bluuebunny/crossref_metadata_2025 huggingface dataset:
Time-dependent Seismic Footprint of Thermal Loading for Geothermal Activities in Fractured Carbonate Reservoirs
Authors: Wassing B. B. T. , Candela T. , Osinga S. , Peters E. , Buijze L. , Fokker P. A. , Van Wees J. D.
Published: September 2021

This paper describes and deploys a workflow to assess the evolution of seismicity associated to injection of cold fluids close to a fault. We employ a coupled numerical thermo-hydro-mechanical simulator to simulate the evolution of pressures, temperatures and stress on the fault. Adopting rate-and-state seismicity theory we assess induced seismicity rates from stressing rates at the fault. Seismicity rates are then used to derive the time-dependent frequency-magnitude distribution of seismic events. We model the seismic response of a fault in a highly fractured and a sparsely fractured carbonate reservoir. Injection of fluids into the reservoir causes cooling of the reservoir, thermal compaction and thermal stresses. The evolution of seismicity during injection is non-stationary: we observe an ongoing increase of the fault area that is critically stressed as the cooling front propagates from the injection well into the reservoir. During later stages, models show the development of an aseismic area surrounded by an expanding ring of high seismicity rates at the edge of the cooling zone. This ring can be related to the “passage” of the cooling front. We show the seismic response of the fault, in terms of the timing of elevated seismicity and seismic moment release, depends on the fracture density, as it affects the temperature decrease in the rock volume and thermo-elastic stress change on the fault. The dense fracture network results in a steeper thermal front which promotes stress arching, and leads to locally and temporarily high Coulomb stressing and seismicity rates. We derive frequency-magnitude distributions and seismic moment release for a low-stress subsurface and a tectonically active area with initially critically stressed faults. The evolution of seismicity in the low-stress environment depends on the dimensions of the fault area that is perturbed by the stress changes. The probability of larger earthquakes and the associated seismic risk are thus reduced in low-stress environments. For both stress environments, the total seismic moment release is largest for the densely spaced fracture network. Also, it occurs at an earlier stage of the injection period: the release is more gradually spread in time and space for the widely spaced fracture network.
Ocean Mesoscale Variability: A Case Study on the Mediterranean Sea From a Re-Analysis Perspective
Authors: Bonaduce Antonio , Cipollone Andrea , Johannessen Johnny A. , Staneva Joanna , Raj Roshin P. , Aydogdu Ali
Published: September 2021

The mesoscale variability in the Mediterranean Sea is investigated through eddy detection techniques. The analysis is performed over 24 years (1993–2016) considering the three-dimensional (3D) fields from an ocean re-analysis of the Mediterranean Sea (MED-REA). The objective is to achieve a fit-for-purpose assessment of the 3D mesoscale eddy field. In particular, we focus on the contribution of eddy-driven anomalies to ocean dynamics and thermodynamics. The accuracy of the method used to disclose the 3D eddy contributions is assessed against pointwise in-situ measurements and observation-based data sets. Eddy lifetimes ≥ 2 weeks are representative of the 3D mesoscale field in the basin, showing a high probability (> 60%) of occurrence in the areas of the main quasi-stationary mesoscale features. The results show a dependence of the eddy size and thickness on polarity and lifetime: anticyclonic eddies (ACE) are significantly deeper than cyclonic eddies (CE), and their size tends to increase in long-lived structures which also show a seasonal variability. Mesoscale eddies result to be a significant contribution to the ocean dynamics in the Mediterranean Sea, as they account for a large portion of the sea-surface height variability at temporal scales longer than 1 month and for the kinetic energy (50–60%) both at the surface and at depth. Looking at the contributions to ocean thermodynamics, the results exhibit the existence of typical warm (cold) cores associated with ACEs (CEs) with exceptions in the Levantine basin (e.g., Shikmona gyre) where a structure close to a mode-water ACE eddy persists with a positive salinity anomaly. In this area, eddy-induced temperature anomalies can be affected by a strong summer stratification in the surface water, displaying an opposite sign of the anomaly whether looking at the surface or at depth. The results show also that temperature anomalies driven by long-lived eddies (≥ 4 weeks) can affect up to 15–25% of the monthly variability of the upper ocean heat content in the Mediterranean basin.
A Novel Nomogram for Individualized Gonadotropin Starting Dose in GnRH Antagonist Protocol
Authors: Li Yubin , Duan Yuwei , Yuan Xi , Cai Bing , Xu Yanwen , Yuan Yuan
Published: September 2021

Controlled ovarian stimulation (COS) is one of the most vital parts of in vitro fertilization-embryo transfer (IVF-ET). At present, no matter what kinds of COS protocols are used, clinicians have to face the challenge of selection of gonadotropin starting dose. Although several nomograms have been developed to calculate the appropriate gonadotropin starting dose in gonadotropin releasing hormone (GnRH) agonist protocol, no nomogram was suitable for GnRH antagonist protocol. This study aimed to develop a predictive nomogram for individualized gonadotropin starting dose in GnRH antagonist protocol. Single-center prospective cohort study was conducted, with 198 women aged 20-45 years underwent IVF/intracytoplasmic sperm injection (ICSI)-ET cycles. Blood samples were collected on the second day of the menstrual cycle. All women received ovarian stimulation using GnRH antagonist protocol. Univariate and multivariate analysis were performed to identify predictive factors of ovarian sensitivity (OS). A nomogram for gonadotropin starting dose was developed based on the multivariate regression model. Validation was performed using concordance statistics and bootstrap resampling. A multivariate regression model based on serum anti-Müllerian hormone (AMH) level, antral follicle count (AFC), and body mass index (BMI) was developed and accounted for 59% of the variability of OS. An easy-to-use predictive nomogram for gonadotropin starting dose was established with excellent accuracy. The concordance index (C-index) of the nomogram was 0.833 (95% CI, 0.829-0.837). Internal validation using bootstrap resampling further showed the good performance of the nomogram. In conclusion, gonadotropin starting dose in antagonist protocol can be predicted precisely by a novel nomogram.
A Multi-Step Prediction Method for Wind Power Based on Improved TCN to Correct Cumulative Error
Authors: Luo Haifeng , Dou Xun , Sun Rong , Wu Shengjun
Published: September 2021

