bluuebunny/crossref_metadata_2025 huggingface dataset:
Heart failure and late-onset Alzheimer’s disease: A Mendelian randomization study
Authors: Arega Yibeltal , Shao Yongzhao
Published: November 2022

Some observational studies suggested that heart failure (HF) is associated with increased risk of late-onset Alzheimer’s disease (AD). On the other hand, a recently published Two-Sample Mendelian Randomization (2SMR) study was reported as inconclusive but the estimated odds ratios (ORs) were less than one indicating a potential causal association between genetically predicted HF and lowered risk of AD. Both HF and AD are quite common among elderly persons and frequently occur together resulting in a series of severe medical challenges and increased financial burden on healthcare. It is of great medical and financial interest to further investigate the statistical significance of the potential causal associations between genetically predicted HF and lowered risk of AD using large independent cohorts. To fill this important knowledge gap, the present study used the 2SMR method based on summary data from a recently published large genome-wide association study (GWAS) for AD on subjects with European ancestry. The 2SMR analysis provided statistically significant evidence of an association with ORs less than one between genetically predicted HF and late-onset AD (Inverse Variance Weighted, OR = 0.752, p = 0.004; MR Egger, OR = 0.546, p = 0.100; Weighted Median, OR = 0.757, p = 0.014). Further investigations of the significant associations between HF and late-onset AD, including specific genes related to the potential protective effect of HF-related medications on cognitive decline, are warranted.
Exploring the causal relationship between gastroesophageal reflux and oral lesions: A mendelian randomization study
Authors: Shu Linjing , Tong Xu
Published: November 2022

Background: Clinical observations and retrospective studies have observed that patients with gastroesophageal reflux disease (GERD) have an increased probability of dental erosion, periodontitis and oral mucosal lesions and other common oral lesions. However, whether there is a genetic causal relationship between GERD and the occurrence of oral lesions has not been reported.

Methods: In this study, we extracted instrumental variables from the largest published summary statistics of the oral lesion phenotype GWAS in UK Biobank (UKBB) and GERD GWAS. Then, we performed a causal inference analysis between GERD and common oral lesions by mendelian randomization (MR) analysis with the R package “TwoSampleMR”.

Results: We observed a significant causal relationship between GERD and several common oral lesion phenotypes (painful gums, loose teeth, toothache, and mouth ulcers). GERD showed a positive correlation with the occurrence of these oral lesions. After removing outlier SNPs via the MR-PRESSO package, our conclusions were still robust.

Conclusion: Our findings provide the first evidence for a genetic causal effect of GERD on oral lesion pathogenesis. For patients with confirmed GERD, attention should be paid to taking interventions to prevent the occurrence of oral lesions.
Decreased absolute number of peripheral regulatory T cells in patients with idiopathic retroperitoneal fibrosis
Authors: Liu Lu , Yan Huanhuan , Wang Yanyan , Xie Yuhuan , Jiang Lei , Zhao Jinfang , Gao Chong , Li Xiaofeng , Wang Caihong
Published: November 2022

Objective

In order to determine whether the immune balance of T helper 17(Th17)/regulatory T(Treg) is related to the pathogenesis of idiopathic retroperitoneal fibrosis (IRPF), we analyzed the differences in peripheral blood lymphocytes, CD4+T cell subsets and cytokines between patients with IRPF and healthy people to clarify the CD4+T cell subsets, especially Treg cell subsets, and the role of cytokines in the pathogenesis of IRPF.

Methods

This study included 22 patients with IRPF, 36 patients with IgG4-related diseases (IgG4-RD) without retroperitoneal fibrosis (RPF), and 28 healthy controls. The absolute numbers and percentage of peripheral blood lymphocyte subsets and CD4+T cell subsets in each group were detected by flow cytometry, and the serum cytokine level was detected by flow cytometric bead array (CBA).

Results

Compared with the healthy group, the absolute value of B cells in peripheral blood of IRPF patients was significantly decreased, and T, natural killer (NK), CD4+ and CD8+ were not significantly abnormal. The absolute numbers of Th2 cells were lower than healthy group(p=0.043). In particular, the absolute numbers of Treg cells were significantly lower than healthy group(p<0.001), while the absolute numbers of Th17 cells increased(p=0.682). Th17/Treg was significantly higher than healthy group (p< 0.001). Cytokine analysis showed that the level of interleukin (IL)-4 in IRPF patients was higher than healthy group(p=0.011), IL-6, IL-10, IL-17, TNF-α and IFN-γ were significantly higher than healthy group (all p<0.001). Receiver operating characteristic (ROC) curves showed that IL-10 and TNF-α could distinguish bilateral ureteral dilatation in IRPF patients, with areas under the ROC curve (AUCs) of 0.813 (95% CI:0.607-1.000, p=0.026) and 0.950 (95% CI:0.856-1.000, p=0.001), respectively. IL-6 could distinguish bilateral ureteral obstruction, with an AUC of 0.861 (95% CI: 0.682-1.000, p=0.015).

