bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuropilin 1 regulates bone marrow vascular regeneration and hematopoietic reconstitution
Authors: Termini Christina M. , Pang Amara , Fang Tiancheng , Roos Martina , Chang Vivian Y. , Zhang Yurun , Setiawan Nicollette J. , Signaevskaia Lia , Li Michelle , Kim Mindy M. , Tabibi Orel , Lin Paulina K. , Sasine Joshua P. , Chatterjee Avradip , Murali Ramachandran , Himburg Heather A. , Chute John P.
Published: November 2021

Ionizing radiation and chemotherapy deplete hematopoietic stem cells and damage the vascular niche wherein hematopoietic stem cells reside. Hematopoietic stem cell regeneration requires signaling from an intact bone marrow (BM) vascular niche, but the mechanisms that control BM vascular niche regeneration are poorly understood. We report that BM vascular endothelial cells secrete semaphorin 3 A (SEMA3A) in response to myeloablation and SEMA3A induces p53 – mediated apoptosis in BM endothelial cells via signaling through its receptor, Neuropilin 1 (NRP1), and activation of cyclin dependent kinase 5. Endothelial cell – specific deletion ofNrp1orSema3aor administration of anti-NRP1 antibody suppresses BM endothelial cell apoptosis, accelerates BM vascular regeneration and concordantly drives hematopoietic reconstitution in irradiated mice. In response to NRP1 inhibition, BM endothelial cells increase expression and secretion of the Wnt signal amplifying protein, R spondin 2. Systemic administration of anti - R spondin 2 blocks HSC regeneration and hematopoietic reconstitution which otherwise occurrs in response to NRP1 inhibition. SEMA3A – NRP1 signaling promotes BM vascular regression following myelosuppression and therapeutic blockade of SEMA3A – NRP1 signaling in BM endothelial cells accelerates vascular and hematopoietic regeneration in vivo.
Phase transitions in natural C-O-H-N-S fluid inclusions - implications for gas mixtures and the behavior of solid H2S at low temperatures
Authors: Sośnicka Marta , Lüders Volker
Published: November 2021

C–O–H–N–S-bearing fluids are known as one of the most challenging geochemical systems due to scarcity of available experimental data. H2S-rich fluid systems were recognized in a wide array of world-class mineral deposits and hydrocarbon reservoirs. Here we report on a nature of low-temperature (T ≥ −192 °C) phase transitions observed in natural CH4–H2S–CO2–N2–H2O fluid inclusions, which are modeled as closed thermodynamic systems and thus serve as natural micro-laboratories representative of the C–O–H–N–S system. For the first time, we document solid–solid H2S (α ↔ β ↔ γ) transitions, complex clathrates and structural transformations of solid state H2S in natural inclusion gas mixtures. The new data on Raman spectroscopic features and a complete sequence of phase transition temperatures in the gas mixtures contribute to scientific advancements in fluid geochemistry. Enhanced understanding of the phase equilibria in the C–O–H–N–S system is a prerequisite for conscientious estimation of P-T-V-X properties, necessary to model the geologic evolution of hydrocarbon and mineral systems. Our findings are a driver for the future research expeditions to extraterrestrial H2S-rich planetary systems owing to their low temperature environments.
Crystal structures of phosphatidyl serine synthase PSS reveal the catalytic mechanism of CDP-DAG alcohol O-phosphatidyl transferases
Authors: Centola Martin , van Pee Katharina , Betz Heidi , Yildiz Özkan
Published: November 2021

Phospholipids are the major components of the membrane in all type of cells and organelles. They also are critical for cell metabolism, signal transduction, the immune system and other critical cell functions. The biosynthesis of phospholipids is a complex multi-step process with high-energy intermediates. Several enzymes in different metabolic pathways are involved in the initial phospholipid synthesis and its subsequent conversion. While the “Kennedy pathway” is the main pathway in mammalian cells, in bacteria and lower eukaryotes the precursor CDP-DAG is used in the de novo pathway by CDP-DAG alcohol O-phosphatidyl transferases to synthetize the basic lipids. Here we present the high-resolution structures of phosphatidyl serine synthase from Methanocaldococcus jannaschii crystallized in four different states. Detailed structural and functional analysis of the different structures allowed us to identify the substrate binding site and show how CDP-DAG, serine and two essential metal ions are bound and oriented relative to each other. In close proximity to the substrate binding site, two anions were identified that appear to be highly important for the reaction. The structural findings were confirmed by functional activity assays and suggest a model for the catalytic mechanism of CDP-DAG alcohol O-phosphatidyl transferases, which synthetize the phospholipids essential for the cells.
A rechargeable aqueous manganese-ion battery based on intercalation chemistry
Authors: Bi Songshan , Wang Shuai , Yue Fang , Tie Zhiwei , Niu Zhiqiang
Published: November 2021

