bluuebunny/crossref_metadata_2025 huggingface dataset:
Adenoviral transfer of hemopexin gene attenuates oxidative stress and apoptosis in cultured primary cortical neuron cell exposed to blood clot
Authors: Liu Yi , Tan Changhong , Li Weina , Liu Xi , Wang Xin , Gui Yuejiang , Qin Lu , Deng Fen , Hu Changlin , Chen Lifen
Published: August 2020

Background

A growing body of experimental evidence suggests that hemin released from heme is a potent oxidant and accumulates in intracranial hematomas. Hemopexin (Hpx) decreases hemin accumulation and catabolism by nerve cells. In previous study, we observed thatHpxgene knockout aggravated striatal injury and worsened behavioral deficits of mice subjected to intracerebral hemorrhage.

Aim

To examine the effect of Hpx on oxidative damage and apoptosis in cultured nerve cells with blood clot.

Methods

Neuron and glial cells were transfected with adenoviralHpxgene. Transfected primary neuron-glial cells were co-cultured with 50 μl of arterial blood clot using insert transwells. The sham group was co-coulture with 50 μl of DMEM/F12, which contained 28 μl of serum; the control group was transfected with adenoviral vector. At 12 and 24 h, the level of malonaldehyde (MDA), surperoxide dismutase (SOD) concentration, glutathione (GSH), apoptosis, expression of HO-1 and caspase-3 were detected.

Results

MDA level was decreased (P< 0.01) whereas SOD and GSH concentration were increased in the Hpx group (P< 0.05 andP< 0.01, respectively). Results of flow cytometry revealed no significant difference in apoptosis between the Hpx group and model group at 12 h. However, the percentage of cells undergoing apoptosis in the Hpx group was decreased at 24 h compared with the model group (P< 0.01). HO-1 expression decreased in the Hpx group at 24 h (P< 0.01) while caspase-3 expression decreased at both 12 and 24 h (P< 0.011 andP< 0.05, respectively) compared with the model group.

Conclusion

Hpx protected nerve cells exposed to blood from injury by anti-oxidation and a decrease in the expression of HO-1 and caspase-3.
ESSENCE, the Electronic Surveillance System for the Early Notification of Community-Based Epidemics
Authors: Burkom Howard S. , Loschen Wayne A. , Wojcik Richard A. , Holtry Rekha S. , Punjabi Monika A. , Siwek Martina M. , Lewis Sheri H.
Published: August 2020

The Electronic Surveillance System for the Early Notification of Community-Based Epidemics (ESSENCE) is a secure web-based tool that enables health care practitioners to monitor health indicators of public health importance for detection and tracking of disease outbreaks, consequences of severe weather, and other events of concern. The ESSENCE concept began in an internally funded project at the Johns Hopkins University Applied Physics Laboratory (JHU/APL), advanced with funding from the State of Maryland, and broadened in 1999 as a collaboration with the Walter Reed Army Institute for Research. Versions of the system have been further developed by JHU/APL in multiple military and civilian programs for timely detection and tracking of health threats. Features of ESSENCE include spatial and temporal statistical alerting, custom querying, user-defined alert notifications, geographical mapping, remote data capture, and event communications. These features allow ESSENCE users to gather and organize the resulting wealth of information into a coherent view of population health status and communicate findings among users. The resulting broad utility, applicability and adaptability of this system led to adoption of ESSENCE by the Centers for Disease Control and Prevention (CDC), numerous state and local health departments, and the Department of Defense (DOD) both nationally and globally. With emerging high-consequence communicable diseases and other health conditions, the continued user-requirements-driven enhancements of ESSENCE demonstrate an adaptable disease surveillance capability focused on the everyday needs of public health. The challenge of a live system for widely distributed users with multiple different data sources and high throughput requirements has driven an novel, evolving architecture design.
3Din situimaging of female reproductive tract reveals molecular signatures of fertilizing spermatozoa in mice
Authors: Ded Lukas , Hwang Jae Yeon , Miki Kiyoshi , Shi Huanan F. , Chung Jean-Ju
Published: August 2020

Out of millions of ejaculated sperm, only a few reach the fertilization site in mammals. Flagellar Ca2+signaling nanodomains, organized by multi-subunit CatSper calcium channel complexes, are pivotal for sperm migration in the female tract, implicating CatSper-dependent mechanisms in sperm selection. Here, using biochemical and pharmacological studies, we demonstrate that CatSper1 is an O-linked glycosylated protein, undergoing capacitation-induced processing dependent on Ca2+and phosphorylation cascades. CatSper1 processing correlates with protein tyrosine phosphorylation (pY) development in sperm cells capacitatedin vitroandin vivo. Using 3Din situmolecular imaging and ANN-based automatic detection of sperm distributed along the cleared female tract, we demonstrate that all spermatozoa past the UTJ possess intact CatSper1 signals. Together, we reveal that fertilizing mouse spermatozoain situare characterized by intact CatSper channel, lack of pY, and reacted acrosomes. These findings provide molecular insight into sperm selection for successful fertilization in the female reproductive tract.
Specific Dynamic Variations in the Peripheral Blood Lymphocyte Subsets in COVID-19 and Severe Influenza A Patients: A Retrospective Observational Study
Authors: Qian Fang , Gao Guiju , Song Yangzi , Xu Yanli , Wang Aibin , Wang Sa , Hao Yiwei , Chen Meiling , Ma Xiaoyang , Zhao Tianwei , Guo Xiaodi , Chen Zhihai , Zhang Fujie
Published: August 2020

Background

Both COVID-19 and influenza A contribute to increased mortality among the elderly and those with existing comorbidities. Changes in the underlying immune mechanisms determine patient prognosis. This study aimed to analyze the role of lymphocyte subsets in the immunopathogenesisof COVID-19 and severe influenza A, and examined the clinical significance of their alterations in the prognosis and recovery duration.

