bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammatory Manifestation of Middle Cerebral Artery Atherosclerotic Plaque Enhancement on High-resolution Vessel Wall MRI
Authors: Wu Xiao , Huang LiXin , Lu Li-Ming , Luo Bin , Cai Wang-Qing , Wang Sheng-Wen
Published: May 2022

Background and purpose: Gadolinium enhancement on high-resolution vessel wall magnetic resonance imaging (HR-VWI) is a marker of instability in intracranial atherosclerotic plaques. This study aims to evaluate the role of hematological inflammatory indicators (the neutrophil-to-lymphocyte ratio [NLR], the lymphocyte-to-monocyte ratio [LMR], and systemic immune inflammation index [SII]) in predicting middle cerebral artery (MCA) atherosclerotic plaque enhancement.Methods: Adult patients diagnosed with MCA atherosclerotic stenosis from August 2018 to October 2021 were recruited retrospectively. Clinical and laboratory data, including neutrophil, lymphocyte, monocyte, and platelet counts, were collected, and then the NLR, LMR, and SII were calculated. The hematological inflammatory indicators were compared in MCA atherosclerotic stenosis patients with and without plaque enhancement. Multivariable logistic regression analyses were performed to explore the factors that can predict MCA atherosclerotic plaque enhancement. We also used receiver operating characteristic curve analysis to assess the discriminative ability of inflammatory indicators in predicting plaque enhancement.Results: Forty-two patients (mean age 57.3 ± 9.5 and 66.7% male) were included. A higher NLR (P = 0.001) and SII (P = 0.017) and a lower LMR (P < 0.001) were significantly associated with MCA plaque enhancement. The cutoff value of the admission LMR that best-discriminated plaque enhancement was 4.0 (72.2% sensitivity and 87.5% specificity) on the receiver operating characteristic curve analysis. The NLR, LMR, and plaque enhancement were significantly associated with symptomatic MCA stenosis, and the multiple logistic regression analysis showed that only plaque enhancement was an independent risk factor for symptomatic MCA stenosis.Conclusion: There was a significant correlation between plaque enhancement and hematological inflammatory indicators. The LMR was an independent risk factor for MCA atherosclerotic plaque enhancement, and an LMR ≤ 4.0 may predict plaque enhancement.
IL4-dependent M2 macrophage mediates fibrotic scar formation and functional restoration via Sonic Hedgehog/TGFβ1 axis in the early stage of cerebral ischemia in rats
Authors: Huang Jiagui , Ren Jiangxia , Chen Yue , Tian Mingfen , Zhou Li , Wen Jun , Song Xiaosong , Wu Youlin , Yang Qinghuan , Jiang Peiran , Wang Jiani , Yang Qin
Published: May 2022

Background: Fibrotic scar of the central nervous system (CNS) has dual roles for inhibiting axon regeneration and promoting repair. However, it is poorly understood for formed and regulated mechanisms. M2 macrophages regulate fibrotic scar formation after heart, lung, kidney, and CNS injury, but the regulated mechanisms are unclear. Interleukin 4 (IL4) plays a decisive role for M2 macrophage polarization. Sonic Hedgehog (Shh) signaling can regulate fibrosis of central and peripheral tissues. Therefore, we hypothesized that IL4-dependent M2 macrophage regulated fibrotic scar formation and functional restoration via Shh/TGFβ1 axis in the early stage of cerebral ischemia in rats. Methods: Rats after middle cerebral artery occlusion/reperfusion (MCAO/R) were injected with drugs and adenovirus vectors by intracerebroventricular injection. Invasive macrophages, fibrotic scar, Shh signaling, neovascularization, and cell apoptosis were then detected. Cultured macrophages were treated with drugs and adenovirus vectors, and evaluated the underlying mechanism using western blot and immunofluorescence. We also examined the effects of macrophage conditioned medium on the functions of fibroblasts.Results: We found that cerebral ischemia induced persistent fibrosis and massive macrophages infiltration in the ischemic core in rats. Moreover, numbers of infiltrated macrophages were a robust positive correlation with fibronectin (FN) expression. Depletion of circulating monocyte-derived macrophages by clodronate liposomal attenuated fibrotic scar. Further, IL4 was strongly enhanced in the ischemic cerebral tissues and IL4-dependant M2 macrophages polarization was susceptible to fibrotic scar formation in the ischemic core in rats. At the same time, macrophage conditioned medium could directly promote fibroblast proliferation as well as extracellular matrix (ECM) proteins generation in vitro. Using pharmacological and genetic approaches, we showed that Shh protein, secreted by M2 macrophage, promoted fibrogenesis in vitro and in vivo, which was mediated by secreting key fibrosis-associated regulatory proteins TGFβ1 and MMP9. At the same time, IL4-afforded functional restoration on angiogenesis, cell apoptosis and infarct volume in the ischemic core from MCAO/R rats were markedly impaired by the Shh signaling inhibitor, and parallel with the extent of fibrosis. Conclusions: We identified that IL4-dependent M2 macrophage regulated fibrotic scar formation via Shh/TGFβ1 axis, thereby enhancing angiogenesis and reducing ischemic injury.
A tuff interlayer in deep potash-bearing salt rocks and its implication for potash mineralization in the Simao Basin, southwestern China
Authors: Miao Zhong-ying , Zheng Mian-ping , Lou Peng-cheng , Wang Dong , Xu Qi-hui , Xu Jian-ming
Published: May 2022