Wind power generation is likely to hinder the safe and stable operations of power systems for its irregularity, intermittency, and non-smoothness. Since wind power is continuously connected to power systems, the step length required for predicting wind power is increasingly extended, thereby causing an increasing cumulative error. Correcting the cumulative error to predict wind power in multi-step is an urgent problem that needs to be solved. In this study, a multi-step wind power prediction method was proposed by exploiting improved TCN to correct the cumulative error. First, multi-scale convolution (MSC) and self-attentiveness (SA) were adopted to optimize the problem that a single-scale convolution kernel of TCN is difficult to extract temporal and spatial features at different scales of the input sequence. The MSC-SA-TCN model was built to recognize and extract different features exhibited by the input sequence to improve the accuracy and stability of the single-step prediction of wind power. On that basis, the multi-channel time convolutional network with multiple input and multiple output codec technologies was adopted to build the nonlinear mapping between the output and input of the TCN multi-step prediction. The method improved the problem that a single TCN is difficult to tap the different nonlinear relationships between the multi-step prediction output and the fixed input. The MMED-TCN multi-step wind power prediction model was developed to separate linearity and nonlinearity between input and output to reduce the multi-step prediction error. An experimental comparative analysis was conducted based on the measured data from two wind farms in Shuangzitai, Liaoning, and Keqi, Inner Mongolia. As revealed from the results, the MAE and RMSE of the MMED-TCN-based multi-step prediction model achieved the cumulative mean values of 0.0737 and 0.1018. The MAE and RMSE metrics outperformed those of the VMD-AMS-TCN and MSC-SA-TCN models. It can be seen that the wind power prediction method proposed in this study could improve the feature extraction ability of TCN for input sequences and the ability of mining the mapping relationship between multiple inputs and multiple outputs. The method is superior in terms of the accuracy and stability of wind power prediction.
Genomic Profiling Reveals the Molecular Landscape of Gastrointestinal Tract Cancers in Chinese Patients
Authors: Zhu Chunrong , Zhu Liangjun , Gu Yanhong , Liu Ping , Tong Xiaoling , Wu Guozhong , Zhu Wenyu , Shen Wenxiang , Bao Hua , Ma Xiangyuan , Yu Ruoying , Wu Xue , Zhu Dongqin , Shu Yongqian , Feng Jifeng
Published: September 2021

Gastrointestinal tract cancers have high incidence and mortality in China, but their molecular characteristics have not been fully investigated. We sequenced 432 tumor samples from the colorectum, stomach, pancreas, gallbladder, and biliary tract to investigate cancer-related mutations and detail the landscape of microsatellite instability (MSI), tumor mutation burden (TMB), and chromosomal instability (CIN). We observed the highest TMB in colorectal and gastric cancers and the lowest TMB in gastrointestinal stromal tumors (GISTs). Twenty-four hyper-mutated tumors were identified only in colorectal and gastric cancers, with a significant enrichment of mutations in the polymerase genes (POLE,POLD1, andPOLH) and mismatch repair (MMR) genes. Additionally, CIN preferentially occurred in colorectal and gastric cancers, while pancreatic, gallbladder, and biliary duct cancers had a much lower CIN. High CIN was correlated with a higher prevalence of malfunctions in chromosome segregation and cell cycle genes, including the copy number loss ofWRN,NAT1,NF2, andBUB1B, and the copy number gain ofMYC,ERBB2,EGFR, andCDK6. In addition,TP53mutations were more abundant in high-CIN tumors, whilePIK3CAmutations were more frequent in low-CIN tumors. In colorectal and gastric cancers, tumors with MSI demonstrated much fewer copy number changes than microsatellite stable (MSS) tumors. In colorectal and gastric cancers, the molecular characteristics of tumors revealed the mutational diversity between the different anatomical origins of tumors. This study provides novel insights into the molecular landscape of Chinese gastrointestinal cancers and the genetic differences between tumor locations, which could be useful for future clinical patient stratification and targeted interventions.
The Landscapes of Full-Length Transcripts and Splice Isoforms as Well as Transposons Exonization in the Lepidopteran Model System, Bombyx mori
Authors: Dai Zongrui , Ren Jianyu , Tong Xiaoling , Hu Hai , Lu Kunpeng , Dai Fangyin , Han Min-Jin
Published: September 2021