Methods

By retrospectively reviewing of patients in four groups (healthy controls, severe influenza A, non-severe COVID-19 and severe COVID-19) who were admitted to Ditan hospital between 2018 to 2020, we performed flow cytometric analysis and compared the absolute counts of leukocytes, lymphocytes, and lymphocyte subsets of the patients at different time points (weeks 1- 4).

Results

We reviewed the patients’ data of 110 healthy blood donors, 80 Non-severe-COVID-19, 19 Severe-COVID-19 and 43 severe influenza A. We found total lymphocytes (0.93 ×109/L, 0.84 ×109/L vs 1.78 ×109/L, P < 0.0001) and lymphocyte subsets (T cells, CD4+ and CD8+ T cell subsets) of both severe patients to be significantly lower than those of healthy donors at early infection stages. Further, significant dynamic variations were observed at different time points (weeks 1–4).

Conclusions

Our study indicates lymphopenia to be associated with disease severity and suggests the plausible role of lymphocyte subsets in disease progression, which in turn affects prognosis and recovery duration in patients with severe COVID-19 and influenza A.
The Histological Diagnosis of Colonic Adenocarcinoma by Applying Partial Self Supervised Learning
Authors: Bukhari Syed Usama Khalid , Syed Asmara , Bokhari Syed Khuzaima Arsalan , Hussain Syed Shahzad , Armaghan Syed Umar , Shah Syed Sajid Hussain
Published: August 2020

Background

The cancer of colon is one of the important cause of morbidity and mortality in adults. For the management of colonic carcinoma, the definitive diagnosis depends on the histological examination of biopsy specimens. With the development of whole slide imaging, the convolutional neural networks are being applied to diagnose colonic carcinoma by digital image analysis.

Aim

The main aim of the current study is to assess the application of deep learning for the histopathological diagnosis of colonic adenocarcinoma by analysing the digitized pathology images.

Materials & Methods

The images of colonic adenocarcinoma and non neoplastic colonic tissue have been acquired from the two datasets. The first dataset contains ten thousand images which were used to train and validate the convolutional neural network (CNN) architecture. From the second dataset (Colorectal Adenocarcinoma Gland (CRAG) Dataset) 40% of the images were used as a train set while 60% of the images were used as test dataset. Two histopathologists also evaluated these images. In this study, three variants of CNN (ResNet-18, ResNet-34 and ResNet-50) have been employed to evaluate the images.

Results

In the present study, three CNN architectures(ResNet-18, ResNet-30, and ResNet-50) were applied for the classification of digitized images of colonic tissue. The accuracy (93.91%) of ResNet-50 was the highest which is followed by ResNet-30 and ResNet-18 with the accuracy of 93.04% each.

Conclusion

Based on the findings of the present study and analysis of previously reported series, the development of computer aided technology to evaluate the surgical specimens for the diagnosis of malignant tumors could provide a significant assistance to pathologists.
Programming animal physiology and behaviors through engineered bacteria
Authors: Gao Baizhen , Sun Qing
Published: August 2020

A central goal of synthetic biology is to predictably and efficiently reprogram living systems to perform computations and carry out specific biological tasks. Although there have been many advances in the bio-computational design of living systems, these advances have mainly been applied to microorganisms or cell lines; programming animal behavior and altering animal physiology remain challenges for synthetic biology because of the system complexity. Here, we present a bacteria-animal symbiont system in which engineered bacteria recognize external signals and modulate animal gene expression, twitching behavior, and fat metabolism through RNA interference. By using genetic circuits in bacteria to control RNA expression, we programmed the physiology and behavior of the model animalCaenorhabditis eleganswith logic gates. We anticipate that engineered bacteria can be used more extensively to program animal metabolism and behaviors for agricultural, therapeutic, and basic science applications.

One Sentence Summary

Animal physiology and behaviors are programmed via engineered bacteria.
Sampling SARS-CoV-2 proteomes for predicted CD8 T-cell epitopes as a tool for understanding immunogenic breadth and rational vaccine design
Authors: Hare Jonathan , Morrison David , Nielsen Morten
Published: August 2020

Predictive models for vaccine design have become a powerful and necessary resource for the expeditiousness design of vaccines to combat the ongoing SARS-CoV-2 global pandemic. Here we use the power of these predicted models to assess the sequence diversity of circulating SARS-CoV-2 proteomes in the context of an individual’s CD8 T-cell immune repertoire to identify potential. defined regions of immunogenicity. Using this approach of expedited and rational CD8 T-cell vaccine design, it may be possible to develop a therapeutic vaccine candidate with the potential for both global and local coverage.
A SARS-CoV-2 neutralizing antibody protects from lung pathology in a COVID-19 hamster model
Authors: Kreye Jakob , Reincke S Momsen , Kornau Hans-Christian , Sánchez-Sendin Elisa , Corman Victor Max , Liu Hejun , Yuan Meng , Wu Nicholas C. , Zhu Xueyong , Lee Chang-Chun D. , Trimpert Jakob , Höltje Markus , Dietert Kristina , Stöffler Laura , von Wardenburg Niels , van Hoof Scott , Homeyer Marie A , Hoffmann Julius , Abdelgawad Azza , Gruber Achim D , Bertzbach Luca D , Vladimirova Daria , Li Lucie Y , Barthel Paula Charlotte , Skriner Karl , Hocke Andreas C , Hippenstiel Stefan , Witzenrath Martin , Suttorp Norbert , Kurth Florian , Franke Christiana , Endres Matthias , Schmitz Dietmar , Jeworowski Lara Maria , Richter Anja , Schmidt Marie Luisa , Schwarz Tatjana , Müller Marcel Alexander , Drosten Christian , Wendisch Daniel , Sander Leif E , Osterrieder Nikolaus , Wilson Ian A , Prüss Harald
Published: August 2020