Aqueous rechargeable metal batteries are intrinsically safe due to the utilization of low-cost and non-flammable water-based electrolyte solutions. However, the discharge voltages of these electrochemical energy storage systems are often limited, thus, resulting in unsatisfactory energy density. Therefore, it is of paramount importance to investigate alternative aqueous metal battery systems to improve the discharge voltage. Herein, we report reversible manganese-ion intercalation chemistry in an aqueous electrolyte solution, where inorganic and organic compounds act as positive electrode active materials for Mn2+ storage when coupled with a Mn/carbon composite negative electrode. In one case, the layered Mn0.18V2O5·nH2O inorganic cathode demonstrates fast and reversible Mn2+ insertion/extraction due to the large lattice spacing, thus, enabling adequate power performances and stable cycling behavior. In the other case, the tetrachloro-1,4-benzoquinone organic cathode molecules undergo enolization during charge/discharge processes, thus, contributing to achieving a stable cell discharge plateau at about 1.37 V. Interestingly, the low redox potential of the Mn/Mn2+ redox couple vs. standard hydrogen electrode (i.e., −1.19 V) enables the production of aqueous manganese metal cells with operational voltages higher than their zinc metal counterparts.
Engineering of a fluorescent chemogenetic reporter with tunable color for advanced live-cell imaging
Authors: Benaissa Hela , Ounoughi Karim , Aujard Isabelle , Fischer Evelyne , Goïame Rosette , Nguyen Julie , Tebo Alison G. , Li Chenge , Le Saux Thomas , Bertolin Giulia , Tramier Marc , Danglot Lydia , Pietrancosta Nicolas , Morin Xavier , Jullien Ludovic , Gautier Arnaud
Published: November 2021

Biocompatible fluorescent reporters with spectral properties spanning the entire visible spectrum are indispensable tools for imaging the biochemistry of living cells and organisms in real time. Here, we report the engineering of a fluorescent chemogenetic reporter with tunable optical and spectral properties. A collection of fluorogenic chromophores with various electronic properties enables to generate bimolecular fluorescent assemblies that cover the visible spectrum from blue to red using a single protein tag engineered and optimized by directed evolution and rational design. The ability to tune the fluorescence color and properties through simple molecular modulation provides a broad experimental versatility for imaging proteins in live cells, including neurons, and in multicellular organisms, and opens avenues for optimizing Förster resonance energy transfer (FRET) biosensors in live cells. The ability to tune the spectral properties and fluorescence performance enables furthermore to match the specifications and requirements of advanced super-resolution imaging techniques.
WFS1 functions in ER export of vesicular cargo proteins in pancreatic β-cells
Authors: Wang Linlin , Liu Hongyang , Zhang Xiaofei , Song Eli , Wang You , Xu Tao , Li Zonghong
Published: November 2021

The sorting of soluble secretory proteins from the endoplasmic reticulum (ER) to the Golgi complex is mediated by coat protein complex II (COPII) vesicles and thought to required specific ER membrane cargo-receptor proteins. However, these receptors remain largely unknown. Herein, we show that ER to Golgi transfer of vesicular cargo proteins requires WFS1, an ER-associated membrane protein whose loss of function leads to Wolfram syndrome. Mechanistically, WFS1 directly binds to vesicular cargo proteins including proinsulin via its ER luminal C-terminal segment, whereas pathogenic mutations within this region disrupt the interaction. The specific ER export signal encoded in the cytosolic N-terminal segment of WFS1 is recognized by the COPII subunit SEC24, generating mature COPII vesicles that traffic to the Golgi complex. WFS1 deficiency leads to abnormal accumulation of proinsulin in the ER, impeding the proinsulin processing as well as insulin secretion. This work identifies a vesicular cargo receptor for ER export and suggests that impaired peptide hormone transport underlies diabetes resulting from pathogenic WFS1 mutations.
Differential susceptibility of reef-building corals to deoxygenation reveals remarkable hypoxia tolerance
Authors: Johnson Maggie D. , Swaminathan Sara D. , Nixon Emily N. , Paul Valerie J. , Altieri Andrew H.
Published: November 2021

Ocean deoxygenation threatens the persistence of coastal ecosystems worldwide. Despite an increasing awareness that coastal deoxygenation impacts tropical habitats, there remains a paucity of empirical data on the effects of oxygen limitation on reef-building corals. To address this knowledge gap, we conducted laboratory experiments with ecologically important Caribbean coralsAcropora cervicornisandOrbicella faveolata. We tested the effects of continuous exposure to conditions ranging from extreme deoxygenation to normoxia (~ 1.0 to 6.25 mg L−1dissolved oxygen) on coral bleaching, photophysiology, and survival. Coral species demonstrated markedly different temporal resistance to deoxygenation, and within a species there were minimal genotype-specific treatment effects.Acropora cervicornissuffered tissue loss and mortality within a day of exposure to severe deoxygenation (~ 1.0 mg L−1), whereasO. faveolataremained unaffected after 11 days of continuous exposure to 1.0 mg L−1. Intermediate deoxygenation treatments (~ 2.25 mg L−1, ~ 4.25 mg L−1) elicited minimal responses in both species, indicating a low oxygen threshold for coral mortality and coral resilience to oxygen concentrations that are lethal for other marine organisms. These findings demonstrate the potential for variability in species-specific hypoxia thresholds, which has important implications for our ability to predict how coral reefs may be affected as ocean deoxygenation intensifies. With deoxygenation emerging as a critical threat to tropical habitats, there is an urgent need to incorporate deoxygenation into coral reef research, management, and action plans to facilitate better stewardship of coral reefs in an era of rapid environmental change.
Structural exploration with AlphaFold2-generated STAT3α structure reveals selective elements in STAT3α-GRIM-19 interactions involved in negative regulation
Authors: Mishra Seema , Kumar Santosh , Choudhuri Kesaban Sankar Roy , Longkumer Imliyangla , Koyyada Praveena , Kharsyiemiong Euphinia Tiberius
Published: November 2021

