bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of the theory of stochastic processes and Monte-Carlo simulations for the analysis of the operation of charging stations for electric vehicles
Authors: Hanka László
Published: May 2022

Considering the development of the Electric Vehicle industry, and the growing number of such vehicles in public transport, the charging problem of these vehicles is essential. The service process of a charging station seems a fundamental question, that must be analyzed.

Using the theory of stochastic processes, especially the Poisson process and the queuing theory; the characterization of the process can be studied. Some fundamental system parameters like the average waiting time, the average time in the system, the average time in the queue, and the average length of the queue, etc., can be modeled by the queuing theory using the service rate, the charging rate, and the number of servers, etc., as parameters.

Using the conclusions of this model, and considering the demands of Electric Vehicle users, the necessary/minimal/optimal number of servers, parking lots, etc. can be estimated. Using the theory of the Markov process, a stochastic model can be proposed for studying the long-term characterization of Electric Vehicle owners’ charging behavior; that which’s problem is strongly affected by the properties of charging stations. In this article, the queuing model and the Monte-Carlo method are presented for characterizing a charging station. For every calculation, Matlab has been used.
Comparison of Methods for Calculating the Heating of Plastic Gears
Authors: Marada Imre , Bihari János
Published: May 2022

Accurate determination of heating is significantly more important for plastic gears, even in simpler applications than for steel gears. These gears are often used without lubrication or with a single, lifetime lubrication. The load capacity of materials is significantly affected by temperature, even in ordinary cases. Even today, heating is often calculated for different heating cases according to the calculation method of VDI 2545 or the modified VDI 2545, although these methods have been proven to be obsolete. Since the main direction of our research is to explore the design features of drive units equipped with small plastic gears, we tried to assess in advance, using a series of calculations, how much difference there is between the results obtained with obsolete and modern calculation methods. In this article, we present the basic characteristics of the calculation methods and compare the results obtained for some m>1 mm and m<0,5 mm gears.
Design Issues for Slot-Die Coating Heads - Case Study
Authors: Sarka Ferenc , Tóbis Zsolt
Published: May 2022

In this article, the authors briefly present the development, features, operating principles, and typical applications of slot-die technology. Slot-die technology is a coating method in which a consistent thickness, coating layer, can be applied to a receiving surface in an almost completely closed system. The technology was first used in the production of films but is now used for the application of a wide variety of coatings (e.g., plastics), from battery production, through semiconductor production, to solar cell production. It can also be used to make membrane air filters / filters, which can help to overcome today’s covid epidemic. Due to the proliferation of electric cars, the production of batteries has become an increasing slice of industrial production. In this article we present in detail, in a systematic way, the information gathered during the literature search, which we used in our work. In this article we present with a case study, the problems and experiences that arose during the design and manufacture of a coating machine operating under laboratory conditions. The construction of the machine was done with the technical assistance of a joint project with an industrial partner. The laboratory machine will be suitable for sheet-to-sheet coating. The article presents strength and deformation simulations along with the experience gained during the production of the coating machine.
Recovery of K by NH4HSO4 low-temperature roasting from brown corundum Fly Ash
Authors: Lin Xin , Chen Chaoyi , Li Junqi , Wang Gangan , Ning Deyang
Published: May 2022

Brown corundum dust ash(BCFA) is an industrial solid waste from the brown corundum production process. The alkali metal is a key factor limiting its comprehensive use. Currently, BCFA is mainly stockpiled and occupies a large amount of land. Its fine particles are easy to cause air pollution. The addition of NH4HSO4 allows for the effective extraction of K from BCFA and the efficient use of BCFA. Under optimum conditions: NH4HSO4 to BCFA mass ratio of 1.2:1, the roasting temperature of 240 °C, roasting time of 2 h, water leaching time of 90 min, water leaching temperature of 65 °C water leaching liquid to solid ratio of 3:1, the leaching rate of K from BCFA reached 97%. The leachate was crystallised by evaporation to obtain K, N compound fertiliser for agricultural use. The leaching residue is mainly Al and Si, which can be used for the preparation of refractory materials, aluminium and silicon molecular sieves, construction materials and other raw materials.
CBETor: a hybrid-kinetic particle-in-cell code for cross-beam energy transfer simulation
Authors: JIAO Jinlong , WANG Hezi , ZHOU Hongyu , YIN Yan , QIAO Bin , ZHUO Hongbin
Published: May 2022

