bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitrogenases in Oxygen Minimum Zone Waters
Authors: Reeder Christian Furbo , Löscher Carolin Regina
Published: July 2022

Biological dinitrogen (N2) fixation is the pathway making the large pool of atmospheric N2 available to marine life. Besides direct rate measurements, a common approach to explore the potential for N2 fixation in the ocean is a screening-based targeting the key functional marker gene nifH, coding for a subunit of the nitrogenase reductase. As novel sequencing techniques improved, our understanding of the diversity of marine N2 fixers grew exponentially. However, one aspect of N2 fixation in the ocean is often underexplored, which are the two alternative types of the key enzyme of N2 fixation, the nitrogenase. Altogether there are three isoenzymes, the most common Mo-Fe nitrogenase Nif, the Fe-Fe nitrogenase Anf, and the V-Fe nitrogenase Vnf, which differ regarding their genetic organization, as well as their metal co-enzymes. While Mo is only available in the presence of at least traces of oxygen (O2), V and Fe are available if O2 is absent. Therefore, low O2 and anoxic ocean environments could be an ideal place to explore the diversity of the different isotypes of the nitrogenases. Most phylogenetic studies, however, were only based on the functional marker gene nifH, encoding for a subunit of the Nif nitrogenase, and thus limited in representing the diversity of alternative nitrogenases. Here, we screened metagenomes and -transcriptomes from O2 minimum zones off Peru, from the Bay of Bengal, and the anoxic Saanich Inlet to explore the diversity of genes involved in N2 fixation. We identified genes related to all three nitrogenases, and a generally increased diversity as compared to our previous nifH based on studies from OMZ waters. While we could not confirm gene expression of alternative nitrogenases from our transcriptomic, we detected diazotrophs harboring the genetic potential for alternative nitrogenases. We suggest that alternative nitrogenases may not be used under conditions present in those waters, however, depending on trace metal availability they may become active under future ocean deoxygenation.
Coupled Carbonate Chemistry - Harmful Algae Bloom Models for Studying Effects of Ocean Acidification on Prorocentrum minimum Blooms in a Eutrophic Estuary
Authors: Li Renjian , Li Ming , Glibert Patricia M.
Published: July 2022

Eutrophic estuaries have suffered from a proliferation of harmful algal blooms (HABs) and acceleration of ocean acidification (OA) over the past few decades. Despite laboratory experiments indicating pH effects on algal growth, little is understood about how acidification affects HABs in estuaries that typically feature strong horizontal and vertical gradients in pH and other carbonate chemistry parameters. Here, coupled hydrodynamic–carbonate chemistry–HAB models were developed to gain a better understanding of OA effects on a high biomass HAB in a eutrophic estuary and to project how the global anthropogenic CO2 increase might affect these HABs in the future climate. Prorocentrum minimum in Chesapeake bay, USA, one of the most common HAB species in estuarine waters, was used as an example for studying the OA effects on HABs. Laboratory data on P. minimum grown under different pH conditions were applied in the development of an empirical formula relating growth rate to pH. Hindcast simulation using the coupled hydrodynamic-carbonate chemistry–HAB models showed that the P. minimum blooms were enhanced in the upper bay where pH was low. On the other hand, pH effects on P. minimum growth in the mid and lower bay with higher pH were minimal, but model simulations show surface seaward estuarine flow exported the higher biomass in the upper bay downstream. Future model projections with higher atmospheric pCO2 show that the bay-wide averaged P. minimum concentration during the bloom periods increases by 2.9% in 2050 and 6.2% in 2100 as pH decreases and 0.2 or 0.4, respectively. Overall the model results suggest OA will cause a moderate amplification of P. minimum blooms in Chesapeake bay. The coupled modeling framework developed here can be applied to study the effects of OA on other HAB species in estuarine and coastal environments.
On the Viability of Quantum Annealers to Solve Fluid Flows
Authors: Ray Navamita , Banerjee Tirtha , Nadiga Balu , Karra Satish
Published: July 2022

This paper explores the suitability of upcoming novel computing technologies, particularly adiabatic annealing based quantum computers, to solve fluid dynamics problems that form a critical component of several science and engineering applications. For our experiments, we start with a well-studied one-dimensional simple flow problem, and provide a framework to convert such problems in continuum to a form amenable for deployment on such quantum annealers. Since the DWave annealer returns multiple states sampling the energy landscape of the problem, we explore multiple solution selection strategies to approximate the solution of the problem. We analyze the continuum solutions obtained both qualitatively and quantitatively as well as their sensitivities to the particular solution selection scheme.
Calcium Ions Signaling: Targets for Attack and Utilization by Viruses
Authors: Qu Yang , Sun Yingjie , Yang Zengqi , Ding Chan
Published: July 2022

Calcium, as a second intracellular messenger, participate in various physiological and biochemical processes, including cell growth and proliferation, energy metabolism, information transfer, cell death, and immune response. Ca2+channels or pumps in plasma and organelle membranes and Ca2+-related proteins maintain Ca2+homeostasis by regulating Ca2+inflow, outflow and buffering to avoid any adverse effects caused by Ca2+overload or depletion. Thus, Ca2+signaling also provides a target for virus invasion, replication, proliferation and release. After hijacking the host cell, viruses exploit Ca2+signaling to regulate apoptosis and resist host immunity to establish persistent infection. In this review, we discuss cellular Ca2+signaling and channels, interaction of calcium-associated proteins with viruses, and host cell fate, as well as the role of Ca2+in cell death and antiviral response during viral infection.
Brucella melitensis Wzm/Wzt System: Changes in the Bacterial Envelope Lead to Improved Rev1Δwzm Vaccine Properties
Authors: Mena-Bueno Sara , Poveda-Urkixo Irati , Irazoki Oihane , Palacios Leyre , Cava Felipe , Zabalza-Baranguá Ana , Grilló María Jesús
Published: July 2022