The domesticated silkworm, Bombyx mori, is an important model system for the order Lepidoptera. Currently, based on third-generation sequencing, the chromosome-level genome of Bombyx mori has been released. However, its transcripts were mainly assembled by using short reads of second-generation sequencing and expressed sequence tags which cannot explain the transcript profile accurately. Here, we used PacBio Iso-Seq technology to investigate the transcripts from 45 developmental stages of Bombyx mori. We obtained 25,970 non-redundant high-quality consensus isoforms capturing ∼60% of previous reported RNAs, 15,431 (∼47%) novel transcripts, and identified 7,253 long non-coding RNA (lncRNA) with a large proportion of novel lncRNA (∼56%). In addition, we found that transposable elements (TEs) exonization account for 11,671 (∼45%) transcripts including 5,980 protein-coding transcripts (∼32%) and 5,691 lncRNAs (∼79%). Overall, our results expand the silkworm transcripts and have general implications to understand the interaction between TEs and their host genes. These transcripts resource will promote functional studies of genes and lncRNAs as well as TEs in the silkworm.
Genetic Diversity of 17 Autochthonous Italian Chicken Breeds and Their Extinction Risk Status
Authors: Soglia Dominga , Sartore Stefano , Lasagna Emiliano , Castellini Cesare , Cendron Filippo , Perini Francesco , Cassandro Martino , Marzoni Margherita , Iaffaldano Nicolaia , Buccioni Arianna , Dabbou Sihem , Castillo Annelisse , Maione Sandra , Bianchi Chiara , Profiti Margherita , Sacchi Paola , Cerolini Silvia , Schiavone Achille
Published: September 2021

The preservation of genetic variability of autochthonous poultry breeds is crucial in global biodiversity. A recent report revealed small breed size and potential risk of extinction of all native Italian poultry breeds; therefore, a correct assessment of their genetic diversity is necessary for a suitable management of their preservation. In this work, we provided an overview of the contribution to poultry biodiversity of some Italian autochthonous breeds reared in conservation centers devoted to local biodiversity preservation. The level of genetic diversity, molecular kinship, inbreeding, contribution to overall genetic diversity, and rate of extinction of each breed were analyzed with a set of 14 microsatellite loci in 17 autochthonous chicken breeds. To evaluate genetic variability, total number (Na), and effective number (Ne) of alleles, observed (Ho) and expected (He) heterozygosity, and F (Wright’s inbreeding coefficient) index were surveyed. The contribution of each analyzed breed to genetic diversity of the whole dataset was assessed using MolKin3.0; global genetic diversity and allelic richness contributions were evaluated. All the investigated loci were polymorphic; 209 alleles were identified (94 of which private alleles). The average number of alleles per locus was 3.62, and the effective number of alleles was 2.27. The Ne resulted lower in all breeds due to the presence of low-frequency alleles that can be easily lost by genetic drift, thus reducing the genetic variability of the breeds, and increasing their risk of extinction. The global molecular kinship was 27%, the average breed molecular kinship was 53%, and the mean inbreeding rate 43%, with a self-coancestry of 78%. Wright’s statistical analysis showed a 41% excess of homozygous due to breed genetic differences (34%) and to inbreeding within the breed (9%). Genetic variability analysis showed that 11 breeds were in endangered status. The contribution to Italian poultry genetic diversity, estimated as global genetic diversity, and ranged from 30.2 to 98.5%. In conclusion, the investigated breeds maintain a unique genetic pattern and play an important role in global Italian poultry biodiversity, providing a remarkable contribution to genetic variability.
Suggestive Evidence for Causal Effect of Leptin Levels on Risk for Anorexia Nervosa: Results of a Mendelian Randomization Study
Authors: Peters Triinu , Antel Jochen , Naaresh Roaa , Laabs Björn-Hergen , Föcker Manuel , Albers Nicola , Bühlmeier Judith , Hinney Anke , Libuda Lars , Hebebrand Johannes
Published: September 2021

Genetic correlations suggest a coexisting genetic predisposition to both low leptin levels and risk for anorexia nervosa (AN). To investigate the causality and direction of these associations, we performed bidirectional two-sample Mendelian randomization (MR) analyses using data of the most recent genome-wide association study (GWAS) for AN and both a GWAS and an exome-wide-association-study (EWAS) for leptin levels. Most MR methods with genetic instruments from GWAS showed a causal effect of lower leptin levels on higher risk of AN (e.g. IVW b = −0.923, p = 1.5 × 10−4). Because most patients with AN are female, we additionally performed analyses using leptin GWAS data of females only. Again, there was a significant effect of leptin levels on the risk of AN (e.g. IVW b = −0.826, p = 1.1 × 10−04). MR with genetic instruments from EWAS showed no overall effect of leptin levels on the risk for AN. For the opposite direction, MR revealed no causal effect of AN on leptin levels. If our results are confirmed in extended GWAS data sets, a low endogenous leptin synthesis represents a risk factor for developing AN.
Global Analysis of the Genetic Variations in miRNA-Targeted Sites and Their Correlations With Agronomic Traits in Rapeseed
Authors: Xu Pengfei , Zhu Yantao , Zhang Yanfeng , Jiang Jianxia , Yang Liyong , Mu Jianxin , Yu Xiang , He Yuke
Published: September 2021