The lithology and genesis of a dark gray clastic interlayer firstly and only encountered within the deepest potassium-rich salt body in the Simao Basin, southwestern China, were analyzed with SEM and ICP-MS. The petrology, mineralogy, element geochemistry analyses of the layer reveal that: 1) the layer contains crystal fragments with irregular cracks, angular volcanic glasses as well as quartz crystals with gulf corrosion edge and explosion cracks. 2) The main mineral components are chlorite, illite, biotite, quartz, crystal fragments, glass shard, anhydrite, gypsum, magnesite, pyrite, molybdenite, clinopyroxene, and zircon. 3) The rare earth element patterns, Zr/TiO2 and Nb/Y diagrams as well as boron content, all indicate a volcanic origin of the layer. Based on these observations, the layer is suggested to be an altered tuff associated with variety of volcanic fragments dominated by chlorite and formed after alteration of a parent tuff in an alkaline, salty, and low-temperature water body. The discovery of the layer not only indicates that the potash-bearing salt rocks could have taken in volcanic materials during these volcanic activities, but also provides a possibility of reliable zircon U-Pb dating for the absolute age of the host rock, which is vital for the genetic mechanism study of this deeply buried salt body. Furthermore, the layer may carry with it valuable information of volcanic and tectonic activities triggered by the closure of Meso-Tethys.
Voxelwise structural equation modeling: Which model explains cognitive change in the ageing brain?
Authors: Koten Jan Willem , Koschutnig Karl , Wood Guilherme
Published: May 2022

In this diffusion tension imaging study, voxel wise structural equation modeling was used to unravel the relation between white matter, cognition, and age. In total four models were tested but only two models survived the testing procedure. The independent factor model predicts that there is no relation between white matter and cognition although both systems are affected by age. The cognitive mediation model predicts that the relation between age and white matter is mediated through cognition. Roughly 60 percent of the observed voxels were in agreement with the independent factor model while 16 percent of the observed voxels were in agreement with the cognitive mediation model.
Title of the paper: Panobinostat (LBH589) increase survival in adult xenografic model of Acute Lymphoblastic Leukemia with t(4;11) but promotes antagonistic effects in combination with MTX and 6MP
Authors: Moreno Daniel Antunes , Junior Howard Lopes Ribeiro , Laranjeira Angelo Brunelli Albertoni , Cruzeiro Gustavo Alencastro Veiga , Borges Kleiton Silva , Salomão Karina Bezerra , Ramalho Fernando Silva , Yunes José Andres , Silva Cleide Lúcia Araújo , Rego Eduardo Magalhães , Scrideli Carlos Alberto , Tone Luiz Gonzaga
Published: May 2022

Patients diagnosed with acute lymphoblastic leukemia (ALL) bearing t(4;11)/MLL-AF4 have aggressive clinical features, poor prognosis and there’s an urgent need for new therapies to improve outcomes. Panobinostat (LBH589) has been identified as a potential therapeutic agent for ALL with t(4;11) and studies suggest that the antineoplastic effects is associated with reduced MLL-AF4 fusion protein and reduced expression of HOX genes. Here, we evaluated the in vitro effects of the combination of LBH589 with methotrexate (MTX) or 6-mercaptopurine (6MP) by cell proliferation assays and Calcusyn software in ALL cell line (RS4;11); the in vivo effects of LBH589 in xenotransplanted NOD-scid IL2Rgammanull mice meansuring human lymphoblasts by flow cytometry; and the expression of HOX genes by qPCR after treatment in an adult model of ALL with t(4;11). LBH589 combination with MTX or 6MP did not promote synergistic effects in RS4;11 cell line. LBH589 treatment leads to increased overall survival and reduction of blasts in xenotransplanted mice but caused no significant changes in HOXA7, HOXA9, HOXA10, and MEIS1 expression. The LBH589, alone, showed promising antineoplastic effects in vivo and may represent a potential agent for chemotherapy in ALL patients with t(4;11).
Practical examining performance of the FDM 3D printed parts
Authors: Baraheni Mohammad , Shabgard Mohammad Reza , Tabatabaee Ali Mahdavi , Adhami Amir Hossein
Published: May 2022

Fused Deposition Modelling (FDM) is a 3D-printing technique that is used for prototyping. Because of FDM application in various industries such as medical instruments and aerospace, the produced part surface quality, dimensional accuracy and mechanical properties are brought to attention in recent years. Optimizing the process parameters helps to enhance the mentioned products properties. In this paper, influential process parameters including print speed, infill percentage and nozzle temperature were selected to examine. That was concluded nozzle temperature and infill percentage increasing and print speed decreasing enhance dimensional accuracy. Density of the FDM part was affected mostly by infill percentage. Desirability method was used in order to conduct optimization. That was resulted nozzle temperature of 240°C, infill percentage of 50% and print speed of 54 mm/min are the optimum parameters. Besides, verification tests were carried out and maximum error of 7.5% were reported which shows the optimization confidence. In the following, part geometry influence on the final part surface roughness and dimensional accuracy was examined. The experiments demonstrated cube geometry has the least surface roughness and dimensional error that was due to independent motion of the axes. Also cone geometry has the highest dimensional error and surface roughness which was due to simultaneous axes motion and lateral face with lower than 90°.
Long-term upland-paddy rotation effect on the soil C and N stocks in the middle and lower reaches of the Yangtze River
Authors: Wang Mengjia , Feng Xiangqian , Ma Hengyu , Chu Guang , Xu Chunmei , Liu Yuanhui , Zhang Xiufu , Wang Danying , Chen Song
Published: May 2022

