bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization With Gene Mutations in Han Chinese Patients With Hypospadias and Function Analysis of a Novel AR Genevariant
Authors: Chen Lifen , Wang Junqi , Lu Wenli , Xiao Yuan , Ni Jihong , Wang Wei , Ma Xiaoyu , Dong Zhiya
Published: June 2021

It is estimated that around 10–20% of hypospadias are caused by genetic abnormalities worldwide although the spectrum of associated genes does vary across different ethnicities. The prevalence of hypospadias among the Chinese population has been increasing the last couple of decades. However, the pathogenesis underlying the disease and its associated genetic abnormality remains unclear. Here we performed a genetic analysis of 81 children with karyotype 46, XY and the hypospadias phenotype in order to characterize the genetic components that contribute to the development of hypospadias in Chinese patients. 15 candidate genes, including sex determination genes-SOX9, SRY, NR0B1 (DAX1), NR5A1 (SF1), DHH, sex differentiation genes-AR, SRD5A2, MAMLD1, INSL3, and hypospadias-associated genes-FGF8, FGF10, BMP4, BMP7, ATF3, and MID1 were screened by using next generation sequencing. A total of 18 patients were found to have mutations identified by PCR and sequencing, including 11 cases of SRD5A2 genes, 6 cases of AR genes, and 1 case of MID1 gene, respectively. One novel missense mutation p.I817N was discovered in AR gene. Further molecular analysis found that subcellular localization of the ARI817N was the same as that of wild type ARWT in the absence or presence of hormone. But it led to 50% reduction in AR-induced transcriptional activity in the presence of either the synthetic androgen R1881 or the natural ligand dihydrotestosterone. Our results indicate that SRD5A2 and AR genes are two top candidate genes associated with 46, XY hypospadias in Chinese patients. Further epidemiological and genetic analysis are still needed to further clarify the pathogenesis of hypospadias in Han Chinese patients.
A Time-Resolved Diffusion Technique for Detection of the Conformational Changes and Molecular Assembly/Disassembly Processes of Biomolecules
Authors: Nakasone Yusuke , Terazima Masahide
Published: June 2021

Biological liquid–liquid phase separation (LLPS) is driven by dynamic and multivalent interactions, which involves conformational changes and intermolecular assembly/disassembly processes of various biomolecules. To understand the molecular mechanisms of LLPS, kinetic measurements of the intra- and intermolecular reactions are essential. In this review, a time-resolved diffusion technique which has a potential to detect molecular events associated with LLPS is presented. This technique can detect changes in protein conformation and intermolecular interaction (oligomer formation, protein-DNA interaction, and protein-lipid interaction) in time domain, which are difficult to obtain by other methods. After the principle and methods for signal analyses are described in detail, studies on photoreactive molecules (intermolecular interaction between light sensor proteins and its target DNA) and a non-photoreactive molecule (binding and folding reaction of α-synuclein upon mixing with SDS micelle) are presented as typical examples of applications of this unique technique.
Genomic Prediction of Yield Traits in Single-Cross Hybrid Rice (Oryza sativa L.)
Authors: Labroo Marlee R. , Ali Jauhar , Aslam M. Umair , de Asis Erik Jon , dela Paz Madonna A. , Sevilla M. Anna , Lipka Alexander E. , Studer Anthony J. , Rutkoski Jessica E.
Published: June 2021

Hybrid rice varieties can outyield the best inbred varieties by 15 – 30% with appropriate management. However, hybrid rice requires more inputs and management than inbred rice to realize a yield advantage in high-yielding environments. The development of stress-tolerant hybrid rice with lowered input requirements could increase hybrid rice yield relative to production costs. We used genomic prediction to evaluate the combining abilities of 564 stress-tolerant lines used to develop Green Super Rice with 13 male sterile lines of the International Rice Research Institute for yield-related traits. We also evaluated the performance of their F1 hybrids. We identified male sterile lines with good combining ability as well as F1 hybrids with potential further use in product development. For yield per plant, accuracies of genomic predictions of hybrid genetic values ranged from 0.490 to 0.822 in cross-validation if neither parent or up to both parents were included in the training set, and both general and specific combining abilities were modeled. The accuracy of phenotypic selection for hybrid yield per plant was 0.682. The accuracy of genomic predictions of male GCA for yield per plant was 0.241, while the accuracy of phenotypic selection was 0.562. At the observed accuracies, genomic prediction of hybrid genetic value could allow improved identification of high-performing single crosses. In a reciprocal recurrent genomic selection program with an accelerated breeding cycle, observed male GCA genomic prediction accuracies would lead to similar rates of genetic gain as phenotypic selection. It is likely that prediction accuracies of male GCA could be improved further by targeted expansion of the training set. Additionally, we tested the correlation of parental genetic distance with mid-parent heterosis in the phenotyped hybrids. We found the average mid-parent heterosis for yield per plant to be consistent with existing literature values at 32.0%. In the overall population of study, parental genetic distance was significantly negatively correlated with mid-parent heterosis for yield per plant (r = −0.131) and potential yield (r = −0.092), but within female families the correlations were non-significant and near zero. As such, positive parental genetic distance was not reliably associated with positive mid-parent heterosis.
Identification of Atrial Fibrillation-Associated Genes ERBB2 and MYPN Using Genome-Wide Association and Transcriptome Expression Profile Data on Left–Right Atrial Appendages
Authors: Meng Xiangguang , Nie Yali , Wang Keke , Fan Chen , Zhao Juntao , Yuan Yiqiang
Published: June 2021

