bluuebunny/crossref_metadata_2025 huggingface dataset:
The CDK1/TFCP2L1/ID2 cascade offers a novel combination therapy strategy in a preclinical model of bladder cancer
Authors: Heo Jinbeom , Lee Jinyoung , Nam Yun Ji , Kim YongHwan , Yun HongDuck , Lee Seungun , Ju Hyein , Ryu Chae-Min , Jeong Seon Min , Lee Jinwon , Lim Jisun , Cho Yong Mee , Jeong Eui Man , Hong Bumsik , Son Jaekyoung , Shin Dong-Myung
Published: June 2022

Aberrant activation of embryogenesis-related molecular programs in urothelial bladder cancer (BC) is associated with stemness features related to oncogenic dedifferentiation and tumor metastasis. Recently, we reported that overexpression of transcription factor CP2-like protein-1 (TFCP2L1) and its phosphorylation at Thr177 by cyclin-dependent kinase-1 (CDK1) play key roles in regulating bladder carcinogenesis. However, the clinical relevance and therapeutic potential of this novel CDK1-TFCP2L1 molecular network remain elusive. Here, we demonstrated that inhibitor of DNA binding-2 (ID2) functions as a crucial mediator by acting as a direct repressive target of TFCP2L1 to modulate the stemness features and survival of BC cells. Low ID2 and high CDK1 expression were significantly associated with unfavorable clinical characteristics. TFCP2L1 downregulated ID2 by directly binding to its promoter region. Consistent with these findings, ectopic expression of ID2 or treatment with apigenin, a chemical activator of ID2, triggered apoptosis and impaired the proliferation, suppressed the stemness features, and reduced the invasive capacity of BC cells. Combination treatment with the specific CDK1 inhibitor RO-3306 and apigenin significantly suppressed tumor growth in an orthotopic BC xenograft animal model. This study demonstrates the biological role and clinical utility of ID2 as a direct target of the CDK1-TFCP2L1 pathway for modulating the stemness features of BC cells.
hnRNPC induces isoform shifts in miR-21-5p leading to cancer development
Authors: Park Seokju , Yang Hee Doo , Seo Jwa-Won , Nam Jin-Wu , Nam Suk Woo
Published: June 2022

MicroRNA (miRNA) processing is a critical step in mature miRNA production. Its dysregulation leads to an increase in miRNA isoforms with heterogenous 5′-ends (isomiRs), which can recognize distinct target sites because of their shifted seed sequence. Although some miRNA genes display productive expression of their 5′-isomiRs in cancers, how their production is controlled and how 5′-isomiRs affect tumor progression have yet to be explored. In this study, based on integrative analyses of high-throughput sequencing data produced by our group and publicly available data, we demonstrate that primary miR-21 (pri-miR-21) is processed into the cancer-specific isomiR isomiR-21-5p | ±1, which suppresses growth hormone receptor (GHR) in liver cancer. Treatment with antagomirs against isomiR-21-5p | ±1 inhibited the in vitro tumorigenesis of liver cancer cells and allowed the recovery of GHR, whereas the introduction of isomiR-21-5p | ±1 mimics attenuated these effects. These effects were validated in a mouse model of spontaneous liver cancer. Heterogeneous nuclear ribonucleoprotein C and U2 small nuclear RNA auxiliary factor 2 were predicted to bind upstream of pre-miR-21 via a poly-(U) motif and influence Drosha processing to induce the production of isomiR-21-5p | ±1. Our findings suggest an oncogenic function for the non-canonical isomiR-21-5p | ±1 in liver cancer, and its production was shown to be regulated by hnRNPC.
MYCN induces cell-specific tumorigenic growth in RB1-proficient human retinal organoid and chicken retina models of retinoblastoma
Authors: Blixt Maria K. E. , Hellsand Minas , Konjusha Dardan , Zhang Hanzhao , Stenfelt Sonya , Åkesson Mikael , Rafati Nima , Tararuk Tatsiana , Stålhammar Gustav , All-Eriksson Charlotta , Ring Henrik , Hallböök Finn
Published: June 2022

Retinoblastoma is a rare, intraocular paediatric cancer that originates in the neural retina and is most frequently caused by bi-allelic loss of RB1 gene function. Other oncogenic mutations, such as amplification and increased expression of the MYCN gene, have been found even with proficient RB1 function. In this study, we investigated whether MYCN over-expression can drive carcinogenesis independently of RB1 loss-of-function mutations. The aim was to elucidate the events that result in carcinogenesis and identify the cancer cell-of-origin. We used the chicken retina, a well-established model for studying retinal neurogenesis, and established human embryonic stem cell-derived retinal organoids as model systems. We over-expressed MYCN by electroporation of piggyBac genome-integrating expression vectors. We found that over-expression of MYCN induced tumorigenic growth with high frequency in RB1-proficient chicken retinas and human organoids. In both systems, the tumorigenic cells expressed markers for undifferentiated cone photoreceptor/horizontal cell progenitors. The over-expression resulted in metastatic retinoblastoma within 7–9 weeks in chicken. Cells expressing MYCN could be grown in vitro and, when orthotopically injected, formed tumours that infiltrated the sclera and optic nerve and expressed markers for cone progenitors. Investigation of the tumour cell phenotype determined that the potential for neoplastic growth was embryonic stage-dependent and featured a cell-specific resistance to apoptosis in the cone/horizontal cell lineage, but not in ganglion or amacrine cells. We conclude that MYCN over-expression is sufficient to drive tumorigenesis and that a cell-specific resistance to apoptosis in the cone/horizontal cell lineage mediates the cancer phenotype.
Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening
Authors: Zheng Rui , Yang Wenhao , Wen Yuting , Xie Liang , Shi Fang , Lu Danli , Luo Jiaxin , Li Yan , Zhang Rui , Chen Ting , Chen Lina , Xu Wenming , Liu Hanmin
Published: June 2022