MicroRNAs (miRNAs) and their target genes play vital roles in crops. However, the genetic variations in miRNA-targeted sites that affect miRNA cleavage efficiency and their correlations with agronomic traits in crops remain unexplored. On the basis of a genome-wide DNA re-sequencing of 210 elite rapeseed (Brassica napus) accessions, we identified the single nucleotide polymorphisms (SNPs) and insertions/deletions (INDELs) in miRNA-targeted sites complementary to miRNAs. Variant calling revealed 7.14 million SNPs and 2.89 million INDELs throughout the genomes of 210 rapeseed accessions. Furthermore, we detected 330 SNPs and 79 INDELs in 357 miRNA target sites, of which 33.50% were rare variants. We also analyzed the correlation between the genetic variations in miRNA target sites and 12 rapeseed agronomic traits. Eleven SNPs in miRNA target sites were significantly correlated with phenotypes in three consecutive years. More specifically, three correlated SNPs within the miRNA-binding regions of BnSPL9-3, BnSPL13-2, and BnCUC1-2 were in the loci associated with the branch angle, seed weight, and silique number, respectively; expression profiling suggested that the variation at these 3 miRNA target sites significantly affected the expression level of the corresponding target genes. Taken together, the results of this study provide researchers and breeders with a global view of the genetic variations in miRNA-targeted sites in rapeseed and reveal the potential effects of these genetic variations on elite agronomic traits.
Role of Interleukin-17 in Acute Pancreatitis
Authors: Li Guanqun , Chen Hongze , Liu Liwei , Xiao Peng , Xie Yu , Geng Xinglong , Zhang Tao , Zhang Yang , Lu Tianqi , Tan Hongtao , Li Le , Sun Bei
Published: September 2021

Acute pancreatitis (AP) is a leading cause of death and is commonly accompanied by systemic manifestations that are generally associated with a poor prognosis. Many cytokines contribute to pancreatic tissue damage and cause systemic injury. Interleukin-17 (IL-17) is a cytokine that may play a vital role in AP. Specifically, IL-17 has important effects on the immune response and causes interactions between different inflammatory mediators in the AP-related microenvironment. In this literature review, we will discuss the existing academic understanding of IL-17 and the impacts of IL-17 in different cells (especially in acinar cells and immune system cells) in AP pathogenesis. The clinical significance and potential mechanisms of IL-17 on AP deterioration are emphasized. The evidence suggests that inhibiting the IL-17 cytokine family could alleviate the pathogenic process of AP, and we highlight therapeutic strategies that directly or indirectly target IL-17 cytokines in acute pancreatitis.
Immunization With Bovine Herpesvirus-4-Based Vector Delivering PPRV-H Protein Protects Sheep From PPRV Challenge
Authors: Rodríguez-Martín Daniel , Rojas José Manuel , Macchi Francesca , Franceschi Valentina , Russo Luca , Sevilla Noemí , Donofrío Gaetano , Martín Verónica
Published: September 2021

The Morbillivirus peste des petits ruminants virus (PPRV) is the causal agent of a highly contagious disease that mostly affects sheep and goats and produces considerable losses in developing countries. Current PPRV control strategies rely on live-attenuated vaccines, which are not ideal, as they cannot differentiate infected from vaccinated animals (DIVA). Recombinant vector-based vaccines expressing viral subunits can provide an alternative to conventional vaccines, as they can be easily paired with DIVA diagnostic tools. In the present work, we used the bovine herpesvirus-4-based vector (BoHV-4-A) to deliver PPRV hemagglutinin H antigen (BoHV-4-A-PPRV-H-ΔTK). Vaccination with BoHV-4-A-PPRV-H-ΔTK protected sheep from virulent PPRV challenge and prevented virus shedding. Protection correlated with anti-PPRV IgGs, neutralizing antibodies and IFN-γ-producing cells induced by the vaccine. Detection of antibodies exclusively against H-PPRV in animal sera and not against other PPRV viral proteins such as F or N could serve as a DIVA diagnostic test when using BoHV-4-A-PPRV-H-ΔTK as vaccine. Our data indicate that BoHV-4-A-PPRV-H-ΔTK could be a promising new approach for PPRV eradication programs.
Characterization of Organ-Specific Regulatory B Cells Using Single-Cell RNA Sequencing
Authors: Yang Si-Yu , Long Jie , Huang Meng-Xing , Luo Pan-Yue , Bian Zhen-Hua , Xu Ya-Fei , Wang Cheng-Bo , Yang Shu-Han , Li Liang , Selmi Carlo , Gershwin M. Eric , Zhao Zhi-Bin , Lian Zhe-Xiong
Published: September 2021

Regulatory B cells (Breg) are considered as immunosuppressive cells. Different subsets of Breg cells have been identified both in human beings and in mice. However, there is a lack of unique markers to identify Breg cells, and the heterogeneity of Breg cells in different organs needs to be further illuminated. In this study, we performed high-throughput single-cell RNA sequencing (scRNA-seq) and single-cell B-cell receptor sequencing (scBCR-seq) of B cells from the murine spleen, liver, mesenteric lymph nodes, bone marrow, and peritoneal cavity to better define the phenotype of these cells. Breg cells were identified based on the expression of immunosuppressive genes and IL-10-producing B (B10) cell-related genes, to define B10 and non-B10 subsets in Breg cells based on the score of the B10 gene signatures. Moreover, we characterized 19 common genes significantly expressed in Breg cells, including Fcrl5, Zbtb20, Ccdc28b, Cd9, and Ptpn22, and further analyzed the transcription factor activity in defined Breg cells. Last, a BCR analysis was used to determine the clonally expanded clusters and the relationship of Breg cells across different organs. We demonstrated that Atf3 may potentially modulate the function of Breg cells as a transcription factor and that seven organ-specific subsets of Breg cells are found. Depending on gene expression and functional modules, non-B10 Breg cells exhibited activated the TGF-β pathway, thus suggesting that non-B10 Breg cells have specific immunosuppressive properties different from conventional B10 cells. In conclusion, our work provides new insights into Breg cells and illustrates their transcriptional profiles and BCR repertoire in different organs under physiological conditions.
Generalized Modules for Membrane Antigens as Carrier for Polysaccharides: Impact of Sugar Length, Density, and Attachment Site on the Immune Response Elicited in Animal Models
Authors: Micoli Francesca , Alfini Renzo , Di Benedetto Roberta , Necchi Francesca , Schiavo Fabiola , Mancini Francesca , Carducci Martina , Oldrini Davide , Pitirollo Olimpia , Gasperini Gianmarco , Balocchi Cristiana , Bechi Nicoletta , Brunelli Brunella , Piccioli Diego , Adamo Roberto
Published: September 2021

