bluuebunny/crossref_metadata_2025 huggingface dataset:
Menstrual Cycle in Trauma-Related Disorders: A Mini-Review
Authors: Mu Eveline , Thomas Elizabeth H. X. , Kulkarni Jayashri
Published: May 2022

Fluctuations of sex hormones across the menstrual cycle have been linked to exacerbation of symptoms of psychiatric disorders. Women diagnosed with trauma-related disorders such as post-traumatic stress disorder (PTSD) and borderline personality disorder (BPD) have reported worsening of mood symptoms at various phases of their menstrual cycle. There is also considerable overlap between PTSD, BPD, and complex-PTSD (cPTSD) symptoms, suggesting similar biological underpinnings. This mini-review examines the influence of sex hormones and the menstrual cycle on PTSD, BPD, and cPTSD symptoms, and discusses the involvement of the hypothalamic-pituitary-adrenal (HPA) axis. We review literature showing that PTSD and BPD symptoms fluctuate with the menstrual cycle, though the effect of the menstrual cycle phase appears to be inconsistent, warranting future research. Based on the reported phasic vulnerability in individuals with PTSD and BPD, it is plausible to assume that women diagnosed with the newly introduced cPTSD may experience similar difficulties. However, no study to date has addressed this. This review highlights the importance of considering an individual's trauma history as it may influence symptom severity and diagnosis, and the phase of the menstrual cycle at the time of diagnosis. This review also highlights that additional work is needed to clarify the influence of estradiol and progesterone fluctuations on trauma-related symptoms, especially in cPTSD. Continued research on menstrual cycle vulnerability and trauma will lead to better informed management and treatment of PTSD, BPD, and cPTSD.
Heterogeneity of ILC2s in the Intestine; Homeostasis and Pathology
Authors: Sunaga Shogo , Tsunoda Junya , Teratani Toshiaki , Mikami Yohei , Kanai Takanori
Published: May 2022

Group 2 innate lymphoid cells (ILC2s) were identified in 2010 as a novel lymphocyte subset lacking antigen receptors, such as T-cell or B-cell receptors. ILC2s induce local immune responses characterized by producing type 2 cytokines and play essential roles for maintaining tissue homeostasis. ILC2s are distributed across various organs, including the intestine where immune cells are continuously exposed to external antigens. Followed by luminal antigen stimulation, intestinal epithelial cells produce alarmins, such as IL-25, IL-33, and thymic stromal lymphopoietin, and activate ILC2s to expand and produce cytokines. In the context of parasite infection, the tuft cell lining in the epithelium has been revealed as a dominant source of intestinal IL-25 and possesses the capability to regulate ILC2 homeostasis. Neuronal systems also regulate ILC2s through neuropeptides and neurotransmitters, and interact with ILC2s bidirectionally, a process termed “neuro-immune crosstalk”. Activated ILC2s produce type 2 cytokines, which contribute to epithelial barrier function, clearance of luminal antigens and tissue repair, while ILC2s are also involved in chronic inflammation and tissue fibrosis. Recent studies have shed light on the contribution of ILC2s to inflammatory bowel diseases, mainly comprising ulcerative colitis and Crohn’s disease, as defined by chronic immune activation and inflammation. Modern single-cell analysis techniques provide a tissue-specific picture of ILC2s and their roles in regulating homeostasis in each organ. Particularly, single-cell analysis helps our understanding of the uniqueness and commonness of ILC2s across tissues and opens the novel research area of ILC2 heterogeneity. ILC2s are classified into different phenotypes depending on tissue and phase of inflammation, mainly inflammatory and natural ILC2 cells. ILC2s can also switch phenotype to ILC1- or ILC3-like subsets. Hence, recent studies have revealed the heterogeneity and plasticity of ILC2, which indicate dynamicity of inflammation and the immune system. In this review, we describe the regulatory mechanisms, function, and pathological roles of ILC2s in the intestine.
A Predictive Role of Autoantibodies Against the Epitope aa168–183 of ENO1 in the Occurrence of Miscarriage Related to Thyroid Autoimmunity
Authors: He Xiaoqing , Liu Yifu , Wang Haoyu , Sun Wei , Lu Yihan , Shan Zhongyan , Teng Weiping , Li Jing
Published: May 2022

Objective

The aim of the research is to study the association between the serum levels of autoantibodies against one important epitope (168FMILPVGAANFREAMR183, designated as P6) of α-enolase (ENO1-P6Abs) and miscarriage among euthyroid females with thyroid autoimmunity (TAI).

Methods

Anti-ENO1-P6 total IgG was investigated in 432 euthyroid women, and its four subclasses were analyzed in 184 euthyroid women. The serum FT4, TSH, TgAb, and TPOAb levels were determined using an electrochemiluminescence immunoassay. The serum ENO1-P6Ab and anti-protein disulfide isomerase A3 autoantibody (PDIA3Ab) levels were determined using an enzyme-linked immunosorbent assay.