The parametric instability related to ion motion and the resulting cross-beam energy transfer are important aspects in the physics of inertial confinement fusion. The numerical simulation of the above physical problems still faces great technical challenges. This paper introduces a 2D hybrid-kinetic particle-in-cell (PIC) code, CBETor. In this code, the motion of ions is described by the kinetic method, the motion of electrons is described by the simplified fluid method and the propagation of laser in plasma is described by solving the wave equation. We use CBETor and the popular fully kinetic PIC code EPOCH to simulate the stimulated Brillouin scattering and cross-beam energy transfer process, respectively. The physical images are in good agreement, but CBETor can significantly reduce the amount of calculation. With the premise of correctly simulating the ion dynamics, our hybrid-kinetic code can effectively suppress the noise of numerical simulation and significantly expand the simulation scale of physical problems. CBETor is very suitable for simulating the physical process dominated by ion motion in the interaction of medium intensity laser and underdense plasma.
The demographics of talipes equinovarus in Indiana, with a particular emphasis on comparisons between clubfoot types
Authors: Akinyoola Lawrence A. , Gunderson Zachary J. , Sun Seungyup , Fitzgerald Ryan , Caltoum Christine B. , Christman Tyler , Bielski Robert , Loder Randall T.
Published: May 2022

Talipes equinovarus (TEV) can be an isolated idiopathic deformity or associated with various syndromes. The purpose of our study was to examine the demographics of TEV in Indiana. All TEV patients from 2010 to 2019 from our institution were reviewed, recording standard demographic variables. The socioeconomic level of the family was determined using the 2018 Area Deprivation Index (ADI). There were 568 patients; 456 had idiopathic TEV and 112 syndromic. Within the idiopathic group, 69.1% were male, 92.1% were typical and 7.9% were atypical. Medical issues during the pregnancy occurred in 19.5%, maternal smoking in 2.9%, hypertension in 3.9% and diabetes in 5.3%. The most common syndromic patients were myelomeningocele (29%) and arthrogryposis (17%). Patients with syndromic TEV had more bilateral involvement (68.2% vs. 45.2%) and other associated congenital deformities (67.0% vs. 11.4%). TEV was less common in Hispanics and Asians but more common in Whites and Blacks (P = 0.003). Complex TEVs were less frequent in White (6.9%) and Black (5.0%) and more common in Hispanic (30%) children (P = 0.0002). The ADI demonstrated no difference in prevalence across socioeconomic levels. There were no differences by state ADI levels for TEV type (syndromic/idiopathic), sex, maternal smoking or illicit drug use, or typical/complex TEV. This study is the first to describe the demographics of TEV in Indiana, demographic differences between typical and complex types of clubfeet, and TEV patients using the ADI. TEV did not show any difference in prevalence by socioeconomic level.
The use of intraovarian injection of autologous platelet rich plasma (PRP) in patients with poor ovarian response and premature ovarian insufficiency
Authors: Herlihy Nola S. , Seli Emre
Published: May 2022

Purpose of review

Intraovarian injection of platelet rich plasma (PRP) is a novel treatment for patients with poor ovarian response (POR) and primary ovarian insufficiency (POI). This article reviews the latest literature on the effect of PRP on markers of ovarian reserve, oocyte and embryo yield, and live birth for these poor prognosis patients.

Recent findings

Several case series and one prospective trial have demonstrated improvements in markers of ovarian reserve in patients with POI and POR and improved oocyte and embryo yields in patients with POR. These studies report multiple live births in patients who had previously failed treatment. The positive effects of PRP persist throughout the literature despite the fact that multiple protocols for preparing and injecting PRP exist, with no consensus on the optimal protocol.

Intra-ovarian injection of PRP is a promising new technology for poor prognosis patients. Rigorous and appropriately controlled clinical trials are warranted to confirm the utility of this treatment for improving patients’ ability to successfully conceive.
The effects of limb laterality and age on the inflammation and bone turnover of the acromioclavicular shoulder joint: 18F-fluorodeoxyglucose and 18F-sodium-fluoride-PET/computed tomography study
Authors: Park Peter Sang Uk , McDonald Elysia , Singh Shashi Bhushan , Raynor William Y. , Werner Thomas J. , Høilund-Carlsen Poul Flemming , Alavi Abass
Published: May 2022

Purpose

The acromioclavicular (AC) joint is a common site of injury and degenerative changes such as osteoarthritis (OA) of the shoulder. Physical manifestations of OA are preceded by molecular changes, detection of which may enhance early prophylaxis and monitoring of disease progression. In this study, we investigate the use of 18F-FDG and 18F-NaF-PET/CT to assess the effects of limb laterality and age on the inflammation and bone turnover of the AC shoulder joint.