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC50of 3.1 ng/ml. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.
Multifractal Analysis of SARS-CoV-2 Coronavirus genomes using the wavelet transform
Authors: Ouadfeul Sid-Ali
Published: August 2020

In this paper, the 1D Wavelet Transform Modulus Maxima lines (WTMM) method is used to investigate the Long-Range Correlation (LRC) and to estimate the so-called Hurst exponent of 21 isolate RNA sequence downloaded from the NCBI database of patients infected by SARS-CoV-2, Coronavirus, the Knucleotidic, Purine, Pyramidine, Ameno, Keto and GC DNA coding are used. Obtained results show the LRC character in the most sequences; except some sequences where the anti-correlated or the Classical Brownian motion character is observed, demonstrating that the SARS-Cov2 coronavirus undergoes mutation from a country to another or in the same country, they reveals also the complexity and the heterogeneous genome structure organization far from the equilibrium and the self-organization.
Hydroxychloroquine Safety Outcome within Approved Therapeutic Protocol for Covid-19 Outpatients in Saudi Arabia
Authors: Mohana Abdulrhman , Sulaiman Tarek , Mahmoud Nagla , Hassanein Mustafa , Alfaifi Amel , Alenazi Eissa , Radwan Nashwa , AlKhalifah Nasser , Elkady Ehab , Almohaizeie Abdullah , AboGazalah Fouad , AbdulKareem Khaled , AlGhofaili Fahad , Jokdar Hani , Alrabiah Fahad
Published: August 2020

Background

Healthcare systems globally has been challenged following the COVID-19 pandemic, since late 2019. Multiple approaches and strategies have been performed to relieve the pressure and support existing healthcare systems. The Saudi Arabian Ministry of Health (MOH) launched an initiative to support the National Healthcare System. Since the 5th of June 2020, 238 outpatient fever clinics were established across Saudi Arabia.

Methods

A cross-sectional study included 2,733 eligible patients subjected to MOH treatment protocol (hydroxychloroquine and zinc) and revisited the clinics within 3-7 days after treatment initiation. This study aimed to assess the safety outcome and reported adverse events from hydroxychloroquine use among suspected COVID-19 patients. The data was collected through an electronic link and cross-checked with that of the national database (Health Electronic Surveillance Network, HESN) and reports from the MOH Morbidity and Mortality (M&M) Committee.

Results

Majority of the cases were males (70.4%). Upon reassessing the studied participants within 3-7 days, 240 patients (8.8%) discontinued the treatment protocol because of the development of side effects (4.1%) and for non-clinical reasons in the remaining (4.7%). Medication side effects overall were reported among (6.7%) of all studied participants, including mainly cardiovascular adverse events (2.5%), followed by gastrointestinal (GI) symptoms (2.4%). No Intensive Care Unit (ICU) admission or death were reported among these patients.

Conclusion

In our study, results show that the use of hydroxychloroquine for COVID-19 patients in mild to moderate cases in an outpatient setting, within the protocol recommendation and inclusion/exclusion criteria, is safe, highly tolerable, and with minimum side effects.
Histone demethylase complexes KDM3A and KDM3B cooperate with OCT4/SOX2 to construct pluripotency gene regulatory network
Authors: Zhu Zhenshuo , Wu Xiaolong , Li Qun , Zhang Juqing , Yu Shuai , Shen Qiaoyan , Zhou Zhe , Pan Qin , Yue Wei , Qin Dezhe , Zhang Ying , Zhao Wenxu , Zhang Rui , Peng Sha , Li Na , Zhang Shiqiang , Lei Anmin , Miao Yi-Liang , Liu Zhonghua , Chen Xingqi , Wang Huayan , Liao Mingzhi , Hua Jinlian
Published: August 2020

The pluripotency gene regulatory network of porcine-induced pluripotent stem cells (piPSCs), especially in epigenetics, remains elusive. To determine this biological function of epigenetics, we cultured piPSCs in different culture conditions. We found that activation of pluripotent gene- and pluripotency-related pathways requires the erasure of H3K9 methylation modification which was further influenced by mouse embryonic fibroblast (MEF) served feeder. By dissecting the dynamic change of H3K9 methylation during loss of pluripotency, we demonstrated that the H3K9 demethylases KDM3A and KDM3B regulated global H3K9me2/me3 level and that their co-depletion led to the collapse of the pluripotency gene regulatory network. Immunoprecipitation-mass spectrometry (IP-MS) provided evidence that KDM3A and KDM3B formed a complex to perform H3K9 demethylation. The genome-wide regulation analysis revealed that OCT4 (O) and SOX2 (S), the core pluripotency transcriptional activators, maintained the pluripotent state of piPSCs depending on the H3K9 hypomethylation. Further investigation revealed that O/S cooperating with histone demethylase complex containing KDM3A and KDM3B promoted pluripotency genes expression to maintain the pluripotent state of piPSCs. Together, these data offer a unique insight into the epigenetic pluripotency network of piPSCs.