Conclusions

Our study showed that IRPF patients had reduced Treg cells and indeed had Th17/Treg imbalance, which may be related to the pathogenesis of the disease. The levels of IL-6, IL-10 and TNF-α appear to be associated with the progression of IRPF.
Case report: CD38-directed CAR-T cell therapy: A novel immunotherapy targeting CD38- positive blasts overcomes TKI and chemotherapy resistance of myeloid chronic myeloid leukemia in blastic phase
Authors: Cui Qingya , Liang Peiqi , Dai Haiping , Cui Wei , Cai Mengjie , Ding Zixuan , Ma Qinfen , Yin Jia , Li Zheng , Liu Sining , Kang Liqing , Yao Li , Cen Jiannong , Shen Hongjie , Zhu Mingqing , Yu Lei , Wu Depei , Tang Xiaowen
Published: November 2022

Resistance to tyrosine kinase inhibitor (TKI) is a tough problem in the treatment of chronic myeloid leukemia in blastic phase (CML-BP), which was often associated with acquired mutations in the kinase domain and not eliminating the leukemic stem cells. The efficacy of TKI or combination with chemotherapy in CML-BP remains unsatisfactory. Chimeric antigen receptor T (CAR-T) cell immunotherapy may overcome TKI and chemotherapy resistance. However, lack of ideal targetable antigens is a major obstacle for treating patients with myeloid malignancies. CD38 is known to be expressed on most (acute myeloid leukemia) AML cells, and its lack of expression on hematopoietic stem cells renders it as a potential therapeutic target for myeloid CML-BP. We develop a CD38-directed CAR-T cell therapy for AML, and two patients with myeloid CML-BP were enrolled (NCT04351022). Two patients, harboring E255K and T315I mutation in the ABL kinase domain, respectively, were resistant to multiple TKIs (imatinib, dasatinib, nilotinib, and ponatinib) and intensive chemotherapy. The blasts in the bone marrow of two patients exhibited high expression of CD38. After tumor reduction chemotherapy and lymphodepletion chemotherapy, 1 × 107 CAR-T-38 cells per kilogram of body weight were administered. They achieved minimal residual disease–negative and BCR::ABL1-negative complete remission and experienced grade II cytokine release syndrome manifesting as fever. Our data highlighted that CAR-T-38 cell therapy may overcome TKI and chemotherapy resistance in patients with myeloid CML-BP.
Dysregulated inflammasome activity in intestinal inflammation – Insights from patients with very early onset IBD
Authors: Illig David , Kotlarz Daniel
Published: November 2022

Inflammatory bowel disease (IBD) is a multifactorial disorder triggered by imbalances of the microbiome and immune dysregulations in genetically susceptible individuals. Several mouse and human studies have demonstrated that multimeric inflammasomes are critical regulators of host defense and gut homeostasis by modulating immune responses to pathogen- or damage-associated molecular patterns. In the context of IBD, excessive production of pro-inflammatory Interleukin-1β has been detected in patient-derived intestinal tissues and correlated with the disease severity or failure to respond to anti-tumor necrosis factor therapy. Correspondingly, genome-wide association studies have suggested that single nucleotide polymorphisms in inflammasome components might be associated with risk of IBD development. The relevance of inflammasomes in controlling human intestinal homeostasis has been further exemplified by the discovery of very early onset IBD (VEO-IBD) patients with monogenic defects affecting different molecules in the complex regulatory network of inflammasome activity. This review provides an overview of known causative monogenic entities of VEO-IBD associated with altered inflammasome activity. A better understanding of the molecular mechanisms controlling inflammasomes in monogenic VEO-IBD may open novel therapeutic avenues for rare and common inflammatory diseases.
Prognosis stratification in breast cancer and characterization of immunosuppressive microenvironment through a pyrimidine metabolism-related signature
Authors: Luo Yongzhou , Tian Wenwen , Lu Xiuqing , Zhang Chao , Xie Jindong , Deng Xinpei , Xie Yi , Yang Shuhui , Du Wei , He Rongfang , Wei Weidong
Published: November 2022

Pyrimidine metabolism is a hallmark of cancer and will soon become an essential part of cancer therapy. In the tumor microenvironment, cells reprogram pyrimidine metabolism intrinsically and extracellularly, thereby promoting tumorigenesis. Metabolites in pyrimidine metabolism have a significant impact on promoting cancer advancement and modulating immune system responses. In preclinical studies and practical clinical applications, critical targets in pyrimidine metabolism are acted upon by drugs to exert promising therapeutic effects on tumors. However, the pyrimidine metabolism in breast cancer (BC) is still largely underexplored. In this study, 163 credible pyrimidine metabolism-related genes (PMGs) were retrieved, and their somatic mutations and expression levels were determined. In addition, by using The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases, 12 PMGs related to the overall survival (OS) were determined using the univariate Cox regression analysis. Subsequently, by performing the LASSO Cox hazards regression analysis in the 12 PMGs in TCGA-BRCA dataset, we developed a prognosis nomogram using eight OS-related PMGs and then verified the same in the METABRIC, GSE96058, GSE20685, GSE42568 and GSE86166 data. Moreover, we validated relationships between the pyrimidine metabolism index (PMI) and the survival probability of patients, essential clinical parameters, including the TNM stage and the PAM50 subtypes. Next, we verified the predictive capability of the optimum model, including the signature, the PAM50 subtype, and age, using ROC analysis and calibration curve, and compared it with other single clinical factors for the predictive power of benefit using decision curve analysis. Finally, we investigated the potential effects of pyrimidine metabolism on immune checkpoints, tumor-infiltrating immune cells, and cytokine levels and determined the potential implications of pyrimidine metabolism in BC immunotherapy. In conclusion, our findings suggest that pyrimidine metabolism has underlying prognostic significance in BC and can facilitate a new management approach for patients with different prognoses and more precise immunotherapy.
Combined proteomics and single cell RNA-sequencing analysis to identify biomarkers of disease diagnosis and disease exacerbation for systemic lupus erythematosus
Authors: Li Yixi , Ma Chiyu , Liao Shengyou , Qi Suwen , Meng Shuhui , Cai Wanxia , Dai Weier , Cao Rui , Dong Xiangnan , Krämer Bernhard K. , Yun Chen , Hocher Berthold , Hong Xiaoping , Liu Dongzhou , Tang Donge , He Jingquan , Yin Lianghong , Dai Yong
Published: November 2022

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease for which there is no cure. Effective diagnosis and precise assessment of disease exacerbation remains a major challenge.