More reliable methods are needed to uncover novel biomarkers associated with atrial fibrillation (AF). Our objective is to identify significant network modules and newly AF-associated genes by integrative genetic analysis approaches. The single nucleotide polymorphisms with nominal relevance significance from the AF-associated genome-wide association study (GWAS) data were converted into the GWAS discovery set using ProxyGeneLD, followed by merging with significant network modules constructed by weighted gene coexpression network analysis (WGCNA) from one expression profile data set, composed of left and right atrial appendages (LAA and RAA). In LAA, two distinct network modules were identified (blue: p = 0.0076; yellow: p = 0.023). Five AF-associated biomarkers were identified (ERBB2, HERC4, MYH7, MYPN, and PBXIP1), combined with the GWAS test set. In RAA, three distinct network modules were identified and only one AF-associated gene LOXL1 was determined. Using human LAA tissues by real-time quantitative polymerase chain reaction, the differentially expressive results of ERBB2, MYH7, and MYPN were observed (p < 0.05). This study first demonstrated the feasibility of fusing GWAS with expression profile data by ProxyGeneLD and WGCNA to explore AF-associated genes. In particular, two newly identified genes ERBB2 and MYPN via this approach contribute to further understanding the occurrence and development of AF, thereby offering preliminary data for subsequent studies.
Large Animal Models of Vascularized Composite Allotransplantation: A Review of Immune Strategies to Improve Allograft Outcomes
Authors: Matar Abraham J. , Crepeau Rebecca L. , Mundinger Gerhard S. , Cetrulo Curtis L. , Torabi Radbeh
Published: June 2021

Over the past twenty years, significant technical strides have been made in the area of vascularized composite tissue allotransplantation (VCA). As in solid organ transplantation, the allogeneic immune response remains a significant barrier to long-term VCA survival and function. Strategies to overcome acute and chronic rejection, minimize immunosuppression and prolong VCA survival have important clinical implications. Historically, large animals have provided a valuable model for testing the clinical translatability of immune modulating approaches in transplantation, including tolerance induction, co-stimulation blockade, cellular therapies, and ex vivo perfusion. Recently, significant advancements have been made in these arenas utilizing large animal VCA models. In this comprehensive review, we highlight recent immune strategies undertaken to improve VCA outcomes with a focus on relevant preclinical large animal models.
Unraveling the Mystery Surrounding Post-Acute Sequelae of COVID-19
Authors: Ramakrishnan Rakhee K. , Kashour Tarek , Hamid Qutayba , Halwani Rabih , Tleyjeh Imad M.
Published: June 2021

More than one year since its emergence, corona virus disease 2019 (COVID-19) is still looming large with a paucity of treatment options. To add to this burden, a sizeable subset of patients who have recovered from acute COVID-19 infection have reported lingering symptoms, leading to significant disability and impairment of their daily life activities. These patients are considered to suffer from what has been termed as “chronic” or “long” COVID-19 or a form of post-acute sequelae of COVID-19, and patients experiencing this syndrome have been termed COVID-19 long-haulers. Despite recovery from infection, the persistence of atypical chronic symptoms, including extreme fatigue, shortness of breath, joint pains, brain fogs, anxiety and depression, that could last for months implies an underlying disease pathology that persist beyond the acute presentation of the disease. As opposed to the direct effects of the virus itself, the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is believed to be largely responsible for the appearance of these lasting symptoms, possibly through facilitating an ongoing inflammatory process. In this review, we hypothesize potential immunological mechanisms underlying these persistent and prolonged effects, and describe the multi-organ long-term manifestations of COVID-19.
Stem Cells and Innate Immunity in Aquatic Invertebrates: Bridging Two Seemingly Disparate Disciplines for New Discoveries in Biology
Authors: Ballarin Loriano , Karahan Arzu , Salvetti Alessandra , Rossi Leonardo , Manni Lucia , Rinkevich Baruch , Rosner Amalia , Voskoboynik Ayelet , Rosental Benyamin , Canesi Laura , Anselmi Chiara , Pinsino Annalisa , Tohumcu Begüm Ece , Jemec Kokalj Anita , Dolar Andraž , Novak Sara , Sugni Michela , Corsi Ilaria , Drobne Damjana
Published: June 2021

The scopes related to the interplay between stem cells and the immune system are broad and range from the basic understanding of organism’s physiology and ecology to translational studies, further contributing to (eco)toxicology, biotechnology, and medicine as well as regulatory and ethical aspects. Stem cells originate immune cells through hematopoiesis, and the interplay between the two cell types is required in processes like regeneration. In addition, stem and immune cell anomalies directly affect the organism’s functions, its ability to cope with environmental changes and, indirectly, its role in ecosystem services. However, stem cells and immune cells continue to be considered parts of two branches of biological research with few interconnections between them. This review aims to bridge these two seemingly disparate disciplines towards much more integrative and transformative approaches with examples deriving mainly from aquatic invertebrates. We discuss the current understanding of cross-disciplinary collaborative and emerging issues, raising novel hypotheses and comments. We also discuss the problems and perspectives of the two disciplines and how to integrate their conceptual frameworks to address basic equations in biology in a new, innovative way.
HLA-G/ILTs Targeted Solid Cancer Immunotherapy: Opportunities and Challenges
Authors: Lin Aifen , Yan Wei-Hua
Published: June 2021