Erasure of H3K9 methylation in porcine pluripotent stem cells depends on the complex of transcription factors OCT4/SOX2 and histone demethylase KDM3A/KDM3B.
Cell surface fluctuations regulate early embryonic lineage sorting
Authors: Yanagida Ayaka , Revell Christopher , Stirparo Giuliano G. , Corujo-Simon Elena , Aspalter Irene M. , Peters Ruby , De Belly Henry , Cassani Davide A. D. , Achouri Sarra , Blumenfeld Raphael , Franze Kristian , Paluch Ewa K. , Nichols Jennifer , Chalut Kevin J.
Published: August 2020

In development, lineage segregation of multiple lineages must be coordinated in time and space. An important example is the mammalian inner cell mass (ICM), in which the primitive endoderm (PrE, founder of the yolk sac) physically segregates from the epiblast (EPI, founder of the foetus). The physical mechanisms that determine this spatial segregation between EPI and PrE are still poorly understood. Here, we identify an asymmetry in cell-cell affinity, a mechanical property thought to play a significant role in tissue sorting in other systems, between EPI and PrE precursors (pEPI and pPrE). However, a computational model of cell sorting indicated that these differences alone appeared insufficient to explain the spatial segregation. We also observed significantly greater surface fluctuations in pPrE compared to pEPI. Including the enhanced surface fluctuation in pPrE in our simulation led to robust cell sorting. We identify phospho-ERM regulated membrane tension as an important mediator of the increased surface fluctuations in pPrE. Using aggregates of engineered cell lines with different surface fluctuation levels cells with higher surface fluctuations were consistently excluded to the outside of the aggregate. These cells behaved similarly when incorporated in the embryo. Surface fluctuations-driven segregation is reminiscent of activity-induced phase separation, a sorting phenomenon in colloidal physics. Together, our experiments and model identify dynamic cell surface fluctuations, in addition to static mechanical properties, as a key factor for orchestrating the correct spatial positioning of the founder embryonic lineages.
Impacts ofDesulfobacteralesandChromatialeson sulfate reduction in the subtropical mangrove ecosystem as revealed by SMDB analysis
Authors: Mo Shuming , Li Jinhui , Li Bin , Yu Ran , Nie Shiqing , Zhang Zufan , Liao Jianping , Jiang Qiong , Yan Bing , Jiang Chengjian
Published: August 2020

Sulfate reduction is an important process in the sulfur cycle. However, the relationship between this process and the genotype of microorganisms involved in subtropical mangrove ecosystems is poorly understood. A dedicated and efficient gene integration database of sulfur metabolism has not been established yet. In this study, a sulfur metabolism gene integrative database (SMDB) had been constructed successfully. The database achieved high coverage, fast retrieval, and low false positives. Then the sulfate reduction by microorganisms in subtropical mangroves ecosystem had been evaluated quickly and accurately with SMDB database. Due to the environmental factors, dissimilatory sulfite reductase was significantly high in mangrove samples. Sulfide, Fe, and available sulfur were found to be the key environmental factors that influence the dissimilatory sulfate reduction, in which sulfur compounds could be utilized as potential energy sources for microorganism. Taxonomic assignment of dissimilatory sulfate-reduction genes revealed thatDesulfobacteralesandChromatialesare completely responsible for this process. Sulfite reductase can help the community cope with the toxic sulfite produced by these Bacteria order. Collectively, these findings demonstrated thatDesulfobacteralesandChromatialesplay essential roles in dissimilatory sulfate reduction.
A lesson from COVID-19 on inaccessibility of web-based information for disabled populations worldwide
Authors: Dror Amiel A. , Layous Eli , Mizrachi Matti , Daoud Amani , Eisenbach Netanel , Morozov Nicole G. , Srouji Samer , Avraham Karen B. , Sela Eyal
Published: August 2020

Many government websites and mobile content are inaccessible for people with vision, hearing, and cognitive disabilities. The COVID-19 pandemic highlighted these disparities when health authority website information, critical in providing resources for curbing the spread of the virus, remained inaccessible for disabled populations. The Web Content Accessibility Guidelines provide comparatively universally accepted guidelines for website accessibility. We utilized these parameters to examine the number of countries with or without accessible health authority websites. The resulting data indicate a dearth of countries with websites accessible for persons with disabilities. Methods of information dissemination must take into consideration individuals with disabilities, particularly in times of global health crises.
Sweet chirality: the taste of l- and d-glucose stereoisomers
Authors: Dubovski Nitzan , Shoshan-Galeczki Yaron Ben , Malach Einav , Niv Masha Y
Published: August 2020

Chirality plays a key role in biomolecular recognition. Typically, a change in chirality will dramatically affect ligand–receptor binding. However, bothd-glucose and its enantiomerl-glucose elicit sweet taste in humans. We show thatl- andd-glucose are perceived as similarly sweet by humans, and that in cell-based functional assays, both enantiomers activate the human sweet taste receptor TAS1R2/TAS1R3. We hypothesize that bothl- andd-glucose occupy the orthosteric binding site in the VFT domain of TAS1R2. Using induced-fit docking to a homology model of this domain, we identify two subpockets in this binding site. The model suggests that glucose molecules can bind in either of these subpockets, which overlap with the predicted positions of monosaccharide units of sucrose. One subpocket is close to the hinge between the two lobes, and overlaps with aspartame and neotame site, the second subpocket overlaps with that described for sweetness enhancers. These findings suggest a framework for rational design of sweeteners combinations.
Structure and Dynamics of HIV-1 Env Trimers on Native Virions Engaged in Living T Cells
Authors: Carlon-Andres Irene , Malinauskas Tomas , Padilla-Parra Sergi
Published: August 2020