Primary cilia dyskinesia (PCD) is a rare genetic disease caused by ciliary structural or functional defects. It causes severe outcomes in patients, including recurrent upper and lower airway infections, progressive lung failure, and randomization of heterotaxy. To date, although 50 genes have been shown to be responsible for PCD, the etiology remains elusive. Meanwhile, owing to the lack of a model mimicking the pathogenesis that can be used as a drug screening platform, thereby slowing the development of related therapies. In the current study, we identified compound mutation of DNAH9 in a patient with PCD with the following clinical features: recurrent respiratory tract infections, low lung function, and ultrastructural defects of the outer dynein arms (ODAs). Bioinformatic analysis, structure simulation assay, and western blot analysis showed that the mutations affected the structure and expression of DNAH9 protein. Dnah9 knock-down (KD) mice recapitulated the patient phenotypes, including low lung function, mucin accumulation, and increased immune cell infiltration. Immunostaining, western blot, and co-immunoprecipitation analyses were performed to clarify that DNAH9 interacted with CCDC114/GAS8 and diminished their protein levels. Furthermore, we constructed an airway organoid of Dnah9 KD mice and discovered that it could mimic the key features of the PCD phenotypes. We then used organoid as a drug screening model to identify mitochondrial-targeting drugs that can partially elevate cilia beating in Dnah9 KD organoid. Collectively, our results demonstrated that Dnah9 KD mice and an organoid model can recapture the clinical features of patients with PCD and provide an excellent drug screening platform for human ciliopathies.
A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood
Authors: Kurniansyah Nuzulul , Goodman Matthew O. , Kelly Tanika N. , Elfassy Tali , Wiggins Kerri L. , Bis Joshua C. , Guo Xiuqing , Palmas Walter , Taylor Kent D. , Lin Henry J. , Haessler Jeffrey , Gao Yan , Shimbo Daichi , Smith Jennifer A. , Yu Bing , Feofanova Elena V. , Smit Roelof A. J. , Wang Zhe , Hwang Shih-Jen , Liu Simin , Wassertheil-Smoller Sylvia , Manson JoAnn E. , Lloyd-Jones Donald M. , Rich Stephen S. , Loos Ruth J. F. , Redline Susan , Correa Adolfo , Kooperberg Charles , Fornage Myriam , Kaplan Robert C. , Psaty Bruce M. , Rotter Jerome I. , Arnett Donna K. , Morrison Alanna C. , Franceschini Nora , Levy Daniel ,   the NHLBI Trans-Omics in Precision Medicine (TOPMed) Consortium, Bis Joshua C. , Guo Xiuqing , Taylor Kent D. , Lin Henry J. , Haessler Jeffrey , Gao Yan , Smith Jennifer A. , Liu Simin , Wassertheil-Smoller Sylvia , Manson JoAnn E. , Rich Stephen S. , Redline Susan , Correa Adolfo , Kooperberg Charles , Fornage Myriam , Kaplan Robert C. , Psaty Bruce M. , Rotter Jerome I. , Arnett Donna K. , Franceschini Nora , Levy Daniel , Sofer Tamar , Sofer Tamar
Published: June 2022

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called “PRSsum”, forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.
The antenna of far-red absorbing cyanobacteria increases both absorption and quantum efficiency of Photosystem II
Authors: Mascoli Vincenzo , Bhatti Ahmad Farhan , Bersanini Luca , van Amerongen Herbert , Croce Roberta
Published: June 2022

Cyanobacteria carry out photosynthetic light-energy conversion using phycobiliproteins for light harvesting and the chlorophyll-rich photosystems for photochemistry. While most cyanobacteria only absorb visible photons, some of them can acclimate to harvest far-red light (FRL, 700–800 nm) by integrating chlorophyll f and d in their photosystems and producing red-shifted allophycocyanin. Chlorophyll f insertion enables the photosystems to use FRL but slows down charge separation, reducing photosynthetic efficiency. Here we demonstrate with time-resolved fluorescence spectroscopy that on average charge separation in chlorophyll-f-containing Photosystem II becomes faster in the presence of red-shifted allophycocyanin antennas. This is different from all known photosynthetic systems, where additional light-harvesting complexes increase the overall absorption cross section but slow down charge separation. This remarkable property can be explained with the available structural and spectroscopic information. The unique design is probably important for these cyanobacteria to efficiently switch between visible and far-red light.
A forward Brillouin fibre laser
Authors: Bashan Gil , Diamandi H. Hagai , Zehavi Elad , Sharma Kavita , London Yosef , Zadok Avi
Published: June 2022