Immune checkpoint inhibitors (ICIs) have become a promising immunotherapy for cancers. Human leukocyte antigen-G (HLA-G), a neoantigen, its biological functions and clinical relevance have been extensively investigated in malignancies, and early clinical trials with “anti-HLA-G strategy” are being launched for advance solid cancer immunotherapy. The mechanism of HLA-G as a new ICI is that HLA-G can bind immune cell bearing inhibitory receptors, the immunoglobulin-like transcript (ILT)-2 and ILT-4. HLA-G/ILT-2/-4 (HLA-G/ILTs) signaling can drive comprehensive immune suppression, promote tumor growth and disease progression. Though clinical benefits could be expected with application of HLA-G antibodies to blockade the HLA-G/ILTs signaling in solid cancer immunotherapy, major challenges with the diversity of HLA-G isoforms, HLA-G/ILTs binding specificity, intra- and inter-tumor heterogeneity of HLA-G, lack of isoform-specific antibodies and validated assay protocols, which could dramatically affect the clinical efficacy. Clinical benefits of HLA-G-targeted solid cancer immunotherapy may be fluctuated or even premature unless major challenges are addressed.
Internal Disulfide Bonding and Glycosylation of Interleukin-7 Protect Against Proteolytic Inactivation by Neutrophil Metalloproteinases and Serine Proteases
Authors: Vandooren Jennifer , Pereira Rafaela Vaz Sousa , Ugarte-Berzal Estefania , Rybakin Vasily , Noppen Sam , Stas Melissa R. , Bernaerts Eline , Ganseman Eva , Metzemaekers Mieke , Schols Dominique , Proost Paul , Opdenakker Ghislain
Published: June 2021

Interleukin 7 (IL-7) is a cell growth factor with a central role in normal T cell development, survival and differentiation. The lack of IL-7–IL-7 receptor(R)-mediated signaling compromises lymphoid development, whereas increased signaling activity contributes to the development of chronic inflammation, cancer and autoimmunity. Gain-of-function alterations of the IL-7R and the signaling through Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are enriched in T cell acute lymphoblastic leukemia (T-ALL) and autocrine production of IL-7 by T-ALL cells is involved in the phenotypes of leukemic initiation and oncogenic spreading. Several IL-7-associated pathologies are also characterized by increased presence of matrix metalloproteinase-9 (MMP-9), due to neutrophil degranulation and its regulated production by other cell types. Since proteases secreted by neutrophils are known to modulate the activity of many cytokines, we investigated the interactions between IL-7, MMP-9 and several other neutrophil-derived proteases. We demonstrated that MMP-9 efficiently cleaved human IL-7 in the exposed loop between the α-helices C and D and that this process is delayed by IL-7 N-linked glycosylation. Functionally, the proteolytic cleavage of IL-7 did not influence IL-7Rα binding and internalization nor the direct pro-proliferative effects of IL-7 on a T-ALL cell line (HPB-ALL) or in primary CD8+human peripheral blood mononuclear cells. A comparable effect was observed for the neutrophil serine proteases neutrophil elastase, proteinase 3 and combinations of neutrophil proteases. Hence, glycosylation and disulfide bonding as two posttranslational modifications influence IL-7 bioavailability in the human species: glycosylation protects against proteolysis, whereas internal cysteine bridging under physiological redox state keeps the IL-7 conformations as active proteoforms. Finally, we showed that mouse IL-7 does not contain the protease-sensitive loop and, consequently, was not cleaved by MMP-9. With the latter finding we discovered differences in IL-7 biology between the human and mouse species.
Identification and Validation of Immune-Related Methylation Clusters for Predicting Immune Activity and Prognosis in Breast Cancer
Authors: Yang Anli , Zhou Ying , Kong Yanan , Wei Xiaoli , Ye Feng , Zhang Lijuan , Zhong Xian , Li Mingyue , Lu Shilin , An Xin , Xiao Weikai
Published: June 2021

The role of DNA methylation of breast cancer-infiltrating immune cells has not been fully explored. We conducted a cohort-based retrospective study analyzing the genome-wide immune-related DNA methylation of 1057 breast cancer patients from the TCGA cohort and GSE72308 cohort. Based on patients’ overall survival (OS), a prognostic risk score system using 18 immune-related methylation genes (IRMGs) was established and further validated in an independent cohort. Kaplan–Meier analysis showed a clear separation of OS between the low- and high-risk groups. Patients in the low-risk group had a higher immune score and stromal score compared with the high-risk group. Moreover, the characteristics based on 18-IRMGs signature were related to the tumor immune microenvironment and affected the abundance of tumor-infiltrating immune cells. Consistently, the 18-IRMGs signatures showed similar influences on immune modulation and survival in another external validation cohort (GSE72308). In conclusion, the proposed 18-IRMGs signature could be a potential marker for breast cancer prognostication.
A Case Study in Connecting Fisheries Management Challenges With Models and Analysis to Support Ecosystem-Based Management in the California Current Ecosystem
Authors: Tommasi Desiree , deReynier Yvonne , Townsend Howard , Harvey Chris J. , Satterthwaite William H. , Marshall Kristin N. , Kaplan Isaac C. , Brodie Stephanie , Field John C. , Hazen Elliott L. , Koenigstein Stefan , Lindsay Joshua , Moore Kathleen , Muhling Barbara , Pfeiffer Lisa , Smith James A. , Sweeney Jonathan , Wells Brian , Jacox Michael G.
Published: June 2021