STAT3, an important transcription factor constitutively activated in cancers, is bound specifically by GRIM-19 and this interaction inhibits STAT3-dependent gene expression. GRIM-19 is therefore, considered as an inhibitor of STAT3 and may be an effective anti-cancer therapeutic target. While STAT3 exists in a dimeric form in the cytoplasm and nucleus, it is mostly present in a monomeric form in the mitochondria. Although GRIM-19-binding domains of STAT3 have been identified in independent experiments, yet the identified domains are not the same, and hence, discrepancies exist. Human STAT3-GRIM-19 complex has not been crystallised yet. Dictated by fundamental biophysical principles, the binding region, interactions and effects of hotspot mutations can provide us a clue to the negative regulatory mechanisms of GRIM-19. Prompted by the very nature of STAT3 being a challenging molecule, and to understand the structural basis of binding and interactions in STAT3α-GRIM-19 complex, we performed homology modelling and ab-initio modelling with evolutionary information using I-TASSER and avant-garde AlphaFold2, respectively, to generate monomeric, and subsequently, dimeric STAT3α structures. The dimeric form of STAT3α structure was observed to potentially exist in an anti-parallel orientation of monomers. We demonstrate that during the interactions with both unphosphorylated and phosphorylated STAT3α, the NTD of GRIM-19 binds most strongly to the NTD of STAT3α, in direct contrast to the earlier works. Key arginine residues at positions 57, 58 and 68 of GRIM-19 are mainly involved in the hydrogen-bonded interactions. An intriguing feature of these arginine residues is that these display a consistent interaction pattern across unphosphorylated and phosphorylated monomers as well as unphosphorylated dimers in STAT3α-GRIM-19 complexes. MD studies verified the stability of these complexes. Analysing the binding affinity and stability through free energy changes upon mutation, we found GRIM-19 mutations Y33P and Q61L and among GRIM-19 arginines, R68P and R57M, to be one of the top-most major and minor disruptors of binding, respectively. The proportionate increase in average change in binding affinity upon mutation was inclined more towards GRIM-19 mutants, leading to the surmise that GRIM-19 may play a greater role in the complex formation. These studies propound a novel structural perspective of STAT3α-GRIM-19 binding and inhibitory mechanisms in both the monomeric and dimeric forms of STAT3α as compared to that observed from the earlier experiments, these experimental observations being inconsistent among each other.
In vivo optical imaging-guided targeted sampling for precise diagnosis and molecular pathology
Authors: Sahu Aditi , Oh Yuna , Peterson Gary , Cordova Miguel , Navarrete-Dechent Cristian , Gill Melissa , Alessi-Fox Christi , Gonzalez Salvador , Phillips William , Wilson Steven , Afzalneia Reza , Rose Raven , Mohsen Abu-Akeel , Bello Danielle , Marghoob Ashfaq , Rossi Anthony , Wolchok Jedd D. , Merghoub Taha , Rotemberg Veronica , Jason Chen Chih-Shan , Rajadhyaksha Milind
Published: November 2021

Conventional tissue sampling can lead to misdiagnoses and repeated biopsies. Additionally, tissue processed for histopathology suffers from poor nucleic acid quality and/or quantity for downstream molecular profiling. Targeted micro-sampling of tissue can ensure accurate diagnosis and molecular profiling in the presence of spatial heterogeneity, especially in tumors, and facilitate acquisition of fresh tissue for molecular analysis. In this study, we explored the feasibility of performing 1–2 mm precision biopsies guided by high-resolution reflectance confocal microscopy (RCM) and optical coherence tomography (OCT), and reflective metallic grids for accurate spatial targeting. Accurate sampling was confirmed with either histopathology or molecular profiling through next generation sequencing (NGS) in 9 skin cancers in 7 patients. Imaging-guided 1–2 mm biopsies enabled spatial targeting for in vivo diagnosis, feature correlation and depth assessment, which were confirmed with histopathology. In vivo 1-mm targeted biopsies achieved adequate quantity and high quality of DNA for next-generation sequencing. Subsequent mutational profiling was confirmed on 1 melanoma in situ and 2 invasive melanomas, using a 505-gene mutational panel called Memorial Sloan Kettering-Integrated mutational profiling of actionable cancer targets (MSK-IMPACT). Differential mutational landscapes, in terms of number and types of mutations, were found between invasive and in situ melanomas in a single patient. Our findings demonstrate feasibility of accurate sampling of regions of interest for downstream histopathological diagnoses and molecular pathology in both in vivo and ex vivo settings with broad diagnostic, therapeutic and research potential in cutaneous diseases accessible by RCM-OCT imaging.
Immunoprotective effect of an in silico designed multiepitope cancer vaccine with BORIS cancer-testis antigen target in a murine mammary carcinoma model
Authors: Mahdevar Elham , Kefayat Amirhosein , Safavi Ashkan , Behnia Amirhossein , Hejazi Seyed Hossein , Javid Amaneh , Ghahremani Fatemeh
Published: November 2021