Methods

We performed peripheral blood mononuclear cell (PBMC) proteomics of a discovery cohort, including patients with active SLE and inactive SLE, patients with rheumatoid arthritis (RA), and healthy controls (HC). Then, we performed a machine learning pipeline to identify biomarker combinations. The biomarker combinations were further validated using enzyme-linked immunosorbent assays (ELISAs) in another cohort. Single-cell RNA sequencing (scRNA-seq) data from active SLE, inactive SLE, and HC PBMC samples further elucidated the potential immune cellular sources of each of these PBMC biomarkers.

Results

Screening of the PBMC proteome identified 1023, 168, and 124 proteins that were significantly different between SLE vs. HC, SLE vs. RA, and active SLE vs. inactive SLE, respectively. The machine learning pipeline identified two biomarker combinations that accurately distinguished patients with SLE from controls and discriminated between active and inactive SLE. The validated results of ELISAs for two biomarker combinations were in line with the discovery cohort results. Among them, the six-protein combination (IFIT3, MX1, TOMM40, STAT1, STAT2, and OAS3) exhibited good performance for SLE disease diagnosis, with AUC of 0.723 and 0.815 for distinguishing SLE from HC and RA, respectively. Nine-protein combination (PHACTR2, GOT2, L-selectin, CMC4, MAP2K1, CMPK2, ECPAS, SRA1, and STAT2) showed a robust performance in assessing disease exacerbation (AUC=0.990). Further, the potential immune cellular sources of nine PBMC biomarkers, which had the consistent changes with the proteomics data, were elucidated by PBMC scRNAseq.

Discussion

Unbiased proteomic quantification and experimental validation of PBMC samples from two cohorts of patients with SLE were identified as biomarker combinations for diagnosis and activity monitoring. Furthermore, the immune cell subtype origin of the biomarkers in the transcript expression level was determined using PBMC scRNAseq. These findings present valuable PBMC biomarkers associated with SLE and may reveal potential therapeutic targets.
Unexpected ocular morphological changes after corneal refractive surgery: A review
Authors: De Bernardo Maddalena , Pagliarulo Sergio , Rosa Nicola
Published: November 2022

Corneal refractive surgery (CRS) currently is widely used to correct refractive errors because of its efficacy and reliability. Several studies dealt with the corneal modification induced by this type of surgery, but it is still debated if CRS can induce unexpected changes namely anterior chamber depth (ACD) and axial length (AL). A literature review was performed, including all articles regarding CRS and eye-variations from 1999 to December 2021. Excluding articles about specific systemic conditions (e.g., pregnancy), pathological conditions, post-surgical complications or about only corneal flattening and thinning post CRS, we found nine studies that met the search criteria. We divided the found articles according to the type of surgery performed (radial keratotomy, PRK/LASEK, lasik) and analyzed the results about ACD and AL. Finally, according to the literature, we can conclude that CRS not only gives a corneal flattening, thinning and biomechanical changes, but also induces AL and ACD decrease. This makes the AL and ACD measurements obtained before CRS uselessness in case of IOL power calculation.
Circulating tissue inhibitor of metalloproteinases 1 (TIMP-1) at COVID-19 onset predicts severity status
Authors: Brusa Stefano , Terracciano Daniela , Bruzzese Dario , Fiorenza Mariano , Stanziola Lucia , Pinchera Biagio , Valente Valeria , Gentile Ivan , Cittadini Antonio , Mormile Ilaria , Mormile Mauro , Portella Giuseppe
Published: November 2022

Background

Systemic biomarkers for severity of SARS-CoV-2 infection are of great interest. In this study, we evaluated a set of collagen metabolites and extracellular matrix remodeling biomarkers including procollagen type III amino terminal propeptide (PIIINP), tissue inhibitor of metalloproteinases 1 (TIMP-1) and hyaluronic acid (HA) as prognostic indicators in COVID-19 patients.

Methods

Ninety COVID-19 patients with the absence of chronic liver diseases were enrolled. Serum PIIINP, TIMP-1, and HA were measured and correlated with inflammatory indices and clinical variables. Patients were stratified for disease severity according to WHO criteria in two groups, based on the requirement of oxygen support.

Results

Serum TIMP-1, but not PIIINP and HA was significantly higher in patients with WHO score ≥5 compared to patients with WHO score <5 [PIIINP: 7.2 (5.4–9.5) vs. 7.1 (4.5–9.9), p = 0.782; TIMP-1: 298.1 (20.5–460) vs. 222.2 (28.5–452.8), p = 0.01; HA: 117.1 (55.4–193.7) vs. 75.1 (36.9–141.8), p = 0.258]. TIMP-1 showed moderate correlation with CRP (r = 0.312, p = 0.003) and with LDH (r = 0.263, p = 0.009). CRP and serum LDH levels were significantly higher in COVID-19 patients with WHO score ≥5 compared to the group of patients with WHO score < 5 [15.8 (9–44.5) vs. 9.3 (3.4–33.8), p = 0.039 and 373 (282–465) vs. 289 (218–383), p = 0.013, respectively].