The lipopolysaccharide (LPS) O-polysaccharide (O-PS) is the main virulence factor in Brucella. After synthesis in the cytoplasmic membrane, O-PS is exported to the periplasm by the Wzm/Wzt system, where it is assembled into a LPS. This translocation also engages a bactoprenol carrier required for further biosynthesis pathways, such as cell wall biogenesis. Targeting O-PS export by blockage holds great potential for vaccine development, but little is known about the biological implications of each Wzm/Wzt moiety. To improve this knowledge and to elucidate its potential application as a vaccine, we constructed and studied wzm/wzt single- and double-deletion mutants, using the attenuated strain Brucella melitensis Rev1 as the parental strain. This allowed us to describe the composition of Brucella peptidoglycan for the first time. We observed that these mutants lack external O-PS yet trigger changes in genetic transcription and in phenotypic properties associated with the outer membrane and cell wall. The three mutants are highly attenuated; unexpectedly, Rev1Δwzm also excels as an immunogenic and effective vaccine against B. melitensis and Brucella ovis in mice, revealing that low persistence is not at odds with efficacy. Rev1Δwzm is attenuated in BeWo trophoblasts, does not infect mouse placentas, and is safe in pregnant ewes. Overall, these attributes and the minimal serological interference induced in sheep make Rev1Δwzm a highly promising vaccine candidate.
Changes in Protonation States of In-Pathway Residues can Alter Ligand Binding Pathways Obtained From Spontaneous Binding Molecular Dynamics Simulations
Authors: Girame Helena , Garcia-Borràs Marc , Feixas Ferran
Published: July 2022

Protein-ligand binding processes often involve changes in protonation states that can be key to recognize and orient the ligand in the binding site. The pathways through which (bio)molecules interplay to attain productively bound complexes are intricate and involve a series of interconnected intermediate and transition states. Molecular dynamics (MD) simulations and enhanced sampling techniques are commonly used to characterize the spontaneous binding of a ligand to its receptor. However, the effect of protonation state changes of in-pathway residues in spontaneous binding MD simulations remained mostly unexplored. Here, we used molecular dynamics simulations to reconstruct the trypsin-benzamidine binding pathway considering different protonation states of His57. This residue is part of the trypsin catalytic triad and is located more than 10 Å away from Asp189, which is responsible for benzamidine binding in the trypsin S1 pocket. Our MD simulations showed that the binding pathways that benzamidine follow to target the S1 binding site are critically dependent on the His57 protonation state. Binding of benzamidine frequently occurs when His57 is protonated in the delta nitrogen while the binding process is significantly less frequent when His57 is positively charged. Constant-pH MD simulations retrieved the equilibrium populations of His57 protonation states at trypsin active pH offering a clearer picture of benzamidine recognition and binding. These results indicate that properly accounting for protonation states of distal residues can be important in spontaneous binding MD simulations.
An Improved Surgical Technique to Increase Neck Width of Elastase-Induced Aneurysm Model in Rabbits: A Prospective Study
Authors: Zhang Yang , He Yu , Tang ChaoJie , Wu YuFan , Gu Yi , Gu BinXian , Chen Li , Gao WenWei , Zhou ZhiGuo , Qi YouKe , Mao FaJiang , Sun YongNing , Wang Wu
Published: July 2022

Background

Rabbit elastase-induced aneurysms have widely been used to test various endovascular materials over the past two decades. However, wide-necked aneurysms cannot be stably constructed.

Objective

The purpose of the study was to increase the neck width of the elastase-induced aneurysm model in rabbits via an improved surgical technique with two temporary clips.

Materials and Methods

Fifty-four elastase-induced aneurysms in rabbits were successfully created. Group 1 was (n = 34) composed of cases in which two temporary aneurysm clips were placed closely medially and laterally to the origin of the right common carotid artery (RCCA), respectively. Group 2 (n = 20) included cases in which a single temporary aneurysm clip was placed crossed the origin of RCCA. Digital subtraction angiography (DSA) was performed before and immediately after elastase incubation and 3 weeks later. The diameter of the origin of RCCA before and immediately after elastase incubation and aneurysm sizes of the two groups were measured and compared. Moreover, the correlation analysis was performed between the diameter of the origin of RCCA immediately after elastase incubation and aneurysm neck width.

Results

The mean aneurysm neck and dome width of group 1 were both significantly larger than that of group 2 (p-value < 0.001 and p-value = 0.005, respectively). Moreover, the proportion of wide-necked aneurysms (neck width ≥4 mm) in group 1 was significantly larger than that in group 2 (p-value = 0.004) and the mean dome to neck ratio (D/N) of group 1 was smaller than that of group 2 (p-value = 0.008). Furthermore, there was a positive correlation between the diameter of the origin of RCCA immediately after elastase incubation and aneurysm neck width.