In our previous study, immunoinformatic tools were used to design a novel multiepitope cancer vaccine based on the most immunodominant regions of BORIS cancer-testis antigen. The final vaccine construct was an immunogenic, non-allergenic, and stable protein consisted of multiple cytotoxic T lymphocytes epitopes, IFN-γ inducing epitopes, and B cell epitopes according to bioinformatic analyzes. Herein, the DNA sequence of the final vaccine construct was placed into the pcDNA3.1 vector as a DNA vaccine (pcDNA3.1-VAC). Also, the recombinant multiepitope peptide vaccine (MPV) was produced by a transfected BL21 E. coli strain using a recombinant pET-28a vector and then, purified and screened by Fast protein liquid chromatography technique (FPLC) and Western blot, respectively. The anti-tumor effects of prophylactic co-immunization with these DNA and protein cancer vaccines were evaluated in the metastatic non-immunogenic 4T1 mammary carcinoma in BALB/c mice. Co-immunization with the pcDNA3.1-VAC and MPV significantly (P < 0.001) increased the serum levels of the MPV-specific IgG total, IgG2a, and IgG1. The splenocytes of co-immunized mice exhibited a significantly higher efficacy to produce interleukin-4 and interferon-γ and proliferation in response to MPV in comparison with the control. The prophylactic co-immunization regime caused significant breast tumors’ growth inhibition, tumors’ weight decrease, inhibition of metastasis formation, and enlarging tumor-bearing mice survival time, without any considerable side effects. Taking together, this cancer vaccine can evoke strong immune response against breast tumor and inhibits its growth and metastasis.
Anti-breast cancer synthetic peptides derived from the Anabas testudineus skin mucus fractions
Authors: Najm Ahmed Abdul Kareem , Azfaralariff Ahmad , Dyari Herryawan Ryadi Eziwar , Othman Babul Airianah , Shahid Muhammad , Khalili Nahid , Law Douglas , Syed Alwi Sharifah Sakinah , Fazry Shazrul
Published: November 2021

Previous study has shown the antimicrobial activities of mucus protein extracted from Anabastestudineus. In this study, we are interested in characterizing the anticancer activity of the A.testudineus antimicrobial peptides (AMPs). The mucus was extracted, fractioned, and subjected to antibacterial activity testing to confirm the fish's AMPs production. The cytotoxic activity of each fraction was also identified. Fraction 2 (F2), which shows toxicity against MCF7 and MDA-MB-231 were sent for peptide sequencing to identify the bioactive peptide. The two peptides were then synthetically produced and subjected to cytotoxic assay to prove their efficacy against cancer cell lines. The IC50 for AtMP1 against MCF7 and MDA-MB-231 were 8.25 ± 0.14 μg/ml and 9.35 ± 0.25 μg/ml respectively, while for AtMP2 it is 5.89 ± 0.14 μg/ml and 6.97 ± 0.24 μg/ml respectively. AtMP1 and AtMP2 treatment for 48 h induced breast cancer cell cycle arrest and apoptosis by upregulating the p53, which lead to upregulate pro-apoptotic BAX gene and downregulate the anti-apoptotic BCL-2 gene, consequently, trigger the activation of the caspase-3. This interaction was supported by docking analysis (QuickDBD, HPEPDOCK, and ZDOCK) and immunoprecipitation. This study provided new prospects in the development of highly effective and selective cancer therapeutics based on antimicrobial peptides.
Characterization of gliadin, secalin and hordein fractions using analytical techniques
Authors: Rani Monika , Sogi Dalbir Singh , Gill Balmeet Singh
Published: November 2021

Prolamins, alcohol soluble storage proteins of the Triticeae tribe of Gramineae family, are known as gliadin, secalin and hordein in wheat, rye and barley respectively. Prolamins were extracted from fifteen cultivars using DuPont protocol to study their physiochemical, morphological and structural characteristics. SDS-PAGE of prolamins showed well resolved low molecular weight proteins with significant amount of albumin and globulin as cross-contaminant. The β-sheet (32.72–37.41%) and β-turn (30.36–37.91%) were found higher in gliadins, while α-helix (20.32–28.95%) and random coil (9.05–10.28%) in hordeins. The high colloidal stability as depicted by zeta-potential was observed in gliadins (23.5–27.0 mV) followed secalins (11.2–16.6 mV) and hordeins (4.1–7.8 mV). Surface morphology by SEM illustrated the globular particle arrangement in gliadins, sheet like arrangement in secalins and stacked flaky particle arrangement in hordeins fraction. TEM studies showed that secalin and hordein fractions were globular in shape while gliadins in addition to globular structure also possessed rod-shaped particle arrangement. XRD pattern of prolamin fractions showed the ordered crystalline domain at 2θ values of 44.1°, 37.8° and 10.4°. The extracted prolamins fractions showed amorphous as well as crystalline structures as revealed by XRD and TEM analysis. Space saving hexagonal molecular symmetry was also observed in TEM molecular arrangement of prolamins which has profound application in development of plant-based polymers and fibres.
The significance of neural inter-frequency power correlations
Authors: Savolainen Oscar W.
Published: November 2021

It is of great interest in neuroscience to determine what frequency bands in the brain have covarying power. This would help us robustly identify the frequency signatures of neural processes. However to date, to the best of the author’s knowledge, a comprehensive statistical approach to this question that accounts for intra-frequency autocorrelation, frequency-domain oversampling, and multiple testing under dependency has not been undertaken. As such, this work presents a novel statistical significance test for correlated power across frequency bands for a broad class of non-stationary time series. It is validated on synthetic data. It is then used to test all of the inter-frequency power correlations between 0.2 and 8500 Hz in continuous intracortical extracellular neural recordings in Macaque M1, using a very large, publicly available dataset. The recordings were Current Source Density referenced and were recorded with a Utah array. The results support previous results in the literature that show that neural processes in M1 have power signatures across a very broad range of frequency bands. In particular, the power in LFP frequency bands as low as 20 Hz was found to almost always be statistically significantly correlated to the power in kHz frequency ranges. It is proposed that this test can also be used to discover the superimposed frequency domain signatures of all the neural processes in a neural signal, allowing us to identify every interesting neural frequency band.
A pilot study of high-intensity interval training in older adults with treatment naïve chronic lymphocytic leukemia
Authors: MacDonald Grace , Sitlinger Andrea , Deal Michael A. , Hanson Erik D. , Ferraro Stephanie , Pieper Carl F. , Weinberg J. Brice , Brander Danielle M. , Bartlett David B.
Published: November 2021