Conclusion

In patients with COVID-19, circulating TIMP-1 was associated with disease severity and with systemic inflammatory index, suggesting that TIMP-1 could represent a promising non-invasive prognostic biomarker in COVID-19 patients. Interestingly, our results prompted that serum TIMP-1 level may potentially be used to select the patients for therapeutic approaches targeting matrix metalloproteases pathway.
Comprehensive assessment of age-specific mortality rate and its incremental changes using a composite measure: A sub-national analysis of rural Indian women
Authors: Sharma Divya , Kiran Tanvi , Goel Kapil , Junaid K. P. , Rajagopal Vineeth , Gupta Madhu , Kaundal Himika , Sharma Saraswati , Bahl Ankit
Published: November 2022

Background

Diverse socio-economic and cultural issues contribute to adverse health outcomes and increased mortality rates among rural Indian women across different age categories. The present study aims to comprehensively assess age-specific mortality rates (ASMR) and their temporal trends using a composite measure at the sub-national level for rural Indian females to capture cross-state differences.

Materials and methods

A total of 19 states were included in the study to construct a composite age-specific mortality index for 2011 (base year) and 2018 (reference year) and examine the incremental changes in the index values across these years at the sub-national level in India. Sub-index values were calculated for each component age group and were subsequently used to compute the composite ASMR index using the geometric mean method. Based on the incremental changes, the performance of states was categorized into four different typologies.

Results

Improvement in mortality index scores in the 0–4 years age group was documented for all states. The mortality rates for the 60+ age group were recorded to be high for all states. Kerala emerged as the overall top performer in terms of mortality index scores, while Bihar and Jharkhand were at the bottom of the mortality index table. The overall mortality composite score has shown minor improvement from base year to reference year at all India level.

Conclusion

An overall reduction in the mortality rates of rural Indian women has been observed over the years in India. However, in states like Bihar and Jharkhand, mortality is high and has considerable scope for improvement. The success of public health interventions to reduce the under-five mortality rate is evident as the female rural mortality rates have reduced sizably for all states. Nevertheless, there is still sizable scope for reducing mortality rates for other component age groups. Additionally, there is a need to divert attention toward the female geriatric (60+ years) population as the mortality rates are still high.
Endoscopic therapy of anastomotic diverticulum combined with stercorolith incarceration: A case report
Authors: Liu Yi , Chen Zhihao , Dou Lizhou , Liu Siyao , Zhang Yueming , Liu Yong , Wang Guiqi
Published: November 2022

Diverticulosis is a commonly acquired disease of the lower gastrointestinal tract, which may be associated with significant morbidity and adverse effects on quality of life. Although several national guidelines focused on the treatment of diverticulosis, multiple controversies remained regarding the disease management of diverticulosis. For some controversial issues, such as the role of antibiotics in mild diverticulitis, when and how to operate on patients with acute diverticulitis, there is no conclusion yet. To our knowledge, this is the first report of endoscopic therapy for anastomotic diverticulitis caused by stercorolith incarceration. In the current case, a 49-year-old woman complained of recurrent subumbilical pain without obvious inducement for half a year. Colonoscopy showed anastomotic diverticulum combined with stercorolith incarceration. After local inflammation relieved by conservative treatment, the patients received endoscopic mucosal incision and lithotomy. Then the diverticulum was closed with titanium clips. The abdominal pain of patient was completely relieved, and the reexamination of colonoscopy showed that the wound healed well after 1 year of follow-up. This case suggests that for anastomotic diverticulitis caused by stercorolith incarceration, endoscopic therapy can remove the stimulation factors better and avoid the recurrence and progression of the disease compared with conservative treatment. Moreover, endoscopic therapy achieves the maximum in minimally invasive surgery and reduces complications and surgical costs compared with radical surgery.
Changes in soil properties and the phoD-harboring bacteria of the alfalfa field in response to phosphite treatment
Authors: Li Zhenyi , Wang Jixiang , Wu Yao , Hu Jingyun , Cong Lili , Yang Chao , Fu Jinmin , Sun Juan
Published: November 2022