Conclusion

The improved surgical technique with two temporary clips, focusing on the direct contact of elastase with the origin of RCCA, could increase the neck width of elastase-induced aneurysm models in rabbits.
Comparison of Auditory Steady-State Responses With Conventional Audiometry in Older Adults
Authors: Tarawneh Hadeel Y. , Sohrabi Hamid R. , Mulders Wilhelmina H. A. M. , Martins Ralph N. , Jayakody Dona M. P.
Published: July 2022

Behavioral measures, such as pure-tone audiometry (PTA), are commonly used to determine hearing thresholds, however, PTA does not always provide reliable hearing information in difficult to test individuals. Therefore, objective measures of hearing sensitivity that require little-to-no active participation from an individual are needed to facilitate the detection and treatment of hearing loss in difficult to test people. Investigation of the reliability of the auditory steady-state response (ASSR) for measuring hearing thresholds in older adults is limited. This study aimed to investigate if ASSR can be a reliable, objective measure of frequency specific hearing thresholds in older adults. Hearing thresholds were tested at 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz in 50 participants aged between 60 and 85 years old, using automated PTA and ASSR. Hearing thresholds obtained from PTA and ASSR were found to be significantly correlated (p < .001) in a cohort consisting of participants with normal hearing or mild hearing loss. ASSR thresholds were significantly higher as compared to PTA thresholds, but for the majority of cases the difference remained within the clinically acceptable range (15 dB). This study provides some evidence to suggest that ASSR can be a valuable tool for estimating objective frequency-specific hearing thresholds in older adults and indicate that ASSR could be useful in creating hearing treatment plans for older adults who are unable to complete behavioral PTA. Further research on older adults is required to improve the methodological features of ASSR to increase consistency and reliability, as well as minimize some of the limitations associated with this technique.
A Remarkable Case of Acute Motor-Sensory Axonal Polyneuropathy (AMSAN) Variant of Guillain Barré Syndrome, in a Diabetic Patient Infected With COVID-19: A Case Report and Review of the Literature
Authors: Ali Sajjad , Karam Alvina , Lalani Aarish , Jawed Sadia , Moin Musfirah , Douba Zain , Ali Murtaza
Published: July 2022

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease- 2019 (COVID-19), has been a global epidemic in our healthcare system. SARS-CoV-2 primarily affects the respiratory system, but neurological involvement has also been reported, including Guillain–Barré syndrome (GBS) development.

Case Presentation

A 58-year-old male with known co-morbid hypertension and type 2 diabetes mellitus presented to the emergency room with complaints of worsening shortness of breath, dry cough, and fever for the past 10 days. On day 20 of hospitalization, he developed neurological symptoms after being tested positive for COVID-19. A neuroelectrophysiology study was conducted to evaluate neurological symptoms and suggested that the patient suffers from acute motor-sensory axonal polyneuropathy (AMSAN). CSF analysis showed elevated protein levels that confirmed the diagnosis of GBS. He was subsequently treated with oral prednisolone and IVIG, which improved neurological symptoms.

Conclusion

Ever since the emergence of COVID-19, GBS has surfaced as to its potentially dangerous outcome. Healthcare professionals should be mindful of GBS and should rule it out in anyone having sensory symptoms or weakness during or after a COVID-19 infection. Its early detection and treatment can result in improved clinical outcomes.
Reductionistic Explanations of Cognitive Information Processing: Bottoming Out in Neurochemistry
Authors: Bechtel William
Published: July 2022

A common motivation for engaging in reductionistic research is to ground explanations in the most basic processes operative in the mechanism responsible for the phenomenon to be explained. I argue for a different motivation—directing inquiry to the level of organization at which the components of a mechanism enable the work that results in the phenomenon. In the context of reductionistic accounts of cognitive information processing I argue that this requires going down to a level that is largely overlooked in these discussions, that of chemistry. In discussions of cognitive information processing, the brain is often viewed as essentially an electrical switching system and many theorists treat electrical switching as the level at which mechanistic explanations should bottom out. I argue, drawing on examples of peptidergic and monoaminergic neurons, that how information is processed is determined by the specific chemical reactions occurring in individual neurons. Accordingly, mechanistic explanations of cognitive information processing need to take into account the chemical reactions involved.
Assessment of Expression of Regulatory T Cell Differentiation Genes in Autism Spectrum Disorder
Authors: Akbari Mohammadarian , Eghtedarian Reyhane , Hussen Bashdar Mahmud , Eslami Solat , Taheri Mohammad , Neishabouri Seyedeh Morvarid , Ghafouri-Fard Soudeh
Published: July 2022