Fibre lasers based on backward stimulated Brillouin scattering provide narrow linewidths and serve in signal processing and sensing applications. Stimulated Brillouin scattering in fibres takes place in the forward direction as well, with amplification bandwidths that are narrower by two orders of magnitude. However, forward Brillouin lasers have yet to be realized in any fibre platform. In this work, we report a first forward Brillouin fibre laser, using a bare off-the-shelf, panda-type polarisation maintaining fibre. Pump light in one principal axis provides Brillouin amplification for a co-propagating lasing signal of the orthogonal polarisation. Feedback is provided by Bragg gratings at both ends of the fibre cavity. Single-mode, few-modes and multi-mode regimes of operation are observed. The lasing threshold exhibits a unique environmental sensitivity: it is elevated when the fibre is partially immersed in water due to the broadening of forward Brillouin scattering spectra. The results establish a new type of fibre laser, with potential for ultra-high coherence and precision sensing of media outside the cladding.
Binding and structural basis of equine ACE2 to RBDs from SARS-CoV, SARS-CoV-2 and related coronaviruses
Authors: Xu Zepeng , Kang Xinrui , Han Pu , Du Pei , Li Linjie , Zheng Anqi , Deng Chuxia , Qi Jianxun , Zhao Xin , Wang Qihui , Liu Kefang , Gao George Fu
Published: June 2022

The origin and host range of SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), are important scientific questions as they might provide insight into understanding of the potential future spillover to infect humans. Here, we tested the binding between equine angiotensin converting enzyme 2 (eqACE2) and the receptor binding domains (RBDs) of SARS-CoV, SARS-CoV-2 prototype (PT) and variant of concerns (VOCs), as well as their close relatives bat-origin coronavirus (CoV) RaTG13 and pangolin-origin CoVs GX/P2V/2017 and GD/1/2019. We also determined the crystal structures of eqACE2/RaTG13-RBD, eqACE2/SARS-CoV-2 PT-RBD and eqACE2/Omicron BA.1-RBD. We identified S494 of SARS-COV-2 PT-RBD as an important residue in the eqACE2/SARS-COV-2 PT-RBD interaction and found that N501Y, the commonly recognized enhancing mutation, attenuated the binding affinity with eqACE2. Our work demonstrates that horses are potential targets for SARS-CoV-2 and highlights the importance of continuous surveillance on SARS-CoV-2 and related CoVs to prevent spillover events.
A ternary heterogeneous hydrogel with strength elements for resilient, self-healing, and recyclable epidermal electronics
Authors: Wang Ziya , Xu Xiuru , Xu Yingtian , Lin Waner , Peng Zhengchun
Published: June 2022

Epidermal sensing devices, which mimic functionalities and mechanical properties of natural skin, offer great potential for real-time health monitoring via continuous checking of vital signs. However, most existing skin-mounted electronics use a flexible film with high elastic modulus, which hinders physical activity and causes interfacial delamination and skin irritation. The compliance of hydrogel-based devices can firmly conform to complex, curved surfaces without introducing excessive interfacial stresses. However, most hydrogels still suffer from the weakness of stable and reproducible sensing. In this work, we report a skin-friendly epidermal electronic made of a resilient, self-healing, and recyclable polyvinyl alcohol (PVA) hydrogel. The hydrogel is reinforced through a ternary heterogeneous network for good mechanical robustness while maintaining high stretchability and exceptional conformability. Simultaneously, the abundant dynamic hydrogen bonds give the hydrogel rapid self-healing ability. The assembled hydrogel epidermal electronic is able to stably monitor multiple physiological signals as well as sense the strain level of the skin motion and joint bending. The unique, versatile, environmental and biological friendly epidermal electronics will have broad applications in health care, human-machine interface, augmented reality, and so on.
Metal-organic framework modified hydrophilic polyvinylidene fluoride porous membrane for efficient degerming selective oil/water emulsion separation
Authors: Ye Qin , Xu Jia-Min , Zhang Yi-Jie , Chen Shu-Han , Zhan Xue-Qing , Ni Wang , Tsai Lung-Chang , Jiang Tao , Ma Ning , Tsai Fang-Chang
Published: June 2022

Developing a new type of superhydrophilic/underwater superoleophobic oil/water separation membrane with high separation efficiency, high throughput and bacteria separation has essential theoretical and practical significance for treating oily and medical wastewater. This work modified commercial PVDF membranes by knife coating and cross-linking, and PVDF/PVA/LPB/MOF hybrid separation membranes are manufactured. Hydrophilic polyvinyl alcohol (PVA) endows the separation membrane with good hydrophilicity. Lauramidopropyl Betaine (LPB) enhances intermolecular hydrogen bonding and improves the mechanical properties of the membrane. A Metal-organic framework (MOF) with excellent biocompatibility, UiO-66-NH2, plays a vital role in the separation of bacteria. The results of the morphology and surface chemistry of characterization analysis show that the PVDF/PVA/LPB/MOF hybrid separation membrane exhibits excellent superhydrophilicity (with a contact angle of 2°) and high-water flux (15600 L/m2h) and high separation efficiency (99%), and the nature of filtering bacteria while separating oil. After modification, the separation efficiency increased from 30% to 99%, showing strong oil stain resistance. Our finding suggests that the new type of super-hydrophilic/underwater superoleophobic oil/water separation membrane has potential value in practical applications.
ReaLSAT, a global dataset of reservoir and lake surface area variations
Authors: Khandelwal Ankush , Karpatne Anuj , Ravirathinam Praveen , Ghosh Rahul , Wei Zhihao , Dugan Hilary A. , Hanson Paul C. , Kumar Vipin
Published: June 2022