Methods

We analyzed FDG and NaF-PET/CT scans of 41 females (mean age of 43.9 ± 14.2 years) and 45 males (mean age of 44.5 ± 13.8 years) using a semiquantitative technique based on predefined ROI.

Results

There was a greater NaF uptake in the right side of the AC joint compared with the left in both females (left: 2.22 ± 1.00; right: 3.08 ± 1.18; P < 0.0001) and males (left: 2.57 ± 1.49; right: 2.99 ± 1.40; P = 0.003). No consistent correlation between age and NaF or FDG uptakes were found in both females and males. There was also a positive correlation between FDG and NaF uptakes in both left (P = 0.01; r = 0.37) and right (P = 0.0006; r = 0.53) AC joints of male subjects.

Conclusion

Our study is the first to reveal the varying effect of right–left limb laterality and aging on FDG and NaF uptake at the AC joint. Future studies correlating the history of shoulder trauma, pain, and degenerative change with FDG and NaF-PET/CT findings will be critical in the adoption of molecular imaging in the clinical setting.
Supergenes on steroids
Authors: Maney Donna L. , Küpper Clemens
Published: May 2022

At the birth of supergenes, the genomic landscape is dramatically re-organized leading to pronounced differences in phenotypes and increased intrasexual diversity. Two of the best-studied supergenes in vertebrates are arguably the inversion polymorphisms on chromosomes 2 and 11 in the white-throated sparrow (
Zonotrichia albicollis
) and the ruff (
Calidris pugnax
), respectively. In both species, regions of suppressed recombination determine plumage coloration and social behavioural phenotypes. Despite the apparent lack of gene overlap between these two supergenes, in both cases the alternative phenotypes seem to be driven largely by alterations in steroid hormone pathways. Here, we explore the interplay between genomic architecture and steroid-related genes. Due to the highly pleiotropic effects of steroid-related genes and their universal involvement in social behaviour and transcriptomic regulation, processes favouring their linkage are likely to have substantial effects on the evolution of behavioural phenotypes, individual fitness, and life-history strategies. We propose that inversion-related differentiation and regulatory changes in steroid-related genes lie at the core of phenotypic differentiation in both of these interesting species.

This article is part of the theme issue ‘Genetic basis of adaptation and speciation: from loci to causative mutations’.
Bacteroides propionicigenes sp. nov., isolated from human faeces
Authors: Sun Xin-Wei , Abdugheni Rashidin , Huang Hao-Jie , Wang Yu-Jing , Jiang Min-Zhi , Liu Chang , Zhou Nan , Jiang He , Liu Shuang-Jiang
Published: May 2022

An anaerobic bacterial strain, designated as NSJ-90T, was isolated from the faeces of a healthy adult in China. Cells of strain NSJ-90T were Gram-stain-negative, non-motile, non-spore-forming and rod-shaped. Based on 16S rRNA gene sequence analysis, strain NSJ-90T belonged to the genus

Bacteroides

and was phylogenetically closely related to

Bacteroides clarus

YIT 12056T (16S rRNA gene identity was 97.04 %). The DNA G+C content of strain NSJ-90T was 44.85 mol% (calculated from the genome). The average nucleotide identity between strain NSJ-90T and

B. clarus

YIT 12056T was 87.60 %. The major cellular fatty acids (>10 %) of strain NSJ-90T were iso-C15 : 0, anteiso-C15 : 0 and iso-C17 : 0 3-OH. Menaquinone-10 was detected as the respiratory quinone. The major products of glucose fermentation were acetic, propionic and isovaleric acids. Based on its phylogenetic, phenotypic and chemotaxonomic characteristics, we propose that strain NSJ-90T represents a novel species of the genus

Bacteroides

, for which the name Bacteroides propionicigenes sp. nov. is proposed. The type strain is NSJ-90T (=CGMCC 1.17886T=KCTC 25305T).
Immunization with a bicistronic DNA vaccine modulates systemic IFN-γ and IL-10 expression against Vibrio cholerae infection
Authors: Ahmad Zamri Najwa , Rusli Muhammad Ehsan Fitri , Mohamad Yusof Loqman , Rosli Rozita
Published: May 2022

Introduction. Cholera is an acute enteric infection caused by

Vibrio cholerae

, particularly in areas lacking access to clean water. Despite the global effort to improve water quality in these regions, the burden of cholera in recent years has not yet declined. Interest has therefore extended in the use of bicistronic DNA vaccine encoding ctxB and tcpA genes of

V. cholerae

as a potential vaccine.