Dysfunction of regulatory T cells (Tregs) has been shown to affect the etiology of autism spectrum disorder (ASD). Differentiation of this group of T cells has been found to be regulated by a group of long non-coding RNAs (lncRNAs). In this study, we have examined the expression of five lncRNAs that regulate this process in the blood samples of ASD cases compared with controls. These lncRNAs were FOXP3 regulating long intergenic non-coding RNA (FLICR), MAF transcriptional regulator RNA (MAFTRR), NEST (IFNG-AS1), RNA component of mitochondrial RNA processing endoribonuclease (RMRP), and Th2 cytokine locus control region (TH2-LCR). Expression of RMRP was significantly lower in total ASD cases compared to controls [expression ratio (95% CI) = 0.11 (0.08–0.18), adjusted P-value < 0.0001]. This pattern was also detected in both men and women cases compared with corresponding controls [expression ratio (95% CI) = 0.15 (0.08–0.29) and 0.08 (0.03–0.2), respectively]. Likewise, expression of NEST was reduced in total cases and cases among men and women compared with corresponding controls [expression ratio (95% CI) = 0.2 (0.14–0.28); 0.22 (0.12–0.37); and 0.19 (0.09–0.43), respectively; adjusted P-value < 0.0001]. Lastly, FLICR was downregulated in total cases and cases among both boys and girls compared with matched controls [expression ratio (95% CI) = 0.1 (0.06–0.19); 0.19 (0.08–0.46); and 0.06 (0.01–0.21), respectively; adjusted P-value < 0.0001]. These three lncRNAs had appropriate diagnostic power for differentiation of ASD cases from controls. Cumulatively, our study supports dysregulation of Treg-related lncRNAs in patients with ASD and suggests these lncRNAs as proper peripheral markers for ASD.
The Impact of Varying Food Availability on Gene Expression in the Liver: Testing the Match-Mismatch Hypothesis
Authors: Feige-Diller Janina , Herrera-Rivero Marisol , Witten Anika , Stoll Monika , Kaiser Sylvia , Richter S. Helene , Sachser Norbert
Published: July 2022

Background

During early phases of life, such as prenatal or early postnatal development and adolescence, an organism's phenotype can be shaped by the environmental conditions it experiences. According to the Match-Mismatch hypothesis (MMH), changes to this environment during later life stages can result in a mismatch between the individual's adaptations and the prevailing environmental conditions. Thus, negative consequences in welfare and health can occur. We aimed to test the MMH in the context of food availability, assuming adolescence as a sensitive period of adaptation.

Methods

We have previously reported a study of the physiological and behavioral effects of match and mismatch conditions of high (ad libitum) and low (90% of ad libitum intake) food availability from adolescence to early adulthood in female C57BL/6J mice (n = 62). Here, we performed RNA-sequencing of the livers of a subset of these animals (n = 16) to test the effects of match and mismatch feeding conditions on the liver transcriptome.

Results

In general, we found no effect of the match-mismatch situations. Contrarily, the amount of food available during early adulthood (low vs. high) drove the differences we observed in final body weight and gene expression in the liver, regardless of the amount of food available to the animals during adolescence. Many of the differentially expressed genes and the corresponding biological processes found to be overrepresented overlapped, implicating common changes in various domains. These included metabolism, homeostasis, cellular responses to diverse stimuli, transport of bile acids and other molecules, cell differentiation, major urinary proteins, and immunity and inflammation.

Conclusions

Our previous and present observations found no support for the MMH in the context of low vs high food availability from adolescence to early adulthood in female C57BL/6J mice. However, even small differences of approximately 10% in food availability during early adulthood resulted in physiological and molecular changes with potential beneficial implications for metabolic diseases.
Cold Atmospheric Plasma Conveys Selectivity Against Hepatocellular Carcinoma Cells via Triggering EGFR(Tyr1068)-Mediated Autophagy
Authors: Wang Danjun , Zhang Jianying , Cai Linhan , Dai Xiaofeng
Published: July 2022

Hepatocellular carcinomas remain as a global health threat given its high mortality rate. We have previously identified the selectivity of cold atmospheric plasma (CAP) against multiple types of malignant tumors and proposed it as a promising onco-therapeutic strategy. Here, we investigated its roles in controlling hepatocellular carcinoma malignancy and one possible driving molecular mechanism. By focusing on post-translational modifications including acetylation, phosphorylation, and ubiquitination, we identified the crosstalk between EGFR acetylation and EGFR(Tyr1068) phosphorylation and their collective roles in determining LC3B ubiquitination and proposed the EGFR/p-JNK/BIRC6/LC3B axis in CAP-triggered autophagy. Our study not only demonstrated the selectivity of CAP against hepatocellular carcinoma malignancy and confirmed its roles as an onco-therapeutic tool but also opened the horizon of translating CAP into clinics toward a broader scope that included human longevity and anti-aging.
Exome Sequencing Reveals Genetic Variability and Identifies Chronic Prognostic Loci in Chinese Sarcoidosis Patients
Authors: Zhang Qian , Huang Hui , Zhang Meijun , Fang Chuling , Wang Na , Jing Xiaoyan , Guo Jian , Sun Wei , Yang Xiaoyu , Xu Zuojun
Published: July 2022

Background

Sarcoidosis is an inflammatory disease characterized by non-caseating granuloma formation in various organs, with several recognized genetic and environmental risk factors. Despite substantial progress, the genetic determinants associated with its prognosis remain largely unknown.

Objectives

This study aimed to identify the genetic changes involved in sarcoidosis and evaluate their clinical relevance.

Methods

We performed whole-exome sequencing (WES) in 116 sporadic sarcoidosis patients (acute sarcoidosis patients, n=58; chronic sarcoidosis patients, n=58). In addition, 208 healthy controls were selected from 1000 G East Asian population data. To identify genes enriched in sarcoidosis, Fisher exact tests were performed. The identified genes were included for further pathway analysis using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, we used the STRING database to construct a protein network of rare variants and Cytoscape to identify hub genes of signaling pathways.

