bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zilucoplan, a macrocyclic peptide inhibitor of human complement component 5, uses a dual mode of action to prevent terminal complement pathway activation
Authors: Tang Guo-Qing , Tang Yalan , Dhamnaskar Ketki , Hoarty Michelle D. , Vyasamneni Rohit , Vadysirisack Douangsone D. , Ma Zhong , Zhu Nanqun , Wang Jian-Guo , Bu Charlie , Cong Bestine , Palmer Elizabeth , Duda Petra W. , Sayegh Camil , Ricardo Alonso 
Published: August 2023

IntroductionThe complement system is a key component of the innate immune system, and its aberrant activation underlies the pathophysiology of various diseases. Zilucoplan is a macrocyclic peptide that binds and inhibits the cleavage/activation of human complement component 5 (C5). We present in vitro and ex vivo data on the mechanism of action of zilucoplan for the inhibition of C5 activation, including two clinically relevant C5 polymorphisms at R885.MethodsThe interaction of zilucoplan with C5, including for clinical C5 R885 variants, was investigated using surface plasmon resonance (SPR), hemolysis assays, and ELISA. The interference of C5b6 formation by zilucoplan was investigated by native gel analysis and hemolysis assay. The permeability of zilucoplan in a reconstituted basement membrane was assessed by the partition of zilucoplan on Matrigel-coated transwell chambers.ResultsZilucoplan specifically bound human complement C5 with high affinity, competitively inhibited the binding of C5 to C3b, and blocked C5 cleavage by C5 convertases and the assembly of the cytolytic membrane attack complex (MAC, or C5b9). Zilucoplan fully prevented the in vitro activation of C5 clinical variants at R885 that have been previously reported to respond poorly to eculizumab treatment. Zilucoplan was further demonstrated to interfere with the formation of C5b6 and inhibit red blood cell (RBC) hemolysis induced by plasmin-mediated non-canonical C5 activation. Zilucoplan demonstrated greater permeability than a monoclonal C5 antibody in a reconstituted basement membrane model, providing a rationale for the rapid onset of action of zilucoplan observed in clinical studies.ConclusionOur findings demonstrate that zilucoplan uses a dual mode of action to potently inhibit the activation of C5 and terminal complement pathway including wild-type and clinical R885 variants that do not respond to eculizumab treatment. These data may be relevant to the clinically demonstrated benefits of zilucoplan.
Megakaryocyte NLRP3 hyperactivation induces mild anemia and potentiates inflammatory response in mice
Authors: Bourne Joshua H. , Campos Joana , Hopkin Sophie J. , Whitworth Katharine , Palis James , Senis Yotis A. , Rayes Julie , Iqbal Asif J. , Brill Alexander 
Published: August 2023

BackgroundThe NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been described in both immune cells and platelets, but its role in the megakaryocyte (MK) lineage remains elusive.ObjectiveThe aim of this study was to explore the role of NLRP3 inflammasome in megakaryocytes and platelets.MethodsWe generated Nlrp3A350V/+/Gp1ba-CreKI/+ mice carrying a mutation genetically similar to the one observed in human Muckle–Wells syndrome, which leads to hyperactivity of NLRP3 specifically in MK and platelets.ResultsPlatelets from the mutant mice expressed elevated levels of both precursor and active form of caspase-1, suggesting hyperactivity of NLRP3 inflammasome. Nlrp3A350V/+/Gp1ba-CreKI/+ mice developed normally and had normal platelet counts. Expression of major platelet receptors, platelet aggregation, platelet deposition on collagen under shear, and deep vein thrombosis were unchanged. Nlrp3A350V/+/Gp1ba-CreKI/+ mice had mild anemia, reduced Ter119+ cells in the bone marrow, and splenomegaly. A mild increase in MK TGF-β1 might be involved in the anemic phenotype. Intraperitoneal injection of zymosan in Nlrp3A350V/+/Gp1ba-CreKI/+ mice induced increased neutrophil egression and elevated levels of a set of proinflammatory cytokines, alongside IL-10 and G-CSF, in the peritoneal fluid as compared with control animals.ConclusionMK/platelet NLRP3 inflammasome promotes the acute inflammatory response and its hyperactivation in mice leads to mild anemia and increased extramedullary erythropoiesis.
The marine diatom Thalassiosira rotula: chemical profile and antioxidant activity of hydroalcoholic extracts
Authors: Frleta Matas Roberta , Popović Marijana , Čagalj Martina , Šimat Vida 
Published: August 2023