Results

The serum levels of anti-ENO1-P6 total IgG, IgG2, IgG3, and IgG4 were significantly higher in euthyroid TAI females than in non-TAI controls. Additionally, anti-ENO1-P6 total IgG and its 4 subtypes were all markedly higher in euthyroid TAI females with pregnancy loss than those without miscarriage. Moreover, logistic regression analysis showed that highly expressed anti-ENO1-P6 total IgG, IgG1, IgG2, and IgG3 subtypes in the serum were all independent risk factors for euthyroid TAI-related miscarriage, and its IgG1 was also for non-TAI-related abortion. According to the trend test, the prevalence of miscarriage was increased in a titer-dependent manner with the raised levels of serum anti-ENO1-P6 total IgG and IgG1, IgG2, and IgG3 subtypes among euthyroid TAI females. The receiver operating characteristic curve analysis of anti-ENO1-P6 total IgG and IgG1, IgG2, and IgG3 subclass expressions in the serum for miscarriage prediction in euthyroid TAI females exhibited that the total areas under the curves were 0.773 ± 0.041, 0.761 ± 0.053, 0.827 ± 0.043, and 0.760 ± 0.050, respectively (all P <0.0001). Their corresponding optimal cut-off OD450 values were 0.68 (total IgG), 0.26 (IgG1), 0.97 (IgG2), and 0.48 (IgG3), with sensitivities of 70.8, 87.5, 83.3, and 85.4%, and specificities of 70.8, 59.1, 77.3, and 56.8%, respectively. There was an additive interaction between serum anti-ENO1-P6 and anti-PDIA3 total IgGs on the development of miscarriage (RERI = 23.6, AP = 0.79, SI = 5.37).

Conclusion

The highly expressed ENO1-P6Abs may be important risk factors for euthyroid TAI-related miscarriage. The serum levels of ENO1-P6Abs may become good predictive markers for pregnancy loss in euthyroid TAI females, especially its IgG2 subclass expression.
Inflammasomes and Pyroptosis of Liver Cells in Liver Fibrosis
Authors: Gan Can , Cai Qiuyu , Tang Chengwei , Gao Jinhang
Published: May 2022

Inflammasomes are multiprotein complexes that can sense danger signals and activate caspase-1 to mediate pro-inflammatory cytokines release and pyroptotic cell death. There are two main canonical and non-canonical signaling pathways that trigger inflammasome activation. Inflammasomes are expressed and assembled in parenchymal and nonparenchymal cells in response to liver injury in the liver. Additionally, the hepatocytes, biliary epithelial cells (cholangiocytes), hepatic stellate cells (HSCs), hepatic macrophages, and liver sinusoidal endothelial cells (LSECs) contribute to liver fibrosis via different mechanisms. However, the underlying mechanism of the inflammasome and pyroptosis in these liver cells in liver fibrosis remains elusive. This review summarizes the activation and function of inflammasome complexes and then discusses the association between inflammasomes, pyroptosis, and liver fibrosis. Unlike other similar reviewers, we will focus on the effect of inflammasome activation and pyroptosis in the various liver cells during the development of liver fibrosis. We will also highlight the latest progress of pharmacological intervention in inflammasome-mediated liver fibrosis.
The Association Between Serum Complement 4 and Kidney Disease Progression in Idiopathic Membranous Nephropathy: A Multicenter Retrospective Cohort Study
Authors: Liu Jing , Zha Yang , Zhang Peng , He Peng , He Lijie
Published: May 2022

Introduction

Complement system plays an important role in the pathogenesis of idiopathic membranous nephropathy (IMN), however, the relationship between serum complement 4 (C4) and kidney disease progression in IMN is unclear. This study aims to investigate the association of serum C4 level with the risk of kidney disease progression among patients with IMN.

Methods

The retrospective cohort assessed 1,254 participants with biopsy-proven IMN from three centers in Xi ‘an, Shaanxi Province, China. Baseline serum C4 levels were measured at renal biopsy. The association between baseline serum C4 and the risk of renal function progression, defined as a 30% decline in renal function or end stage renal disease, was evaluated in Cox proportional hazards models.

Results

A total of 328 patients with IMN and nephrotic proteinuria were eligible, and 11.3% (37/328) of them attained the renal function progression events after a median follow-up of 51 months (37-59 months). After adjustment for other confounders, a higher value of serum C4 was independently associated with a higher risk of renal function progression event with a hazard ratio (HR) of 4.76 (95% confidence interval [95% CI], 1.77-12.79) per natural log-transformed C4. In reference to the low level of C4, the adjusted HRs were 2.72 (95% CI, 1.02-7.24) and 3.65 (95% CI, 1.39-9.60), respectively, for the median and high levels of C4 (P for trend=0.008). Additionally, the results were robust and reliable in the sensitivity and subgroup analyses.

Conclusion

Among patients with IMN and nephrotic proteinuria, serum C4 at renal biopsy is an independent predictor for kidney disease progression regardless of other confounders.
Occurrences and Functions of Ly6Chi and Ly6Clo Macrophages in Health and Disease
Authors: Li Yuan-hui , Zhang Yu , Pan Gang , Xiang Li-xin , Luo Ding-cun , Shao Jian-zhong
Published: May 2022

Macrophages originating from the yolk sac or bone marrow play essential roles in tissue homeostasis and disease. Bone marrow-derived monocytes differentiate into Ly6Chiand Ly6Clomacrophages according to the differential expression of the surface marker protein Ly6C. Ly6Chiand Ly6Clocells possess diverse functions and transcriptional profiles and can accelerate the disease process or support tissue repair and reconstruction. In this review, we discuss the basic biology of Ly6Chiand Ly6Clomacrophages, including their origin, differentiation, and phenotypic switching, and the diverse functions of Ly6Chiand Ly6Clomacrophages in homeostasis and disease, including in injury, chronic inflammation, wound repair, autoimmune disease, and cancer. Furthermore, we clarify the differences between Ly6Chiand Ly6Clomacrophages and their connections with traditional M1 and M2 macrophages. We also summarize the limitations and perspectives for Ly6Chiand Ly6Clomacrophages. Overall, continued efforts to understand these cells may provide therapeutic approaches for disease treatment.
Finite Element Analysis on Inelastic Mechanical Behavior of Composite Beams Strengthened With Carbon-Fiber-Reinforced Polymer Laminates Under Negative Moment
Authors: Song Aiming , Xu Hongtao , Luo Qi , Wan Shui
Published: May 2022