Results

WES and Fisher’s exact test identified 1,311 variants in 439 protein-coding genes. A total of 135 single nucleotide polymorphisms (SNPs) on 30 protein-coding genes involved in the immunological process based on the GO and KEGG enrichment analysis. Pathway enrichment analysis showed osteoclast differentiation and cytokine–cytokine receptor interactions. Three missense mutations (rs76740888, rs149664918, and rs78251590) in two genes (PRSS3 and CNN2) of immune-related genes showed significantly different mutation frequencies between the disease group and healthy controls. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis of the clinical features and mutation loci showed that the missense variant (rs76740888, Chr9:33796673 G>A) of PRSS3 [p=0.04, odds ratio (OR) = 2.49] was significantly associated with chronic disease prognosis. Additionally, the top two hub genes were CCL4 and CXCR4 based on protein–protein interaction (PPI) network analysis.

Conclusion

Our study provides new insights into the molecular pathogenesis of sarcoidosis and identifies novel genetic alterations in this disease, especially PRSS3, which may be promising targets for future therapeutic strategies for chronic sarcoidosis.
CAR-T Cells in the Treatment of Urologic Neoplasms: Present and Future
Authors: Zhang Zhengchao , Li Dong , Yun Heng , Liu Wei , Chai Keqiang , Tong Jie , Zeng Tongwei , Gao Zhenghua , Xie Yongqiang
Published: July 2022

In recent years, with the breakthrough of CAR-T cells in the treatment of hematological tumors, they are increasingly being used to treat solid tumors, including urologic neoplasms. There are many relatively specific targets for urologic neoplasms, especially prostate cancer. Besides, urologic neoplasms tend to progress more slowly than tumors in other organs of the body, providing ample time for CAR-T cell application. Therefore, CAR-T cells technology has inherent advantages in urologic neoplasms. CAR-T cells in the treatment of urologic neoplasms have been extensively studied and preliminary achievements have been made. However, no breakthrough has been made due to the problems of targeting extra-tumor cytotoxicity and poor anti-tumor activity. we systematacially summarized the research actuality of CAR-T cells in urologic neoplasms, discussed the potential value and difficulties of the research. The application of CAR-T cells in the treatment of urologic neoplasms requires improvement of function through screening for better targets, modification of CAR structures, or in combination with other antitumor approaches.
Using Period Analysis to Timely Assess and Predict 5-Year Relative Survival for Liver Cancer Patients From Taizhou, Eastern China
Authors: Wang Youqing , Zhang Luyao , Han Fang , Li Runhua , Cheng Yongran , Jiang Xiyi , Wang Liangyou , Chen Jinfei , Ji Jianguang , Zhang Yuhua , Chen Tianhui
Published: July 2022

Introduction

While timely assessment of long-term survival for patients with liver cancer is essential for the evaluation of early detection and screening programs of liver cancer, those data are extremely scarce in China. We aimed to timely and accurately assess long-term survival for liver cancer patients in eastern China.

Methods

Patients diagnosed with liver cancer during 2004–2018 from four cancer registries with high-quality data from Taizhou, eastern China, were included. The period analysis was used to calculate the 5-year relative survival (RS) for overall and the stratification by sex, age at diagnosis, and region. The projected 5-year RS of liver cancer patients during 2019–2023 was also assessed using a model-based period analysis.

Results

The overall 5-year RS for patients with liver cancer during 2014–2018 reached 32.4%, being 29.3% for men and 36.1% for women. The 5-year RS declined along with aging, decreasing from 38.2% for age <45 years to 18.8% for age >74 years, while the 5-year RS for urban area was higher compared to rural area (36.8% vs. 29.3%). The projected overall 5-year RS of liver cancer patients could reach 41.4% during the upcoming period 2019–2023.

Conclusions

We provided, for first time in China using the period analysis, the most up-to-date 5-year RS for patients with liver cancer from Taizhou, eastern China, and also found that the 5-year RS for liver cancer patients have improved greatly during 2004–2018, which has important implications for the timely evaluation of early detection and screening programs for patients with liver cancer in eastern China.
Patient Derived Organoids Confirm That PI3K/AKT Signalling Is an Escape Pathway for Radioresistance and a Target for Therapy in Rectal Cancer
Authors: Wanigasooriya Kasun , Barros-Silva Joao D. , Tee Louise , El-asrag Mohammed E. , Stodolna Agata , Pickles Oliver J. , Stockton Joanne , Bryer Claire , Hoare Rachel , Whalley Celina M. , Tyler Robert , Sillo Toritseju , Yau Christopher , Ismail Tariq , Beggs Andrew D.
Published: July 2022

Objectives

Partial or total resistance to preoperative chemoradiotherapy occurs in more than half of locally advanced rectal cancer patients. Several novel or repurposed drugs have been trialled to improve cancer cell sensitivity to radiotherapy, with limited success. We aimed to understand the mechanisms of resistance to chemoradiotherapy in rectal cancer using patient derived organoid models.

Design

To understand the mechanisms underlying this resistance, we compared the pre-treatment transcriptomes of patient-derived organoids (PDO) with measured radiotherapy sensitivity to identify biological pathways involved in radiation resistance coupled with single cell sequencing, genome wide CRISPR-Cas9 and targeted drug screens.