Lakes and reservoirs, as most humans experience and use them, are dynamic bodies of water, with surface extents that increase and decrease with seasonal precipitation patterns, long-term changes in climate, and human management decisions. This paper presents a new global dataset that contains the location and surface area variations of 681,137 lakes and reservoirs larger than 0.1 square kilometers (and south of 50 degree N) from 1984 to 2015, to enable the study of the impact of human actions and climate change on freshwater availability. Within its scope for size and region covered, this dataset is far more comprehensive than existing datasets such as HydroLakes. While HydroLAKES only provides a static shape, the proposed dataset also has a timeseries of surface area and a shapefile containing monthly shapes for each lake. The paper presents the development and evaluation of this dataset and highlights the utility of novel machine learning techniques in addressing the inherent challenges in transforming satellite imagery to dynamic global surface water maps.
Presenting the Compendium Isotoporum Medii Aevi, a Multi-Isotope Database for Medieval Europe
Authors: Cocozza Carlo , Cirelli Enrico , Groß Marcus , Teegen Wolf-Rüdiger , Fernandes Ricardo
Published: June 2022

Here we present theCompendium Isotoporum Medii Aevi (CIMA), an open-access database gathering more than 50,000 isotopic measurements for bioarchaeological samples located within Europe and its margins, and dating between 500 and 1500 CE. This multi-isotope (δ13C, δ15N, δ34S, δ18O, and87Sr/86Sr) archive of measurements on human, animal, and plant archaeological remains also includes a variety of supporting information that offer, for instance, a taxonomic characterization of the samples, their location, and chronology, in addition to data on social, religious, and political contexts. Such a dataset can be used to identify data gaps for future research and to address multiple research questions, including those related with studies on medieval human lifeways (i.e. human subsistence, spatial mobility), characterization of paleo-environmental and -climatic conditions, and on plant and animal agricultural management practices. Brief examples of such applications are given here and we also discuss how the integration of large volumes of isotopic data with other types of archaeological and historical data can improve our knowledge of medieval Europe.
The performance of ensemble-based free energy protocols in computing binding affinities to ROS1 kinase
Authors: Wan Shunzhou , Bhati Agastya P. , Wright David W. , Wade Alexander D. , Tresadern Gary , van Vlijmen Herman , Coveney Peter V.
Published: June 2022

Optimization of binding affinities for compounds to their target protein is a primary objective in drug discovery. Herein we report on a collaborative study that evaluates a set of compounds binding to ROS1 kinase. We use ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling) protocols to rank the binding free energies. The predicted binding free energies from ESMACS simulations show good correlations with experimental data for subsets of the compounds. Consistent binding free energy differences are generated for TIES and ESMACS. Although an unexplained overestimation exists, we obtain excellent statistical rankings across the set of compounds from the TIES protocol, with a Pearson correlation coefficient of 0.90 between calculated and experimental activities.
Understanding and predicting the functional consequences of missense mutations in BRCA1 and BRCA2
Authors: Aljarf Raghad , Shen Mengyuan , Pires Douglas E. V. , Ascher David B.
Published: June 2022

BRCA1 and BRCA2 are tumour suppressor genes that play a critical role in maintaining genomic stability via the DNA repair mechanism. DNA repair defects caused by BRCA1 and BRCA2 missense variants increase the risk of developing breast and ovarian cancers. Accurate identification of these variants becomes clinically relevant, as means to guide personalized patient management and early detection. Next-generation sequencing efforts have significantly increased data availability but also the discovery of variants of uncertain significance that need interpretation. Experimental approaches used to measure the molecular consequences of these variants, however, are usually costly and time-consuming. Therefore, computational tools have emerged as faster alternatives for assisting in the interpretation of the clinical significance of newly discovered variants. To better understand and predict variant pathogenicity in BRCA1 and BRCA2, various machine learning algorithms have been proposed, however presented limited performance. Here we present BRCA1 and BRCA2 gene-specific models and a generic model for quantifying the functional impacts of single-point missense variants in these genes. Across tenfold cross-validation, our final models achieved a Matthew's Correlation Coefficient (MCC) of up to 0.98 and comparable performance of up to 0.89 across independent, non-redundant blind tests, outperforming alternative approaches. We believe our predictive tool will be a valuable resource for providing insights into understanding and interpreting the functional consequences of missense variants in these genes and as a tool for guiding the interpretation of newly discovered variants and prioritizing mutations for experimental validation.
Spatial distribution and ecological risk assessment of potentially toxic metals in the Sundarbans mangrove soils of Bangladesh
Authors: Islam Md Mahfuz , Akther Sayada Momotaz , Hossain Md Faruque , Parveen Zakia
Published: June 2022