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the USA, affecting predominantly older adults. CLL is characterized by low physical fitness, reduced immunity, and increased risk of secondary malignancies and infections. One approach to improving CLL patients’ physical fitness and immune functions may be participation in a structured exercise program. The aims of this pilot study were to examine physical and immunological changes, and feasibility of a 12-week high-intensity interval training (HIIT) combined with muscle endurance-based resistance training on older adults with treatment naïve CLL. We enrolled eighteen participants with CLL aged 64.9 ± 9.1 years and assigned them to groups depending on distance lived from our fitness center. Ten participants (4 M/6F) completed HIIT and six participants (4 M/2F) completed a non-exercising control group (Controls). HIIT consisted of three 30-min treadmill sessions/week plus two concurrent 30-min strength training sessions/week. Physical and immunological outcomes included aerobic capacity, muscle strength and endurance, and natural killer (NK) cell recognition and killing of tumor cells. We confirmed feasibility if > 70% of HIIT participants completed > 75% of prescribed sessions and prescribed minutes, and if > 80% of high-intensity intervals were at a heart rate corresponding to at least 80% of peak aerobic capacity (VO2peak). Results are presented as Hedge’s G effect sizes (g), with 0.2, 0.5 and 0.8 representing small, medium and large effects, respectively. Following HIIT, leg strength (g = 2.52), chest strength (g = 1.15) and seated row strength (g = 3.07) were 35.4%, 56.1% and 39.5% higher than Controls, respectively, while aerobic capacity was 3.8% lower (g = 0.49) than Controls. Similarly, following HIIT, in vitro NK-cell cytolytic activity against the K562 cell line (g = 1.43), OSU-CLL cell line (g = 0.95), and autologous B-cells (g = 1.30) were 20.3%, 3.0% and 14.6% higher than Controls, respectively. Feasibility was achieved, with HIIT completing 5.0 ± 0.2 sessions/week and 99 ± 3.6% of the prescribed minutes/week at heart rates corresponding to 89 ± 2.8% of VO2peak. We demonstrate that 12-weeks of supervised HIIT combined with muscle endurance-based resistance training is feasible, and that high adherence and compliance are associated with large effects on muscle strength and immune function in older adults with treatment naïve CLL.

Trial registration: NCT04950452.
Drug repurposing for COVID-19 using graph neural network and harmonizing multiple evidence
Authors: Hsieh Kanglin , Wang Yinyin , Chen Luyao , Zhao Zhongming , Savitz Sean , Jiang Xiaoqian , Tang Jing , Kim Yejin
Published: November 2021

Since the 2019 novel coronavirus disease (COVID-19) outbreak in 2019 and the pandemic continues for more than one year, a vast amount of drug research has been conducted and few of them got FDA approval. Our objective is to prioritize repurposable drugs using a pipeline that systematically integrates the interaction between COVID-19 and drugs, deep graph neural networks, and in vitro/population-based validations. We first collected all available drugs (n = 3635) related to COVID-19 patient treatment through CTDbase. We built a COVID-19 knowledge graph based on the interactions among virus baits, host genes, pathways, drugs, and phenotypes. A deep graph neural network approach was used to derive the candidate drug’s representation based on the biological interactions. We prioritized the candidate drugs using clinical trial history, and then validated them with their genetic profiles, in vitro experimental efficacy, and population-based treatment effect. We highlight the top 22 drugs including Azithromycin, Atorvastatin, Aspirin, Acetaminophen, and Albuterol. We further pinpointed drug combinations that may synergistically target COVID-19. In summary, we demonstrated that the integration of extensive interactions, deep neural networks, and multiple evidence can facilitate the rapid identification of candidate drugs for COVID-19 treatment.
Survival outcomes of management in metastatic gastric adenocarcinoma patients
Authors: Hu Huang-Ming , Tsai Hui-Jen , Ku Hsiu-Ying , Lo Su-Shun , Shan Yan-Shen , Chang Hung-Chi , Chao Yee , Chen Jen-Shi , Chen Shu-Chen , Chiang Chun-Ju , Li Anna Fen-Yau , Wang Hsiu-Po , Wang Tsang-En , Bai Li-Yuan , Wu Ming-Shiang , Chen Li-Tzong , Liu Tsang-Wu , Yang Yi-Hsin
Published: November 2021

Chemotherapy is generally considered as the main treatment for metastatic gastric adenocarcinoma. The role of gastrectomy for metastatic gastric cancer without obvious symptoms is controversial. The objective of this study is to investigate survival outcomes of treatment modalities using a real-world data setting. A retrospective cohort study was designed using the Taiwan Cancer Registry database. We identified the treatment modalities and used Kaplan–Meier estimates and Cox regressions to compare patient survival outcomes. From 2008 to 2015, 5599 gastric adenocarcinoma patients were diagnosed with metastatic disease (M1). The median overall survival (OS) of patients with surgery plus chemotherapy had the longest survival of 14.2 months. The median OS of the patients who received chemotherapy alone or surgery alone was 7.0 and 3.9, respectively. Age at diagnosis, year of diagnosis, tumor grade, and treatment modalities are prognostic factors for survival. The hazard ratios for patients who received surgery plus chemotherapy, surgery alone, and supportive care were 0.47 (95% CI 0.44–0.51), 1.22 (95% CI 1.1–1.36), and 3.23 (95% CI 3.01–3.46), respectively, by multivariable Cox regression analysis when using chemotherapy alone as a referent. Chemotherapy plus surgery may have a survival benefit for some selected gastric adenocarcinoma patients with metastatic disease.
Unexpected benzene oxidation in collisions with superoxide anions
Authors: Guerra Carlos , Kumar Sarvesh , Aguilar-Galindo Fernando , Díaz-Tendero Sergio , Lozano Ana I. , Mendes Mónica , Limão-Vieira Paulo , García Gustavo
Published: November 2021