One of the significant challenges to using information and ideas generated through ecosystem models and analyses for ecosystem-based fisheries management is the disconnect between modeling and management needs. Here we present a case study from the U.S. West Coast, the stakeholder review of NOAA’s annual ecosystem status report for the California Current Ecosystem established by the Pacific Fisheries Management Council’s Fisheries Ecosystem Plan, showcasing a process to identify management priorities that require information from ecosystem models and analyses. We then assess potential ecosystem models and analyses that could help address the identified policy concerns. We screened stakeholder comments and found 17 comments highlighting the need for ecosystem-level synthesis. Policy needs for ecosystem science included: (1) assessment of how the environment affects productivity of target species to improve forecasts of biomass and reference points required for setting harvest limits, (2) assessment of shifts in the spatial distribution of target stocks and protected species to anticipate changes in availability and the potential for interactions between target and protected species, (3) identification of trophic interactions to better assess tradeoffs in the management of forage species between the diet needs of dependent predators, the resilience of fishing communities, and maintenance of the forage species themselves, and (4) synthesis of how the environment affects efficiency and profitability in fishing communities, either directly via extreme events (e.g., storms) or indirectly via climate-driven changes in target species availability. We conclude by exemplifying an existing management process established on the U.S. West Coast that could be used to enable the structured, iterative, and interactive communication between managers, stakeholders, and modelers that is key to refining existing ecosystem models and analyses for management use.
Opening Marine Long-Term Ecological Science: Lesson Learned From the LTER-Italy Site Northern Adriatic Sea
Authors: Minelli Annalisa , Sarretta Alessandro , Oggioni Alessandro , Bergami Caterina , Bastianini Mauro , Bernardi Aubry Fabrizio , Camatti Elisa , Pugnetti Alessandra
Published: June 2021

This work presents a practical case study of the Open Science principles applied to the valorization of a long-term marine dataset collected in the Northern Adriatic Sea, one of the Long-Term Ecological Research (LTER) sites of the LTER-Italy network. The dataset covers a temporal range of 50 years (1965–2015), and it is composed of abiotic, and phyto- and zooplankton data, for a total of 21 parameters. The case study involved many actions, which will be described here, distinguishing between the ones affecting the whole research project workflow and those acting more specifically on the dataset. We evaluate strengths, weaknesses, and possible improvements for each action. The present study pointed out that, despite the initial and still some remaining mistrust, opening research projects is more than a best practice. It is (i) important because it improves research transparency (increasing researchers’ credibility, replicability of science, and products reuse), (ii) required by many international initiatives and regulations, and (iii) enriching because it encourages cooperation between scientists across different fields and laboratories.
A New Operational Seasonal Thermal Stress Prediction Tool for Coral Reefs Around Australia
Authors: Spillman Claire M. , Smith Grant A.
Published: June 2021

Seasonal forecasts of sea surface temperature (SST) have become increasingly important tools in recent years for reef managers to help inform and coordinate management responses to mass coral bleaching events. This manuscript presents new operational thermal stress forecast products for prediction of coral bleaching risk, based on the seasonal ensemble prediction system ACCESS-S1 (Australian Community Climate and Earth System Simulator–Seasonal Version 1). These accumulated thermal stress products form critical tools for reef management, providing advance warning of high thermal stress, and increased risk of coral bleaching in the coming season. Degree Heating Months (DHM) consider both the magnitude and duration of thermal stress, both of which are important in determining reef impacts. Both hindcast and operational realtime DHM forecasts are assessed for past bleaching events across Australia, and the impacts of different drivers and local forcings between regions compared. Generally, the model has the highest skill when forecasting events driven by large scale climate drivers such as the El Niño Southern Oscillation (ENSO) which impacts coral reefs on all sides of Australia. ACCESS-S1 hindcasts indicate higher skill on the west Australian coast than the Great Barrier Reef for summer months, except for the North West Shelf. Realtime forecasts of the 2020 Great Barrier Reef coral bleaching event, used operationally by reef managers throughout this event, are also presented. This work advances our understanding of the 2020 event, provides skill assessments for the new DHM products, and discusses the use of a stationary baseline in a changing climate. High DHM values can indicate an increased risk of marine heatwaves, which are likely to have increasing impacts on Australia’s reef systems in the future under a warming climate.
Effectiveness and Safety of Adding Bevacizumab to Platinum-Based Chemotherapy as First-Line Treatment for Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis
Authors: Liu Yi , Li Hui-Min , Wang Ran
Published: June 2021

Background and Objective: Previous studies have evaluated the efficacy (OS, overall survival; PFS, progression-free survival; ORR, objective response rate) and adverse events of bevacizumab combined with platinum-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer (NSCLC) compared with chemotherapy alone. However, the results were inconsistent.

Methods: We conducted a comprehensive search of PubMed, EMBASE, and Cochrane Library for potentially eligible articles. The outcomes were evaluated in terms of risk ratio (RR) or hazard ratio (HR) and the associated 95% confidence intervals (CIs). Meta-analysis was performed using the Stata 12.0 software, and subgroup analyses were performed based on the treatment and bevacizumab dose.