At present, there are growing concerns over the increasing release of trace metals in the Sundarbans mangrove areas in Bangladesh due to nearby shipbreaking and metallurgical industries, untreated waste discharge, navigation activities, and other natural processes that deposit trace metals into soils. The current study investigated the spatial distribution, contamination level, and ecotoxicity of eight trace metals (Fe, Mn, Cu, Zn, Pb, Cd, Cr, Ni) in Sundarbans soils. Results revealed that all the trace metals except Cr were present in higher concentrations compared to Earth’s shale and/or upper continental crust. Principal component analysis and Pearson correlation showed strong positive correlations (p < 0.05) between Fe, Mn, Cu, and Zn; Ni with Mn and Cr. There were significant associations (p < 0.05) of % clay and total organic carbon (TOC) with Pb-Ni-Cr and negative correlations of pH with all the trace metals. The hierarchical cluster analysis grouped Pb, Ni, and Cd into one distinct cluster, suggesting they are derived from the same sources, possibly from anthropogenic activities. Geo accumulation index (I-geo), enrichment factor (EF), contamination factor (CF), and spatial distribution showed moderately polluted soils with Ni, Pb, and Cd (EF = 3–7.4, CF = 1–2.8, I-geo = 0–0.9) and low pollution by Zn, Cu, Fe, and Mn (EF < 3, CF < 1, I-geo < 0). The ecological risk index (RI) revealed that S-4 (RI = 114.02) and S-5 (RI = 100.04) belonged to moderate risk, and other areas posed a low risk (RI < 95). The individual contribution of Cd (25.9–73.7%), Pb (9.2–29.1%), and Ni (9.6–26.4%) to RI emphasized these metals were the foremost concern in the Sundarbans mangroves due to their long persistence time and high toxicity, even if they were present in low concentrations.
Profiling gut microbiota and bile acid metabolism in critically ill children
Authors: Kean Iain Robert Louis , Wagner Joseph , Wijeyesekera Anisha , De Goffau Marcus , Thurston Sarah , Clark John A. , White Deborah K. , Ridout Jenna , Agrawal Shruti , Kayani Riaz , O’Donnell Roddy , Ramnarayan Padmanabhan , Peters Mark J. , Klein Nigel , Holmes Elaine , Parkhill Julian , Baker Stephen , Pathan Nazima
Published: June 2022

Broad-spectrum antimicrobial use during the treatment of critical illness influences gastrointestinal fermentation endpoints, host immune response and metabolic activity including the conversion of primary to secondary bile acids. We previously observed reduced fermentation capacity in the faecal microbiota of critically ill children upon hospital admission. Here, we further explore the timecourse of the relationship between the microbiome and bile acid profile in faecal samples collected from critically ill children. The microbiome was assayed by sequencing of the 16S rRNA gene, and faecal water bile acids were measured by liquid chromatography mass spectrometry. In comparison to admission faecal samples, members of theLachnospiraceaerecovered during the late-acute phase (days 8–10) of hospitalisation. Patients with infections had a lower proportion ofLachnospiraceaein their gut microbiota than controls and patients with primary admitting diagnoses. Keystone species linked to ecological recovery were observed to decline with the length of PICU admission. These species were further suppressed in patients with systemic infection, respiratory failure, and undergoing surgery. Bile acid composition recovers quickly after intervention for critical illness which may be aided by the compositional shift inLachnospiraceae. Our findings suggest gut microbiota recovery can be readily assessed via measurement of faecal bile acids.
High generation of reactive oxygen species from neutrophils in patients with severe COVID-19
Authors: Veenith Tonny , Martin Helena , Le Breuilly Martin , Whitehouse Tony , Gao-Smith Fang , Duggal Niharika , Lord Janet M. , Mian Rubina , Sarphie David , Moss Paul
Published: June 2022

Neutrophilia and an elevated neutrophil:lymphocyte ratio are both characteristic features of severe COVID-19 infection. However, functional neutrophil responses have been poorly investigated in this setting. We utilised a novel PMA-based stimulation assay to determine neutrophil-derived reactive oxygen species (ROS) generation in patients with severe COVID-19 infection, non-COVID related sepsis and healthy study participants. ROS production was markedly elevated in COVID-19 patients with median values ninefold higher than in healthy controls and was particularly high in patients on mechanical ventilation. ROS generation correlated strongly with neutrophil count and elevated levels were also seen in patients with non-COVID related sepsis. Relative values, adjusted for neutrophil count, were high in both groups but extreme low or high values were seen in two patients who died shortly after testing, potentially indicating a predictive value for neutrophil function. Our results show that the high levels of neutrophils observed in patients with COVID-19 and sepsis exhibit functional capacity for ROS generation. This may contribute to the clinical features of acute disease and represents a potential novel target for therapeutic intervention.
Hilab system, a new point-of-care hematology analyzer supported by the Internet of Things and Artificial Intelligence
Authors: Gasparin Aléxia Thamara , Araujo Claudiane Isabel Franco , Schmitt Patricia , Cardoso Mônica Ribas , Perussolo Maiara Carolina , de Jesus Thainá Caroline Schuartz , Santiago Erika Bergamo , Silva Ivan Lucas Reis , de Sousa Ricardo Gurgel , Teng Flavia Zhu , Severo Evair Borges , Ribeiro Victor Henrique Alves , Cardoso Milena Andreuzo , Silva Fernanda D’Amico , de Araujo Perazzoli Carolina Rodrigues , de Holanda Farias João Samuel , de Almeida Bernardo Montesanti Machado , Rogal Júnior Sergio Renato , Figueredo Marcus Vinícius Mazega
Published: June 2022