Superoxide anions colliding with benzene molecules at impact energies from 200 to 900 eV are reported for the first time to form massive complexes. With the aid of quantum chemistry calculations, we propose a mechanism in which a sudden double ionization of benzene and the subsequent electrostatic attraction between the dication and the anion form a stable covalently bonded C6H6O2+ molecule, that evolves towards the formation of benzene-diol conformers. These findings lend support to a model presenting a new high energy anion-driven chemistry as an alternative way to form complex molecules.
Inhibitory properties of crude microalgal extracts on the in vitro replication of cyprinid herpesvirus 3
Authors: Fritzsche Stefanie , Blenk Patrik , Christian Jürgen , Castiglione Kathrin , Becker Anna Maria
Published: November 2021

Microalgae are possible sources of antiviral substances, e.g. against cyprinid herpesvirus 3 (CyHV-3). Although this virus leads to high mortalities in aquacultures, there is no treatment available yet. Hence, ethanolic extracts produced with accelerated solvent extraction from six microalgal species (Arthrospira platensis,Chlamydomonas reinhardtii,Chlorella kessleri,Haematococcus pluvialis,Nostoc punctiformeandScenedesmus obliquus) were examined in this study. An inhibition of the in vitro replication of CyHV-3 could be confirmed for all six species, with the greatest effect for theC. reinhardtiiandH. pluvialiscrude extracts. At still non-cytotoxic concentrations, viral DNA replication was reduced by over 3 orders of magnitude each compared to the untreated replication controls, while the virus titers were even below the limit of detection (reduction of 4 orders of magnitude). When pre-incubating both cells and virus withC. reinhardtiiandH. pluvialisextracts before inoculation, the reduction of viral DNA was even stronger (> 4 orders of magnitude) and no infectious viral particles were detected. Thus, the results of this study indicate that microalgae and cyanobacteria are a promising source of natural bioactive substances against CyHV-3. However, further studies regarding the isolation and identification of the active components of the extracts are needed.
Genetic diversity of Norway spruce ecotypes assessed by GBS-derived SNPs
Authors: Korecký Jiří , Čepl Jaroslav , Stejskal Jan , Faltinová Zuzana , Dvořák Jakub , Lstibůrek Milan , El-Kassaby Yousry A.
Published: November 2021

We investigated the genetic structure of three phenotypically distinct ecotypic groups of Norway spruce (Picea abies) belonging to three elevational classes; namely, low- (acuminata), medium- (europaea),and high-elevation (obovata) form, each represented by 150 trees. After rigorous filtering, we used 1916 Genotyping-by-Sequencing generated SNPs for analysis. Outputs from three multivariate analysis methods (Bayesian clustering algorithm implemented in STRUCTURE, Principal Component Analysis, and the Discriminant Analysis of Principal Components) indicated the presence of a distinct genetic cluster representing the high-elevation ecotypic group. Our findings bring a vital message to forestry practice affirming that artificial transfer of forest reproductive material, especially for stands under harsh climate conditions, should be considered with caution.
Dynamic monitoring of urban built-up object expansion trajectories in Karachi, Pakistan with time series images and the LandTrendr algorithm
Authors: Yan Xinrong , Wang Juanle
Published: November 2021

In the complex process of urbanization, retrieving its dynamic expansion trajectories with an efficient method is challenging, especially for urban regions that are not clearly distinguished from the surroundings in arid regions. In this study, we propose a framework for extracting spatiotemporal change information on urban disturbances. First, the urban built-up object areas in 2000 and 2020 were obtained using object-oriented segmentation method. Second, we applied LandTrendr (LT) algorithm and multiple bands/indices to extract annual spatiotemporal information. This process was implemented effectively with the support of the cloud computing platform of Earth Observation big data. The overall accuracy of time information extraction, the kappa coefficient, and average detection error were 83.76%, 0.79, and 0.57 a, respectively. These results show that Karachi expanded continuously during 2000–2020, with an average annual growth rate of 4.7%. However, this expansion was not spatiotemporally balanced. The coastal area developed quickly within a shorter duration, whereas the main newly added urban regions locate in the northern and eastern inland areas. This study demonstrated an effective framework for extract the dynamic spatiotemporal change information of urban built-up objects and substantially eliminate the salt-and-pepper effect based on pixel detection. Methods used in our study are of general promotion significance in the monitoring of other disturbances caused by natural or human activities.
Self-controlling photonic-on-chip networks with deep reinforcement learning
Authors: Do Nguyen , Truong Dung , Nguyen Duy , Hoai Minh , Pham Cuong
Published: November 2021