Observations of the effects of long-term paddy-upland rotations on soil carbon (C) and nitrogen (N) stocks are scarce. This experiment used four paddy-upland rotation systems with summer rice as the main crop: rice-winter fallow (RF), rice-potato with rice straw mulch and return (RP), rice-wheat (RW), and rice-Chinese milk vetch (RC) with the return of winter crop residues (from 2003 to the present) to examine the soil C and N stock characteristics in the 0–50 cm soil layer. The results showed that in the topsoil at 50 cm, compared to RF, both RP and RC increased the soil organic carbon (SOC) stock by 19.67% and 15.29%, the total nitrogen (TN) stock by 20.40% and 18.54%, and the available nitrogen (AN) density by 61.54% and 34.44%, respectively; in particular, the increases in the TN and AN at 20–30 cm were likely to increase the rice yield. RW increased only the AN density by 30.24% compared with RF. Furthermore, the highest SOC, TN, and AN densities were all observed in RP. Except for TN at 30–40 cm, the densities of SOC, TN, and AN in RP were slightly greater than those in the other treatments due to the high C and N concentrations at 0–40 cm; thus rice-potato with rice straw mulch was the best choice for increasing soil C and N accumulation and improving rice yield. In addition, SOC, TN, and AN had obvious stratification and surface aggregation characteristics at 0–50 cm, and 72.17%–83.37% of the total SOC stock, 75.70%–80.48% of the total TN stock and 75.69%–81.08% of the total AN density were concentrated in the top 30 cm. However, the characteristics were dependent on the residues.
Research on non-destructive testing of hotpot oil quality by Fluorescence Hyperspectral Technology combined with machine learning
Authors: Zou Zhiyong , Wu Qingsong , Wang Jian , Xu lijia , Zhou Man , Lu Zhiwei , He Yong , Wang Yuchao , Liu Bi , Zhao Yongpeng , Zhao Yongpeng
Published: May 2022

Eating repeatedly used hotpot oil will cause serious harm to human health. In order to realize rapid non-destructive testing of hotpot oil quality, a modeling experiment method of fluorescence hyperspectral technology combined with machine learning algorithm was proposed. Five preprocessing algorithms are used to preprocess the original spectral data, which realizes data denoising and reduces the influence of baseline drift and tilt. The characteristic bands extracted from the spectral data show that the best characteristic bands for the two-classification model and the six-classification model are concentrated between 469–962 nm and 534–809 nm, respectively. Using the PCA algorithm to visualize the spectral data, the results show the distribution of the six types of samples intuitively, and indicate that the data can be classified. Based on the modeling analysis of the characteristic bands, the results show that the best two-classification models and the best six-classification models are MF-RF-RF and MF-XGBoost-LGB models, respectively, and the classification accuracy reaches 100%. Compared with the traditional model, the error is greatly reduced, and the calculation time is also saved. This study confirms that the use of fluorescence hyperspectral technology combined with machine learning algorithms provides a new theory and method for hotpot oil quality detection.
A placenta-on-a-chip model to determine the regulation of FKBPL and galectin-3 in preeclampsia
Authors: Ghorbanpour Masoumeh , Richards Claire , Pienaar Dillan , Sesperez Kimberly , Es.c Hamidreza Aboulkheyr , Nikolic Valentina , Orlic Natasa Karadzov , Mikovic Zeljko , Stefanovic Milan , Cakic Zoran , Alqudah Abdelrahim , Cole Louise , Gorrie Catherine , McGrath Kristine , Kavurma Mary M. , Warkianib Majid Ebrahimi , McClements Lana
Published: May 2022

Preeclampsia is a pregnancy-specific cardiovascular disorder and a leading cause of morbidity and mortality in pregnancy. Although inappropriate placental development and growth are recognized as root causes of preeclampsia, pathogenic mechanisms are poorly understood due to limited models of the disease, particularly in early pregnancy. Here, we first confirm the aberrant expression of important vascular and inflammatory proteins, FK506-binding protein like (FKBPL) and galectin-3 (Gal-3), in human plasma and placental tissue from women with/without preeclampsia. We then employ a 3D microfluidic placental model incorporating human umbilical vein endothelial cells (HUVECs) and a first trimester trophoblast cell line (ACH-3P) to investigate FKBPL and Gal-3 signalling in inflammatory conditions. In human samples, both circulating (n = 17 controls; n = 30 preeclampsia) and placental (n ≥ 6) FKBPL and Gal-3 levels were increased in preeclampsia compared to heathy controls (plasma: FKBPL, p < 0.0001; Gal-3, p < 0.01; placenta: FKBPL, p < 0.05; Gal-3, p < 0.01), indicative of vascular dysfunction in preeclampsia. In our placenta-on-a-chip model, we show that endothelial cells are critical for trophoblast-mediated migration and that trophoblasts effectively remodel the vasculature recapitulating placental development. Inflammatory cytokine tumour necrosis factor-α (10ng/ml) modulates both FKBPL and Gal-3 signalling in conjunction with trophoblast migration and impairs vasculature (p < 0.005). Our placenta-on-a-chip recapitulates aspects of aberrant placentation in preeclampsia and represents a promising platform for further placental research.
miRNA-96-5p alleviates liver fibrosis by targeting FN1 and inhibiting ECM-receptor interaction pathway
Authors: Zhang Yong , Gu Tengfei , Jiang Yuhang , Song Chao , Wang Rong , Xu Sanrong , Zhu Xinguo
Published: May 2022