The cosmopolitan centric diatom Thalassiosira rotula produces compounds in its natural habitat that can inhibit copepod reproduction. Moreover, it has been reported to possess compounds with therapeutic effects beneficial for health care. In this experiment, the extraction yield, total phenolic content (TPC), antioxidant activity by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging ability, ferric reducing/antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC), and chemical profile by gas chromatography-mass spectrometry (GC-MS) analyses of T. rotula were investigated. Extractions were performed with 50% and 70% ethanol. A higher extraction yield [0.21 ± 0.01 g extract/g dry weight (DW) diatom] was observed for 70% ethanol. In addition, higher TPC (5.80 ± 0.32 mg gallic acid equivalents (GAE)/g DW diatom) and antioxidant activity [DPPH inhibition of 17.53% ± 0.56%, FRAP of 766.67 ± 34.69 µM Trolox equivalents (TE), and ORAC of 58.87 ± 2.03 µM TE] were observed for this extract. Myristic acid, palmitelaidic acid, palmitic acid, eicosapentaenoic acid, 24-methylenecholesterol, and docosapentaenoic acid were identified as dominant compounds in both extracts, while extraction in 70% ethanol yielded a higher content of fatty acids such as myristic acid, eicosapentaenoic acid, docosapentaenoic acid, and sterol 24-methylenecholesterol. Thus, it can be concluded that extraction of T. rotula with 70% ethanol improves antioxidant activity and provides a higher yield of compounds such as polyunsaturated fatty acids and sterols. Therefore, the species T. rotula could be considered a sustainable source of essential fatty acids and other bioactive compounds for further applications.
Genetic and geographic influence on phenotypic variation in European sarcoidosis patients
Authors: Freitag-Wolf Sandra , Schupp Jonas C. , Frye Björn C. , Fischer Annegret , Anwar Raihanatul , Kieszko Robert , Mihailović-Vučinić Violeta , Milanowski Janusz , Jovanovic Dragana , Zissel Gernot , Bargagli Elena , Rottoli Paola , Bumbacea Dragos , Jonkers René , Ho Ling-Pei , Gaede Karoline I. , Dubaniewicz Anna , Marshall Ben G. , Günther Andreas , Petrek Martin , Keane Michael P. , Haraldsdottir Sigridur O. , Bonella Francesco , Grah Christian , Peroš-Golubičić Tatjana , Kadija Zamir , Pabst Stefan , Grohé Christian , Strausz János , Safrankova Martina , Millar Ann , Homolka Jiří , Wuyts Wim A. , Spencer Lisa G. , Pfeifer Michael , Valeyre Dominique , Poletti Venerino , Wirtz Hubertus , Prasse Antje , Schreiber Stefan , Dempfle Astrid , Müller-Quernheim Joachim 
Published: August 2023

IntroductionSarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures.MethodsAfter obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations.ResultsIn the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement.DiscussionThe observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene–environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.
Visualization of the entire process of rice spikelet infection by Ustilaginoidea virens through nondestructive inoculation
Authors: Hu Xianfeng , Wang Jian , Zhang Yubo , Wu Xiaomao , Li Rongyu , Li Ming 
Published: August 2023

IntroductionRice false smut caused by Ustilaginoidea virens, is a destructive fungal disease encountered in many rice-producing areas worldwide. To determine the process by which U. virens infects rice spikelets in the field.MethodsThe green fluorescent protein-labeled U. virens was used as an inoculum to conduct artificial inoculation on rice at the booting stage via non-destructive panicle sheath instillation inoculation.ResultsThe results showed that the conidia of U. virens germinated on the surface of rice glumes and produced hyphae, which clustered at the mouth of rice glumes and entered the glumes through the gap between the palea and lemma. The conidia of U. virens colonized in rice floral organs, which led to pollen abortion of rice. U. virens wrapped the whole rice floral organ, and the floral organ-hyphae complex gradually expanded to open the glumes to form a rice false smut ball, which was two to three times larger than that observed in normal rice.DiscussionPanicle sheath instillation inoculation was shown to be a non-destructive inoculation method that could simulate the natural infection of U. virens in the field. The entire infection process of U. virens was visualized, providing a theoretical reference for formulating strategies to control rice false smut in the field.
Genetic analysis of acute intermittent porphyria caused by novel classical splicing variant in the insertion region of 29-residue specific to human HMBS protein
Authors: Liang Lei , Meng Haixia , Wu Haotian , Zhao Jianrong 
Published: August 2023