We present a novel photonic chip design for high bandwidth four-degree optical switches that support high-dimensional switching mechanisms with low insertion loss and low crosstalk in a low power consumption level and a short switching time. Such four-degree photonic chips can be used to build an integrated full-grid Photonic-on-Chip Network (PCN). With four distinct input/output directions, the proposed photonic chips are superior compared to the current bidirectional photonic switches, where a conventionally sizable PCN can only be constructed as a linear chain of bidirectional chips. Our four-directional photonic chips are more flexible and scalable for the design of modern optical switches, enabling the construction of multi-dimensional photonic chip networks that are widely applied for intra-chip communication networks and photonic data centers. More noticeably, our photonic networks can be self-controlling with our proposed Multi-Sample Discovery model, a deep reinforcement learning model based on Proximal Policy Optimization. On a PCN, we can optimize many criteria such as transmission loss, power consumption, and routing time, while preserving performance and scaling up the network with dynamic changes. Experiments on simulated data demonstrate the effectiveness and scalability of the proposed architectural design and optimization algorithm. Perceivable insights make the constructed architecture become the self-controlling photonic-on-chip networks.
Biallelic inheritance in a single Pakistani family with intellectual disability implicates new candidate gene RDH14
Authors: Pastore Stephen F. , Muhammad Tahir , Harripaul Ricardo , Lau Rebecca , Khan Muhammad Tariq Masood , Khan Muhammad Ismail , Islam Omar , Kang Changsoo , Ayub Muhammad , Jelani Musharraf , Vincent John B.
Published: November 2021

In a multi-branch family from Pakistan, individuals presenting with palmoplantar keratoderma segregate in autosomal dominant fashion, and individuals with intellectual disability (ID) segregate in apparent autosomal recessive fashion. Initial attempts to identify the ID locus using homozygosity-by-descent (HBD) mapping were unsuccessful. However, following an assumption of locus heterogeneity, a reiterative HBD approach in concert with whole exome sequencing (WES) was employed. We identified a known disease-linked mutation in the polymicrogyria gene, ADGRG1, in two affected members. In the remaining two (living) affected members, HBD mapping cross-referenced with WES data identified a single biallelic frameshifting variant in the gene encoding retinol dehydrogenase 14 (RDH14). Transcription data indicate that RDH14 is expressed in brain, but not in retina. Magnetic resonance imaging for the individuals with this RDH14 mutation show no signs of polymicrogyria, however cerebellar atrophy was a notable feature. RDH14 in HEK293 cells localized mainly in the nucleoplasm. Co-immunoprecipitation studies confirmed binding to the proton-activated chloride channel 1 (PACC1/TMEM206), which is greatly diminished by the mutation. Our studies suggest RDH14 as a candidate for autosomal recessive ID and cerebellar atrophy, implicating either disrupted retinoic acid signaling, or, through PACC1, disrupted chloride ion homeostasis in the brain as a putative disease mechanism.
Hydrochemical analysis and identification of open-pit mine water sources: a case study from the Dagushan iron mine in Northeast China
Authors: Liu Qianling , Zhang Zhongjian , Zhang Bin , Mu Wenping , Zhang Huijie , Li Yutao , Xu Nengxiong
Published: November 2021

The identification of open-pit mine water sources is of great significance in preventing water disasters. Combined with hydrochemistry and multivariate statistical analysis, this paper systematically analyzed the hydraulic connections between aquifers and the complex seepage water sources in the pit and roadway of Dagushan iron mine through qualitative analysis and quantitative calculation. According to the hydrochemical characteristics of the study area, the causes of seepage water at different positions in the mining area were reasonably explained. The results show that there is a possible hydraulic connection or similar source of water body between the bedrock fissure aquifer and the eluvium pore aquifer. The water seepage of 2# roadway mainly comes from bedrock fissure aquifer in the north of mining area. The reason for serious water seepage in the 3# roadway and the western side of the pit is that the fault connects the shallow alluvial pore aquifer and bedrock fissure aquifer. The source of water on the southern side pit comes from the river and groundwater on the southern side of the mine. The results presented here provide significant guidance for the management of mine water seepage problems.
Synthesis and characterization of genistein magnetic molecularly imprinted polymers and their application in soy sauce products
Authors: Xie Ziqi , Luo Yunjing , Na Zhen , Zhang Wei , Zong Yufei
Published: November 2021

In this study, a novel method based on genistein magnetic molecularly imprinted polymers (Gen-MMIPs) was developed utilizing a surface molecular imprinting technique, in which genistein was used as the template molecule and Fe3O4 was used as the carrier. The synthesis of Gen-MMIPs was characterized by using scanning electron microscopy (SEM) and transmission electron microscopy (TEM), which indicated that the diameter of the Gen-MMIPs was approximately 500 nm. Via analysis with a vibrating sample magnetometer (VSM), the saturation magnetization of Gen-MMIPs was determined to be 24.79 emu g−1. Fourier transform infrared (FT-IR) spectroscopy showed that polymer groups were on the surface of the magnetic carrier. Adsorption experiments suggested that the genistein adsorption capability of Gen-MMIPs was 5.81 mg g−1, and adsorption equilibrium was achieved within 20 min. Gen-MMIPs as dispersive solid-phase extraction (dSPE) adsorbents combined with HPLC were used to selectively separate genistein in soy sauce samples, and the recoveries ranged from 85.7 to 88.5% with relative standard deviations (RSDs) less than 5%, which proved that this method can be used for the detection of genistein residues in real samples.
Effect of CYP2C19 polymorphisms on serum valproic level acid in Chinese Han patients with schizophrenia
Authors: Wang S. , Li J. , Song M. , Yan P. , Ju X. , Liu J. , Wang C. , Shi J.
Published: November 2021