This work studies the improvement in the inelastic mechanical property of steel-concrete composite beams strengthened by carbon-fiber-reinforced polymer (CFRP) laminates under a negative moment. First, the monotonic loading test was designed and performed on an inverted simply supported beam to simulate the negative moment regions of continuous composite beams. Second, the finite element analysis (FEA) on flexural capacity and cracking resistance in negative moment regions of the composite beams was carried out with ANSYS software. A series of mechanical indexes including the load-deflection curve, component strain, and crack propagation were obtained from the FEA model and verified through the test data. The results showed that the FEA model can accurately predict the general mechanical behavior of composite beams under negative moments, and the calculation results considering the interface slip effect were closer to the experimental values. Finally, based on the FEA model, the parametric study on static behavior in negative moment regions of composite beams strengthened with/without CFRP laminates was conducted. The effects of the CFRP layout width, layout position, layer number, longitudinal reinforcement ratio, and shear connection degree on the bearing capacity of the composite beams were considered. The CFRP laminates can effectively improve the bending resistance of composite beams under negative moments. At a low reinforcement ratio, the bearing capacity was greatly affected by the layout width and layer number of the CFRP laminates, but the rate of increase was not significant when the layer number was more than 3. The reinforcement ratio had a great influence on the bearing capacity of composite beams under negative moments, but the influence of the shear connection degree was not remarkable.
A Novel Technique for the Evaluation and Interpretation of Elastography in Salivary Gland Involvement in Primary Sjögren Syndrome
Authors: Barbosa-Cobos Rosa Elda , Torres-González Rubén , Meza-Sánchez Ana Victoria , Ventura-Ríos Lucio , Concha-Del-Río Luz Elena , Ramírez-Bello Julián , Álvarez-Hernández Everardo , Meléndez-Mercado Claudia Irene , Enríquez-Sosa Favio Edmundo , Samuria-Flores Cinthia Jahoska , Lugo-Zamudio Gustavo Esteban , Hernández-Díaz Cristina
Published: May 2022

Ultrasound (US) of major salivary glands (MSG) evaluates echogenicity, border features and vascularization, with elastography, it can detect tissue elasticity and glandular fibrosis, related to inflammation in Primary Sjögren’s syndrome (pSS). This study aimed to develop a novel technique by pixel analysis for evaluation and interpretation of elastography in MSG in pSS. A cross-sectional and observational multicenter study was conducted. The US of MSG performed in orthogonal planes in grayscale, Doppler, and shear-wave elastography. For elastography images of each gland were analyzed with the open-source program ImageJ to perform a pixel analysis. Statistical analysis was performed with the IBM-SPSS v25 program. Fifty-nine women with a mean age of 57.69 (23–83) years were recruited; pSS mean duration of 87 (5–275) months, and 12 healthy women without sicca symptoms as a control group with a mean age of 50.67 (42–60) years. Intragroup analysis showed p-values >0.05 between sicca symptoms, ocular/dryness tests, biopsy, US, and pixel analysis; correlation between Hocevar and pixel analysis was not found (rho < 0.1, p >0.5). MSG anatomical size was 41.7 ± 28.2 mm vs. 67.6 ± 8.8 mm (p ≤ 0.0001); unstimulated whole saliva flow rate was 0.80 ± 0.80 ml/5 min vs. 1.85 ± 1.27 ml/5 min (p = 0.016). The elastography values (absolute number of pixels) were 572.38 ± 99.21 vs. 539.69 ± 93.12 (p = 0.290). A cut-off point risk for pSS identified with less than 54% of red pixels in the global MSG mass [OR of 3.8 95% CI (1.01–15.00)]. Pixel analysis is a new tool that could lead to a better understanding of the MSG chronic inflammatory process in pSS.
Harmonization of Multiple SARS-CoV-2 Reference Materials Using the WHO IS (NIBSC 20/136): Results and Implications
Authors: Windsor William Jonathan , Roell Yannik , Tucker Heidi , Cheng Chi-An , Suliman Sara , Peek Laura J. , Pestano Gary A. , Lee William T. , Zeichhardt Heinz , Lamb Molly M. , Kammel Martin , Wang Hui , Kedl Ross , Rester Cody , Morrison Thomas E. , Davenport Bennet J. , Carson Kyle , Yates Jennifer , Howard Kelly , Kulas Karen , Walt David R. , Dafni Aner , Taylor Daniel , Chu May
Published: May 2022

Background

There is an urgent need for harmonization between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology platforms and assays prior to defining appropriate correlates of protection and as well inform the development of new rapid diagnostic tests that can be used for serosurveillance as new variants of concern (VOC) emerge. We compared multiple SARS-CoV-2 serology reference materials to the WHO International Standard (WHO IS) to determine their utility as secondary standards, using an international network of laboratories with high-throughput quantitative serology assays. This enabled the comparison of quantitative results between multiple serology platforms.

Methods

Between April and December 2020, 13 well-characterized and validated SARS-CoV-2 serology reference materials were recruited from six different providers to qualify as secondary standards to the WHO IS. All the samples were tested in parallel with the National Institute for Biological Standards and Control (NIBSC) 20/136 and parallel-line assays were used to calculate the relevant potency and binding antibody units.

Results

All the samples saw varying levels of concordance between diagnostic methods at specific antigen–antibody combinations. Seven of the 12 candidate materials had high concordance for the spike-immunoglobulin G (IgG) analyte [percent coefficient of variation (%CV) between 5 and 44%].