Background The abnormal expression of microRNAs (miRNAs) was involved in the pathological process of liver fibrosis, but their accurate molecular mechanisms remain to be fully clarified.Aim To evaluate the role of miRNA-96-5p (miR-96-5p) in hepatic stellate cells (HSCs) activation and liver fibrosis.Methods The differentially expressed mRNAs (DEMs) and signal pathways about hepatic fibrosis were analyzed and screened from Gene Expression Omnibus (GEO) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to evaluate the biological significance and enriched pathways of the DEMs. The upstream miRNAs of DEMs were predicted by bioinformatics websites. The regulatory effects of miRNA on liver fibrosis through the target gene were verified in HSCs and in mouse CCl\(_4\)-induced liver fibrosis models.Results ECM-receptor interaction pathway was the most enriched pathway related to liver fibrosis through the GO and KEGG analysis of GEO database. Fibronectin1 (FN1) was up-regulated most significantly in the ECM-receptor pathway. Besides, miR-96-5p was considered to be the direct regulated miRNA of FN1 by bioinformatics websites prediction, qRT-PCR, Western blotting, and dual luciferase reporter assay. Finally, the effects of miR-96-5p up-regulation inhibit the activation of HSCs and alleviate CCl4-induced liver fibrosis by regulating FN1 and the ECM-receptor interaction pathway were confirmed in mice.Conclusions Our findings indicate that the up-regulation of miR-96-5p can inhibit activity of HSCs and alleviate liver fibrosis by inhibiting FN1 and ECM-receptor interaction pathway.
Useful vertical latissimus dorsi flap for partial breast reconstruction in every tumor location
Authors: Lee Jong Ho , Ryu Jeong Yeop , Choi Kang Young , Yang Jung Dug , Chung Ho Yun , Cho Byung Chae , Kang Byungju , Lee Jeeyeon , Park Ho Yong , Lee Joon Seok
Published: May 2022

BackgroundWe conducted a prospective cohort study to evaluate effective technique for breast reconstruction after partial mastectomy due to breast cancer. Depending on the location of the cancer and the amount excised, what method to employ is often difficult to determine. Here, we present a new technique, using the vertical LD flap, that can be used in all partial mastectomies and can almost hide scarring. We also compare these results to the mini-LD flap. MethodsWe analyzed a total of 50 and 47 patients, who underwent breast reconstruction with the mini-LD flap and the vertical LD flap, respectively. Immediately after cancer excision, work on reconstruction began. The skin flap for vertical LD was designed in a planaria shape, such that it may be hidden as much as possible and minimize bulging during closure, and the LD muscle flap was designed with a sufficient distance in the inferior direction.ResultsOur finding showed that the vertical LD flap group required significantly less total operation time than the mini-LD flap group. While the mini-LD flap resulted in a scar that was difficult to hide, the donor site scar of the vertical LD flap could not be seen easily, and no scar was visible on the back. ConclusionsThe vertical LD flap is capable of all partial breast reconstruction, can reconstruct defects in all breast regions, and requires a rather small volume of the flap. The patients show relatively fast recovery after the operation and high patient satisfaction.
A new Schiff base derivative based on the ratiometric fluorescent chemosensor for detection of Mg2+ ions and Spectroscopy applications
Authors: Marimuthu Pitchai , Ramu Andy
Published: May 2022

A novel ratiometric fluorescence sensor, (E)-N'-((8-hydroxyquinolin-2-yl) methylene) thiophene-2-carbohydrazide has been constructed for the selective and sensitive detection of Mg2+ ion. Fluorescence sensing of Mg2+ is highly solvent as well as imine structure dependent. It showed a significant fluorescence ratiometric towards Mg2+ions. The receptor 8-HQC-2TCH exhibited a good binding constant and lowest detection limit for Mg2+. These phenomena result from the rapid coordination between Mg2+ and 8-HQC-2TCH in the presence of Mg2+, which leads to the theoretical ratiometric of the fluorescence of probe. On the basis of these findings, ratiometric fluorescence sensor for the detection of Mg2+ ion reveals a good linear response to Mg2+ ranging from 0 to 60 mM with a detection limit of 3.9 x 10-7 M. Furthermore, the sensing assay is applicable to detecting Mg2+ in real samples.
Anti-hyperalgesic effects of photobiomodulation therapy (904 nm) on streptozotocin-induced diabetic neuropathy: A role for MAPK pathway and calcium dynamics
Authors: Vieira Willians Fernando , Malange Kauê Franco , de Magalhães Silviane Fernandes , Lemes Júlia Borges Paes , Santos Gilson Gonçalves dos , Nishijima Catarine Massucato , de Oliveira Alexandre Leite Rodrigues , Cruz-Höfling Maria Alice da , Parada Carlos Amilcar , Tambeli Cláudia Herrera
Published: May 2022

Several recent studies have established the efficacy of photobiomodulation therapy (PBMT) in painful clinical conditions. Diabetic neuropathy (DN) can be related to activating mitogen-activated protein kinases (MAPK), such as p38, in the peripheral nerve. MAPK pathway is activated in response to extracellular stimuli, including interleukins TNF-α and IL-1β. We verified the pain relief potential of PBMT in streptozotocin (STZ)-induced diabetic neuropathic rats and its influence on the MAPK pathway regulation and calcium (Ca2+) dynamics. We then observed that PBMT applied to the L4-L5 dorsal root ganglion (DRG) region reduced the intensity of hyperalgesia, decreased TNF-α and IL-1β levels, and p38-MAPK mRNA expression in DRG of diabetic neuropathic rats. DN induced the activation of phosphorylated p38 (p-38) MAPK co-localized with TRPV1+ neurons; PBMT partially prevented p-38 activation. DN was related to an increase of p38-MAPK expression due to proinflammatory interleukins, and the PBMT (904 nm) treatment counteracted this condition. Also, the sensitization of DRG-neurons by the hyperglycemic condition demonstrated during the Ca2+ dynamics was reduced by PBMT, contributing to its anti-hyperalgesic effects.
Novel Prognosis and Therapeutic response model of Immune-related lncRNA pairs in Clear Cell Renal Cell Carcinoma
Authors: Wang Gang , Liu Panhong , Li Jiangfeng , Jin Ke , Zheng Xiangyi , Xie Liping
Published: May 2022