The HIV-1 envelope glycoprotein (Env) mediates viral entry into the host cell. Although the highly dynamic nature of Env intramolecular conformations has been shown with single molecule spectroscopy in vitro, the bona fide Env intra- and intermolecular mechanics when engaged in live T cells remains unknown. We used both, two photon fast fluorescence lifetime imaging detection of single-molecule Förster Resonance Energy Transfer and single molecule photobleaching to reveal transitions between intramolecular and intermolecular conformations that mediate Env clustering. Furthermore, we show that three broad neutralizing anti-Env antibodies directed to different epitopes destabilise Env intramolecular dynamics and their clusters when engaged to living T cells. Importantly, our results show that Env clustering is a common conformation across different HIV-1 Env strains, which depends on efficient virus maturation, and that is disrupted upon binding of Env to CD4 or to neutralizing antibodies. Thus, this study illuminates how different intramolecular conformations and clusters of Env mediate HIV-1 Env–T cell interactions in real time and therefore might control immune evasion.
SIMON: open-source knowledge discovery platform
Authors: Tomic Adriana , Tomic Ivan , Waldron Levi , Geistlinger Ludwig , Kuhn Max , Spreng Rachel L. , Dahora Lindsay C. , Seaton Kelly E. , Tomaras Georgia , Hill Jennifer , Duggal Niharika A. , Pollock Ross D. , Lazarus Norman R. , Harridge Stephen D.R. , Lord Janet M. , Khatri Purvesh , Pollard Andrew J. , Davis Mark M.
Published: August 2020

Data analysis and knowledge discovery has become more and more important in biology and medicine with the increasing complexity of the biological datasets, but necessarily sophisticated programming skills and in-depth understanding of algorithms needed pose barriers to most biologists and clinicians to perform such research. We have developed a modular open-source software SIMON to facilitate the application of 180+ state-of-the-art machine learning algorithms to high-dimensional biomedical data. With an easy to use graphical user interface, standardized pipelines, automated approach for machine learning and other statistical analysis methods, SIMON helps to identify optimal algorithms and provides a resource that empowers non-technical and technical researchers to identify crucial patterns in biomedical data.
Aspartate-phobia of thermophiles as a reaction to deleterious chemical transformations
Authors: Villain Etienne , Fort Philippe , Kajava Andrey V
Published: August 2020

Prokaryotes growing at high temperatures have a high proportion of charged residues in their proteins to stabilize their 3D structure. By mining 175 disparate bacterial and archaeal proteomes we found that, against the general trend for charged residues, the frequency of aspartic acid residues decreases strongly as natural growth temperature increases. In search of the explanation, we hypothesized that the reason for such unusual correlation is the deleterious consequences of spontaneous chemical transformations of aspartate at high temperatures. Our subsequent statistical analysis supported this hypothesis. First, knowing that these chemical modifications are higher in the unfolded polypeptide chains, we observed the most pronounced decrease of Asp frequency with temperature within intrinsically disordered regions. Second, it is known that the reaction rate of the chemical transformations of Asp is highest with the smallest downstream residue Gly and noticeably reduced for bulky residues. In agreement with this, the frequency of Gly residues downstream of Asp decreases with optimal growth temperature, while the frequency of bulky residues significantly increases. Thus, our analysis suggests that organisms have likely adapted to high temperatures by minimizing the harmful consequences of spontaneous chemical transformations of Asp residues.
MultiGWAS: An integrative tool for Genome Wide Association Studies (GWAS) in tetraploid organisms
Authors: Garreta L. , Cerón-Souza I. , Palacio M.R. , Reyes-Herrera P.H.
Published: August 2020

The Genome-Wide Association Studies (GWAS) are essential to determine the genetic bases of either ecological or economic phenotypic variation across individuals within populations of the model and non-model organisms. For this research question, the GWAS replication testing different parameters and models to validate the results’ reproducibility is common. However, straightforward methodologies that manage both replication and tetraploid data are still missing. To solve this problem, we designed the MultiGWAS, a tool that does GWAS for diploid and tetraploid organisms by executing in parallel four software, two designed for polyploid data (GWASpoly and SHEsis) and two for diploids data (GAPIT and TASSEL). MultiGWAS has several advantages. It runs either in the command line or in a graphical interface; it manages different genotype formats, including VCF. Moreover, it allows control for population structure, relatedness, and several quality control checks on genotype data. Besides, MultiGWAS can test for additive and dominant gene action models, and through a proprietary scoring function, select the best model to report its associations. Finally, it generates several reports that facilitate identifying false associations from both the significant and the best-ranked association SNP among the four software. We tested MultiGWAS with public tetraploid potato data for tuber shape and several simulated data under both additive and dominant models. These tests demonstrated that MultiGWAS is better at detecting reliable associations than using each of the four software individually. Moreover, the parallel analysis of polyploid and diploid software that only offers Multi-GWAS demonstrates its utility in understanding the best genetic model behind the SNP association in tetraploid organisms. Therefore, MultiG-WAS probed to be an excellent alternative for wrapping GWAS replication in diploid and tetraploid organisms in a single analysis environment.
Multiple regions of primate orofacial sensorimotor cortex encode bite force and gape
Authors: Arce-McShane Fritzie I. , Sessle Barry J. , Ram Yasheshvini , Balcer Carrie A. , Ross Callum F. , Hatsopoulos Nicholas G.
Published: August 2020