Conclusion

Despite some concordance between laboratories, qualification of secondary materials to the WHO IS using arbitrary international units or binding antibody units per milliliter (BAU/ml) does not provide any benefit to the reference materials overall, due to the lack of consistent agreeable international unit (IU) or BAU/ml conversions between laboratories. Secondary standards should be qualified to well-characterized reference materials, such as the WHO IS, using serology assays that are similar to the ones used for the original characterization of the WHO IS.
Transcriptome Analysis of Viable but Non-Culturable Brettanomyces bruxellensis Induced by Hop Bitter Acids
Authors: He Yang , Zhao Junfeng , Yin Hua , Deng Yuan
Published: May 2022

The viable but non-culturable (VBNC) state has been studied in detail in bacteria. However, it has received much less attention in eukaryotic cells. The induction of a VBNC beer-spoilage yeast (Brettanomyces bruxellensis) by hop bitter acids with different concentrations and its recovery were studied in this work. B. bruxellensis cells were completely induced into the VBNC state by treatment of 250 mg/L hop bitter acids for 2 h. The addition of catalase at a concentration of 2,000 U/plate on YPD agars enabled these VBNC cells to recover their culturability within 2 days. Moreover, the transcriptome profiling revealed that 267 and 197 genes were significantly changed upon VBNC state entry and resuscitation, respectively. The differentially expressed genes involved in the peroxisome activities, ABC transporter, organic acid metabolism, and TCA cycle were mainly downregulated in the VBNC cells. In contrast, the amino acid and carbohydrate metabolism, cell division, and DNA replication were promoted. This study supplies a theoretical basis for microbial risk assessment in the brewing industry.
Microbial Valorization of Lignin to Bioplastic by Genome-Reduced Pseudomonas putida
Authors: Zong Qiu-Jin , Xu Tao , Liu He , Xu Li , Zhang Ren-Kuan , Li Bing-Zhi , Liu Zhi-Hua , Yuan Ying-Jin
Published: May 2022

As the most abundant natural aromatic resource, lignin valorization will contribute to a feasible biobased economy. Recently, biological lignin valorization has been advocated since ligninolytic microbes possess proficient funneling pathways of lignin to valuable products. In the present study, the potential to convert an actual lignin stream into polyhydroxyalkanoates (PHAs) had been evaluated using ligninolytic genome-reduced Pseudomonas putida. The results showed that the genome-reduced P. putida can grow well on an actual lignin stream to successfully yield a high PHA content and titer. The designed fermentation strategy almost eliminated the substrate effects of lignin on PHA accumulation. Employing a fed-batch strategy produced the comparable PHA contents and titers of 0.35 g/g dried cells and 1.4 g/L, respectively. The molecular mechanism analysis unveiled that P. putida consumed more small and hydrophilic lignin molecules to stimulate cell growth and PHA accumulation. Overall, the genome-reduced P. putida exhibited a superior capacity of lignin bioconversion and promote PHA accumulation, providing a promising route for sustainable lignin valorization.
Still Wanting to Win: Reward System Stability in Healthy Aging
Authors: Opitz Laura , Wagner Franziska , Rogenz Jenny , Maas Johanna , Schmidt Alexander , Brodoehl Stefan , Klingner Carsten M.
Published: May 2022

Healthy aging is accompanied by multi-faceted changes. Especially within the brain, healthy aging exerts substantial impetus on core parts of cognitive and motivational networks. Rewards comprise basic needs, such as food, sleep, and social contact. Thus, a functionally intact reward system remains indispensable for elderly people to cope with everyday life and adapt to their changing environment. Research shows that reward system function is better preserved in the elderly than most cognitive functions. To investigate the compensatory mechanisms providing reward system stability in aging, we employed a well-established reward paradigm (Monetary Incentive Delay Task) in groups of young and old participants while undergoing EEG measurement. As a new approach, we applied EEG connectivity analyses to assess cortical reward-related network connectivity. At the behavioral level, our results confirm that the function of the reward system is preserved in old age. The mechanisms identified for maintaining reward system function in old age do not fit into previously described models of cognitive aging. Overall, older adults exhibit lower reward-related connectivity modulation, higher reliance on posterior and right-lateralized brain areas than younger adults, and connectivity modulation in the opposite direction than younger adults, with usually greater connectivity during non-reward compared to reward conditions. We believe that the reward system has unique compensatory mechanisms distinct from other cognitive functions, probably due to its etymologically very early origin. In summary, this study provides important new insights into cortical reward network connectivity in healthy aging.
Evidence for Dopamine Abnormalities Following Acute Methamphetamine Exposure Assessed by Neuromelanin-Sensitive Magnetic Resonance Imaging
Authors: Tang Fei , Liu Hui , Zhang Xiao Jie , Zheng Hui Hui , Dai Yong Ming , Zheng Li Yun , Yang Wen Han , Du Yan Yao , Liu Jun
Published: May 2022

Background

Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) is a newly developed MRI technique that provides a non-invasive way to indirectly measure of dopamine (DA) function. This study aimed to determine NM concentrations in brain regions following acute methamphetamine (MA) administration using NM-MRI and to explore whether NM-MRI can be used as a biomarker of DA function in non-neurodegenerative diseases.

Methods

Baseline NM-MRI, T1-weighted and T2-weighted images were acquired from 27 rats before drug/placebo injection. The control group (n = 11) received acute placebo (Normal saline), while the experimental group (n = 16) received acute MA. NM-MRI scans were performed 5, 30, 60 and 90 min after injection. Regions of interest (ROIs), including the caudate putamen (CP), nucleus accumbens (NAc), hippocampus (HIP), substantia nigra (SN) and crus cerebri (CC), were manually drawn by an experienced radiologist. NM-MRI signal intensity in five brain regions at different time points (baseline and 5, 30, 60, and 90 min) were analyzed.