Background
Clear cell renal cell carcinoma (ccRCC) is the most common type of renal carcinoma. It is particularly important to accurately judge the prognosis of patients. Since most tumor prediction models depend on the specific expression level of related genes. Therefore, a better model needs to be constructed.
Objective
To provide an immune-related lncRNA (irlncRNAs) tumor prognosis model, which independent of the specific gene expression levels.
Methods
First, we downloaded and sorted out the data of ccRCC in TCGA database and screened irlncRNAs by co-expression analysis, and then obtained the differently expressed irlncRNA (DEirlncRNA) pairs by univariate analysis. In addition, we modified Lasso penalized regression. Subsequently, the ROC curve was drawn, compare the area under the curve, calculate the Akaike information standard value of the 5-year receiver operating characteristic curve, and determine the cut-off point to establish the best model to distinguish the high- or low-disease-risk group of ccRCC. Subsequently, we reassessed the model from the perspectives of survival, clinic-pathological characteristics, tumor-infiltrating immune cells, chemotherapeutics efficacy, and immunosuppressed biomarkers.
Results
A total of 17 DEirlncRNAs pairs were identified, all of them were included in the Cox regression model. With the cut-off point, we can better distinguish patients according to different factors, such as survival status, invasive clinic-pathological features, tumor immune infiltration, whether chemotherapy is sensitive or not, and expression of immunosuppressive biomarkers.
Conclusion
We constructed irlncRNA model by pairing, which can better get rid of the dependence on the expression level of the target genes, to obtain a better clinical prediction.
Short-lived booster effect and stable CD8+ T cell memory after 3rd COVID-19 vaccine dose
Authors: Reinscheid Matthias , Luxenburger Hendrik , Karl Vivien , Graeser Anne , Giese Sebastian , Ciminski Kevin , Reeg David , Oberhardt Valerie , Röhlen Natascha , Lang-Meli Julia , Heim Kathrin , Gross Nina , Baum Christina , Rieg Siegbert , Speer Claudius , Emmerich Florian , Breisinger Susanne , Steinmann Daniel , Bengsch Bertram , Boettler Tobias , Kochs Georg , Schwemmle Martin , Thimme Robert , Neumann-Haefelin Christoph , Hofmann Maike
Published: May 2022

Reports of waning immunity after COVID-19 vaccination (1-3) have recently led to large booster vaccination campaigns. Previous studies showed that basic immunization with two mRNA vaccine doses elicits a robust spike-specific CD8+ T cell response (4-6). The effect of mRNA booster vaccination on the spike-specific CD8+ T cell response remains, however, unclear. Indeed, very little is known about the efficacy, duration and effects on long-term immunity and recall responses in breakthrough infections. In this study, we show that spike-specific CD8+ T cells are immediately and vigorously activated and expanded in all tested individuals after the 3rd and 4th mRNA vaccine shots. However, this CD8+ T cell boost response is characterized by a steep contraction and lasts only for about 30-60 days compared to a prolonged contraction after natural infection. Booster vaccination did not affect long-term spike-specific CD8+ T cell immunity reflected by a stable stem cell memory pool that already reached maximum frequencies after basic immunization. Accordingly, rapid and full-fledged recall responses of boosted spike-specific CD8+ T cells were detectable after breakthrough infection with delta and omicron. Thus, in addition to the previously reported cross-reactivity (7-12) also a robust activation and effector response determines the efficacy of the CD8+ T cell response targeting emerging variants of concern. Neutralizing antibody responses displayed hardly any boost effect towards omicron, further highlighting the relevance of spike-specific CD8+ T cell immunity. In sum, these data will inform future vaccination strategies facing the next COVID-19 wave expected for late 2022/early 2023.
Bioactive Volatile Compounds from Penicillium digitatum-Infected Apples: Oviposition Attractants for Yellow Peach Moth Conogethes punctiferalis (Lepidoptera: Crambidae)
Authors: Guo Honggang , Miao Shuangzhen , Ai Pengpeng , Zhang Minzhao , Yan Zhe , Yan Zengguang , Du Yanli
Published: May 2022

Plant-associated microbes critically shape the dynamics of plant- and insect-associated communities. In previous studies, we reported that the yellow peach moth Conogethes punctiferalis (YPM) preferred to Penicillium digitatum-infected apples (PDA) for oviposition. However, the underlying mechanisms remains unclear. In the present study, the behavioral and physiological experiments were conducted to determine how P. digitatum affects the oviposition selection of YPM females via altering host plant volatile organic compounds (VOCs). YPM females were attracted to and laid more eggs on PDA than on fungi non-infected apples (NIA), mechanically damaged apples (MDA), and P. digitatum in potato dextrose agar medium (PPD). Four-arm olfactometer assays further confirmed that odors in PDA were responsible for the attractiveness of YPM females. PCA of the 38 VOCs revealed a clear separation of PDA from NIA, MDA, and PPD, including methyl 2-methylbutyrate, styrene, methyl caproate, butyl caprylate, and n-tetradecane that were specifically emitted by PDA. Moreover, when P. digitatum-induced specific VOCs in individual or synthetic blends consisting of methyl 2-methylbutyrate, butyl caprylate, or n-tetradecane were added to apples, a significant selection rate of YPM females choosing apples occurred, suggesting that these three specific VOCs acted as predominant olfactory signals for YPM females to PDA. Taken together, the microbe P. digitatum was an important driver of the interactions between YPMs and host plants by altering plant volatiles. These findings may form the basis for developing attractant baits for field trapping YPMs in the future.
Is Babesiosis a Rare Zoonosis in Spain? Its Impact on the Spanish Health System Over 23 Years.
Authors: Almeida Hugo , López-Bernus Amparo , Rodríguez-Alonso Beatriz , Alonso-Sardón Montserrat , Romero-Alegría Ángela , Velasco-Tirado Virginia , Pardo-Lledias Javier , Muro Antonio , Belhassen-García Moncef
Published: May 2022