Valproic acid is an anticonvulsant, which is also widely used for treating psychiatric disorders. Some clinical trials have demonstrated benefits of valproic acid augmentation therapy in schizophrenia. Interindividual variability in valproic acid dose and serum concentration may reflect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing enzymes. The aim of this study was to determine the relationship between serum concentrations of valproic acid and single nucleotide polymorphisms of the cytochrome P450 (CYP) 2C19 gene in patients with schizophrenia. All patients had been receiving fixed dose of valproic acid for at least 2 weeks. The daily doses were 0.5–1.5 g. No other drugs except olanzapine were coadministered. Serum concentrations of valproic acid were measured using the ultra-high performance liquid chromatography method with mass-spectrometric detection. The CYP2C19 (CYP2C19*2 G681A rs4244285 and CYP2C19*3 G636A rs4986893) genotypes were identified by real-time PCR analyses. The mean concentration/dose ratios of valproic acid were significantly higher in patients with CYP2C19 *1/*2 genotype (P < 0.01) or CYP2C19 *2/*3 genotype (P < 0.01) than in those with CYP2C12 *1/*1 genotype. The mean concentration/dose ratios of valproic acid were significantly higher in patients with 1 (P < 0.01) or 2 (P < 0.01) mutated alleles for CYP2C19 than in those without mutated alleles. And the post hoc analysis revealed that the result has acceptable statistical (power (1 – β) = 0.8486 at type I  level of 0.05) to support the observed significant associations for CYP2C19 SNPs and serum C/D ratios of valproic acid. The findings of this study suggest that the genetic polymorphisms of CYP2C19 significantly affect the steady-state serum concentrations of valproic acid in Chinese Han population. The determination of the CYP2C19 genotypes may be useful for dosing adjustment in schizophrenia patients on valproic acid therapy.
Shift in demographic structure and increased reproductive activity of loggerhead turtles in the French Mediterranean Sea revealed by long-term monitoring
Authors: Girard Fanny , Catteau Sidonie , Gambaiani Delphine , Gérigny Olivia , Sénégas Jean Baptiste , Moisson Pierre , Claro Françoise
Published: November 2021

Climate-induced environmental changes are profoundly impacting marine ecosystems and altering species distribution worldwide. Migratory organisms, including sea turtles, are expected to be particularly sensitive to these variations. Here, we studied changes in the size structure and reproductive activity of loggerhead turtles in the French Mediterranean over 30 years. Overall, there was a significant increase in the size of observed loggerheads between 1990 and 2020. However, this increase was only significant during the breeding/nesting season (May to September) and was driven by the increased presence of adults. Furthermore, nesting activity along the French coast was detected in 2002 for the first time in more than 50 years, and has become frequent after 2014, with nests discovered every year. The number of eggs laid as well as incubation duration and success varied among sites but fell within the range reported at established Mediterranean nesting sites. These observations, along with recent reports of breeding activity and evidence of significant sea surface warming, suggest that the north-western Mediterranean basin has become increasingly suitable to loggerhead turtles. We postulate that this range expansion is the result of climate change and propose that emerging nesting activity in France should be closely monitored and guarded against human activities.
Oral microbiome associated with lymph node metastasis in oral squamous cell carcinoma
Authors: Eun Young-Gyu , Lee Jung-Woo , Kim Seung Woo , Hyun Dong-Wook , Bae Jin-Woo , Lee Young Chan
Published: November 2021

Oral microbiota can alter cancer susceptibility and progression by modulating metabolism and inflammation. We assessed the association between the oral microbiome and lymph node (LN) metastasis in oral squamous cell carcinoma (OSCC). We collected a total of 54 saliva samples from patients with OSCC before surgery. LN metastasis was assessed based on postoperative pathological examination. We used QIIME2, linear discriminant analysis effect size (LEfSe), and PICRUSt2 methods to analyze microbial dysbiosis. A random forest classifier was used to assess whether the oral microbiome could predict LN metastasis. Among the 54 OSCC samples, 20 had LN metastasis, and 34 had no evidence of metastasis. There was a significant difference in β-diversity between the metastasis and no metastasis groups. Through LEfSe analysis, the metastasis group was enriched in the genera Prevotella, Stomatobaculum, Bifidobacterium, Peptostreptococcaceae, Shuttleworthia and Finegoldia. Pathways related to signal peptidase II were predominant in the no metastasis group. The RF model showed a modestly high accuracy for predicting metastasis. Differences in microbial community composition and functions were observed in the oral microbiome of patients with OSCC with and without LN metastasis. However, the finding that specific taxa may be associated with LN metastasis should be verified in a further prospective study.
Bacteriological concentration of peritoneal drainage fluid could make an early diagnosis of anastomotic leakage following rectal resection
Authors: Ge Wei , Gong Hai-yan , Xia Yong-quan , Shao Li-hua , Shen Han , Chen Gang
Published: November 2021

To investigate that the bacteriological concentration and pH value in peritoneal drainage fluid might serve as indicators of early diagnosis of anastomotic leakage following rectal resection. We prospectively analyzed consecutive patients who were treated for rectal diseases with anastomosis at the department of general surgery, the affiliated hospital of Nanjing University Medical School between August 2018 and December 2020. The bacteriological concentration and the pH value in peritoneal drainage fluid were tested on the first, fourth, seventh days postoperatively. A total of 300 consecutive patients underwent rectal resection were tested. 21 patients present with AL and the overall AL rate was 7%. The bacteriological concentration in peritoneal drainage fluid of AL group was significantly higher than that in non-AL group. The AUC value was 0.98 (95% confidence intervals 0.969–1.000) according to the ROC curve. The best cut-off value was 1143/uL. The sensitivity and specificity were 100% and 93.19% respectively. There was no difference of pH value between the AL and non-AL groups. According the results of present study, a high bacteriological concentration in peritoneal drainage fluid is a good marker for predicting and diagnosing AL following rectal resection. However, owing to the limitation of the sample, there was no validation attempt in the study. A large sample study is needed to validate the conclusion.