Results: Six randomized controlled trials with 2,465 patients were included in this meta-analysis. The results demonstrated that bevacizumab significantly increased OS (HR = 0.87, 95% CI 0.79–0.96), extended PFS (HR = 0.65, 95% CI 0.54–0.77), and increased ORR (ES = 0.40, 95% CI 0.31–0.48) when added to first-line platinum-based chemotherapy in patients with advanced NSCLC. Subgroup analyses showed that only the higher dose (15 mg/kg) of bevacizumab plus carboplatin–paclitaxel significantly extended the OS and PFS, but both 7.5 mg/kg and 15 mg/kg of bevacizumab improved ORR. However, both 7.5 mg/kg and 15 mg/kg of bevacizumab could only increase PFS and ORR, but not extend OS, when added to cisplatin–gemcitabine. Bevacizumab significantly increased the risk of grade ≥3 events of febrile neutropenia, haemorrhagic events, hypertension, leukopenia, neutropenia, and proteinuria.

Conclusion: Bevacizumab significantly increases OS, PFS, and ORR when added to first-line platinum-based chemotherapy in patients with advanced NSCLC, with no new safety signals found. Moreover, bevacizumab (15 mg/kg) plus carboplatin–paclitaxel is a better alternative in increasing OS to carboplatin–paclitaxel and bevacizumab (7.5 mg/kg and 15 mg/kg) plus cisplatin–gemcitabine.
Up State of the SARS-COV-2 Spike Homotrimer Favors an Increased Virulence for New Variants
Authors: Giron Carolina Corrêa , Laaksonen Aatto , Barroso da Silva Fernando Luís
Published: June 2021

The COVID-19 pandemic has spread worldwide. However, as soon as the first vaccines—the only scientifically verified and efficient therapeutic option thus far—were released, mutations combined into variants of SARS-CoV-2 that are more transmissible and virulent emerged, raising doubts about their efficiency. This study aims to explain possible molecular mechanisms responsible for the increased transmissibility and the increased rate of hospitalizations related to the new variants. A combination of theoretical methods was employed. Constant-pH Monte Carlo simulations were carried out to quantify the stability of several spike trimeric structures at different conformational states and the free energy of interactions between the receptor-binding domain (RBD) and angiotensin-converting enzyme II (ACE2) for the most worrying variants. Electrostatic epitopes were mapped using the PROCEEDpKa method. These analyses showed that the increased virulence is more likely to be due to the improved stability to the S trimer in the opened state, in which the virus can interact with the cellular receptor, ACE2, rather than due to alterations in the complexation RBD-ACE2, since the difference observed in the free energy values was small (although more attractive in general). Conversely, the South African/Beta variant (B.1.351), compared with the SARS-CoV-2 wild type (wt), is much more stable in the opened state with one or two RBDs in the up position than in the closed state with three RBDs in the down position favoring the infection. Such results contribute to understanding the natural history of disease and indicate possible strategies for developing new therapeutic molecules and adjusting the vaccine doses for higher B-cell antibody production.
Alleviation of C⋅C Mismatches in DNA by the Escherichia coli Fpg Protein
Authors: Tesfahun Almaz Nigatu , Alexeeva Marina , Tomkuvienė Miglė , Arshad Aysha , Guragain Prashanna , Klungland Arne , Klimašauskas Saulius , Ruoff Peter , Bjelland Svein
Published: June 2021

DNA polymerase III mis-insertion may, where not corrected by its 3′→ 5′ exonuclease or the mismatch repair (MMR) function, result in all possible non-cognate base pairs in DNA generating base substitutions. The most thermodynamically unstable base pair, the cytosine (C)⋅C mismatch, destabilizes adjacent base pairs, is resistant to correction by MMR in Escherichia coli, and its repair mechanism remains elusive. We present here in vitro evidence that C⋅C mismatch can be processed by base excision repair initiated by the E. coli formamidopyrimidine-DNA glycosylase (Fpg) protein. The kcat for C⋅C is, however, 2.5 to 10 times lower than for its primary substrate 8-oxoguanine (oxo8G)⋅C, but approaches those for 5,6-dihydrothymine (dHT)⋅C and thymine glycol (Tg)⋅C. The KM values are all in the same range, which indicates efficient recognition of C⋅C mismatches in DNA. Fpg activity was also exhibited for the thymine (T)⋅T mismatch and for N4- and/or 5-methylated C opposite C or T, Fpg activity being enabled on a broad spectrum of DNA lesions and mismatches by the flexibility of the active site loop. We hypothesize that Fpg plays a role in resolving C⋅C in particular, but also other pyrimidine⋅pyrimidine mismatches, which increases survival at the cost of some mutagenesis.
Inexpensive Apparatus for High-Quality Imaging of Microbial Growth on Agar Plates
Authors: Smith Parker , Schuster Martin
Published: June 2021

The ability to capture images of results or processes is an important tool in the biologist’s tool kit. In microbiology, capturing high-quality images of microbial growth on agar plates is difficult due to the reflective surface of the plates and limitations in common photography techniques. Equipment is available to overcome these challenges, but acquisition costs are high. We have developed and tested an inexpensive and efficient apparatus for high-quality imaging of microbial colonies. The imaging box, as we have named the apparatus, is designed to eliminate glare and reduce reflections on the surface of the plate while providing uniform, diffuse light from all sides. The imaging box was used to capture hundreds of images in research and teaching lab settings.
Association Between Diabetic Retinopathy and Cognitive Impairment: A Systematic Review and Meta-Analysis
Authors: Cheng Dihe , Zhao Xue , Yang Shuo , Wang Guixia , Ning Guang
Published: June 2021