Background
Babesiosis is a zoonosis caused by an intraerythrocytic protozoan of the genus Babesia and transmitted mainly by ticks of the Ixodes spp. complex. There is no comprehensive global incidence in the literature, although the United States, Europe and Asia are considered to be endemic areas. In Europe, the percentage of ticks infected with Babesia spp. ranges from 0.78–51.78%. The incidence of babesiosis in hospitalized patients in Spain is 2.35%. The mortality rate is estimated to be approximately 9% in hospitalized patients but can reach 20% if the disease is transmitted by transfusion.
Objective
To analyze the epidemiological impact of inpatients diagnosed with babesiosis on the National Health System (SNS) of Spain between 1997 and 2019.
Methodology:
A retrospective longitudinal descriptive study that included inpatients diagnosed with babesiosis [ICD-9-CM code 088.82, ICD-10 code B60.0, cases ap2016-2019] in public Spanish NHS hospitals between 1 January 1997 and 31 December 2019 was developed. Data were obtained from the minimum basic dataset (CMBD in Spanish), which was provided by the Ministerio de Sanidad, Servicios Sociales e Igualdad after the receipt of a duly substantiated request and the signing of a confidentiality agreement.
Main findings:
Twenty-nine inpatients diagnosed with babesiosis were identified in Spain between 1997 and 2019 (IR: 0.28 cases/10,000,000 person-years). A total of 82.8% of the cases were men from urban areas who were approximately 46 years old. The mean hospital stay was 20.3 ± 19.2 days, with an estimated cost of €186,925.66. A total of 55.2% of the cases were primary diagnoses, and 79.3% of the cases were hospital readmissions. The mortality rate was 6.9%, which accounted for 2 cases, and both cases had a secondary diagnosis.
Conclusions
Human babesiosis is still a rare zoonosis in Spain, with an incidence rate that has been increasing over the years. Most cases occurred in middle-aged men from urban areas between summer and autumn. The Castilla-La-Mancha and Extremadura regions recorded the highest number of cases. Given the low rate of primary diagnoses and the high number of readmissions, a low clinical suspicion is likely. There was a 6.9% mortality in our study, and 100% of the fatal cases were patients with secondary diagnoses of the disease.
Machine Learning Models to Accelerate the Design of Polymeric Long-Acting Injectables
Authors: Bannigan Pauric , Bao Zeqing , HICKMAN RILEY , Aldeghi Matteo , Häse Florian , Aspuru-Guzik Alán , Allen Christine
Published: May 2022

Long-acting injectables are considered one of the most promising therapeutic strategies for the treatment of chronic diseases as they can afford improved therapeutic efficacy, safety, and patient compliance. The use of polymer materials in such a drug formulation strategy can offer unparalleled diversity owing to the ability to synthesize materials with a wide range of properties. However, the interplay between multiple parameters, including the physicochemical properties of the drug and polymer, make it very difficult to intuitively predict the performance of these systems. This necessitates the development and characterization of a wide array of formulation candidates through extensive and time-consuming in vitro experimentation. Machine learning is enabling leap-step advances in a number of fields including drug discovery and materials science. The current study takes a critical step towards data driven drug formulation development with an emphasis on long-acting injectables. A series of machine learning algorithms were trained and refined for accurate prediction of experimental drug release profiles. Analysis of the best performing model uncovered the properties of the drug and polymer that were identified to be key determinants of drug release. This information can be used to identify promising drug-polymer combinations that result in long-acting injectables with specific drug release behaviour. Importantly, implementation of this data driven approach has the potential to reduce the time, cost and resources associated with formulation development. Datasets and relevant codes used to train the machine learning models have been made openly available to encourage implementation in future drug formulation efforts.
Patient-Reported Supportive Care Needs among Asian American Cancer Patients
Authors: Wang Katarina , Ma Carmen , Li Feng Ming , Truong Angeline , Shariff-Marco Salma , Chu Janet N. , Oh Debora L. , Allen Laura , Kuo Mei-Chin , Wong Ching , Bui Hoan , Chen Junlin , Gomez Scarlett L , Nguyen Tung T. , Tsoh Janice Y.
Published: May 2022

Purpose
Cancer is the leading cause of death for Asian Americans. However, few studies have documented supportive care needs from the perspective of Asian American cancer patients. This study describes the needs reported by Asian American patients with colorectal, liver, or lung cancer over a 6-month period during their treatment.
Methods
Participants were recruited through the Greater Bay Area Cancer Registry and from cancer care providers in San Francisco. Participants self-identified as Asian or Asian American; age 21 or older; speak English, Chinese, or Vietnamese; and have stage I-III colon, rectum, liver, or lung cancer. Participants were matched with a language concordant patient navigator who provided support during a 6-month period. Needs were assessed by surveys at baseline, 3- and 6-months.
Results
Among 24 participants, 58% were 65 years or older, 42% did not complete high school, and 75% had limited English proficiency (LEP). At baseline, the most prevalent needs were cancer information (79%), nutrition and physical activity resources (67%), language assistance (54%), and daily living (50%). At the 3- and 6-month follow-up surveys, there was a higher reported need for mental health resources and healthcare access among participants.
Conclusion
In this pilot study of Asian American cancer patients who predominantly had LEP, participants reported many needs, with cancer information and language assistance as the most prominent. The findings highlight the importance of culturally and linguistically appropriate patient navigators in addressing supportive care needs among cancer patients with LEP.
Trial registration
ClinicalTrails.gov Identifier: NCT03867916
Random sampling associated with microbial profiling leads to overestimated stochasticity inference in community assembly
Authors: Ma Kai , Tu Qichao
Published: May 2022