Results

RNA sequencing enrichment analysis revealed upregulation of PI3K/AKT/mTOR and epithelial mesenchymal transition pathway genes in radioresistant PDOs. Single-cell sequencing of pre & post-irradiation PDOs showed mTORC1 and PI3K/AKT upregulation, which was confirmed by a genome-wide CRSIPR-Cas9 knockout screen using irradiated colorectal cancer (CRC) cell lines. We then tested the efficiency of dual PI3K/mTOR inhibitors in improving cancer cell sensitivity to radiotherapy. After irradiation, significant AKT phosphorylation was detected (p=0.027) which was abrogated with dual PI3K/mTOR inhibitors and lead to significant radiosensitisation of the HCT116 cell line and radiation resistant PDO lines.

Conclusions

The PI3K/AKT/mTOR pathway upregulation contributes to radioresistance and its targeted pharmacological inhibition leads to significant radiosensitisation in CRC organoids, making it a potential target for clinical trials.
Case Report: Recombinant Human Endostatin Plus Chemotherapy for Epidermal Growth Factor Receptor-Negative Miliary Lung Adenocarcinoma
Authors: Zhu Jian , Xu Ya , Huang Wen-Cai , Ji Tao , Ai Guo-Ping , Gao Yan-Hong
Published: July 2022

Except for the traditional chemotherapy, few treatments strategy about miliary intrapulmonary carcinomatosis (MIPC) have been reported in the existing literature. In this report, we primarily discussed the possible etiology and the potentially effective treatment options for a patient with MIPC who benefited from combined treatment. A nonsmoking woman was diagnosed with MIPC at an advanced stage. Gene detection showed an EGFR negative status. She accepted first-line chemotherapy with pemetrexed and cisplatin, and the tumor progressed. Next, PD-1 inhibitors plus pemetrexed and cisplatin were administered, and the tumor remained uncontrolled. After two cycles of recombinant human endostatin plus second-line chemotherapy, the numerous pulmonary nodules had all nearly completely disappeared, while an accentuated decrease in the primary tumor volume was observed. Moreover, biochemical markers, including the patient’s tumor markers, also trended toward normal. This report describes the first case of a MIPC patient who significantly responded to antiangiogenic therapy combined with chemotherapy. Anti-angiogenic therapy may be a possible strategy for the EGFR-negative lung adenocarcinoma population.
Proposed Cellular Function of the Human FAM111B Protein and Dysregulation in Fibrosis and Cancer
Authors: Arowolo Afolake , Malebana Moses , Sunda Falone , Rhoda Cenza
Published: July 2022

FAM111B gene mutations are associated with a hereditary fibrosing poikiloderma known to cause poikiloderma, tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP). In addition, the overexpression of FAM111B has been associated with cancer progression and poor prognosis. This review inferred the molecular function of this gene’s protein product and mutational dysfunction in fibrosis and cancer based on recent findings from studies on this gene. In conclusion, FAM111B represents an uncharacterized protease involved in DNA repair, cell cycle regulation, and apoptosis. The dysregulation of this protein ultimately leads to fibrotic diseases like POIKTMP and cancers via the disruption of these cellular processes by the mutation of the FAM111B gene. Hence, it should be studied in the context of these diseases as a possible therapeutic target.
Identification and Validation of Long Non-Coding RNA LCIIAR as a Biomarker in LUAD
Authors: Ren Wenjun , Yuan Yixiao , Chen Xi , Zhai Haoqing , An Yin , Tang Lin , Wang Juan , Zhang Dahang , Zhang Liren , Cheng Wanli , Wang Xin , Duan Lincan , Mutti Luciano , Han Bin , Wang Ping
Published: July 2022

Lung cancer is the leading cause of cancer-related death worldwide. Therapies for lung cancer have relatively poor outcomes and need to be improved. Lung cancer immune cell infiltration associated RNA (LCIIAR) is a long noncoding RNA (lncRNA), which is overexpressed in human cancers. However, the clinical significance and functional role of LCIIAR in Lung Adenocarcinoma remain unclear. Here, we identified a novel long non-coding RNA (ENSG00000256802), termed LCIIAR (lung cancer immune cell infiltration associated lncRNA), up-regulated in lung cancer tissue and cell lines. We show that increase LCIIAR expression correlated with poor clinical stage and adverse clinical outcomes and that could also serve as an independent unfavorable prognostic factor in patients with Lung Adenocarcinima. GSEA analysis demonstrated that LCIIAR is mainly involved in the regulation of the immune response. We uncovered that elevate LCIIAR expression positively correlated with immune infiltration and immune modulator in Lung Adenocarcinoma. More importantly, we confirmed that silencing of LCIIAR expression significantly inhibits the proliferation, and migration abilities of these tumour cells. We also demonstrated that the LCIIAR/hsa-miR184/SLC16A3/CDCP1 network regulates SLC16A3/CDCP1 overexpression in and is associated with poor prognosis in this tumour. Therefore our findings revealed the critical role of LCIIAR in Lung Adenocarcinoma progression, which may also serve as a prognostic biomarker and novel therapeutic target.
Potential Neuroimmune Interaction in Chronic Pain: A Review on Immune Cells in Peripheral and Central Sensitization
Authors: Yang Jia-Xuan , Wang Hong-Fei , Chen Ji-Zhun , Li Han-Yu , Hu Ji-Chen , Yu An-An , Wen Jun-Jun , Chen Si-Jia , Lai Wei-Dong , Wang Song , Jin Yan , Yu Jie
Published: July 2022