Diabetic retinopathy (DR) is one of the most common microvascular complications associated with diabetes mellitus. However, its correlation with another diabetes-related disorder, cognitive impairment, has not been well studied. This systematic review and meta-analysis aimed to explore the association between DR and cognitive impairment. MEDLINE (PubMed), the Cochrane Library, and EMBASE databases were searched for observational studies that reported an association between DR and cognitive impairment. Data from selected studies were extracted, and a meta-analysis was conducted using fixed-effects modeling. Fifteen observational studies were included in the systematic review, and 10 studies were included in the meta-analysis. The odds ratio of the association between DR and cognitive impairment was 2.24 (95% confidence interval [CI], 1.89–2.66; I2 = 0.8%). The hazard ratio of the association between DR and cognitive impairment was significant in four studies, ranging from 1.09–1.32. Minimal or mild DR was not significantly associated with cognitive impairment (odds ratio [OR], 2.04; 95% CI, 0.87–4.77). However, the association between proliferative DR and cognitive impairment (OR, 3.57; 95% CI, 1.79–7.12; I2 = 16.6%) was not stronger than the association between moderate or worse DR and cognitive impairment (OR, 4.26; 95% CI, 2.01–9.07; I2 = 0.0%). DR is associated with cognitive impairment, and screening for DR will be helpful for the early identification of individuals with cognitive impairment. Further studies are needed to confirm the association between proliferative DR and cognitive impairment.
A Novel DenseNet Generative Adversarial Network for Heterogenous Low-Light Image Enhancement
Authors: Zhang Jingsi , Wu Chengdong , Yu Xiaosheng , Lei Xiaoliang
Published: June 2021

With the development of computer vision, high quality images with rich information have great research potential in both daily life and scientific research. However, due to different lighting conditions, surrounding noise and other reasons, the image quality is different, which seriously affects people's discrimination of the information in the image, thus causing unnecessary conflicts and results. Especially in the dark, the images captured by the camera are difficult to identify, and the smart system relies heavily on high-quality input images. The image collected in low-light environment has the characteristic with high noise and color distortion, which makes it difficult to utilize the image and can not fully explore the rich value information of the image. In order to improve the quality of low-light image, this paper proposes a Heterogenous low-light image enhancement method based on DenseNet generative adversarial network. Firstly, the generative network of generative adversarial network is realized by using DenseNet framework. Secondly, the feature map from low light image to normal light image is learned by using the generative adversarial network. Thirdly, the enhancement of low-light image is realized. The experimental results show that, in terms of PSNR, SSIM, NIQE, UQI, NQE and PIQE indexes, compared with the state-of-the-art enhancement algorithms, the values are ideal, the proposed method can improve the image brightness more effectively and reduce the noise of enhanced image.
Arterial Spin Labeling Imaging Assessment of Cerebrovascular Reactivity in Hypertensive Small Vessel Disease
Authors: Lee Bo-Ching , Tsai Hsin-Hsi , Huang Abel Po-Hao , Lo Yen-Ling , Tsai Li-Kai , Chen Ya-Fang , Wu Wen-Chau
Published: June 2021

Objective: Cerebrovascular reactivity (CVR) represents the phenomenon where cerebral vessels dilate or constrict in response to vasoactive stimuli. CVR impairment may contribute to brain injury due to cerebral small vessel disease (SVD). We aimed to determine the CVR in hypertensive intracerebral hemorrhage (ICH) and to identify its vascular dysfunction.

Methods: A total of 21 patients with spontaneous hypertensive ICH (strictly deep or mixed deep and lobar hemorrhages, mean age 62.5 ± 11.3 years) and 10 control subjects (mean age 66.1 ± 6.0 years) were enrolled for CVR measurement at least 3 months after the symptomatic ICH event. Each participant underwent a brain MRI study, and CVR was calculated as the cerebral blood flow (CBF) reduction using arterial spin labeling (ASL) between baseline and 10 min after an intravenous dipyridamole injection (0.57 mg/kg). Traditional MRI markers for SVD were also evaluated, including cerebral microbleed, white matter hyperintensity, lacune, and MRI-visible enlarged perivascular space, which were used to determine the total small vessel disease score.

Results: Compared to control subjects, hypertensive ICH patients showed reduced CVR in the basal ganglia (CBF reduction 22.4 ± 22.7% vs. 41.7 ± 18.3, p = 0.026), the frontal lobe (15.1 ± 11.9 vs. 26.6 ± 9.9, p = 0.013), and the temporal lobe (14.7 ± 11.1 vs. 26.2 ± 10.0, p = 0.010). These differences remained significant in multivariable models after adjusting for age and sex. Within ICH groups, the CBF reduction in the basal ganglia was significantly correlated with the total small vessel disease score (R = 0.58, p = 0.006), but not with individual MRI markers.