Hypothesis/Gap Statement. The potential of a bicistronic DNA vaccine, pVAX-ctxB-tcpA has not been determined in vitro and in vivo.

Aim. The goal of present study was to evaluate in vitro expression and in vivo potential of pVAX-ctxB-tcpA vaccine against

V. cholerae

.

Methodology. The pVAX-ctxB-tcpA was transiently transfected into mammalian COS-7 cells, and the in vitro expression was assessed using fluorescence and Western blot analyses. Next, the vaccine was encapsulated into sodium alginate using water-in-oil emulsification and evaluated for its efficiency in different pH conditions. Subsequently, oral vaccination using en(pVAX-ctxB-tcpA) was performed in vivo. The animals were challenged with

V. cholerae

O1 El Tor after 2 weeks of vaccination using the Removable Intestinal Tie-Adult Rabbit Diarrhoea (RITARD) model. Following the infection challenge, the rabbits were monitored for evidence of symptoms, and analysed for systemic cytokine expression level (TNF-α, IFN-γ, IL-6 and IL-10) using quantitative real-time polymerase chain reaction.

Results. The in vitro expression of pVAX-ctxB-tcpA was successfully verified via fluorescence and Western blot analyses. Meanwhile, in vivo analysis demonstrated that the en(pVAX-ctxB-tcpA) was able to protect the RITARD model against

V. cholerae

infection due to a lack of evidence on the clinical manifestations of cholera following bacterial challenge. Furthermore, the bicistronic group showed an upregulation of systemic IFN-γ and IL-10 following 12 days of vaccination, though not significant, suggesting the possible activation of both T-helper 1 and 2 types of response. However, upon bacterial challenge, the gene expression of all cytokines did not change.

Conclusion. Our findings suggest that the bicistronic plasmid DNA vaccine, pVAX-ctxB-tcpA, showed a potential role in inducing immune response against cholera through upregulation of in vitro gene and protein expression as well as in vivo cytokine gene expression, particularly IFN-γ and IL-10.
Vitamin C triggers NF-κB-driven epigenomic reprogramming and enhanced immunogenic responses of dendritic cells
Authors: Morante-Palacios Octavio , Godoy-Tena Gerard , Calafell-Segura Josep , Ciudad Laura , Martínez-Cáceres Eva M. , Sardina José Luis , Ballestar Esteban
Published: May 2022

Dendritic cells (DCs) are central in the immune system, bridging the adaptive and innate immune responses. Research on in vitro differentiation of DCs from monocytes provides both in-depth understanding of the analogous in vivo process and potential sources for cancer cell therapy. Active DNA demethylation is crucial in DC differentiation. Vitamin C is a known cofactor of ten-eleven translocation (TET) enzymes, which drive active demethylation. Currently, the effects of vitamin C treatment on human immune cells are poorly understood. In this study, we have studied the epigenomic and transcriptomic reprogramming orchestrated by vitamin C in monocyte-derived DC differentiation and maturation. Vitamin C triggers extensive demethylation at NF-kB/p65 binding sites, together with concordant upregulation of antigen-presentation immune response-related genes during DC maturation. p65 interacts with TET2 and mediates the aforementioned vitamin C-mediated changes, as demonstrated by pharmacological inhibition. Moreover, vitamin C increases TNFβ production in DCs through NF-kB, in concordance with the upregulation of its coding gene and the demethylation of adjacent CpGs. Finally, vitamin C enhances DC’s ability to stimulate the proliferation of autologous antigen-specific T cells. We propose that vitamin C can improve monocyte-derived DC-based cell therapies. Finally, our results provide a feasible mechanism of action for intravenous high-dose vitamin C treatment in patients.
Cytoplasmic HIF-2α correlates to proliferation and predicts worse outcome in sympathetic paraganglioma
Authors: Karakaya Sinan , Gunnesson Lisa , Elias Erik , Martos Salvo Paula , Robledo Mercedes , Nilsson Ola , Wängberg Bo , Abel Frida , Påhlman Sven , Muth Andreas , Mohlin Sofie
Published: May 2022