Chronic pain is a long-standing unpleasant sensory and emotional feeling that has a tremendous impact on the physiological functions of the body, manifesting itself as a dysfunction of the nervous system, which can occur with peripheral and central sensitization. Many recent studies have shown that a variety of common immune cells in the immune system are involved in chronic pain by acting on the peripheral or central nervous system, especially in the autoimmune diseases. This article reviews the mechanisms of regulation of the sensory nervous system by neutrophils, macrophages, mast cells, B cells, T cells, and central glial cells. In addition, we discuss in more detail the influence of each immune cell on the initiation, maintenance, and resolution of chronic pain. Neutrophils, macrophages, and mast cells as intrinsic immune cells can induce the transition from acute to chronic pain and its maintenance; B cells and T cells as adaptive immune cells are mainly involved in the initiation of chronic pain, and T cells also contribute to the resolution of it; the role of glial cells in the nervous system can be extended to the beginning and end of chronic pain. This article aims to promote the understanding of the neuroimmune mechanisms of chronic pain, and to provide new therapeutic ideas and strategies for the control of chronic pain at the immune cellular level.
Case Report: Diagnosis of Mucopolysaccharidosis Type IVA With Compound Heterozygous Galactosamine-6 Sulfatase Variants and Biopsy of Replaced Femoral Heads
Authors: Ma Yiyang , Peng Hao , Hsiang Fuchou , Fang Haoyu , Du Dajiang , Jiang Chenyi , Wang Yehui , Chen Chun , Zhang Changqing , Gao Yun
Published: July 2022

Introduction

Mucopolysaccharidosis Type IVA (MPS IVA) or Morquio A Syndrome, is a rare metabolic disorder caused by compromised galactosamine-6 sulfatase (GALNS) encoded by GALNS gene (NM_000512.5), leading to keratin sulfate (KS), and chondroitin-6-sulfate accumulation in various organs. We present a 17-year-old woman with progressive bilateral hip pain and radiographic evidence of spondyloepiphyseal dysplasia.

Methods

Diagnosis of MPS IVA was made based on whole-exome sequencing (WES) of blood samples collected from the patient and family members, high urinary glycosaminoglycan excretion, supportive clinical manifestations, radiographic examinations, including whole-body X-rays, cervical MRI, and pelvic CT. The patient underwent bilateral total hip arthroplasties sequentially, at a 1-month interval. Femoral heads were preserved for the micro-CT (μCT) analysis and the osteochondral histology examination.

Results

The patient presented with multiple skeletal deformities, including vertebras and long bone deformities. WES disclosed compound heterozygous variants at exon 11 (c.1156C>T) and exon 12 (c.1288C>G) of the GALNS (NM_000512.5). The μCT analysis revealed significant bone quantity loss and microarchitectural change in both weight-bearing area (WBA) and non-weight-bearing area (NWBA) of the femoral heads, while histological analysis showed structural abnormity of articular cartilage in the WBA of the femoral heads.

Conclusion

We have found compound heterozygous variants of GALNS. This is also the first study to report the microarchitectural and histological changes of both subchondral bone and articular cartilage of the femoral head in a patient with MPS IVA.
Adverse Events of DOACs in Children
Authors: Bosch Alessandra , Albisetti Manuela
Published: July 2022

Venous thromboembolism (VTE) has an increasing rate of significance in pediatric patients. The currently standardized anticoagulants (unfractionated heparin, low molecular weight heparin and vitamin K antagonists) and their dose regimens were not comprehensively trialed in pediatric patients. Recently, several direct oral anticoagulants (DOACs) have been studied in clinical trials in the pediatric population and further trials are ongoing. Dabigatran etexilate and rivaroxaban results show that these DOACs are safe and efficient in the treatment and secondary prevention of pediatric VTE. This review will focus on adverse events (AEs) between specific DOACs reported in the clinical trials in children and compare them to standard of care. This will assist clinicians in decision making of selecting the right anticoagulation for their pediatric patients.
ANGPTL4 Regulates Psoriasis via Modulating Hyperproliferation and Inflammation of Keratinocytes
Authors: Zuo Yuyue , Dai Lei , Li Li , Huang Yuqiong , Liu Xinxin , Liu Xin , Duan Xiaoru , Jiang Su , Deng Guo-Min , Chen Hongxiang
Published: July 2022

Background: Psoriasis is characterized by keratinocyte proliferation and massive inflammatory leukocytes infiltration, affecting 0.14%–1.99% of the world’s population. Our aim was to identify novel potential therapeutic strategies for psoriasis.

Methods: Weighted gene co-expression network analysis (WGCNA) was performed to identify gene modules that were closely related to psoriasis based on the GSE30999 dataset, which contained expression data from 85 patients with moderate-to-severe psoriasis. Then, angiopoietin-like 4 (ANGPTL4), one of the most related hub genes, was selected for in vitro and in vivo functional assays. In our experiments, imiquimod (IMQ)-induced psoriasiform dermatitis in mice and human keratinocytes (HaCaT) cells were used to study the potential roles and mechanisms of ANGPTL4 in psoriasis.