Phosphite, a reduced form of orthophosphate, is characterized by high solubility, and transportation efficiency and can be used as potential phosphorus fertilizer, plant biostimulant and supplemental fertilizer in agriculture. However, the effects of phosphite fertilizer on soil properties and microorganisms are poorly understood. This study evaluated the effects of phosphate and phosphite fertilizers on the different forms of phosphorus, alkaline phosphatase (ALP) activity, and phoD-harboring bacterial community in the alfalfa (Medicago sativa) field. The study used four concentrations (30, 60, 90, and 120 mg P2O5 kg−1 soil) of phosphate (KH2PO4) and phosphite (KH2PO3) fertilizers for the alfalfa field treatment. The results showed that both phosphite and phosphate fertilizers increased the total phosphorus (TP) and available phosphorus (AP) contents in the soil. The phosphorus content of the phosphite-treated soil was lower than that of the phosphate-treated one. TP, inorganic phosphate (Pi), and AP negatively regulated ALP activity, which decreased with increasing phosphate and phosphite fertilizers concentrations. Furthermore, high-throughput sequencing analysis identified 6 phyla and 29 families, which were classified from the altered operational taxonomic units (OTUs) of the soil samples. The redundancy analysis (RDA) revealed that pH, TP, AP and Pi were significantly related to the phoD-harboring bacterial community constructure. The different fertilizer treatments altered the key families, contributing to soil ALP activities. Frankiaceae, Sphingomonadaceae, and Rhizobiaceae positively correlated with ALP activity in phosphite-treated soil. Moreover, the structural equation model (SEM) revealed that ALP activity was affected by the phoD-harboring bacterial community through altered organic phosphorus (Po), AP, total nitrogen (TN), soil organic carbon (SOC), and pH levels under phosphate fertilizer treatment. However, the effect was achieved through positive regulation of pH and AP under phosphite fertilizer. Thus, the changes in soil properties and phoD-harboring bacteria in response to phosphate and phosphite treatments differed in the alfalfa field. This study is the first to report the effects of phosphite on the soil properties of an alfalfa field and provides a strong basis for phosphite utilization in the future.

Highlights

– Phosphite and phosphate increase the total phosphorus and available phosphorus.

– The pH was the dominant factor influencing the phoD-harboring bacterial community under phosphite fertilizer.

– The response of soil properties and phoD-harboring bacterial community to phosphate and phosphite fertilizers differed in the alfalfa field.
Application of microalgae Chlamydomonas applanata M9V and Chlorella vulgaris S3 for wheat growth promotion and as urea alternatives
Authors: Sido Mekiso Yohannes , Tian Yinping , Wang Xiaogai , Wang Xinzhen
Published: November 2022

Excessive use of chemical fertilizers to meet the global food demand has caused extensive environmental pollution. Microalgae can be used to enhance agricultural crop production as a potentially sustainable and eco-friendly alternative. In this study, Chlamydomonas applanata M9V and Chlorella vulgaris S3 were isolated from the soil and mass-cultured for use as microalgal fertilizers. The influence of microalgae M9V and S3 on the growth of wheat (Triticum aestivum L.) and soil properties was evaluated and compared with that of chemical urea fertilizer. A pot experiment was conducted with six treatments, i.e., living M9V (M9VL), dead M9V (M9VD), living S3 (S3L), dead S3 (S3D), urea fertilizer (urea), and control without fertilizer (control). M9VL was found to have the best effect on wheat growth promotion, followed by M9VD and S3D. In addition, M9VL resulted in the highest enhancement of shoot fresh weight (166.67 and 125.68%), root dry weight (188.89 and 77.35%), leaf length (26.88 and 14.56%), root length (46.04 and 43.93%), chlorophyll a (257.81 and 82.23%), and chlorophyll b contents (269.00 and 247.27%) comparing to the control and urea treatments, respectively. Moreover, all microalgal fertilizer treatments increased soil organic matter (SOM) by 1.77–23.10%, total carbon (TC) by 7.14–14.46%, and C:N ratio by 2.99–11.73% compared to the control and urea treatments. Overall, this study provided two microalgae strains, M9V and S3, that could promote wheat growth and improve soil properties, thus highlighting the use of microalgae as biofertilizers to reduce the use of chemical fertilizers and promoting sustainable agricultural production.
Oxidative stress strongly restricts the effect of codon choice on the efficiency of protein synthesis in Escherichia coli
Authors: Leiva Lorenzo Eugenio , Elgamal Sara , Leidel Sebastian A. , Orellana Omar , Ibba Michael , Katz Assaf
Published: November 2022

Introduction

The response of enterobacteria to oxidative stress is usually considered to be regulated by transcription factors such as OxyR and SoxR. Nevertheless, several reports have shown that under oxidative stress the levels, modification and aminoacylation of tRNAs may be altered suggesting a role of codon bias in regulation of gene expression under this condition.

Methods

In order to characterize the effects of oxidative stress on translation elongation we constructed a library of 61 plasmids, each coding for the green fluorescent protein (GFP) translationally fused to a different set of four identical codons.

Results

Using these reporters, we observed that GFP production levels vary widely (~15 fold) when Escherichia coli K-12 is cultured in minimal media as a consequence of codon choice variations. When bacteria are cultured under oxidative stress caused by paraquat the levels of GFP produced by most clones is reduced and, in contrast to control conditions, the range of GFP levels is restricted to a ~2 fold range. Restricting elongation of particular sequences does not increase the range of GFP production under oxidative stress, but altering translation initiation rates leads to an increase in this range.

Discussion

Altogether, our results suggest that under normal conditions the speed of translation elongation is in the range of the speed of initiation and, consequently, codon choice impacts the speed of protein synthesis. In contrast, under oxidative stress translation initiation becomes much slower than elongation, limiting the speed of translation such that codon choice has at most only subtle effects on the overall output of translation.
Unveiling chlorpyrifos mineralizing and tomato plant-growth activities of Enterobacter sp. strain HSTU-ASh6 using biochemical tests, field experiments, genomics, and in silico analyses
Authors: Haque Md. Azizul , Hossain Md. Shohorab , Ahmad Iqrar , Akbor Md. Ahedul , Rahman Aminur , Manir Md. Serajum , Patel Harun M. , Cho Kye Man
Published: November 2022