Results

In both the control and experimental groups, at each time point (baseline and 5, 30, 60, and 90 min), the SN exhibited significantly higher NM-MRI signal intensity than the other brain regions (P < 0.05). In addition, acute MA administration resulted in a continuous upward trend in NM-MRI signal intensity in each brain region over time. However, there was no such trend over time in the control group. The NM-MRI signal intensity of SN in the experimental group was significantly higher at the 60 and 90 min compared with that in the control group (P values were 0.042 and 0.042 respectively). Within experimental group, the NM-MRI signal intensity of SN was significantly higher at the 60 and 90 min compared with that before MA administration (P values were 0.023 and 0.011 respectively). Increased amplitudes and rates of NM-MRI signal intensity were higher in the SN than in other brain regions after MA administration.

Conclusion

Our results indicated that NM was mainly deposited in the SN, and the conversion of DA to NM was most significant in the SN after acute MA exposure. Increased DA release induced by acute MA exposure may lead to increased accumulation of NM in multiple brain regions that can be revealed by NM-MRI. NM-MRI may serve as a powerful imaging tool that could have diverse research and clinical applications for detecting pathological changes in drug addiction and related non-neurodegenerative diseases.
Screening of the TMEM151A Gene in Patients With Paroxysmal Kinesigenic Dyskinesia and Other Movement Disorders
Authors: Ma Ling-Yan , Han Lin , Niu Meng , Chen Lu , Yu Ya-Zhen , Feng Tao
Published: May 2022

Background

Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent involuntary movements usually triggered by sudden movements. Mutations in the TMEM151A gene were found to be the causative factor of PKD in recent studies. It has also been revealed that loss-of-function is the mechanism by which TMEM151A mutations cause PKD.

Methods

To investigate the genetic basis of PKD and broaden the clinical spectrum of the TMEM151A mutations, we recruited 181 patients of Chinese origin with movement disorders (MDs), including 39 PRRT2-negative PKD, 3 paroxysmal exercise-induced dyskinesia (PED), 2 paroxysmal non-kinesigenic dyskinesia (PNKD), 127 isolated dystonia, 8 choreas, and 2 myoclonus-dystonia syndromes. Whole-exome sequencing was applied to identify their possible disease-causing mutations. Then, Sanger sequencing was performed for validation and co-segregation analysis. Genetic analysis was also performed on additional family members of patients with TMEM151A mutations. Clinical manifestations of all PKD cases with mutations in TMEM151A reported, so far, were reviewed.

Results

Two novel variants of the TMEM151A gene (NM_153266.4, NP_694998.1), c.627_643dup (p.A215Gfs*53) and c.627delG (p.L210Wfs*52), were identified in 2 patients with PKD by whole-exome sequencing and further Sanger sequencing. Both variants were inherited by the patients from their respective mothers. No mutation of the TMEM151A gene was found in the other type of movement disorders. In reviewing the clinical presentation of TMEM151A-related PKD, no statistically significant difference in the age of onset, family history, duration of attacks, laterality, and phenotype was found between genders. More male patients received treatment and had a good response. A higher proportion of female patients did not receive any treatment, possibly because they had a milder condition of the disease.

Conclusions

This study further validated the role of TMEM151A in PKD. Future studies on protein function will be needed to ascertain the pathogenesis of TMEM151A in PKD.
Acute Ethanol Challenge Differentially Regulates Expression of Growth Factors and miRNA Expression Profile of Whole Tissue of the Dorsal Hippocampus
Authors: Barney Thaddeus M. , Vore Andrew S. , Deak Terrence
Published: May 2022

Acute ethanol exposure produces rapid alterations in neuroimmune gene expression that are both time- and cytokine-dependent. Interestingly, adolescent rats, who often consume binge-like quantities of alcohol, displayed reduced neuroimmune responses to acute ethanol challenge. However, it is not known whether growth factors, a related group of signaling factors, respond to ethanol similarly in adults and adolescents. Therefore, Experiment 1 aimed to assess the growth factor response to ethanol in both adolescents and adults. To test this, adolescent (P29–P34) and adult (P70–P80) Sprague Dawley rats of both sexes were injected with either ethanol (3.5 g/kg) or saline, and brains were harvested 3 h post-injection for assessment of growth factor, cytokine, or miRNA expression. As expected, acute ethanol challenge significantly increased IL-6 and IκBα expression in the hippocampus and amygdala, replicating our prior findings. Acute ethanol significantly decreased BDNF and increased FGF2 regardless of age condition. PDGF was unresponsive to ethanol, but showed heightened expression among adolescent males. Because recent work has focused on the PDE4 inhibitor ibudilast for treatment in alcohol use disorder, Experiment 2 tested whether ibudilast would alter ethanol-evoked gene expression changes in cytokines and growth factors in the CNS. Ibudilast (9.0 mg/kg s.c.) administration 1 h prior to ethanol had no effect on ethanol-induced changes in cytokine or growth factor changes in the hippocampus or amygdala. To further explore molecular alterations evoked by acute ethanol challenge in the adult rat hippocampus, Experiment 3 tested whether acute ethanol would change the miRNA expression profile of the dorsal hippocampus using RNASeq, which revealed a rapid suppression of 12 miRNA species 3 h after acute ethanol challenge. Of the miRNA affected by ethanol, the majority were related to inflammation or cell survival and proliferation factors, including FGF2, MAPK, NFκB, and VEGF. Overall, these findings suggest that ethanol-induced, rapid alterations in neuroimmune gene expression were (i) muted among adolescents; (ii) independent of PDE4 signaling; and (iii) accompanied by changes in several growth factors (increased FGF2, decreased BDNF). In addition, ethanol decreased expression of multiple miRNA species, suggesting a dynamic molecular profile of changes in the hippocampus within a few short hours after acute ethanol challenge. Together, these findings may provide important insight into the molecular consequences of heavy drinking in humans.
Future Directions for Chemosensory Connectomes: Best Practices and Specific Challenges
Authors: Veldhuizen Maria G. , Cecchetto Cinzia , Fjaeldstad Alexander W. , Farruggia Michael C. , Hartig Renée , Nakamura Yuko , Pellegrino Robert , Yeung Andy W. K. , Fischmeister Florian Ph. S.
Published: May 2022