Background: Acute intermittent porphyria (AIP; OMIM#176000) is a genetic disorder that is caused by mutations in the hydroxymethylbilane synthetase (HMBS) gene. This gene encodes the third enzyme in the heme biosynthesis pathway. Human HMBS (hHMBS) contains a 29-residue insert (residues 296-324) at the interface between domains 1 and 3. The function of this insert is currently unknown. In this study, a previously unidentified classical Splicing variant was discovered in the HMBS gene of a female AIP patient from China. The variant was validated through comparison with the patient’s husband and daughter.Methods: Peripheral blood samples were obtained from the patient, the patient’s husband, and their daughter. Gene expression was analyzed using whole exon sequencing and Sanger sequencing. To validate alternative splicing, RNA was extracted from the patient’s peripheral blood and reverse transcribed into cDNA. Aberrant splicing caused by variants was predicted using I-TASSER and PyMOL software to simulate protein structures. Finally, molecular dynamics of the proteins were simulated using the AMBER14sb software.Results: The patient and her daughter have a classical Splicing variant c.912 + 1G&gt;C of the HMBS gene. This variant was not found in the patient’s husband and has not been previously reported in scientific literature. Analysis of the patient’s peripheral blood transcripts revealed that c.912 + 1G&gt;C retained intron 13 and resulted in an exon 13 skipping. Further analysis through homology modelling and molecular dynamics showed that this variant alters the secondary structure of the HMBS protein, leading to functional differences.Conclusion: This research has discovered a new classical Splicing variant c.912 + 1G&gt;C in the HMBS gene that has been identified as pathogenic. This finding not only expands the molecular heterogeneity of AIP but also provides crucial information for genetic diagnosis.
Association of sleep disorders with clinical symptoms and age in Chinese older adult patients with and without cognitive decline
Authors: Mei Xi , Zhao Zheng , Qiu Zhengfa , Wang Juan , Yu Haihang , Zheng Chengying 
Published: August 2023

ObjectiveTo investigate correlation between cognitive function, age, and sleep disturbances.MethodsThis retrospective clinical study enrolled 78 patients with sleep disorders who were divided into three groups: a group of 24 patients with sleep disorders accompanied by cognitive decline (SD-CD); 54 patients with sleep disorders and no cognitive decline (SD-nCD) was divided into two groups, one of 30 patients aged between 60 and 70 years and another of 24 patients aged &gt;70 years. Polysomnography was used to record patients’ sleep indicators throughout night; these included total sleep duration, sleep efficiency (SE), sleep latency, sleep structure and percentage of N1, N2, and N3 stages, rapid eye movement (REM) stage, as well as apnea hypopnea index (AHI), and oxygen saturation (OS). Analysis of variance (ANOVA) for continuous variables and chi-square test for categorical variables were used to analyze variables between different groups. Pearson’s correlation was used to analyze correlation between sleep parameters and mini-mental state examination (MMSE). Blood samples were used to determine their Aβ, Aβ40, Aβ42, total tau, phosphorylated tau protein (ptau), ptau181, ptau217, the inflammatory factor IL-1β, vitamin B12 (VB12), and melatonin levels.ResultsIn the SD-CD group, there was a significant decrease in SE and an increase in N1 stage sleep in older patients and a significant increase in AHI, REM stage AHI, and non-REM stage AHI. In patients with SD-nCD, the minimum OS, minimum OS in the REM period, and minimum OS in the non-REM period were significantly reduced. OS was significantly correlated with cognitive level, as evaluated by the MMSE. The addition of sleep parameters can significantly improve the accuracy of dementia diagnosis. Dementia biomarkers of Aβ and tau proteins in blood showed cognition-related differences, while ptau181 was associated with both cognition and age-related differences. Regression models revealed that age was related to higher levels of cognitive decline before (β = −0.43, P &lt; 0.001) and after (β = −0.38, P &lt; 0.001) adjustment of gender, BMI, and education level. There was a significant mediation effect of relationship between aging and cognitive function by sleep efficiency and N1 stage sleep.ConclusionSleep disorders and low OS are associated with a higher incidence of cognitive decline and dementia.
Not your usual neurodegenerative disease: a case report of neuronal intranuclear inclusion disease with unconventional imaging patterns
Authors: Xu Luyao , Zhang Hongxia , Yuan Hanye , Xie Liwen , Zhang Junliang , Liang Zhigang 
Published: August 2023

BackgroundNeuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative illness with characteristic brain magnetic resonance imaging (MRI) manifestations: diffuse symmetric white-matter hyperintensities in lateral cerebral ventricle areas in fluid-attenuated inversion recovery (FLAIR) and high-intensity signals along the corticomedullary junction of the frontal–parietal–temporal lobes in diffusion weighted imaging (DWI). Here, we report a case of adult-onset NIID who was misdiagnosed with Susac syndrome (SS) due to unusual corpus callosum imaging findings.Case presentationA 39-year-old man presented with chronic headache, blurred vision, tinnitus, and numbness in the hands as initial symptoms, accompanied by cognitive slowing and decreased memory. Brain MRI revealed round hypointense lesions on T1-weighted imaging (T1WI) and hyperintense lesions on T2WI/FLAIR/DWI in the genu and splenium of the corpus callosum. An initial diagnosis of SS was made based on the presence of the SS-typical symptoms and SS-characteristic radiology changes. Furthermore, the patient’s symptoms improved upon completion of a combined pharmacotherapy plan. However, no significant changes were evident 18 months after the brain MRI scan. Eventually, the patient was then diagnosed with NIID based on a skin biopsy and detection of expanded GGC (guanine, guanine, cytosine) repeats in the NOTCH2NLC gene.ConclusionThe present NIID case in which there was simultaneous onset of altered nervous and visual system functioning and atypical imaging findings, the atypical imaging findings may reflect an initial change of NIID leukoencephalopathy.
Association between green tea and coffee consumption and body iron storage in Japanese men and women: a cross-sectional study from the J-MICC Study Saga
Authors: Nanri Hinako , Hara Megumi , Nishida Yuichiro , Shimanoe Chisato , Iwasaka Chiharu , Higaki Yasuki , Tanaka Keitaro 
Published: August 2023