The complete blood count (CBC) is one of the most requested tests by physicians. CBC tests, most realized in conventional hematological analyzers, are restricted to centralized laboratories due to frequent maintenance, large devices, and expensive costs required. On the other hand, most handheld CBC devices commercially available show high prices and are not liable to calibration or control procedures, which results in poor quality compared to standard hematology instruments. The Hilab system is a small-handed hematological platform that uses microscopy and chromatography techniques for blood cells and hematimetric parameters analysis through artificial intelligence, machine learning, and deep learning techniques. For clinical evaluation of the handheld CBC device, 450 blood samples were analyzed. The samples encompassed normal (82%) and pathological conditions (18%), such as thalassemias (2.2%), anemias (6.6%), and infections (9.2%). For all analytes, accuracy, precision, method comparison, and flagging capabilities of the Hilab System, were compared with the Sysmex XE-2100 (Sysmex, Japan) results. The sample source (venous and capillary) influences were also evaluated. Pearson correlation, Student t test, bias, and the Bland–Altman plot of each blood count analyte were calculated and shown. The significance level was set at p ≤ 0.05. For clinical evaluation, Hilab System and the Sysmex XE-2100 showed a strong correlation (r ≥ 0.9) for most evaluated parameters. In the precision study, analytes showed CV inside the limits established according to European Federation of Clinical Chemistry and Laboratory Medicine guidelines. The flagging capabilities of the Hilab system, compared to the manual microscopy technique, presented high sensibility, specificity, and accuracy. Venous and capillary samples (p > 0.05) do not differ statistically. Considering the need for point-of-care CBCs, the study indicated that the Hilab system provides fast, accurate, low cost, and robust analysis for reliable clinical use.
Semiempirical modeling of the effects of the intrinsic and extrinsic optical phonons on the performance of the graphene-based devices
Authors: Jalalvandi Sharare , Darbari Sara , Moravvej-Farshi Mohammad Kazem
Published: June 2022

Surface plasmons in graphene have mainly been affected by intrinsic optical phonons due to the vibrations of the carbon atoms and surface polar optical phonons (S-POPs) of the underlying dielectric surface. This plasmon hybridization dramatically changes the features of the plasmonic devices. However, a complete theoretical model for the graphene impedance to consider the optical phonons effects is yet remained to be developed. Here, we show how to derive a model for graphene impedance to include such impacts on graphene surface plasmons. Earlier models suffer from two limitations—i.e., the inability to show (i) the transformation of a single pure plasmonic mode into multiple hybrid plasmon–phonon excitations and (ii) the damping effect for energies beyond that of the intrinsic optical phonons due to the phonon emission. Our new model overcomes these two limitations. Then, we calculate the extinction spectra for a one-dimensional periodic array of graphene ribbons obtained through the impedance boundary condition method, addressing these obstacles. These spectra are directly related to graphene impedance, modeled using the dielectric function we developed in our earlier work. The extinction spectra show the presented model overcoming the limitations, firmly fitting the experimental data reported by others. Furthermore, we introduce our developed model for graphene to the CST Studio software to verify the accuracy of our extinction relation and impedance model. This study can be a step forward correctly predicting the behavior of graphene-based plasmonic devices.
Identification of mutant gene for Black crystal coat and non-allelic gene interactions in Neogale vison
Authors: Manakhov Andrey D. , Mintseva Maria Yu. , Uralsky Lev I. , Andreeva Tatiana V. , Trapezov Oleg V. , Rogaev Evgeny I.
Published: June 2022

Sable (Martes zibellina) and American mink (Neogale vison) are valuable species characterized by a variety of coat colour produced on fur farms. Black crystal fur phenotype is Mendelian codominant trait: heterozygous animals (Cr/ +) have white guard hairs scattered predominantly on the spine and the head, while homozygous (Cr/Cr) minks have coats resembling the Himalayan (ch/ch) or white Hedlund (h/h) types. It is one of the most recent of more than 35 currently known phenotypic traits of fur colour in American mink. Black crystal fur phenotype was first described in 1984 in the Russian population of mink, which had undergone selection for domestic defensive response to humans. Here, we performed whole-genome sequencing of American mink with Cr/Cr phenotype. We identified a missense mutation in the gene encoding the α-COP subunit of the COPI complex (COPA). The COPI complex mediates retrograde trafficking from the Golgi system to the endoplasmic reticulum and sorting of transmembrane proteins. We observed an interaction between a newly identified mutation in the COPA gene and a mutation in the microphthalmia-associated transcription factor (MITF), the latter mutation led to the formation of the white Hedlund (h/h) phenotype. Double heterozygotes for these mutations have an entirely white coat and a black-eyed phenotype similar to the phenotype of Cr/Cr or h/h minks. Our data could be useful for tracking economically valuable fur traits in mink breeding programs to contribute to global fur production.
Full-state time-varying asymmetric constraint control for non-strict feedback nonlinear systems based on dynamic surface method
Authors: Yang Zhongjun , Dong Chuyan , Zhang Xinyu , Wang Guogang
Published: June 2022

We investigate the tracking control problem for a non-strict feedback nonlinear system with external disturbance and time-varying asymmetric full state constraints. Firstly, the unknown nonlinear term with external disturbance in the system are estimated by fuzzy logic system. The backstepping method is applied to the design of adaptive fuzzy controller. However, to prevent that the constraints are overstepped by introducing an improved log-type time-varying asymmetric barrier Lyapunov function (TABLF) in each step of backstepping design. Secondly, the dynamic surface control (DSC) is introduced in the designed algorithm to solve the computational explosion problem of controller caused by the derivative of control law. The proposed control scheme can speed up the tracking speed of the system. Compared with the previous work, it is verified that the combination of DSC and TABLF can obtain good performance within the constraint range, and can ensure fast and stable tracking convergence under external disturbance. Finally, two simulation examples verify the performance of the adaptive controller.
Morphological parameters of myopic choroidal neovascularization as predictive factors of anti-VEGF treatment response
Authors: Castellino Niccolò , Battaglia Parodi Maurizio , Russo Andrea , Toro Mario Damiano , Fallico Matteo , Bonfiglio Vincenza , Maugeri Agatino Davide , Avitabile Teresio , Longo Antonio
Published: June 2022