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features and presenting as a useful resource. Mutations in the pseudohypoxic marker EPAS1/HIF-2α correlates to an aggressive tumor phenotype. We show that HIF-2α unexpectedly localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2α was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that cytoplasmic HIF-2α expression serves as a useful clinical marker to differentiate subtypes and predicting outcome, and hence can be used for improved targeted treatment in PPGLs.
Herd immunity on chip: recapitulating virus transmission in human society
Authors: Lim Wanyoung , Jung Narina , Zhang Jiande , Chen Zhenzhong , Weon Byung Mook , Park Sungsu
Published: May 2022

Virus transmission is affected by population density, social distancing, and vaccination. This has been simulated only by mathematical models. Here, we report the first experimental model to mimic herd immunity to a human coronavirus using a microfluidic device filled with host cells. The device consists of 444 microchambers filled with susceptible (S0), infected (I0), and unsusceptible (U0) cells at specific ratios. The transmission rate and reproduction numbers were directly proportional to S0 and I0 and inversely proportional to U0. Herd immunity was achieved when the proportion of U0 was at 80% in a fixed number of uninfected (S0+U0) cells. These results were consistent with those from a mathematical model. The device can be used for predicting virus transmission.

One-Sentence Summary

We present the first experimental model enabling the simulation of herd immunity in a microfluidic device filled with host cells to human coronavirus.
Early microglial response, myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes
Authors: Teo Jonathan D , Marian Oana C , Spiteri Alanna G , Nicholson Madeline , Song Huitong , Khor Jasmine XY , McEwen Holly P , Piccio Laura , Fletcher Jessica L , King Nicholas JC , Murray Simon S , Brüning Jens C , Don Anthony S
Published: May 2022

The sphingolipids galactosylceramide (GalCer), sulfatide (ST) and sphingomyelin (SM) are essential for myelin stability and function. GalCer and ST are synthesized mostly from C22-C24 ceramides, generated by Ceramide Synthase 2 (CerS2). To clarify the requirement for C22-C24 sphingolipid synthesis in myelin lipid biosynthesis and stability, we generated mice lacking CerS2 specifically in myelinating cells (CerS2ΔO/ΔO). At 6 weeks of age, normal-appearing myelin had formed in CerS2ΔO/ΔOmice, however there was a reduction in myelin thickness and the percentage of myelinated axons. Pronounced loss of C22-C24 sphingolipids in myelin of CerS2ΔO/ΔOmice was compensated by greatly increased levels of C18 sphingolipids. A distinct microglial population expressing high levels of activation and phagocytic markers such as CD64, CD11c, MHC class II, and CD68 was apparent at 6 weeks of age in CerS2ΔO/ΔOmice, and had increased by 10 weeks. Increased staining for denatured myelin basic protein was also apparent in 6-week-old CerS2ΔO/ΔOmice. By 16 weeks, CerS2ΔO/ΔOmice showed pronounced myelin atrophy, motor deficits, and axon beading, a hallmark of axon stress. 90% of CerS2ΔO/ΔOmice died between 16 and 26 weeks of age. This study highlights the importance of sphingolipid acyl chain length for the structural integrity of myelin, demonstrating how a modest reduction in lipid chain length causes exposure of a denatured myelin protein epitope and expansion of phagocytic microglia, followed by axon pathology, myelin degeneration, and motor deficits. Understanding the molecular trigger for microglial activation should aid the development of therapeutics for demyelinating and neurodegenerative diseases.

Main Points

Oligodendrocytes lacking CerS2 produce myelin using sphingolipids with C16/C18 instead of C22/C24 N-acyl chains

C22/C24 myelin sphingolipids are essential for myelin stability, microglial quiescence, and survival beyond young adulthood

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Layer-Specific Vulnerability is a Mechanism of Topographic Map Aging
Authors: Northall Alicia , Doehler Juliane , Weber Miriam , Vielhaber Stefan , Schreiber Stefanie , Kuehn Esther
Published: May 2022

Topographic maps form a critical feature of cortical organization, yet are poorly described with respect to their microstructure in the living aging brain. We acquired quantitative structural and functional 7T-MRI data from younger and older adults to characterize layer-wise topographic maps of the primary motor cortex (M1). Using parcellation-inspired techniques, we show that qT1 and QSM values of the hand, face, and foot areas differ significantly, revealing microstructurally-distinct cortical fields in M1. We show that these fields are distinct in older adults, and that myelin borders between them do not degenerate. We further show that the output layer 5 of M1 shows a particular vulnerability to age-related increased iron, while layer 5 and the superficial layer show increased diamagnetic substance, likely reflecting calcifications. Taken together, we provide a novel 3D model of M1 microstructure, where body parts form distinct structural units, but layers show specific vulnerability towards increased iron and calcium in older adults. Our findings have implications for understanding sensorimotor organization and aging, in addition to topographic disease spread.
Expansion microscopy reveals subdomains in C. elegans germ granules
Authors: Suen Kin M. , Sheard Thomas M. D. , Lin Chi-Chuan , Milonaityte Dovile , Jayasinghe Izzy , Ladbury John E.
Published: May 2022