Results: WGCNA analysis revealed the turquoise module was most correlated with psoriasis, and ANGPTL4 is one of the most related hub genes that significantly upregulated in psoriasis lesions compared with non-lesional skin. Consistent with the bioinformatic analysis, the expression of ANGPTL4 was significantly upregulated in IMQ-induced psoriasiform skin of mice. Exogenous recombinant ANGPLT4 protein treatment could promote the proliferation and induce the expression of inflammatory cytokines in HaCaTs, whereas silencing of ANGPTL4 effectively inhibited these effects. Then we demonstrated that recombinant ANGPTL4 protein exacerbated psoriasiform inflammation and epidermal hyperproliferation in vivo. Mechanismly, extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) pathways were involved in ANGPTL4-mediated regulation of proliferation and inflammation.

Conclusion: We found ANGPTL4 was significantly increased in IMQ-induced psoriasiform skin of mice. ANGPTL4 could promote keratinocyte proliferation and inflammatory response via ERK1/2 and STAT3 dependent signaling pathways in psoriasis.
Population Pharmacokinetics and Dosing Regimen of Lithium in Chinese Patients With Bipolar Disorder
Authors: Jin Zi-bin , Wu Zhuo , Cui Yi-fan , Liu Xue-peng , Liang Hong-bo , You Jia-yong , Wang Chen-yu
Published: July 2022

Background: Lithium is an effective medication approved for the treatment of bipolar disorder (BD). It has a narrow therapeutic index (TI) and requires therapeutic drug monitoring. This study aimed to conduct a population pharmacokinetics (PPK) analysis of lithium and investigate the appropriateness of the dosing regimen according to different patient characteristics.

Methods: A total of 476 lithium concentrations from 268 patients with bipolar disorder were analyzed using nonlinear mixed-effects modeling. Monte Carlo simulations were employed to investigate the influence of covariates, such as weight, creatinine clearance, and daily doses of lithium concentrations, and to determine the individualized dosing regimens for patients.

Results: Lithium PK was described by a one-compartment model with first-order absorption and elimination processes. The typical estimated apparent clearance was 0.909 L/h−1 with 16.4% between-subject variability in the 62 kg patients with 116 ml/min creatinine clearance and 600 mg daily doses. To achieve a target trough concentration (0.4–0.8 mmol/L) in the maintenance phase, the regimen of 500 mg than 750 mg daily dose was recommended for patients with renal insufficiency and weighing 100 kg.

Conclusion: A PPK model for lithium was developed to determine the influence of patient characteristics on lithium pharmacokinetics. Weight, creatinine clearance, and total daily dose of lithium can affect the drug’s clearance. These results demonstrate the nonlinear renal excretion of lithium; hence, dosage adjustments are recommended for patients with renal insufficiency.
Hepatitis B Virus Reactivation and Mycobacterial Infections Associated With Ustekinumab: A Retrospective Study of an International Pharmacovigilance Database
Authors: Wang Jingjing , Geng Xiaozhen , Zhang Xin , Xiao Yanfeng , Wang Wenjun
Published: July 2022

Background: Reports were recently published on hepatitis B virus reactivation (HBVr), tuberculosis (TB), and atypical mycobacterial infection (AMI) in patients with ustekinumab treatment. However, the literature is limited to case reports and series. The study was aimed to investigate their relationships by using an extensive population-based database.

Methods: Using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database, we collected all cases of HBVr, TB, and AMI between 1 January 2009 and 30 September 2021, for ustekinumab and other drugs. Disproportionality was analyzed using the reporting odds ratio (ROR), which was considered significant when the lower limit of the 95% confidence interval (95% CI) was >1.

Results: Of the 18,760,438 adverse cases reported to FAERS for all drugs, 56,581 cases had been exposed to ustekinumab. Adverse events of HBVr, TB, and AMI were reported in 21, 210, and 20 cases, respectively. The ROR for HBVr with ustekinumab was 2.33 (95% CI, 1.52–3.58), for TB was 5.09 (95% CI, 4.44–5.84), and for AMI was 2.09 (95% CI, 1.35–3.24). In the ustekinumab exposure group, no death occurred in patients with HBVr, but one patient experienced life-threatening liver failure. For those with TB, 24 cases experienced hospitalization and 2 deaths occurred. No death occurred in patients with AMI but eight experienced hospitalization.

Conclusion: We identified positive signals between ustekinumab exposure and HBVr, TB, and AMI in FAERS. Although these complications are rare, clinicians using ustekinumab should be aware of the risks.
Continuous and Discrete Deformation Modes of Mechanical Metamaterials With Ring-Like Unit Cells
Authors: Yang Nan , Zhuang Juncheng , Wei Shichuan , Yu Ying
Published: July 2022

Structures with multiple deformation paths provide a promising platform for robotics and reprogrammable mechanical and thermal deformation materials. Reconfigurations with a multi-path can fulfill many tasks (e.g., walking and grasping) and possess multiple properties (e.g., targeted Poisson’s ratio and thermal expansion coefficient). Here, we proposed a new ring-like kirigami structure and theoretically and experimentally found that for a basic unit, there are four discrete deformation patterns and a continuous shearing deformation pattern; thus, there are a large number of discrete deformation patterns for a multi-unit combination with geometrical compatibility coupled with a shearing deformation mode. Moreover, targeted Poisson’s ratios (either + or -) in the x- and y-directions can be realized by inversely designing the geometrical parameters for a certain deformation path. Additionally, we showed the capability of constructing 2D and 3D cellular structures in various patterns with the proposed ring-like units. The multiple deformation modes demonstrated here open up avenues to design new reprogrammable materials and robots across various scales.