Conclusion: Patients with advanced hypertensive SVD demonstrated impaired vasoconstriction after dipyridamole challenge in the basal ganglia and the frontal and temporal lobes. Our findings provide safe approaches for whole-brain CVR mapping in SVD and identify a potential physiological basis for vascular dysfunction in hypertensive SVD.
Antibody Testing for Neurological Autoimmune Disorders: Evaluation of Best Practices at a Tertiary Referral Center
Authors: Fredrich Sarah E. , Vernino Steven , Blackburn Kyle M.
Published: June 2021

Background:Autoimmune neurology is a rapidly evolving field of study, where best practices for neurological antibody testing have yet to be determined. The growing number of options for antibody panel testing can create confusion amongst ordering clinicians and lead to ordering several concurrent panels (i.e., overlapping evaluations) or repeat panel evaluations. This study determined the frequency of these evaluations for autoimmune and paraneoplastic disorders and investigated how these practices informed clinical decision making and management.

Methods:This was a retrospective observational study of adult patients presenting to University of Texas Southwestern (UTSW) in 2017 with requests for antibody panels for autoimmune encephalitis and paraneoplastic disorders. Individuals with more than one panel requested were defined as either an overlapping evaluation (more than one panel requested within 14 days) or repeat evaluation (more than one panel requested 14 or more days apart). For those individuals with repeat panel testing, the proportion of panels with a change in antibody status or subsequent changes in clinical diagnosis and decision making were recorded.

Results:There was a total of 813 panels sent on 626 individuals. Twenty percent (126 individuals) had more than one panel requested. Only 10% of individuals had a matched serum and CSF evaluation. Forty-seven overlapping evaluations were performed in 46 (7.3%) of the individuals studied. Fifty-four (8.6%) individuals underwent 70 repeat evaluations encompassing 79 panels (9.7% of total panels ordered). Ten repeat evaluations showed a change in antibody status, of which only two were clinically significant. There was a single case where clinical management was affected by repeat autoantibody evaluation.

Conclusions:Ordering practices for suspected autoimmune encephalitis and paraneoplastic disorders are suboptimal with frequent overlapping antibody panel evaluations and non-paired serum/CSF samples at our center. Repeat autoantibody testing is a commonplace practice yet yielded novel information in only a minority of cases. These new results were, as a rule, clinically irrelevant and changed clinical decision making in <1% of cases. There is limited utility in these practice patterns. Future efforts should be directed at the development and standardization of neurological autoimmune and paraneoplastic autoantibody testing practice standards.
The PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study: Rationale, Design and Preliminary Screening Results
Authors: Gijbels Anouk , Trouwborst Inez , Jardon Kelly M. , Hul Gabby B. , Siebelink Els , Bowser Suzanne M. , Yildiz Dilemin , Wanders Lisa , Erdos Balázs , Thijssen Dick H. J. , Feskens Edith J. M. , Goossens Gijs H. , Afman Lydia A. , Blaak Ellen E.
Published: June 2021

Background: It is well-established that the etiology of type 2 diabetes differs between individuals. Insulin resistance (IR) may develop in different tissues, but the severity of IR may differ in key metabolic organs such as the liver and skeletal muscle. Recent evidence suggests that these distinct tissue-specific IR phenotypes may also respond differentially to dietary macronutrient composition with respect to improvements in glucose metabolism.

Objective: The main objective of the PERSON study is to investigate the effects of an optimal vs. suboptimal dietary macronutrient intervention according to tissue-specific IR phenotype on glucose metabolism and other health outcomes.

Methods: In total, 240 overweight/obese (BMI 25 – 40 kg/m2) men and women (age 40 – 75 years) with either skeletal muscle insulin resistance (MIR) or liver insulin resistance (LIR) will participate in a two-center, randomized, double-blind, parallel, 12-week dietary intervention study. At screening, participants undergo a 7-point oral glucose tolerance test (OGTT) to determine the hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), classifying each participant as either “No MIR/LIR,” “MIR,” “LIR,” or “combined MIR/LIR.” Individuals with MIR or LIR are randomized to follow one of two isocaloric diets varying in macronutrient content and quality, that is hypothesized to be either an optimal or suboptimal diet, depending on their tissue-specific IR phenotype (MIR/LIR). Extensive measurements in a controlled laboratory setting as well as phenotyping in daily life are performed before and after the intervention. The primary study outcome is the difference in change in disposition index, which is the product of insulin sensitivity and first-phase insulin secretion, between participants who received their hypothesized optimal or suboptimal diet.

Discussion: The PERSON study is one of the first randomized clinical trials in the field of precision nutrition to test effects of a more personalized dietary intervention based on IR phenotype. The results of the PERSON study will contribute knowledge on the effectiveness of targeted nutritional strategies to the emerging field of precision nutrition, and improve our understanding of the complex pathophysiology of whole body and tissue-specific IR.

Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03708419, clinicaltrials.gov as NCT03708419.
Longitudinal Grouping of Target Volumes for Volumetric-Modulated Arc Therapy of Multiple Brain Metastases
Authors: Xu Yingjie , Miao Junjie , Liu Qingfeng , Huang Peng , Ma Pan , Chen Xinyuan , Men Kuo , Xiao Jianping , Dai Jianrong
Published: June 2021

Purpose

Treatment of multiple brain metastases with single-isocenter volumetric modulated arc therapy causes unnecessary exposure to normal brain tissue. In this study, a longitudinal grouping method was developed to reduce such unnecessary exposure.