Revealing the mechanisms governing the complex community assembly over space and time is a central issue in ecology. Null models have been developed to quantitatively disentangle the relative importance of deterministic vs. stochastic processes in structuring the compositional variations of biological communities. Similar approaches have been recently extended to the field of microbial ecology. However, the profiling of highly diverse biological communities (e.g. microbial communities) is severely influenced by random sampling issues, leading to undersampled community profiles and overestimated β-diversity, which may further affect stochasticity inference in community assembly. By implementing simulated datasets, this study demonstrated that microbial stochasticity inference was also affected due to random sampling issues associated with microbial profiling. The effects on microbial stochasticity inference for the whole community and the abundant subcommunities were different using different randomization methods in generating null communities. The stochasticity of rare subcommunities, however, was persistently overestimated no matter which randomization method was used. Comparatively, the stochastic ratio approach was more sensitive to random sampling issues, whereas the Raup-Crick metric was more affected by randomization methods. As more studies begin to focus on the mechanisms governing abundant and rare subcommunities, we urge cautions be taken for microbial stochasticity inference based on β-diversity, especially for rare subcommunities. Randomization methods to generate null communities shall also be carefully selected. When necessary, the cutoff used for judging the relative importance of deterministic vs. stochastic processes shall be redefined.
Development and validation a pyroptosis related gene prognostic index for metastatic urothelial carcinoma based on immune checkpoint blockade therapy
Authors: Lin Jiaxing , Ding Mengting , Qin# Caipeng , Song Yuxuan , Han Jingli , Yang Wenbo , Du Yiqing , Xu Tao
Published: May 2022

Background
Immune checkpoint blockade (ICB) therapy has become a first-line treatment option for metastatic urothelial carcinoma (mUC) patients who do not meet the criteria of cisplatin. Still, only a few people can benefit from it, so useful predictive markers are needed.
Methods
Download the ICB-based mUC and chemotherapy-based bladder cancer cohorts, and extract the expression data of pyroptosis-related genes (PRG). The LASSO algorithm was used to construct the PRG prognostic index (PRGPI) in the mUC cohort, and we verified the prognostic ability of PRGPI in two mUC and two bladder cancer cohorts.
Results
Most of the PRG in the mUC cohort were immune-activated genes, and a few were immunosuppressive genes. The PRGPI composed of GZMB, IRF1, and TP63 can stratify the risk of mUC. In IMvigor210 and GSE176307 cohorts, the P-values of Kaplan Meier analysis was < 0.01 and 0.002, respectively. PRGPI could also predict ICB response, and the chi-square test of the two cohorts had P-values of 0.002 and 0.046, respectively. In addition, PRGPI can also predict the prognosis of two bladder cancer cohorts based on chemotherapy. The PRGPI and the expression of PDCD1 / CD274 had a high degree of synergistic correlation. The Low PRGPI group showed prominent characteristics of immune infiltration and was enriched in the immune signal activation pathway.
Conclusion
The PRGPI we constructed can effectively predict the treatment response and overall survival rate of mUC patients treated with ICB. The PRGPI can help mUC patients achieve individualized and accurate treatment in the future.
Elraglusib (9-ING-41), a selective small molecule inhibitor of Glycogen Synthase Kinase-3 beta, reduces expression of immune checkpoint molecules PD-1, TIGIT and LAG-3, and enhances CD8+ T cell cytolytic killing of melanoma cells.
Authors: Shaw Gary , Cavalcante Ludimila , Giles Francis , Taylor Alison
Published: May 2022

Background
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with multiple roles in tumour growth, cell invasion and metastasis. We have previously established GSK-3 as an upstream regulator of PD-1 gene expression in CD8 + T cells and demonstrated that GSK-3 inhibition is as effective as anti-PD-1 mAb blockade in controlling tumour growth. Elraglusib (9-ING-41) is a specific small molecule inhibitor of GSK-3β with clinical activity in patients with advanced cancers, including a patient with refractory melanoma whose response provided the rationale for the current study.
Methods
The B16 melanoma mouse model was used to observe the effect of elraglusib on tumour growth either as a single agent or in combination (simultaneously and sequentially) with anti-PD1 mAb treatment. B16 tumour cells were implanted in either the flank, brain or both locations, Kaplan-Meier plots were used to depict survival and significance determined using log rank tests. Expression of the immune checkpoint molecules, TIGIT, LAG-3 and PD-1, were evaluated using flow cytometry alongside expression of the chemokine receptor, CXCR3. Further evaluation of PD-1 expression was determined through RT-qPCR and immunohistochemistry.
Results
We demonstrated that elraglusib has a suppressive effect against melanoma as a single agent and enhanced anti-PD1 therapy. There was a synergistic effect when elraglusib was used in combination with anti-PD1 mAb, and an even greater effect when used as sequential therapy. Suppression of tumour growth was associated with a reduced expression of immune checkpoint molecules, PD-1, TIGIT and LAG-3 with upregulation of CXCR3 expression.
Conclusions
These data highlight the potential of elraglusib as an immune-modulatory agent and demonstrate the benefit of a sequential approach with immune checkpoint inhibition followed by GSK-3β inhibition in melanoma and provide a rationale for clinical investigation of elraglusib combined with immune checkpoint inhibitory molecules, including those targeting PD-1, TIGIT and LAG-3. This has several potential implications for current immunotherapy regimes, including possibly reducing the intensity of anti-PD1 mAb treatment needed for response in patients receiving elraglusib, especially given the benign adverse event profile of elraglusib observed to date. Based on these data, a clinical study of elraglusib, an anti-PD1 mAb and chemotherapy is ongoing (NCT NCT05239182).
The diverging epigenomic landscapes of honeybee queens and workers revealed by multiomic sequencing
Authors: Zhang Yong , He Xu Jiang , Barron Andrew , Li Zhen , Jin Meng Jie , Wang Zilong , Huang Qiang , Zhang Li Zhen , Wu Xiaobo , Yan Wei Yu , Zeng Zhi Jiang
Published: May 2022