The precise control of bite force and gape is vital for effective breakdown and manipulation of food inside the oral cavity during feeding. Yet the role of the orofacial sensorimotor cortex (OSMcx) in the control of bite force and gape is still largely unknown. The aim of this study was to elucidate how individual neurons and populations of neurons in multiple regions of OSMcx differentially encode bite force and gape when subjects(Macaca mulatta)generated different levels of bite force at varying gapes. We examined neuronal activity recorded simultaneously from three microelectrode arrays implanted chronically in the primary motor (MIo), primary somatosensory (SIo), and cortical masticatory (CMA) areas of OSMcx. We used generalized linear models to evaluate encoding properties of individual neurons and utilized dimensionality reduction techniques to decompose population activity into components related to specific task parameters. Individual neurons encoded bite force more strongly than gape in all three OSMCx areas although bite force was a better predictor of spiking activity in MIo versus SIo. Population activity differentiated between levels of bite force and gape while preserving task-independent temporal modulation across the behavioral trial. While activation patterns of neuronal populations were comparable across OSMCx areas, the total variance explained by task parameters was context-dependent and differed across areas. These findings suggest that the cortical control of gape may rely on computations at the population level whereas the strong encoding of bite force at the individual neuron level allows for the precise and rapid control of bite force.

Significance Statement

Biting a piece off an apple requires precise sensorimotor control and coordination of bite force and gape by multiple brain regions. The cortical representations of bite force and gape by individual neurons and large populations of neurons across connected motor and somatosensory areas in orofacial cortex is unknown. Here we showed that bite force was more strongly encoded than gape by individual neurons in primary motor, somatosensory, and cortical masticatory areas. Moreover, bite force was more effectively represented in motor versus somatosensory cortices. At the population level, bite force and gape were distinguishable particularly when gape was randomized from trial-to-trial. The results are important for understanding neurophysiological processes underlying masticatory dysfunctions that may occur in aging, stroke, and Alzheimer’s disease.
Assembly of the algal CO2-fixing organelle, the pyrenoid, is guided by a Rubisco-binding motif
Authors: Meyer Moritz T. , Itakura Alan K. , Patena Weronika , Wang Lianyong , He Shan , Emrich-Mills Tom , Lau Chun S. , Yates Gary , Mackinder Luke C. M. , Jonikas Martin C.
Published: August 2020

Approximately one-third of the Earth’s photosynthetic CO2assimilation occurs in a pyrenoid, an organelle containing the CO2-fixing enzyme Rubisco. How constituent proteins are recruited to the pyrenoid, and how the organelle’s sub-compartments - membrane tubules, a surrounding phase-separated Rubisco matrix, and a peripheral starch sheath - are held together is unknown. Using the model algaChlamydomonas reinhardtii, we discovered that pyrenoid proteins share a sequence motif. We show that the motif is sufficient to target proteins to the pyrenoid and that the motif binds to Rubisco, suggesting a mechanism for targeting. The presence of the Rubisco-binding motif on proteins that localize to the tubules and on proteins that localize to the matrix-starch sheath interface suggests that the motif holds the pyrenoid’s three sub-compartments together. Our findings advance our understanding of pyrenoid biogenesis and illustrate how a single protein motif can underlie the architecture of a complex multi-layered phase-separated organelle.

One Sentence Summary

A ubiquitous Rubisco-binding motif targets proteins to the pyrenoid and holds together the pyrenoid’s three sub-compartments.
Targeting Vitamin-D receptor (VDR) by a small molecule antagonist MeTC7 inhibits PD-L1 but controls THMYCN neuroblastoma growth PD-L1 independently
Authors: Singh Rakesh K. , Kim KyuKwang , Rowswell-Turner Rachael B. , Hansen Jeanne N. , Khazan Negar , Jones Aaron , Sivagnanalingam Umayal , Teramoto Yuki , Goto Takuro , Jian Ye , Battaglia Nicholas , Conley Thomas , Hovanesian Virginia , Yano Naohiro , Pandita Ravina , Arnold Leggy A. , Hopson Russel , Ojha Debasmita , Sharon Ashoke , Ashton John , Miyamoto Hiroshi , Schor Nina F. , Milano Michael T. , Linehan David C. , Gerber Scott A. , Moore Richard G.
Published: August 2020

Vitamin-D receptor (VDR) mRNA is enriched in malignant lung, ovarian and pancreatic tissues and showed poor prognoses. Calcitriol and stable or CRISPR-directed VDR upregulation increased PD-L1mRNA and protein expression in cancer cells in-vitro. A ChIP assay showed the binding of VDR with VDREPD-L1. Stattic, a STAT3 phosphorylation inhibitor blocked calcitriol or VDR overexpression induced PD-L1 upregulation. MeTC7, a VDR antagonist developed by us, reduced PD-L1 expression on macrophages, ovarian, lung, breast, and pancreatic cancer cells in-vitro. In radiotherapy inducible PD-L1 model of orthotopic MC38 murine colon cancer, MeTC7 decreased PD-L1 surface expression, suppressed inflammatory monocytes (IMs) population and increased intra-tumoral CD69+PD1+CD8+T-cells. Intriguingly, MeTC7 reduced TH-MYCN transgenic neuroblastoma tumor growth without affecting PD-L1 and tumor immune milieu. In summary, Vitamin-D/VDR drives PD-L1 expression on cancer cells via STAT-3. Inhibiting VDR exhibited anti-checkpoint effects in orthotopic colon tumors, whereas PDL1-independent and anti-VDR/MYCN effects controlled growth of transgenic neuroblastoma and xenografted tumors.