Ecological chemosensory stimuli almost always evoke responses in more than one sensory system. Moreover, any sensory processing takes place along a hierarchy of brain regions. So far, the field of chemosensory neuroimaging is dominated by studies that examine the role of brain regions in isolation. However, to completely understand neural processing of chemosensation, we must also examine interactions between regions. In general, the use of connectivity methods has increased in the neuroimaging field, providing important insights to physical sensory processing, such as vision, audition, and touch. A similar trend has been observed in chemosensory neuroimaging, however, these established techniques have largely not been rigorously applied to imaging studies on the chemical senses, leaving network insights overlooked. In this article, we first highlight some recent work in chemosensory connectomics and we summarize different connectomics techniques. Then, we outline specific challenges for chemosensory connectome neuroimaging studies. Finally, we review best practices from the general connectomics and neuroimaging fields. We recommend future studies to develop or use the following methods we perceive as key to improve chemosensory connectomics: (1) optimized study designs, (2) reporting guidelines, (3) consensus on brain parcellations, (4) consortium research, and (5) data sharing.
eIF6 as a Promising Diagnostic and Prognostic Biomarker for Poorer Survival of Cutaneous Melanoma
Authors: Zhang Fangyingnan , Waheed Saquib , Armato Ubaldo , Wu Jun , Zhang Chao , Li Zhibin
Published: May 2022

Background

Skin cutaneous melanoma (SKCM) is the deadliest skin cancer and has the most rapidly increasing incidences among all cancer types. Previous research elucidated that melanoma can only be successfully treated with surgical abscission in the early stage. Therefore, reliable and specific biomarkers are crucial to melanoma diagnosis since it often looks like nevi in the clinical manifestations. Moreover, identifying key genes contributing to melanoma progression is also highly regarded as a potential strategy for melanoma therapy. In this respect, translation initiator eIF6 has been proved as a pro-tumor factor in several cancers. However, the role of eIF6 in the skin cutaneous melanoma progression and its potential as a prognostic marker is still unexplored.

Methods

The immunochemical analysis of clinical specimens were served to assess eIF6 expression levels. Gene Expression Profiling Interactive Analysis (GEPIA) database consultations allowed us to find the survival rates of the eIF6-overexpressed patients. eIF6 cellular effects were evaluated in an eIF6-overexpressed A375 cell line constructed with a lentivirus. The analysis of down-stream effectors or pathways was conducted using C-Bioportal and STRING databases.

Results

Our results revealed that eIF6 was highly over-expressed in melanomas compared to normal skin specimens, and thus the abnormally high level of eIF6 can be a diagnostic marker for melanoma. The in silica analysis indicated that patients with eIF6 over-expression had lower survival rates than that low-expression in SKCM. Meanwhile, similar results also could be found in the other four types of cancers. In vitro, over-expression of eIF6 increased the proliferation and migration of melanoma cells. Correspondingly, pan-cancer clustering analysis indicated the expression level of intermediate filament proteins was correlated with that of eIF6 expression. In our study, all over-expressed keratin proteins, in accordance with over-expressed eIF6, had a negative correlation with melanoma prognosis. Moreover, the decreased methylation level of keratin genes suggested a new potential regulation mode of eIF6.

Conclusions

The up-regulated eIF6 could be a potential diagnostic and prognostic biomarker of melanoma. This study also provides insights into the potential role of eIF6 in pan-cancer epigenetic regulation.
SIRT4-Catalyzed Deacetylation of Axin1 Modulates the Wnt/β-Catenin Signaling Pathway
Authors: Wang Yuting , Yue Jicheng , Xiao Mingzhe , Lu Xiaomei , Chin Yuen Eugene
Published: May 2022

Axin1 is a fundamental scaffolding protein of the destruction complex in the canonical Wnt signaling pathway, which plays a critical role in various biological processes. However, how Axin1 is regulated in the activation of the canonical Wnt signaling pathway remains elusive. Here, we report that Axin1 is constitutively acetylated in resting cells. Upon stimulation with Wnt, SIRT4 translocates from mitochondria to the cytoplasm and catalyzes Axin1 deacetylation, thus turning off the destruction complex. In this process, Lys147, a residue in the RGS domain of Axin1, plays a key role. We proved that the Axin1-K147R mutant impairs the assembly of β-TrCP to the destruction complex, which leads to β-catenin accumulation even without Wnt stimulation. In summary, our work proposes a new model for better understanding the initial stage of the canonical Wnt signaling pathway in which SIRT4 translocates from mitochondria into the cytoplasm to deacetylate Axin1-K147 after Wnt stimulation, which results in reduced assembly of β-TrCP to the destruction complex.
A Female With Synchronous Multiple Primary Malignant Tumors in the Esophagogastric Junction, Duodenum and Pancreas: Case Report and Review of the Literature
Authors: Du Yongxing , Duan Yunjie , Zhang Lipeng , Gu Zongting , Zheng Xiaohao , Li Zongze , Wang Chengfeng
Published: May 2022