Nanoparticle systems are being explored for the display of carbohydrate antigens, characterized by multimeric presentation of glycan epitopes and special chemico-physical properties of nano-sized particles. Among them, outer membrane vesicles (OMVs) are receiving great attention, combining antigen presentation with the immunopotentiator effect of the Toll-like receptor agonists naturally present on these systems. In this context, we are testing Generalized Modules for Membrane Antigens (GMMA), OMVs naturally released from Gram-negative bacteria mutated to increase blebbing, as carrier for polysaccharides. Here, we investigated the impact of saccharide length, density, and attachment site on the immune response elicited by GMMA in animal models, using a variety of structurally diverse polysaccharides from different pathogens (i.e.,Neisseria meningitidisserogroup A and C,Haemophilus influenzaetype b, and streptococcus Group A Carbohydrate andSalmonellaTyphi Vi). Anti-polysaccharide immune response was not affected by the number of saccharides per GMMA particle. However, lower saccharide loading can better preserve the immunogenicity of GMMA as antigen. In contrast, saccharide length needs to be optimized for each specific antigen. Interestingly, GMMA conjugates induced strong functional immune response even when the polysaccharides were linked to sugars on GMMA. We also verified that GMMA conjugates elicit a T-dependent humoral immune response to polysaccharides that is strictly dependent on the nature of the polysaccharide. The results obtained are important to design novel glycoconjugate vaccines using GMMA as carrier and support the development of multicomponent glycoconjugate vaccines where GMMA can play the dual role of carrier and antigen. In addition, this work provides significant insights into the mechanism of action of glycoconjugates.
Temporal Changes in Vaginal Microbiota and Genital Tract Cytokines Among South African Women Treated for Bacterial Vaginosis
Authors: Mtshali Andile , San James Emmanuel , Osman Farzana , Garrett Nigel , Balle Christina , Giandhari Jennifer , Onywera Harris , Mngomezulu Khanyisile , Mzobe Gugulethu , de Oliveira Tulio , Rompalo Anne , Mindel Adrian , Abdool Karim Salim S. , Ravel Jacques , Passmore Jo-Ann S. , Abdool Karim Quarraisha , Jaspan Heather B. , Liebenberg Lenine J. P. , Ngcapu Sinaye
Published: September 2021

The standard treatment for bacterial vaginosis (BV) with oral metronidazole is often ineffective, and recurrence rates are high among African women. BV-associated anaerobes are closely associated with genital inflammation and HIV risk, which underscores the importance of understanding the interplay between vaginal microbiota and genital inflammation in response to treatment. In this cohort study, we therefore investigated the effects of metronidazole treatment on the vaginal microbiota and genital cytokines among symptomatic South African women with BV [defined as Nugent score (NS) ≥4] using 16S rRNA gene sequencing and multiplex bead arrays. Among 56 BV-positive women, we observed short-term BV clearance (NS <4) in a proportion of women six weeks after metronidazole treatment, with more than half of these experiencing recurrence by 12 weeks post-treatment. BV treatment temporarily reduced the relative abundance of BV-associated anaerobes (particularly Gardnerella vaginalis and Atopobium vaginae) and increased lactobacilli species (mainly L. iners), resulting in significantly altered mucosal immune milieu over time. In a linear mixed model, the median concentrations of pro-inflammatory cytokines and chemokines were significantly reduced in women who cleared BV compared to pre-treatment. BV persistence and recurrence were strongly associated with mucosal cytokine profiles that may increase the risk of HIV acquisition. Concentrations of these cytokines were differentially regulated by changes in the relative abundance of BVAB1 and G. vaginalis. We conclude that metronidazole for the treatment of BV induced short-term shifts in the vaginal microbiota and mucosal cytokines, while treatment failures promoted persistent elevation of pro-inflammatory cytokine concentrations in the genital tract. These data suggest the need to improve clinical management of BV to minimize BV related reproductive risk factors.
NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton
Authors: Lee E Hui Clarissa , Wong Darren Chen Pei , Ding Jeak Ling
Published: September 2021

Natural killer (NK) cells are innate immune cells which play a key role in shaping the immune response against cancer. Initially hailed for their potential to recognise and eliminate tumour cells, their application has been greatly hindered by the immunosuppressive tumour microenvironment (TME) which suppresses NK functions (e.g., cytotoxicity). This dysfunctional state that is accompanied by phenotypic changes such as upregulation of inhibitory receptors and downregulation of activating receptors, forms the basis of what many researchers have referred to as ‘exhausted’ NK cells. However, there is no consensus on whether these phenotypes are sufficient to define an exhausted state of the NK cell. While recent advances in checkpoint inhibition appear to show promise in early-stage pre-clinical studies, much remains to be fully explored and understood in the context of the TME. The TME is where the NK cells are subjected to interaction with various cell types and soluble factors, which could exert an inhibitory effect on NK cytotoxicity. In this review, we provide an overview of the general markers of NK cell exhaustion viz, the surface activating and inhibitory receptors. We also highlight the potential role of T-box transcription factors in characterising such a dysfunctional state and discuss the often-overlooked mechanism of cell cytoskeletal dynamics in regulating NK cell function. These aspects may further contribute to NK exhaustion or NK revival in cancer and may open new avenues to explore cancer treatment strategies.
Case Report: A Rare Case of Coexisting of Autoimmune Polyglandular Syndrome Type 3 and Isolated Gonadotropin-Releasing Hormone Deficiency
Authors: Jiang Qiuhui , Wu Ting , Zhang Yuxian , Wang Shunhua , Wang Liying , Su Weijuan , Lin Mingzhu , Li Xuejun
Published: September 2021