The objective of this prospective study was to investigate the morphological changes of myopic choroidal neovascularization (mCNV) after treatment with anti-vascular endothelial growth factor and to identify potential features predictive of the final BCVA. OCT and OCTA features were evaluated at baseline and at 1, 6 and 12 months. Parameters investigated were the maturity pattern, presence of mCNV OCT activity signs, subretinal fibrosis and mCNV area. Forty patients (41 eyes) were included in the study. At the final visit, after a mean of 3.1 ± 1.4 injections, BCVA had improved significantly (p = 0.009) and subretinal hyperreflective exudation, subretinal fluid and intraretinal cysts nearly disappeared at 12 months. At baseline, 20 eyes had an immature CNV that were smaller, required less injections (2.5 ± 1.2 vs 3.8 ± 1.4, p = 0.002), they completely regressed in seven eyes and achieved a better BCVA (0.14 ± 0.15 vs 0.40 ± 0.26 logMAR, p < 0.001) when compared to mature CNV. Subretinal fibrosis developed in 19 eyes (46.3%) with lower final BCVA than eyes without fibrosis (0.19 ± 0.24 vs 0.38 ± 0.22 logMAR, p = 0.012). Baseline immature pattern (p = 0.005) and baseline BCVA (p < 0.001) were predictive of final BCVA. Multimodal imaging is useful to define mCNV changes during treatment. OCTA provides prognostic information which cannot achieved by other imaging techniques.
High source–sink ratio at and after sink capacity formation promotes green stem disorder in soybean
Authors: Yamazaki Ryo , Katsube-Tanaka Tomoyuki , Ogiso-Tanaka Eri , Kawasaki Yohei , Shiraiwa Tatsuhiko
Published: June 2022

Green stem disorder (GSD) of soybean is characterized by delayed leaf and stem maturation despite normal pod maturation. Previous studies have suggested that GSD occurrence is promoted by a high source–sink ratio, which is produced by thinning or shade removal at the R5 growth stage (the beginning of seed filling). Here the effects of different times and durations of shade removal after the R5 stage on GSD severity were analyzed. First, shade removal for more than 28 days after R5 increased GSD severity by more than 0.4 point in GSD score. Thinning treatment at R5 increased specific leaf weight by 23%, suppressed stem dry weight reduction, and upregulated 19 genes including those encoding vegetative storage proteins at R5 + 28d, indicating excess source ability relative to sink size. On the contrary, shade removal for 14 days after R5 decreased GSD severity by 0.5 point in GSD score. In this treatment, seed size was smaller, while seed number was significantly larger than control, suggesting that shortage of source ability relative to sink size. These results implied that soybean plants regulate GSD occurrences either positively or negatively according to a source-sink ratio during the R5 to R5 + 28d growth stages.
Measuring collagen injury depth for burn severity determination using polarization sensitive optical coherence tomography
Authors: Cannon Taylor M. , Uribe-Patarroyo Néstor , Villiger Martin , Bouma Brett E.
Published: June 2022

Determining the optimal treatment course for a dermatologic burn wound requires knowledge of the wound’s severity, as quantified by the depth of thermal damage. In current clinical practice, burn depth is inferred based exclusively on superficial visual assessment, a method which is subject to substantial error rates in the classification of partial thickness (second degree) burns. Here, we present methods for direct, quantitative determination of the depth extent of injury to the dermal collagen matrix using polarization-sensitive optical coherence tomography (PS-OCT). By visualizing the depth-dependence of the degree of polarization of light in the tissue, rather than cumulative retardation, we enable direct and volumetric assessment of local collagen status. We further augment our PS-OCT measurements by visualizing adnexal structures such as hair follicles to relay overall dermal viability in the wounded region. Our methods, which we have validated ex vivo with matched histology, offer an information-rich tool for precise interrogation of burn wound severity and healing potential in both research and clinical settings.
Mitochondrial Sirt3 serves as a biomarker for sepsis diagnosis and mortality prediction
Authors: Liu Jingjing , Zhou Gaosheng , Chen Rongping , Tong Zewen , Zhang Hongmin , Wang Xiaoting , Liu Dawei
Published: June 2022