Vitamin-D/VDR induces PD-L1 expression on cancer cells via STAT-3; and targeting VDR by a novel small molecule antagonist MeTC7 exhibits both anti-PD-L1 and anti-VDR/MYCN effects in tumor models.
From the Andes to the desert: First overview of the bacterial community in the Rimac river, the main source of water for Lima, Peru
Authors: Romero Pedro E. , Calla-Quispe Erika , Castillo-Vilcahuaman Camila , Yokoo Mateo , Fuentes-Rivera Hammerly Lino , Ramirez Jorge L. , Ibáñez Alfredo J. , Wong Paolo
Published: August 2020

Background

The Rimac river is the main source of water for Lima, Peru’s capital megacity. The river is constantly affected by different types of contamination including mine tailings in the Andes and urban sewage in the metropolitan area. We aim to produce the first characterization of bacterial communities in the Rimac river using a 16S rRNA amplicon sequencing approach which would be useful to identify bacterial diversity and potential understudied pathogens.

Results

We report a higher diversity in bacterial communities from the Upper and, especially, Middle Rimac compared to the Lower Rimac (Metropolitan zone). Samples were generally grouped according to their geographical location. Bacterial classes Alphaproteobacteria, Bacteroidia, Campylobacteria, Fusobacteriia, and Gammaproteobacteria were the most frequent along the river.Arcobacter cryaerophilus(Campylobacteria) was the most frequent species in the Lower Rimac whileFlavobacterium succinicans(Bacteroidia) andHypnocyclicus(Fusobacteriia) were the most predominant in the Upper Rimac. Predicted metabolic functions in the microbiota include bacterial motility, quorum sensing and xenobiotics metabolism. Additional metabolomic analyses showed the presence natural flavonoids and antibiotics in the Upper Rimac, and herbicides in the Lower Rimac.

Conclusions

The dominance in the Metropolitan area ofArcobacter cryaerophilus, an emergent pathogen associated with fecal contamination and antibiotic multiresistance, but that is not usually reported in traditional microbiological quality assessments, highlights the necessity to apply next-generation sequencing tools to improve pathogen surveillance. We believe that our study will encourage the integration of omics sciences in Peru and its application on current environmental and public health issues.
Statelets: High dimensional predominant shapes in dynamic functional network connectivity
Authors: Rahaman Md Abdur , Damaraju Eswar , Saha Debbrata Kumar , Plis Sergey M. , Calhoun Vince D.
Published: August 2020

Dynamic functional network connectivity (dFNC) analysis is a widely used approach for capturing brain activation patterns, connectivity states, and network organization. However, a typical sliding window plus clustering (SWC) approaches for analyzing dFNC continuously models the system through a fixed set of connectivity patterns or states. It assumes these patterns are span throughout the brain, but in practice, they are more spatially constrained and temporally short-lived. Thus, SWC is not designed to capture transient dynamic changes nor heterogeneity across subjects/time. Here, we adapt time series motifs to model the temporal dynamics of functional connectivity. We propose a state-space data mining approach that combines a probabilistic pattern summarization framework called ‘Statelets’ — a subset of high dimensional state-shape prototypes capturing the dynamics. We handle scale differences using the earth mover distance and utilize kernel density estimation to build a probability density profile for local motifs. We apply the framework to study dFNC collected from patients with schizophrenia (SZ) and healthy control (HC). Results demonstrate SZ subjects exhibit reduced modularity in their brain network organization relative to HC. These statelets in the HC group show more recurrence across the dFNC time-course compared to the SZ. An analysis of the consistency of the connections across time reveals significant differences within visual, sensorimotor, and default mode regions where HC subjects show higher consistency than SZ. The introduced statelet-approach also enables the handling of dynamic information in cross-modal applications to study healthy and disordered brains and multi-modal fusion within a single dataset.
THE YKI-CACTUS (IKBα)-JNK AXIS PROMOTES TUMOR GROWTH AND PROGRESSION IN DROSOPHILA
Authors: Snigdha Kirti , Singh Amit , Kango-Singh Madhuri
Published: August 2020