APS (autoimmune polyglandular syndrome) is defined as the coexistence of at least two kinds of endocrine autoimmune diseases. APS type 3 comprises autoimmune thyroid diseases and other autoimmune diseases but does not involve autoimmune Addison’s disease. So far, APS-3 combined with isolated gonadotropin-releasing hormone (GnRH) reduction caused by the suspected autoimmune hypothalamic disease has not been reported. We recently received a 43-year-old woman with a one-year history of Graves’ disease (GD) and a four-month history of type 1 diabetes presented with hyperthyroidism and hyperglycemia. After the GnRH stimulation test, she was diagnosed with secondary amenorrhea attributed to suspected autoimmune Hypothalamitis and APS type 3 associated with Graves’ disease and Latent Autoimmune Diabetes (LADA). According to this case, the hypothalamus cannot be spared from the general autoimmune process. It is recommended to carry out the GnRH stimulation test when encountering APS patients combined with secondary amenorrhea.
Understanding Local Perceptions of the Drivers/Pressures on the Coastal Marine Environment in Palawan, Philippines
Authors: Madarcos John Roderick V. , Creencia Lota A. , Roberts Bethany R. , White Mathew P. , Nayoan Johana , Morrissey Karyn , Fleming Lora E.
Published: September 2021

The Philippines, as a tropical archipelagic country, is particularly vulnerable to environmental changes affecting coastal and marine settings. However, there are limited studies investigating how these changes are perceived by the local populations who depend directly on the marine environment for their livelihoods, health, and well-being, and who are the most vulnerable to such changes. To explore these issues, we conducted an in-home face-to-face structured survey in 10 coastal communities in Palawan, Philippines (n = 431). As part of the survey, respondents were asked to comment on how important they believed a list of 22 drivers/pressures (e.g., “land-use change”) were in affecting their local marine environment. Statistical analysis of this list using Exploratory Factor Analysis suggested the 22 drivers/pressures could be categorized into 7 discrete groups (or in statistical terms “factors”) of drivers/pressures (e.g., “urbanization,” “unsustainable fishing practices” etc.). We then used ordinary least squared regression to identify similarities and differences between the perspectives within and across communities, using various socio-demographic variables. Results suggested that among the seven identified factors, four were perceived by the local communities as making the marine environment worse, two were perceived as having no impact, and one was perceived to be making the marine environment better. Perceptions differed by gender, education, ethnicity, and study site. A subsequent survey with 16 local coastal resource management experts, suggested that public perceptions of the most critical drivers/pressures were broadly consistent with those of this expert group. Our findings highlight how aware local coastal communities are of the drivers/pressures underpinning the threats facing their livelihoods, health, and well-being. Ultimately, this information can support and inform decisions for the management of local marine resources.
Error on the Estimation of Sand Size Parameters When Using Small Diameter Sieves and a Solution
Authors: Lopez-Garcia Patricia , Muñoz-Perez Juan J. , Contreras Antonio , Vidal Juan , Jigena Bismarck , Santos Juan J. , Romero Jeanette , Contreras Francisco
Published: September 2021

Analyses were carried out to determine the main sand size parameters (median grain size D50 and sorting σ) for beach nourishment purposes using the sieving method aboard a dredger. Due to a lack of space and the need to carry and use the material with ease, the sieves are commonly small (10 cm diameter), and the shaking procedure is usually performed by hand. However, the influence of shaking, either mechanically or manually, has not yet been studied with 10 cm diameter sieves. Therefore, 20 samples were taken from inside the hopper of a trailing suction dredger and sieved both manually and mechanically for 10 min. The results showed that manual sieving yielded higher D50 values than the mechanical procedure. The average error arising from using the manual method was 14%, but it can reach 36.5%. The granulometric analysis carried out for different shaking times has shown that this error is < 5% when at least 20 min of shaking is performed. The mechanical procedure gave always finer sand results. In addition, the overfill ratio calculated for both mechanical and manual results reached differences of up to 48%.
Comparison of Corneal Biomechanics in Post-SMILE, Post-LASEK, and Keratoconic Eyes
Authors: Shang Jianmin , Shen Yang , Jhanji Vishal , Zhou Xueyi , Zhao Jing , Zhao Yu , Zhou Xingtao
Published: September 2021

Significance: Our study found that SP-A1 (stiffness parameter at time of first applanation) was statistically different between post-laser-assisted subepithelial keratomileusis (LASEK) and post-small incision lenticule extraction (SMILE) eyes. The stiffness of keratoconus was lower than that of post-refractive surgery corneas.

Purpose: To compare corneal biomechanics among post-SMILE, post-LASEK, and keratoconic eyes.

Methods: In this retrospective study, 36 eyes of 36 patients after SMILE, 36 eyes of 36 patients after LASEK, and 36 eyes of 36 patients with keratoconus with matching (±5 μm) central corneal thickness (CCT) were examined using Scheimpflug corneal topography (Pentacam HR) and dynamic Scheimpflug analyzer (CorVis ST). Mixed linear model analysis with Bonferroni-adjusted post-hoc comparisons was performed to compare the differences in corneal biomechanics and topographic parameters among the three groups with the CCT and the bIOP (intraocular pressure with biomechanical correction) as the random factor.