The incidence of multiple primary carcinomas (MPCs), which are defined as two or more malignancies detected in an individual person, is gradually increasing around the world. According to the timing of diagnosis for each constituent tumor, MPCs are classified into 2 categories: synchronous MPCs if constituent tumors emerge simultaneously or within 6 months or metachronous MPCs otherwise. In this report, we describe our recent observation and treatment of a female patient with synchronous primary esophagogastric junction adenocarcinoma, duodenal adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). To the best of our knowledge, this combination has not yet been reported in the literature. A crucial aspect is the decision regarding which tumor to treat initially and how to schedule further treatments according to individual tumor hazards. Our multidisciplinary team devised an individualized treatment regimen for this patient. The patient ultimately achieved an overall survival time of 18 months, which was much longer than the median survival time (6~11 months) of patients with locally advanced pancreatic cancer. Moreover, treating this rare combination raised a series of diagnostic, etiological and therapeutic questions, motivating us to carry out a critical review of the literature. In summary, an individualized treatment strategy with input from a dedicated multidisciplinary team and consideration of all options at different points along the disease trajectory is essential to optimize outcomes for patients with MPC.
Combined Radiomic and Visual Assessment for Improved Detection of Lung Adenocarcinoma Invasiveness on Computed Tomography Scans: A Multi-Institutional Study
Authors: Vaidya Pranjal , Bera Kaustav , Linden Philip A. , Gupta Amit , Rajiah Prabhakar Shantha , Jones David R. , Bott Matthew , Pass Harvey , Gilkeson Robert , Jacono Frank , Hsieh Kevin Li-Chun , Lan Gong-Yau , Velcheti Vamsidhar , Madabhushi Anant
Published: May 2022

Objective

The timing and nature of surgical intervention for semisolid abnormalities are dependent upon distinguishing between adenocarcinoma-in-situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (INV). We sought to develop and evaluate a quantitative imaging method to determine invasiveness of small, ground-glass lesions on computed tomography (CT) chest scans.

Methods

The study comprised 268 patients from 4 institutions with resected (<=3 cm) semisolid lesions with confirmed histopathological diagnosis of MIA/AIS or INV. A total of 248 radiomic texture features from within the tumor nodule (intratumoral) and adjacent to the nodule (peritumoral) were extracted from manually annotated lung nodules of chest CT scans. The datasets were randomly divided, with 40% of patients used for training and 60% used for testing the machine classifier (Training DTrain, N=106; Testing, DTest, N=162).

Results

The top five radiomic stable features included four intratumoral (Laws and Haralick feature families) and one peritumoral feature within 3 to 6 mm of the nodule (CoLlAGe feature family), which successfully differentiated INV from MIA/AIS nodules with an AUC of 0.917 [0.867-0.967] on DTrain and 0.863 [0.79-0.931] on DTest. The radiomics model successfully differentiated INV from MIA cases (<1 cm AUC: 0.76 [0.53-0.98], 1-2 cm AUC: 0.92 [0.85-0.98], 2-3 cm AUC: 0.95 [0.88-1]). The final integrated model combining the classifier with the radiologists’ score gave the best AUC on DTest (AUC=0.909, p<0.001).

Conclusions

Addition of advanced image analysis via radiomics to the routine visual assessment of CT scans help better differentiate adenocarcinoma subtypes and can aid in clinical decision making. Further prospective validation in this direction is warranted.
Mediating Pain: Navigating Endometriosis on Social Media
Authors: Holowka Eileen Mary
Published: May 2022

With the rise of social media, many people with endometriosis have turned to platforms such as Facebook and Instagram in the face of lacking care. This qualitative study focuses on why and how people with endometriosis use these platforms. Despite the risks of misinformation and conflict on social media, the results of this research show that many people with endometriosis find these spaces beneficial, particularly for information sharing, social support, representation, and advocacy practices around endometriosis. Using data collected from surveys and interviews, this study reveals that people with endometriosis often use social media to understand, experiment with, and navigate their symptoms and that these efforts deserve recognition by endometriosis researchers and practitioners. This article proposes that, in order to improve future patient-practitioner and patient-researcher relationships for endometriosis, we must understand, not dismiss, the social media practices of those with endometriosis. By understanding how and why patients turn to social media, clinicians and researchers can build toward more patient-oriented futures.
Case Report: Protein-Losing Enteropathy in Association With Tuberculosis-Related Constrictive Pericarditis
Authors: Xi Yue , Chen Zhi , Hao Kun , Liu Xiaorong
Published: May 2022

Protein-losing enteropathy (PLE) is a clinical disorder in which an excessive amount of serum protein is lost into the gastrointestinal tract, resulting in hypoproteinemia and malnutrition. PLE is associated with a wide range of gastrointestinal disorders and the rare complication of constrictive pericarditis. We report a case in which pericardiectomy achieved marked improvement of extremely severe hypoalbuminemia caused by PLE associated with tuberculosis-related constrictive pericarditis. The formation of diarrhea and edema was aggravated by PLE, resulting in hypoalbuminemia. Cardiac computed tomography showed a calcified pericardium. Echocardiography showed decreased cardiac function underlying PLE. Functional imaging with technetium-99m serum albumin identified the region of protein leakage as the intestine. After pericardiectomy, the diarrhea ceased completely. Serum albumin concentrations were increased (3.3–3.7 g/dL), which indicated resolution of the PLE.
A Set of Experimentally Validated Decoys for the Human CC Chemokine Receptor 7 (CCR7) Obtained by Virtual Screening
Authors: Proj Matic , De Jonghe Steven , Van Loy Tom , Jukič Marko , Meden Anže , Ciber Luka , Podlipnik Črtomir , Grošelj Uroš , Konc Janez , Schols Dominique , Gobec Stanislav
Published: May 2022