Materials and Methods

This method has two main aspects: grouping brain lesions longitudinally according to their longitudinal projection positions in beam’s eye view, and rotating the collimator to 90° to make the multiple leaf collimator leaves conform to the targets longitudinally group by group. For 11 patients with multiple (5–30) brain metastases, two single-isocenter volumetric modulated arc therapy plans were generated using a longitudinal grouping strategy (LGS) and the conventional strategy (CVS). The prescription dose was 52 Gy for 13 fractions. Dose normalization to 100% of the prescription dose in 95% of the planning target volume was adopted. For plan quality comparison, Paddick conformity and the gradient index of the planning target volume, and the mean dose, the V100%, V50%, V25%, and V10% volumes of normal brain tissue were calculated.

Results

There were no significant differences between the LGS and CVS plans in Paddick conformity (p = 0.374) and the gradient index (p = 0.182) of the combined planning target volumes or for V100% (p = 0.266) and V50% (p = 0.155) of the normal brain. However, the V25% and V10% of the normal brain which represented the low-dose region were significantly reduced in the LGS plans (p = 0.004 and p = 0.003, respectively). Consistently, the mean dose of the entire normal brain was 12.04 and 11.17 Gy in the CVS and LGS plans, respectively, a significant reduction in the LGS plans (p = 0.003).

Conclusions

The longitudinal grouping method can decrease unnecessary exposure and reduces the low-dose range in normal brain tissue.
Prognosis and Biological Behavior of Gastric Signet-Ring Cell Carcinoma Better or Worse: A Meta-Analysis
Authors: Zhao Shuai , Lv Ling , Zheng Kai , Tian Yu , Zheng Jian-Chun , Jiang Cheng-Gang
Published: June 2021

Background

The clinical pathology of gastric signet-ring cell carcinoma (SRC) is still unclear. This meta-analysis was performed to evaluate the difference in biological behavior and prognosis between SRC and non-signet ring cell carcinoma (NSRC).

Methods

A total of 58 eligible studies were analyzed using RevMan and other auxiliary software. Biological behaviors were compared based on odds ratio (OR) and mean difference (MD). Hazards ratio (HR) was calculated for prognosis based on Kaplan–Meier curves.

Results

Totally, 28,946 SRC patients were compared with 81,917 NSRC patients. Compared with NSRC patients, lower male: female ratio (OR = 0.53, P < 0.01), younger age (MD = −4.89, P < 0.01), more middle location (OR = 1.64, P < 0.01), more depressed type at early stage (OR = 1.31, P < 0.05), higher incidence of Borrmann type IV (OR = 1.96, P < 0.01), less lymph node metastasis at early stage (OR = 0.78, P < 0.05), better prognosis at early stage (HR = 0.59, P < 0.01), and worse prognosis at advanced stage (HR = 1.19, P < 0.01) were associated with SRC patients.

Conclusion

The prognosis of SRC at early stage is better than other types of gastric cancer, while that of SRC at advanced stage is relatively poorer.
CDK10 in Gastrointestinal Cancers: Dual Roles as a Tumor Suppressor and Oncogene
Authors: Bazzi Zainab A. , Tai Isabella T.
Published: June 2021

Cyclin-dependent kinase 10 (CDK10) is a CDC2-related serine/threonine kinase involved in cellular processes including cell proliferation, transcription regulation and cell cycle regulation. CDK10 has been identified as both a candidate tumor suppressor in hepatocellular carcinoma, biliary tract cancers and gastric cancer, and a candidate oncogene in colorectal cancer (CRC). CDK10 has been shown to be specifically involved in modulating cancer cell proliferation, motility and chemosensitivity. Specifically, in CRC, it may represent a viable biomarker and target for chemoresistance. The development of therapeutics targeting CDK10 has been hindered by lack a specific small molecule inhibitor for CDK10 kinase activity, due to a lack of a high throughput screening assay. Recently, a novel CDK10 kinase activity assay has been developed, which will aid in the development of small molecule inhibitors targeting CDK10 activity. Discovery of a small molecular inhibitor for CDK10 would facilitate further exploration of its biological functions and affirm its candidacy as a therapeutic target, specifically for CRC.
Radiation in Combination With Targeted Agents and Immunotherapies for Pediatric Central Nervous System Tumors - Progress, Opportunities, and Challenges
Authors: Qiu Bo , Kline Cassie , Mueller Sabine
Published: June 2021

Pediatric brain tumors are the most common solid tumors in children and represent a heterogenous group of diagnoses. While some are treatable with current standard of care, relapsed/refractory disease is common and some high-risk diagnoses remain incurable. A growing number of therapy options are under development for treatment of CNS tumors, including targeted therapies that disrupt key tumor promoting processes and immunotherapies that promote anti-tumor immune function. While these therapies hold promise, it is likely that single agent treatments will not be sufficient for most high-risk patients and combination strategies will be necessary. Given the central role for radiotherapy for many pediatric CNS tumors, we review current strategies that combine radiation with targeted therapies or immunotherapies. To promote the ongoing development of rational combination treatments, we highlight 1) mechanistic connections between molecular drivers of tumorigenesis and radiation response, 2) ways in which molecular alterations in tumor cells shape the immune microenvironment, and 3) how radiotherapy affects the host immune system. In addition to discussing strategies to maximize efficacy, we review principles that inform safety of combination therapies.