Results: All groups had comparable CCT at baseline. The bIOPs between the three groups were comparable. The mean values of the Belin/Ambrósio Deviation (BAD-D) in the keratoconus group were significantly higher than those of the SMILE (post hoc p < 0.001) and LASEK groups (post hoc p < 0.001). The SP-A1 in the keratoconus group was the lowest when compared with those of the SMILE (post hoc p = 0.003) and LASEK groups (post hoc p < 0.001). The SMILE group SP-A1 values were slightly lower than those of the LASEK group (post hoc p = 0.044).

Conclusions: Keratoconus eyes were significantly softer when compared to post-refractive surgery corneas with comparable corneal thickness in terms of SP-A1 and BAD-D values, while the LASEK group may have the greatest stiffness. Post-SMILE and post-LASEK corneas showed significant differences in SP-A1.
Personalized Prediction of Short- and Long-Term PTH Changes in Maintenance Hemodialysis Patients
Authors: Pirklbauer Markus , Bushinsky David A. , Kotanko Peter , Schappacher-Tilp Gudrun
Published: September 2021

Background: Personalized management of secondary hyperparathyroidism is a critical part of hemodialysis patient care. We used a mathematical model of parathyroid gland (PTG) biology to predict (1) short-term peridialytic intact PTH (iPTH) changes in response to diffusive calcium (Ca) fluxes and (2) to predict long-term iPTH levels.

Methods: We dialyzed 26 maintenance hemodialysis patients on a single occasion with a dialysate Ca concentration of 1.75 mmol/l to attain a positive dialysate-to-blood ionized Ca (iCa) gradient and thus diffusive Ca loading. Intradialytic iCa kinetics, peridialytic iPTH change, and dialysate-sided iCa mass balance (iCaMB) were assessed. Patient-specific PTG model parameters were estimated using clinical, medication, and laboratory data. We then used the personalized PTG model to predict peridialytic and long-term (6-months) iPTH levels.

Results: At dialysis start, the median dialysate-to-blood iCa gradient was 0.3 mmol/l (IQR 0.11). The intradialytic iCa gain was 488 mg (IQR 268). Median iPTH decrease was 75% (IQR 15) from pre-dialysis 277 to post-dialysis 51 pg/ml. Neither iCa gradient nor iCaMB were significantly associated with peridialytic iPTH changes. The personalized PTG model accurately predicted both short-term, treatment-level peridialytic iPTH changes (r = 0.984, p < 0.001, n = 26) and patient-level 6-months iPTH levels (r = 0.848, p < 0.001, n = 13).

Conclusions: This is the first report showing that both short-term and long-term iPTH dynamics can be predicted using a personalized mathematical model of PTG biology. Prospective studies are warranted to explore further model applications, such as patient-level prediction of iPTH response to PTH-lowering treatment.
Discharge Documentation and Follow-Up of Critically Ill Patients With Acute Kidney Injury Treated With Kidney Replacement Therapy: A Retrospective Cohort Study
Authors: Choon Xin Yi , Lumlertgul Nuttha , Cameron Lynda , Jones Andrew , Meyer Joel , Slack Andrew , Vollmer Helen , Barrett Nicholas A. , Leach Richard , Ostermann Marlies
Published: September 2021

Leading organisations recommend follow-up of acute kidney injury (AKI) survivors, as these patients are at risk of long-term complications and increased mortality. Information transfer between specialties and from tertiary to primary care is essential to ensure timely and appropriate follow-up. Our aim was to examine the association between completeness of discharge documentation and subsequent follow-up of AKI survivors who received kidney replacement therapy (KRT) in the Intensive Care Unit (ICU). We retrospectively analysed the data of 433 patients who had KRT for AKI during ICU admission in a tertiary care centre in the UK between June 2017 and May 2018 and identified patients who were discharged from hospital alive. Patients with pre-existing end-stage kidney disease and patients who were transferred from hospitals outside the catchment area were excluded. The primary objective was to assess the completeness of discharge documentation from critical care and hospital; secondary objectives were to determine cardiovascular medications reconciliation after AKI, and to investigate kidney care and outcomes at 1 year. The development of AKI and the need for KRT were mentioned in 85 and 82% of critical care discharge letters, respectively. Monitoring of kidney function post-discharge was recommended in 51.6% of critical care and 36.3% of hospital discharge summaries. Among 35 patients who were prescribed renin-angiotensin-aldosterone system inhibitors before hospitalisation, 15 (42.9%) were not re-started before discharge from hospital. At 3 months, creatinine and urine protein were measured in 88.2 and 11.8% of survivors, respectively. The prevalence of chronic kidney disease stage III or worse increased from 27.2% pre-hospitalisation to 54.9% at 1 year (p < 0.001). Our data demonstrate that discharge summaries of patients with AKI who received KRT lacked essential information. Furthermore, even in patients with appropriate documentation, renal follow-up was poor suggesting the need for more education and streamlined care pathways.
Expression of LOX Suggests Poor Prognosis in Gastric Cancer
Authors: Zhu Jinfeng , Luo Chen , Zhao Jiefeng , Zhu Xiaojian , Lin Kang , Bu Fanqin , Yu Zhonglin , Zou Feilong , Zhu Zhengming
Published: September 2021

Background: Lysyl oxidase (LOX) is a key enzyme for the cross-linking of collagen and elastin in the extracellular matrix. This study evaluated the prognostic role of LOX in gastric cancer (GC) by analyzing the data of The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset.