The chlorpyrifos-mineralizing rice root endophyteEnterobactersp. HSTU-ASh6 strain was identified, which enormously enhanced the growth of tomato plant under epiphytic conditions. The strain solubilizes phosphate and grew in nitrogen-free Jensen’s medium. It secreted indole acetic acid (IAA; 4.8 mg/mL) and ACC deaminase (0.0076 μg/mL/h) and hydrolyzed chlorpyrifos phosphodiester bonds into 3,5,6-trichloro-2-pyridinol and diethyl methyl-monophosphate, which was confirmed by Gas Chromatography – Tandem Mass Spectrometry (GC–MS/MS) analysis.In vitroandin silico(ANI, DDH, housekeeping genes and whole genome phylogenetic tree, and genome comparison) analyses confirmed that the strain belonged to a new species ofEnterobacter. The annotated genome of strain HSTU-ASh6 revealed a sets of nitrogen-fixing, siderophore,acdS, and IAA producing, stress tolerance, phosphate metabolizing, and pesticide-degrading genes. The 3D structure of 28 potential model proteins that can degrade pesticides was validated, and virtual screening using 105 different pesticides revealed that the proteins exhibit strong catalytic interaction with organophosphorus pesticides. Selected docked complexes such as α/β hydrolase–crotoxyphos, carboxylesterase–coumaphos, α/β hydrolase–cypermethrin, α/β hydrolase–diazinon, and amidohydrolase–chlorpyrifos meet their catalytic triads in visualization, which showed stability in molecular dynamics simulation up to 100 ns. The foliar application ofEnterobactersp. strain HSTU-ASh6 on tomato plants significantly improved their growth and development at vegetative and reproductive stages in fields, resulting in fresh weight and dry weight was 1.8–2.0-fold and 1.3–1.6-fold higher in where urea application was cut by 70%, respectively. Therefore, the newly discovered chlorpyrifos-degrading speciesEnterobactersp. HSTU-ASh6 could be used as a smart biofertilizer component for sustainable tomato cultivation.
Advanced assessment through intact glycopeptide analysis of Infliximab’s biologics and biosimilar
Authors: Kim Hyejin , Bang Geul , Park Ye Eun , Park Moonhee , Choi Jung Hoon , Oh Myung Jin , An Hyun Joo , Yoo Jong Shin , Park Youngja Hwang , Kim Jin Young , Hwang Heeyoun
Published: November 2022

Characterization of therapeutic monoclonal antibodies (mAbs) represents a major challenge for analytical sciences due to their heterogeneity associated with post-translational modifications (PTMs). The protein glycosylation requires comprehensive identification, which could influence on the mAbs’ structure and their function. Here, we demonstrated high-resolution tandem mass spectrometry with an ultra-high-performance liquid chromatography for characterization and comparison between biologics and biosimilar of infliximab at an advanced level. Comparing the N- and O-glycopeptides profiles, a total of 49 and 54 glycopeptides was identified for each product of the biologics and biosimilar, respectively. We also discovered one novel N-glycosylation site at the light chain from both biopharmaceuticals and one novel O-glycopeptide at the heavy chain from only biosimilar. Site-specific glycopeptide analysis process will be a robust and useful technique for evaluating therapeutic mAbs and complex glycoprotein products.
Machine learning in renal pathology
Authors: Basso Matthew Nicholas , Barua Moumita , Meyer Julien , John Rohan , Khademi April
Published: November 2022

Introduction

When assessing kidney biopsies, pathologists use light microscopy, immunofluorescence, and electron microscopy to describe and diagnose glomerular lesions and diseases. These methods can be laborious, costly, fraught with inter-observer variability, and can have delays in turn-around time. Thus, computational approaches can be designed as screening and/or diagnostic tools, potentially relieving pathologist time, healthcare resources, while also having the ability to identify novel biomarkers, including subvisual features.

Methods

Here, we implement our recently published biomarker feature extraction (BFE) model along with 3 pre-trained deep learning models (VGG16, VGG19, and InceptionV3) to diagnose 3 glomerular diseases using PAS-stained digital pathology images alone. The BFE model extracts a panel of 233 explainable features related to underlying pathology, which are subsequently narrowed down to 10 morphological and microstructural texture features for classification with a linear discriminant analysis machine learning classifier. 45 patient renal biopsies (371 glomeruli) from minimal change disease (MCD), membranous nephropathy (MN), and thin-basement membrane nephropathy (TBMN) were split into training/validation and held out sets. For the 3 deep learningmodels, data augmentation and Grad-CAM were used for better performance and interpretability.

Results

The BFE model showed glomerular validation accuracy of 67.6% and testing accuracy of 76.8%. All deep learning approaches had higher validation accuracies (most for VGG16 at 78.5%) but lower testing accuracies. The highest testing accuracy at the glomerular level was VGG16 at 71.9%, while at the patient-level was InceptionV3 at 73.3%.