Presence of inflammatory factors in the tumor microenvironment is well known yet their specific role in tumorigenesis is elusive. The core inflammatory pathways are conserved inDrosophila, including the Toll-Like Receptor (TLR) and the Tumor Necrosis Factor (TNF) pathway. We usedDrosophilatumor models to study the role of inflammatory factors in tumorigenesis. Specifically, we co-activated oncogenic forms ofRasV12or its major effector Yorkie (Yki3SA) in polarity deficient cells mutant for tumor suppressor genescribble(scrib) marked by GFP undernubGAL4or in somatic clones. This system recapitulates the clonal origins of cancer, and shows neoplastic growth, invasion and lethality. We investigated if TLR and TNF pathway affect growth ofYki3SAscribRNAiorRasV12scribRNAitumors through activation of tumor promoting Jun N-terminal Kinase (JNK) pathway and its target Matrix Metalloprotease1 (MMP1). We report, TLR component, Cactus (Cact) is highly upregulated inYki3SAscribRNAiorRasV12scribRNAitumors.DrosophilaCactus (mammalian IKBα) acts as an inhibitor of NFKB signaling that plays key roles in inflammatory and immune response. Here we show an alternative role for Cactus, and by extension cytokine mediated signaling, in tumorigenesis. Downregulating Cact affects both tumor progression and invasion. Interestingly, downregulating TNF receptors in tumor cells did not affect their invasiveness despite reducing JNK activity. Genetic analysis suggested that Cact and JNK are key regulators of tumor progression. Overall, we show that Yki plays a critical role in tumorigenesis by controlling Cact, which in turn, mediates tumor promoting JNK oncogenic signaling in tumor cells.
Entraining stepping movements of Parkinson’s patients to alternating subthalamic nucleus deep brain stimulation
Authors: Fischer Petra , He Shenghong , de Roquemaurel Alexis , Akram Harith , Foltynie Thomas , Limousin Patricia , Zrinzo Ludvic , Cagnan Hayriye , Brown Peter , Tan Huiling
Published: August 2020

Patients with advanced Parkinson’s can be treated by deep brain stimulation of the subthalamic nucleus (STN). This affords a unique opportunity to record from this nucleus and stimulate it in a controlled manner. Previous work has shown that activity in the STN is modulated in a rhythmic pattern when Parkinson’s patients perform stepping movements, raising the question whether the STN is involved in the dynamic control of stepping. To answer this question, we tested whether an alternating stimulation pattern resembling the stepping-related modulation of activity in the STN could entrain patients’ stepping movements as evidence of the STN’s involvement in stepping control. Group analyses of ten Parkinson’s patients (one female) showed that alternating stimulation significantly entrained stepping rhythms. We found a remarkably consistent alignment between the stepping and stimulation cycle when the stimulation speed was close to the stepping speed in the five patients that demonstrated significant individual entrainment to the stimulation cycle. Our study provides evidence that the STN is causally involved in dynamic control of step timing, and motivates further exploration of this biomimetic stimulation pattern as a basis for the development of specific deep brain stimulation strategies to ameliorate gait impairments.
Enhancing SNR and generating contrast for cryo-EM images with convolutional neural networks
Authors: Palovcak Eugene , Asarnow Daniel , Campbell Melody G. , Yu Zanlin , Cheng Yifan
Published: August 2020

In cryogenic electron microscopy (cryo-EM) of radiation-sensitive biological samples, both the signal-to-noise ratio (SNR) and the contrast of images are critically important in the image processing pipeline. Classic methods improve low-frequency image contrast experimentally, by imaging with high defocus, or computationally, by applying various types of low-pass filter. These contrast improvements typically come at the expense of high-frequency SNR, which is suppressed by high-defocus imaging and removed by low pass filtration. Here, we demonstrate that a convolutional neural network (CNN) denoising algorithm can be used to significantly enhance SNR and generate contrast in cryo-EM images. We provide a quantitative evaluation of bias introduced by the denoising procedure and its influences on image processing and three-dimensional reconstructions. Our study suggests that besides enhancing the visual contrast of cryo-EM images, the enhanced SNR of denoised images may facilitate better outcomes in the other parts of the image processing pipeline, such as classification and 3D alignment. Overall, our results provide a ground of using denoising CNNs in the cryo-EM image processing pipeline.
Structure of an atypical homodimeric actin capping protein from the malaria parasite
Authors: Bendes Ábris Ádám , Kursula Petri , Kursula Inari
Published: August 2020

Actin capping proteins (CPs) are essential regulators of actin dynamics in all eukaryotes. Their structure and function have been extensively characterized in higher eukaryotes but their role and mechanism of action in apicomplexan parasites remain enigmatic. Here, we present a crystal structure of a unique homodimeric CP from the rodent malaria parasitePlasmodium berghei. In addition, we compare homo- and heterodimeric arrangements ofP. bergheiCPs (PbCPs) in solution. We complement our findings by describing the regulatory effects ofPbCPs on heterologous skeletal muscle α-actin as well as parasite actin. Comprehensive kinetic and steadystate measurements show atypical regulation of actin dynamics;PbCPs facilitate rapid turnover of parasite actin I without affecting the apparent critical concentration. Possibly to rescue actin filament capping in life cycle stages where the CP β-subunit is downregulated, homo- and heterodimericPbCPs show redundant effectsin vitro. However, our data suggest that homodimers may in addition influence actin kinetics by recruiting lateral actin dimers. This unusual function could arise from the absence of a β-subunit, as the asymmetricPbCP homodimer lacks the structural elements essential for canonical barbed end interactions, suggesting a novel CP binding mode. These findings facilitate further studies aimed at elucidating the precise actin filament capping mechanism inPlasmodiumand the eligibility ofPbCPs as drug targets against malaria.

Significance statement

Malaria parasites of the genusPlasmodiumdisplay a unique form of gliding motility, which depends on an unconventional actomyosin motor. Actin capping proteins (CPs) play a major role in regulating parasite motility. Here, we describe a uniquePlasmodium bergheiCP (PbCP) system, behaving contradictory to canonical heterodimeric CPs, more suited to regulate the fast dynamics of the parasite actin system. We present the crystal structure of a distinctive homodimeric form ofPbCP and extensive biochemical data, describing the atypical behavior of eachPbCP form. ThePbCP homodimer displays capping even in the absence of canonical conserved structural elements, suggesting a novel actin-CP interaction mode. These distinct structural properties could provide opportunities for drug design against malaria.