PurposeThis study examined the association between daily green tea and coffee consumption and body iron stores among Japanese middle-aged and older adults.MethodsThis cross-sectional study used data obtained from 2005 to 2007. A total of 10,435 participants were recruited for this study. The participants completed a validated, self-administered food frequency questionnaire on green tea and coffee consumption. A multivariate linear regression analysis was conducted to assess the relationship between green tea and coffee consumption and serum ferritin levels. Additionally, logistic regression analysis was performed to ascertain whether excessive consumption of these beverages was linked to iron deficiency.ResultsWe observed that higher green tea and coffee consumption was associated with lower ferritin levels in men and postmenopausal women, even after adjusting for covariates (all P for trends &lt;0.05). Among premenopausal women, we found an inverse association between green tea consumption and serum ferritin levels, while no significant association was observed for coffee consumption after adjusting for covariates (green tea, P for trend &lt;0.05; coffee, P for trend = 0.08). Notably, the association between these beverages and iron deficiency was found only in postmenopausal women; the odds ratios (95% confidence intervals) for iron deficiency associated with almost None, &lt;1 cup/day, 1–2 cups/day, and ≥ 3 cups/day were 1.00 (reference), 0.78 (0.26–2.49), 1.29 (0.49–3.39), and 1.59 (0.63–4.04) (P for trend = 0.05), respectively, for green tea and 1.00, 1.32 (0.64–2.73), 1.46 (0.68–3.13), and 2.20 (1.06–4.55) (P for trend &lt;0.01), respectively, for coffee.ConclusionHigher green tea and coffee consumption was associated with lower serum ferritin levels in men and postmenopausal women. In premenopausal women, consumption of green tea, but not coffee, was associated with lower serum ferritin levels. However, postmenopausal women who ≥3 cups of coffee demonstrated a higher prevalence of iron deficiency compared to those who consumed almost none.
The incidence and mortality of lung cancer in China: a trend analysis and comparison with G20 based on the Global Burden of Disease Study 2019
Authors: Long Jianhai , Zhai Mimi , Jiang Qin , Li Jiyang , Xu Cixian , Chen Duo 
Published: August 2023

BackgroundLung cancer is a significant health concern in China. There is limited available data of its burden and trends. This study aims to evaluate the trends of lung cancer across different age groups and genders in China and the Group of Twenty (G20) countries, explore the risk factors, and predict the future trends over a 20-year period.MethodsThe data were obtained from the GBD study 2019. The number of cases, age standardized rate (ASR), and average annual percentage changes (AAPC) were used to estimate the trend in lung cancer by age, gender, region and risk factor. The trend of lung cancer was predicted by autoregressive integrated moving average (ARIMA) model by the “xtarimau” command. The joinpoint regression analysis was conducted to identify periods with the highest changes in incidence and mortality. Additionally, the relationship between AAPCs and socio-demographic index (SDI) was explored.ResultsFrom 1990 to 2019, both the incidence and mortality of lung cancer in China and G20 significantly increased, with China experiencing a higher rate of increase. The years with the highest increase in incidence of lung cancer in China were 1998-2004 and 2007-2010. Among the G20 countries, the AAPC in incidence and mortality of lung cancer in the Republic of Korea was the highest, followed closely by China. Although India exhibited similarities, its AAPC in lung cancer incidence and mortality rates was lower than that of China. The prediction showed that the incidence in China will continue to increase. In terms of risk factors, smoking was the leading attributable cause of mortality in all countries, followed by occupational risk and ambient particulate matter pollution. Notably, smoking in China exhibited the largest increase among the G20 countries, with ambient particulate matter pollution ranking second.ConclusionLung cancer is a serious public health concern in China, with smoking and environmental particulate pollution identified as the most important risk factors. The incidence and mortality rates are expected to continue to increase, which places higher demands on China’s lung cancer prevention and control strategies. It is urgent to tailor intervention measures targeting smoking and environmental pollution to contain the burden of lung cancer.