Discussion

The results highlight the potential of both traditional machine learning and deep learning-based approaches for kidney biopsy evaluation.
Case report: Successful simultaneous heart-kidney transplantation across a positive complement-dependent cytotoxic crossmatch
Authors: Yamamoto Takayuki , Pearson Daniel S. , Ababneh Emad I. , Harris Cynthia , Nissaisorakarn Pitchaphon , Mahowald Grace K. , Heher Yael K. , Elias Nahel , Markmann James F. , Lewis Gregory D. , Riella Leonardo V.
Published: November 2022

Preformed donor-specific antibodies are associated with a higher risk of rejection and worse graft survival in organ transplantation. However, in heart transplantation, the risk and benefit balance between high mortality on the waiting list and graft survival may allow the acceptance of higher immunologic risk donors in broadly sensitized recipients. Transplanting donor-recipient pairs with a positive complement dependent cytotoxic (CDC) crossmatch carries the highest risk of hyperacute rejection and immediate graft loss and is usually avoided in kidney transplantation. Herein we report the first successful simultaneous heart-kidney transplant with a T- and B-cell CDC crossmatch positive donor using a combination of rituximab, intravenous immunoglobulin, plasmapheresis, bortezomib and rabbit anti-thymocyte globulin induction followed by eculizumab therapy for two months post-transplant. In the year following transplantation, both allografts maintained stable graft function (all echocardiographic left ventricular ejection fractions ≥ 65%, eGFR>60) and showed no histologic evidence of antibody-mediated rejection. In addition, the patient has not developed any severe infections including cytomegalovirus or BK virus infection. In conclusion, a multitarget immunosuppressive regimen can allow for combined heart/kidney transplantation across positive CDC crossmatches without evidence of antibody-mediated rejection or significant infection. Longer follow-up will be needed to further support this conclusion.
The diagnostic value of the ocular tilt reaction plus head tilt subjective visual vertical (±45°) in patients with acute central vascular vertigo
Authors: Feng Yufei , Zhao Tongtong , Wu Yuexia , Ling Xia , Zhang Menglu , Song Ning , Kim Ji-Soo , Yang Xu
Published: November 2022

Objectives

To investigate the localization diagnostic value of the ocular tilt reaction (OTR) plus head tilt subjective visual vertical (SVV) in patients with acute central vascular vertigo (ACVV).

Methods

We enrolled 40 patients with acute infarction, 20 with unilateral brainstem infarction (BI) and 20 with unilateral cerebellar infarction (CI). We also included 20 patients with unilateral peripheral vestibular disorders (UPVD) as the control group. The participants completed the OTR and SVV during head tilt (±45°) within 1 week of symptom onset.

Results

In patients with ACVV, including that caused by lateral medullary infarction (100%, 2/2), partial pontine infarction (21%, 3/14), and cerebellum infarction (35%, 7/20), we observed ipsiversive OTR, similar to that seen in UPVD patients (80.0%, 16/20). Some of the patients with medial medullary infarction (50%, 1/2), partial pons infarction (42%, 6/14), midbrain infarction (100%, 2/2), and partial cerebellum infarction (30.0%, 6/20) showed contraversive OTR. The skew deviation (SD) of the BI group with ACVV was significantly greater than that of the UPVD group (6.60 ± 2.70° vs. 1.80 ± 1.30°, Z = −2.50, P = 0.012), such that the mean SD of the patients with a pons infarction was 9.50° and that of patients with medulla infarction was 5.00°. In ACVV patients with no cerebellar damage, the area under the curve of the receiver operating characteristic curve corresponding to the use of SD to predict brainstem damage was 0.92 (95%CI: 0.73–1.00), with a sensitivity of 100% and a specificity of 80% when SD ≥ 3°. We found no statistical difference in SD between the UPVD and CI groups (1.33 ± 0.58° vs. 1.80 ± 1.30°, Z = −0.344, P = 0.73). Compared with the UPVD patients, the ACVV patients with a partial pons infarction (43%, 6/14, χ2 = 13.68, P = 0.002) or medulla infarction (25%, 1/4, χ2 = 4.94, P = 0.103) exhibited signs of the ipsiversive E-effect with the contraversive A-effect, while those with a partial medulla infarction (50%, 2/4), pons infarction (43%, 6/14), or cerebellar infarction (60%, 12/20) exhibited a pathological symmetrical increase in the E-effect.

Conclusions

The evaluation of OTR plus head tilt SVV (±45°) in vertigo patients is helpful for identifying and diagnosing ACVV, especially when SD is ≥ 3° or the E-effect is symmetrically increased.
Visual disorders and driving ability in persons with dementia: A mini review
Authors: Papageorgiou Eleni , Tsirelis Daniil , Lazari Katerina , Siokas Vasileios , Dardiotis Efthimios , Tsironi Evangelia E.
Published: November 2022

Background

Impaired driving ability in patients with Alzheimer’s disease (AD) is associated with a decline in cognitive processes and a deterioration of their basic sensory visual functions. Although a variety of ocular abnormalities have been described in patients with AD, little is known about the impact of those visual disorders on their driving performance.

Aim

Aim of this mini-review is to provide an update on the driving ability of patients with dementia and summarize the primary visual disorders affecting their driving behavior.

Methods

Databases were screened for studies investigating dementia, associated visual abnormalities and driving ability.

Results

There is consistent evidence that dementia affects driving ability. Patients with dementia present with a variety of visual disorders, such as visual acuity reduction, visual field defects, impaired contrast sensitivity, decline in color vision and age-related pathological changes, that may have a negative impact on their driving ability. However, there is a paucity in studies describing the impact of oculovisual decline on the driving ability of AD subjects. A bidirectional association between cognitive and visual impairment (VI) has been described.