The role of the epigenome in phenotypic plasticity is unclear presently. Here we used a multiomics approach (RNA-seq, ChIP-seq, ATAC-seq and Hi-C) to explore the nature of the epigenome in developing honeybee (Apis mellifera) workers and queens. Our data showed that the distinct queen and worker epigenomic landscapes form during the developmental process. Differences in gene expression between workers and queens precede other epigenomic modifications, but the epigenomic differences between workers and queens become more extensive and more layered during development. Genes known to be important for caste differentiation were more likely to be multiply differentially regulated by more than one epigenomic system than other differentially expressed genes. This indicates a multidimensional regulation of expression of key genes, presumably to canalise differences in gene expression. Our data indicate that the epigenome interacts with diverging developmental trajectories rather than controlling them since different epigenomic landscapes form in concert with different developmental outcomes.
Effect of age on the structure and activity of the pharynx of the free- living nematode Metarhabditis andrassyana (Rhabditidae)
Authors: FATIMA HIBA , AHMAD IRFAN
Published: May 2022

Study of pharynx in a Metarhabditis andrassyana (Tahseen et al., 2004) revealed that the activity of pharynx declined with age and was also reduced in the absence of E.coli. A comparison between presence and absence of bacteria in the same age group revealed a reduction in both 2 day old individuals and 8 day old individuals. However, when nematodes were placed together in groups of varying numbers, pharyngeal pulsations declined as the numbers of specimens increased from 5 to 15 in the presence or absence of bacteria as a food source with age. In old worms, abnormalities were observed in the structure of the pharynx.
Topology of gene regulatory compartments relative to the nuclear matrix
Authors: Cho Won-Ki , Park Gunhee , Ryu Kwangmin , Lee Junho , Kim Geunhee , Park Tae Lim , Shim Hwanyong , Lee YigJi , Kim Changyeop
Published: May 2022

Inside the nucleus, there are special compartments with characterized functions, some of which are involved in gene expression1. These compartments include transcriptional condensates and nuclear speckles, which contain factors required for transcription and splicing, respectively. While the characteristics of these intranuclear compartments were extensively investigated, spatial relationship between them is yet unclear. Meanwhile, RNA-protein structural network named the nuclear matrix has been observed inside the nucleus and suggested as a framework for the spatial segregation of the intranuclear space2-6. However, concept of the nuclear matrix was not widely accepted due to its lack of in vivo evidence7. Here, we report visualization of the nuclear matrix and intranuclear compartments using super-resolution fluorescence microscopy. We found the nuclear matrix is dynamic in live cells and easily disrupted upon transcription inhibition. Remarkably, we observed an orderly layered distribution of transcriptional condensates and nuclear speckles relative to the nuclear matrix. We also observed a separation of chromosome territories from transcriptional condensates and nuclear speckles by the nuclear matrix. Based on our findings, we propose a topological model for the regulation of transcription across the nuclear matrix.
Differences in mortality risk associated with statin use amongst Asian patients with prostate cancer undergoing androgen deprivation therapy: a retrospective cohort study
Authors: Tse Gary , Lee Yan Hiu Athena , Chan Jeffrey Shi Kai , Hui Jeremy Man Ho , Tang Pias , Liu Kang , Dee Edward , Ng Kenrick , Ng Chi Fai
Published: May 2022

Background: With known anticancer properties, statins have the potential to be an adjuvant cancer therapy, but their associations with mortality in prostate cancer (PCa) remain debatable. This study investigated the associations between statin use concurrent with androgen deprivation therapy (ADT) and mortality risks in Asian patients with PCa. Methods: Adults with PCa receiving any ADT attending public hospitals in Hong Kong between December 1999 and March 2021 were retrospectively identified, with follow-up until September 2021. Patients with <180 days of medical castration without subsequent bilateral orchidectomy, <180 days of concurrent statin use and ADT, or missing total cholesterol level at baseline were excluded. Statin users had ≥180 days of concurrent statin and ADT use, while non-users were those without any statin use. The primary outcome was PCa-related mortality. The secondary outcome was all-cause mortality. Inverse probability treatment weighting was used to balance covariates. Results: 4920 patients were studied (2578 statin users and 2342 non-users; mean age 76.1±8.2 years). Over a mean follow-up of 4.2±3.3 years, statin users had significantly lower risks of PCa-related mortality (weighted hazard ratio (wHR) 0.56 [95% confidence interval 0.48, 0.65], p<0.001) and all-cause mortality (0.57 [0.51, 0.63], p<0.001) regardless of the type of ADT. The associations appeared stronger in patients without chemotherapy or antiandrogens use. Conclusions: Statin use concurrent with ADT was associated with lower risks of mortality in Asian patients with PCa, warranting further studies of its role in the treatment of patients with PCa.