We present a state-of-the-art virtual screening workflow aiming at the identification of novel CC chemokine receptor 7 (CCR7) antagonists. Although CCR7 is associated with a variety of human diseases, such as immunological disorders, inflammatory diseases, and cancer, this target is underexplored in drug discovery and there are no potent and selective CCR7 small molecule antagonists available today. Therefore, computer-aided ligand-based, structure-based, and joint virtual screening campaigns were performed. Hits from these virtual screenings were tested in a CCL19-induced calcium signaling assay. After careful evaluation, none of the in silico hits were confirmed to have an antagonistic effect on CCR7. Hence, we report here a valuable set of 287 inactive compounds that can be used as experimentally validated decoys.
Initiation of Tocilizumab or Baricitinib Were Associated With Comparable Clinical Outcomes Among Patients Hospitalized With COVID-19 and Treated With Dexamethasone
Authors: Wong Carlos K. H. , Lau Kristy T. K. , Au Ivan C. H. , Xiong Xi , Chung Matthew S. H. , Leung Belle Y. C. , Lau Eric H. Y. , Cowling Benjamin J.
Published: May 2022

Objectives: This retrospective cohort study aims to explore head-to-head clinical outcomes and complications associated with tocilizumab or baricitinib initiation among hospitalized COVID-19 patients receiving dexamethasone.

Methods: Among 10,445 COVID-19 patients hospitalized between January 21st 2020 and January 31st 2021 in Hong Kong, patients who had received tocilizumab (n = 165) or baricitinib (n = 76) while on dexamethasone were included. Primary study outcome was time to clinical improvement (at least one score reduction on WHO clinical progression scale). Secondary outcomes were disease progression, viral dynamics, in-hospital death, hyperinflammatory syndrome, and COVID-19/treatment-related complications. Hazard ratios (HR) of event outcomes were estimated using Cox regression models.

Results: The initiation of tocilizumab or baricitinib had no significant differences in time to clinical improvement (HR = 0.86, 95%CI 0.57-1.29, p = 0.459), hospital discharge (HR = 0.85, 95%CI 0.57-1.27, p = 0.418), recovery without the need for oxygen therapy (HR = 1.04, 95%CI 0.64-1.67, p = 0.883), low viral load (HR = 1.49, 95%CI 0.85-2.60, p = 0.162), and positive IgG antibody (HR = 0.97, 95%CI 0.61-1.54, p = 0.909). Time to viral clearance (HR = 1.94, 95%CI 1.01-3.73, p = 0.048) was shorter in the tocilizumab group with marginal significance, compared to that of baricitinib. Meanwhile, the two treatment modalities were not significantly different in their associated risks of in-hospital death (HR = 0.63, 95%CI 0.29-1.35, p = 0.233), severe liver injury (HR = 1.15, 95%CI 0.43-3.08, p = 0.778), acute renal failure (HR = 2.33, 95%CI 0.61-8.82, p = 0.213), hyperinflammatory syndrome (HR = 2.32, 95%CI 0.87-6.25, p = 0.091), thrombotic and bleeding events (HR = 1.39, 95%CI 0.32-6.00, p = 0.658), and secondary infection (HR = 2.97, 95%CI 0.62-14.31, p = 0.173).

Conclusion: Among hospitalized patients with moderate-to-severe COVID-19 on background dexamethasone, the initiation of tocilizumab or baricitinib had generally comparable effects on time to clinical improvement, hospital discharge, recovery, low viral load, and positive IgG antibody; risks of in-hospital death, hepatic and renal complications, hyperinflammatory syndrome, thrombotic and bleeding events, and secondary infection. On the other hand, tocilizumab users might achieve viral clearance slightly faster than baricitinib users. Further studies and clinical trials are needed to confirm our findings regarding the evaluation of tocilizumab and baricitinib in COVID-19 patients with different disease severities, at varying stages or timing of drug initiation, and considering the concomitant use of other therapeutics.
Evaluation of Untargeted Metabolomic Strategy for the Discovery of Biomarker of Breast Cancer
Authors: Ruan Xujun , Wang Yan , Zhou Lirong , Zheng Qiuling , Hao Haiping , He Dandan
Published: May 2022

Discovery of disease biomarker based on untargeted metabolomics is informative for pathological mechanism studies and facilitates disease early diagnosis. Numerous of metabolomic strategies emerge due to different sample properties or experimental purposes, thus, methodological evaluation before sample analysis is essential and necessary. In this study, sample preparation, data processing procedure and metabolite identification strategy were assessed aiming at the discovery of biomarker of breast cancer. First, metabolite extraction by different solvents, as well as the necessity of vacuum-dried and re-dissolution, was investigated. The extraction efficiency was assessed based on the number of eligible components (components with MS/MS data acquired), which was more reasonable for metabolite identification. In addition, a simplified data processing procedure was proposed involving the OPLS-DA, primary screening for eligible components, and secondary screening with constraints including VIP, fold change and p value. Such procedure ensured that only differential candidates were subjected to data interpretation, which greatly reduced the data volume for database search and improved analysis efficiency. Furthermore, metabolite identification and annotation confidence were enhanced by comprehensive consideration of mass and MS/MS errors, isotope similarity, fragmentation match, and biological source confirmation. On this basis, the optimized strategy was applied for the analysis of serum samples of breast cancer, according to which the discovery of differential metabolites highly encouraged the independent biomarkers/indicators used for disease diagnosis and chemotherapy evaluation clinically. Therefore, the optimized strategy simplified the process of differential metabolite exploration, which laid a foundation for biomarker discovery and studies of disease mechanism.