Methods: The Wilcoxon rank-sum test was used to calculate the expression difference of LOX gene in gastric cancer and normal tissues. Western blot and immunohistochemical staining were used to evaluate the expression level of LOX protein in gastric cancer. Kaplan-Meier analysis was used to calculate the survival difference between the high expression group and the low expression group in gastric cancer. The relationship between statistical clinicopathological characteristics and LOX gene expression was analyzed by Wilcoxon or Kruskal-Wallis test and logistic regression. Univariate and multivariate Cox regression analysis was used to find independent risk factors affecting the prognosis of GC patients. Gene set enrichment analysis (GSEA) was used to screen the possible mechanisms of LOX and GC. The CIBERSORT calculation method was used to evaluate the distribution of tumor-infiltrating immune cell (TIC) abundance.

Results: LOX is highly expressed in gastric cancer tissues and is significantly related to poor overall survival. Wilcoxon or Kruskal-Wallis test and Logistic regression analysis showed, LOX overexpression is significantly correlated with T-stage progression in gastric cancer. Multivariate Cox regression analysis on TCGA and GEO data found that LOX (all p < 0.05) is an independent factor for poor GC prognosis. GSEA showed that high LOX expression is related to ECM receptor interaction, cancer, Hedgehog, TGF-beta, JAK-STAT, MAPK, Wnt, and mTOR signaling pathways. The expression level of LOX affects the immune activity of the tumor microenvironment in gastric cancer.

Conclusion: High expression of LOX is a potential molecular indicator for poor prognosis of gastric cancer.
Non-invasive Urine Test for Molecular Classification of Clinical Significance in Newly Diagnosed Prostate Cancer Patients
Authors: Guo Jinan , Zhang Xuhui , Xia Taolin , Johnson Heather , Feng Xiaoyan , Simoulis Athanasios , Wu Alan H. B. , Li Fei , Tan Wanlong , Johnson Allan , Dizeyi Nishtman , Abrahamsson Per-Anders , Kenner Lukas , Xiao Kefeng , Zhang Heqiu , Chen Lingwu , Zou Chang , Persson Jenny L.
Published: September 2021

Objective: To avoid over-treatment of low-risk prostate cancer patients, it is important to identify clinically significant and insignificant cancer for treatment decision-making. However, no accurate test is currently available.

Methods: To address this unmet medical need, we developed a novel gene classifier to distinguish clinically significant and insignificant cancer, which were classified based on the National Comprehensive Cancer Network risk stratification guidelines. A non-invasive urine test was developed using quantitative mRNA expression data of 24 genes in the classifier with an algorithm to stratify the clinical significance of the cancer. Two independent, multicenter, retrospective and prospective studies were conducted to assess the diagnostic performance of the 24-Gene Classifier and the current clinicopathological measures by univariate and multivariate logistic regression and discriminant analysis. In addition, assessments were performed in various Gleason grades/ISUP Grade Groups.

Results: The results showed high diagnostic accuracy of the 24-Gene Classifier with an AUC of 0.917 (95% CI 0.892–0.942) in the retrospective cohort (n = 520), AUC of 0.959 (95% CI 0.935–0.983) in the prospective cohort (n = 207), and AUC of 0.930 (95% 0.912-CI 0.947) in the combination cohort (n = 727). Univariate and multivariate analysis showed that the 24-Gene Classifier was more accurate than cancer stage, Gleason score, and PSA, especially in the low/intermediate-grade/ISUP Grade Group 1–3 cancer subgroups.

Conclusions: The 24-Gene Classifier urine test is an accurate and non-invasive liquid biopsy method for identifying clinically significant prostate cancer in newly diagnosed cancer patients. It has the potential to improve prostate cancer treatment decisions and active surveillance.
Clonidine as an Additive to Local Anesthetics in Caudal Block for Postoperative Analgesia in Pediatric Surgery: A Systematic Review and Meta-Analysis
Authors: Wang Ye , Guo Qianqian , An Qi , Zhao Lin , Wu Meng , Guo Zhenggang , Zhang Changsheng
Published: September 2021

Background: Clonidine is an anesthetic with favorable efficacy and safety profiles for caudal epidural block, but comparisons with other adjuvants need to be confirmed in pediatric patients.

Aim: To investigate the effects of clonidine as an adjuvant in caudal epidural block to improve the intraoperative and postoperative analgesia in pediatric surgery.

Methods: PubMed, Embase, and the Cochrane Library were searched for available papers published up to February 2021. The outcomes were pain score, duration of analgesia, complications, and number of analgesic requirements. The meta-analysis was performed using random-effects models.

Results: Fifteen randomized controlled trials (RCTs) were included. There were no differences between clonidine and the control drug regarding the duration of analgesia (SMD = −0.71, 95%CI: −1.64, 0.23; I2 = 95.5%, Pheterogeneity < 0.001), pain score (SMD = 0.35, 95%CI: −0.28, 0.98; I2 = 80.8%, Pheterogeneity < 0.001), and requirement for additional analgesia (OR = 8.77, 95%CI: 0.70, 110.58, I2 = 81.9%, Pheterogeneity = 0.004), but using clonidine resulted in fewer complications than the control drugs (OR = 0.33, 95%CI: 0.20, 0.54, I2 = 21.8%, Pheterogeneity = 0.217). The sensitivity analysis showed that the results were robust. A publication bias was observed.

Conclusion: Clonidine has the same efficacy as the other adjuvants for caudal epidural block for pediatric surgery but fewer complications. These results support clonidine as an adjuvant to local anesthetic, but additional studies should be conducted.