indicating significant differences in salt tolerance amongst wheat varieties. WSVAS can quantify plant stress caused by salt stress and provides a powerful tool for salt-tolerant wheat breeding.
Exogenous application of stress-related signaling molecules affect growth and cannabinoid accumulation in medical cannabis (Cannabis sativa L.)
Authors: Garrido José , Rico Saleta , Corral Carolina , Sánchez Conchi , Vidal Nieves , Martínez-Quesada Juan José , Ferreiro-Vera Carlos
Published: December 2022

Medical cannabis (Cannabis sativa L.) is a source of bioactive phytochemicals with promising pharmacological and therapeutic applications. Enhancing the accumulation of valuable bioactive compounds is potentially a way of increasing the economic importance of this crop. Signaling molecules like salicylic acid (SA), jasmonic acid (JA), and γ-aminobutyric acid (GABA) are involved in the regulation of plant development and responses to biotic and abiotic stresses. Moreover, several phytohormones regulate plant trichome formation and elicit the synthesis of secondary metabolites in many plant species in both in vitro and in vivo systems. Therefore, exogenously delivered plant signaling molecules have the potential to modify the chemical profiles of medical cannabis. In this study, we found that the foliar application of SA, methyl jasmonate (MeJA), and GABA produces changes in the accumulation of the two major cannabinoids, cannabidiolic acid (CBDA) and Δ9- tetrahydrocannabinolic acid (THCA), in leaves and inflorescences of a medical cannabis variety. MeJA at 0.1 mM increased the CBDA content in inflorescences by 15.6%, while SA and MeJA at 0.1 mM increased CBDA and THCA accumulation in leaves by up to 57.3%. Treatments did not change the expression of genes participating in the final steps of the biosynthetic pathway of cannabinoids: olivetolic acid cyclase (CsOAC-1 and CsOAC-2), 2-acylphloroglucinol 4-prenyltransferase (CsPT4), cannabidiolic acid synthase (CsCBDAS), and tetrahydrocannabinolic acid synthase (CsTHCAS). Trichome density was not significantly different from the control plants in any treatment. Besides, we found strong correlations between several plant growth parameters and cannabinoid yields, showing a direct link between plant fitness and the production of cannabinoids.
9-cis-epoxycarotenoid dioxygenase 1 confers heat stress tolerance in rice seedling plants
Authors: Zhang Yijin , Liu Xiong , Su Rui , Xiao Yunhua , Deng Huabing , Lu Xuedan , Wang Feng , Chen Guihua , Tang Wenbang , Zhang Guilian
Published: December 2022

High temperature is one of the main constraints affecting plant growth and development. It has been reported that abscisic acid (ABA) synthesis gene 9-cis-epoxycarotenoid dioxygenase (NCED) positively regulates plant resistance to salt, cold, and drought stresses. However, little is known about the function of the NCED gene in heat tolerance of rice. Here, we found that OsNCED1 was a heat stress inducible gene. Rice seedlings overexpressing OsNCED1 showed enhanced heat tolerance with more abundant ABA content, whereas the knockout mutant osnced1 accumulated less ABA and showed more sensitive to heat stress. Under heat stress, increased expression of OsNCED1 could reduce membrane damage and reactive oxygen species (ROS) level of plants, and elevate the activity of antioxidant enzymes. Moreover, real time-quantitative PCR (RT-qPCR) analysis showed that overexpression of OsNCED1 significantly activated the expression of genes involved in antioxidant enzymes, ABA signaling pathway, heat response, and defense. Together, our results indicate that OsNCED1 positively regulates heat tolerance of rice seedling by raising endogenous ABA contents, which leads to the improved antioxidant capacity and activated expression of heat and ABA related genes.
Influence of incentive mechanism and fit degree on user’s environmental behavior—Taking Alipay “Ant Forest” in China as an example
Authors: Xiong Na , Ren Ping , Sun Bingteng , He Surong , Jiang Linli , Cui Haitao
Published: December 2022

How to use game elements to motivate users and influence their behavior has become a new research trend, which is vital for enhancing the willingness of potential platform users to participate in environmental protection. This paper aims to analyze the influence of incentive mechanism and fit degree on user’s environmental behavior based on the stimulus-organism-response theory and self-determination theory. The questionnaire data of 500 users was collected and the impact of incentives on user’s environmental behavior was analyzed by structural equation modeling. The results show that economic, value, and social incentives have a significant impact on user’s environmental behavior. Besides, the value and social incentives of “Ant Forest” game platform positively influence user fit (conscious participation, enthusiasm, and platform interaction), but the impact of economic incentive on platform interaction is not statistically significant. From the perspective of user fit, “Ant Forest” game platform can positively promote users to adopt environmental behavior, because it explores users’ needs from their perspective to give full play to the role of game incentives on users' environmental behavior. Additionally, this research provides the practical implications for managers exploring the effects of co-creation processes in developing countries and regions.
Effectiveness of road safety prevention in schools
Authors: von Beesten Silke , Bresges André
Published: December 2022

The World Health Organization estimates that each year, 1.3 million people are killed and more than 50 million people worldwide are injured in road traffic accidents. According to a study conducted by the Allianz Center for Technology, more young people between the ages of 15 and 29 die in traffic accidents than as a result of illness, drugs, suicide, violence, or war events worldwide. That is about 400,000 per year, globally. Worldwide traffic accident prevention campaigns demonstrate the consequences of traffic accidents in an emotionalizing way in order to encourage drivers to adopt conscious safety behaviorviaadequate driving behavior. The consequences of traffic accidents are demonstrated by prevention campaigns often in an emotionalizing way to encourage drivers to adopt safety measurements through adequate driving behavior. Prior research suggests that the emotionalizing effect of the appeals must be accompanied by solution- as well as action-oriented and self-confidence-increasing measures, so that the instructive message is reinforced and does not lead to reactance. Thus, a strong need arose in the schools for a targeted training as the follow-up of emotional prevention campaigns. A suitable training for knowledge acquisition and knowledge transfer into everyday life was developed by means of the design-based research method. To create the targeted follow-up, various methods from cognitive behavioral therapy and common traffic safety programs were adapted. This publication is dedicated to a first explorative research approach in a non-standardized form of a social training. It approaches the question of negative emotional states immediately after aCrash Kurs NRWstage event, which is a prevention program in Germany that targets upper middle school and high school courses and originates from North Rhine-Westphalia. Changes in social behavior and development of participants' own norms, values, and attitudes were observed and documented and are discussed and presented in this article. The result of the survey confirmed prior research and showed visible effects of reactance after the Crash Curs NRW campaign. It was found that a structured follow-up training is suitable to gain reactive behavior from the stage event. Knowledge deficits about the cause and outcome of accidents were successfully addressed in the follow-up. This may have influence the reactance behavior and could be a key factor for successful prevention campaigns. Further publications will observe the connection between knowledge and reactance in subsequent iterative passes of modified follow-ups for the Crash Course NRW Campaign.