The purpose of this study is to determine whether the levels of serum Sirt3 correlate with disease severity and perfusion indicators in septic patients, as well as to assess the clinical value of Sirt3 as a potential novel marker for sepsis diagnosis and mortality prediction. A total of 79 patients in the ICU were included in the study, of which 28 were postoperatively noninfectious and the remaining 51 patients were all diagnosed with sepsis during the study period. The levels of Sirt3 were detected and dynamically monitored by enzyme-linked adsorption method, Pearson or Spearman coefficient for correlation analysis between Sirt3 and clinical indicators, ROC curve for evaluation of diagnosis and mortality prediction, Kaplan–Meier method for the significance of Sirt3 in 28-day survival. The serum levels of Sirt3 were lower in the sepsis patients on day 1 (P < 0.0001), and the septic shock group had lower Sirt3 levels than the sepsis group (P = 0.013). Sirt3 had good negative correlations with SOFA scores both in sepsis and septic shock groups (Pearson: r2 = − 0.424, − 0.518; P = 0.011, 0.040), and Sirt3 correlated strongly with ScvO2 in the septic shock group (Pearson: r2 = − 0.679, P = 0.004) and with PCT in the sepsis group (Pearson: r2 = − 0.409, P = 0.015). Sirt3 not only performed well in identifying sepsis (AUC = 0.995, 95% CI 0.987–1, P < 0.0001) but also greatly enhanced lactate's specificity in detecting septic shock (from 91.43 to 94.29%). Patients in the low Sirt3 group had higher ScvO2, lactate, APACHE II score, SOFA score, longer ICU stays, and worse indicators of inflammation (TNF-α, IL-6) and infection (PCT) than those in the high Sirt3 group (P < 0.05). Additionally, Sirt3 can predict mortality of sepsis (AUC = 0.746, 95% CI 0.571–0.921, P = 0.022), patients with serum Sirt3 < 10.07 pg/ml have a lower 28-day survival (log-rank P = 0.008). Low serum levels of Sirt3 are significantly correlated with the disease severity. At the same time, Sirt3 increases the sensitivity of lactate to detect “cellular hypoxia” in septic shock. Sirt3 is a promising biomarker for the diagnosis of sepsis and predicting mortality risk in septic patients.
Transmission of B.1.617.2 Delta variant between vaccinated healthcare workers
Authors: Kemp Steven A. , Cheng Mark T. K. , Hamilton William L. , Kamelian Kimia ,   The Indian SARS-CoV-2 Genomics Consortium (INSACOG), Chauhan Himanshu , Dikid Tanzin , Gogia Hema , Lall Hemlata , Ponnusamy Kalaiarasan , Verma Kaptan , Dhar Mahesh Shanker , Singh Manoj K. , Datta Meena , Soni Namita , Meena Namonarayan , Madan Preeti , Singh Priyanka , Sharma Ramesh , Sharma Rajeev , Kabra Sandhya , Kumar Sattender , Kumari Swati , Sharma Uma , Chaudhary Urmila , Sivasubbu Sridhar , Scaria Vinod , Wattal Chand , Oberoi J. K. , Raveendran Reena , Datta S. , Das Saumitra , Maitra Arindam , Chinnaswamy Sreedhar , Biswas Nidhan Kumar , Parida Ajay , Raghav Sunil K. , Prasad Punit , Sarin Apurva , Mayor Satyajit , Ramakrishnan Uma , Palakodeti Dasaradhi , Seshasayee Aswin Sai Narain , Thangaraj K. , Bashyam Murali Dharan , Dalal Ashwin , Bhat Manoj , Shouche Yogesh , Pillai Ajay , Abraham Priya , Potdar Varsha Atul , Cherian Sarah S. , Desai Anita Sudhir , Pattabiraman Chitra , Manjunatha M. V. , Mani Reeta S. , Udupi Gautam Arunachal , Nandicoori Vinay , Tallapaka Karthik Bharadwaj , Sowpati Divya Tej , Singh Sujit , Rakshit Partha , Agrawal Anurag , Illingworth Christopher J. R. , Gupta Ravindra K.
Published: June 2022

Breakthrough infections with SARS-CoV-2 Delta variant have been reported in doubly-vaccinated recipients and as re-infections. Studies of viral spread within hospital settings have highlighted the potential for transmission between doubly-vaccinated patients and health care workers and have highlighted the benefits of high-grade respiratory protection for health care workers. However the extent to which vaccination is preventative of viral spread in health care settings is less well studied. Here, we analysed data from 118 vaccinated health care workers (HCW) across two hospitals in India, constructing two probable transmission networks involving six HCWs in Hospital A and eight HCWs in Hospital B from epidemiological and virus genome sequence data, using a suite of computational approaches. A maximum likelihood reconstruction of transmission involving known cases of infection suggests a high probability that doubly vaccinated HCWs transmitted SARS-CoV-2 between each other and highlights potential cases of virus transmission between individuals who had received two doses of vaccine. Our findings show firstly that vaccination may reduce rates of transmission, supporting the need for ongoing infection control measures even in highly vaccinated populations, and secondly we have described a novel approach to identifying transmissions that is scalable and rapid, without the need for an infection control infrastructure.
Visualization of learning-induced synaptic plasticity in output neurons of the Drosophila mushroom body γ-lobe
Authors: Hancock Clare E. , Rostami Vahid , Rachad El Yazid , Deimel Stephan H. , Nawrot Martin P. , Fiala André
Published: June 2022

By learning, through experience, which stimuli coincide with dangers, it is possible to predict outcomes and act pre-emptively to ensure survival. In insects, this process is localized to the mushroom body (MB), the circuitry of which facilitates the coincident detection of sensory stimuli and punishing or rewarding cues and, downstream, the execution of appropriate learned behaviors. Here, we focused our attention on the mushroom body output neurons (MBONs) of the γ-lobes that act as downstream synaptic partners of the MB γ-Kenyon cells (KCs) to ask how the output of the MB γ-lobe is shaped by olfactory associative conditioning, distinguishing this from non-associative stimulus exposure effects, and without the influence of downstream modulation. This was achieved by employing a subcellularly localized calcium sensor to specifically monitor activity at MBON postsynaptic sites. Therein, we identified a robust associative modulation within only one MBON postsynaptic compartment (MBON-γ1pedc > α/β), which displayed a suppressed postsynaptic response to an aversively paired odor. While this MBON did not undergo non-associative modulation, the reverse was true across the remainder of the γ-lobe, where general odor-evoked adaptation was observed, but no conditioned odor-specific modulation. In conclusion, associative synaptic plasticity underlying aversive olfactory learning is localized to one distinct synaptic γKC-to-γMBON connection.