Conclusion

Given the bidirectional association between VI and dementia, vision screening and cognitive assessment of the older driver should aim to identify at-risk individuals and employ timely strategies for treatment of both cognitive and ocular problems. Future studies should characterize the basic visual sensory status of AD patients participating in driving studies, and investigate the impact of vision abnormalities on their driving performance.
Quantitative magnetic resonance spectroscopy of depression: The value of short-term metabolite changes in predicting treatment response
Authors: Wang Ranchao , Shen Yu , Li Guohai , Du Rui , Peng Aiqin
Published: November 2022

Background

Although various prediction models of the antidepressant response have been established, the results have not been effectively applied to heterogeneous depression populations, which has seriously limited their clinical value. This study tried to build a more specific and stable model to predict treatment response in depression based on short-term changes in hippocampal metabolites.

Materials and methods

Seventy-four major depressive disorder (MDD) patients and 20 healthy controls in the test set were prospectively collected and retrospectively analyzed. Subjects underwent magnetic resonance spectroscopy (MRS) once a week during 6 weeks of treatment. Hippocampal regions of interest (ROIs) were extracted by using a voxel iteration scheme combined with standard brain templates. The short-term differences in hippocampal metabolites between and within groups were screened. Then, the association between hippocampal metabolite changes and clinical response was analyzed, and a prediction model based on logistic regression was constructed. In addition, a validation set (n = 60) was collected from another medical center to validate the predictive abilities.

Results

After 2–3 weeks of antidepressant treatment, the differences in indicators (tChowee0–2, tChowee0–3 and NAA week0–3) were successfully screened. Then, the predictive abilities of these three indicators were revealed in the logistic regression model, and the optimal prediction effect was found in d(tCho)week0–3-d(NAA)week0–3 (AUC = 0.841, 95%CI = 0.736-0.946). In addition, their predictive abilities were further confirmed with the validation set.

Limitations

The small sample size and the need for multiple follow-ups limited the statistical ability to detect other findings.

Conclusion

The predictive model in this study presented accurate prediction and strong verification effects, which may provide early guidance for adjusting the treatment regimens of depression and serve as a checkpoint at which the eventual treatment outcome can be predicted.
Modulation of cerebral cortex activity by acupuncture in patients with prolonged disorder of consciousness: An fNIRS study
Authors: Liu Yiwei , Sun Ning , Xiong Jing , Zhou Yuanfang , Ye Xiangyin , Jiang Hua , Guo Hua , Zhi Na , Lu Jingkang , He Peijue , Yang Huilin , Li Qingbin , Sun Ruirui , He Jing
Published: November 2022

Background and objective

Acupuncture is a promising non-pharmacological therapy for patients with prolonged disorder of consciousness (PDOC); however, its underlying mechanism remains uncertain. This study aimed to reveal the modulatory effects of acupuncture on the cerebral cortex activity among patients with PDOC.

Materials and methods

Twenty-eight PDOC patients were randomly assigned to the treatment (n = 14) or control (n = 14) group. The treatment group received one session of acupuncture, while the control group received one session of sham acupuncture. All patients underwent evaluation of the functional connectivity and activation response of the dorsolateral prefrontal cortex (DLPFC), primary motor cortex (M1), and primary somatosensory cortex (S1) via functional near-infrared spectroscopy. We further explored the potential correlation of the consciousness level and activation response/functional connectivity with acupuncture.

Results

Compared to the control group, a single session of acupuncture significantly tended to enhance resting-state functional connectivity (rsFC) in DLPFC-M1, DLPFC-M1, and S1-S1. And the activation level of the DLPFC (both sides) in the acupuncture group is significantly higher than those in sham acupuncture group. However, no significant correlation was found between the consciousness level and activation response/functional connectivity.

Conclusion

One session of acupuncture has a significant modulation of rsFC and activation in the DLPFC, M1, and S1 with PDOC patients. Acupuncture-evoked effect may have some functional significance in PDOC patients. This is an important step toward exploring the acupuncture effects on PDOC patients.
Dynamic changes in fractional amplitude of low-frequency fluctuations in patients with chronic insomnia
Authors: Chen Wei , Wang Hui , Sun Tianze , Wu Qi , Han Wenxuan , Li Qian , Liu Yong , Zhou Yuanping , He Xiuyong
Published: November 2022

Background

Previous neuroimaging studies have mostly focused on changes in static functional connectivity in patients with chronic insomnia (CI). Features of dynamic brain activity in patients with CI have rarely been described in detail. The present study investigated changes in dynamic intrinsic brain activity in patients with CI by dynamic fractional amplitude of low-frequency fluctuation (dfALFF) analysis.

Materials and methods

A total of 30 patients with CI and 27 healthy controls (HCs) were enrolled. We compared dfALFF between these two groups, and examined the correlation between changes in dfALFF and clinical symptoms of CI. Multivariate pattern analysis was performed to differentiate patients with CI from HCs.

Results

Compared with HC subjects, patients with CI showed significantly increased dfALFF in the left insula, right superior temporal gyrus, left parahippocampal gyrus, right amygdala, and bilateral posterior lobes of the cerebellum. Moreover, dfALFF values in the left insula and left parahippocampal gyrus showed a positive correlation with Pittsburgh Sleep Quality Index scores. A logistic regression model was constructed that had 96.7% sensitivity, 80.0% specificity, and 83.0% overall accuracy for distinguishing patients with CI from HCs.

Conclusion

Dynamic local brain activity showed increased instability in patients with CI. The variability in dfALFF in the limbic system and brain areas related to sleep/wakefulness was associated with insomnia symptoms. These findings may provide insight into the neuropathologic basis of CI.