Many membraneless organelles (MLOs) have been shown to form via liquid-liquid phase separation (LLPS). Light and electron microscopy techniques have been indispensable in the identification and characterization of LLPS MLOs. However, for complex MLOs such as the perinuclear germ granule in C. elegans, our understanding of how the organelle as a whole is regulated is hampered by 1) the technical limitations in confocal fluorescence imaging in which only a few granule protein markers can be examined at a time and 2) the inaccessibility of electron microscopy. In this study, we take advantage of the newly developed super-resolution method of expansion microscopy (ExM) and in-situ staining of the whole proteome to examine the C. elegans germ granule, the P granule. We show that in small RNA pathway mutants, the P granule is smaller compared with wild type animals. Furthermore, we investigate the relationship between the P granule and two other germ granules, mutator foci and Z granule, and show that they are located within the same protein-dense regions while occupying distinct subdomains within this ultrastructure. The experimental workflow developed here will serve as an important tool in our understanding of germ granule biology as well as the biological role of LLPS.
Prominent astrocytic alpha-synuclein pathology with unique post-translational modification signatures unveiled across Lewy body disorders
Authors: Altay Melek Firat , Liu Alan King Lun , Holton Janice L. , Parkkinen Laura , Lashuel Hilal A.
Published: May 2022

Alpha-synuclein (aSyn) is a pre-synaptic monomeric protein that can form aggregates in neurons in Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB), and in oligodendrocytes in multiple system atrophy (MSA). Although the accumulation of aSyn in astrocytes has previously been described in PD, PDD and DLB, the biochemical properties of aSyn in this type of pathology and its topographical distribution have not been studied in detail. Here, we present a systematic investigation of aSyn astrocytic pathology, using an expanded toolset of antibodies covering the entire sequence and known post-translational modifications (PTMs) of aSyn in Lewy body (LB) disorders, including sporadic PD, PDD, DLB, familial PD with SNCA G51D mutation and SNCA duplication, and in MSA. Astrocytic aSyn was mainly detected in the limbic cortical regions of LB disorders, but were absent in key pathological regions of MSA. These astrocytic aSyn accumulations were detected only with aSyn antibodies against the mid N-terminal and non-amyloid component (NAC) regions covering aSyn residues 34-99. The astroglial accumulations were negative to canonical aSyn aggregation markers, including p62, ubiquitin and aSyn pS129, but positive for phosphorylated and nitrated forms of aSyn at Tyrosine 39 (Y39), and mostly not resistant to proteinase K. Our findings suggest that astrocytic aSyn accumulations are a major part of aSyn pathology in LB disorders, and possess a distinct sequence and PTM signature that is characterized by both N- and C-terminal truncations and modifications at Y39. To the best of our knowledge, this is the first description of aSyn accumulation made solely from N- and C-terminally cleaved aSyn species and the first report demonstrating that astrocytic aSyn exists as a mixture of Y39 phosphorylated and nitrated species. These observations underscore the critical importance of systematic characterization of aSyn accumulation in different cell types as a necessary step to capturing the diversity of aSyn species and pathology in the brain. Our findings combined with further studies on the role of astrocytic pathology in the progression of LB disorders can pave the way towards identifying novel disease mechanisms and therapeutic targets.
Sweepstakes reproductive success via pervasive and recurrent selective sweeps
Authors: Árnason Einar , Koskela Jere , Halldórsdóttir Katrín , Eldon Bjarki
Published: May 2022

Highly fecund natural populations characterized by high early mortality abound, yet our knowledge about their recruitment dynamics is somewhat rudimentary. This knowledge gap has implications for our understanding of genetic variation, population connectivity, local adaptation, and the resilience of highly fecund populations. The concept of sweepstakes reproductive success, which posits a considerable variance and skew in individual reproductive output, is key to understanding the distribution of individual reproductive success. However, it still needs to be determined whether highly fecund organisms reproduce through sweepstakes and, if they do, the relative roles of neutral and selective sweepstakes. Here we use coalescent-based statistical analysis of population genomic data to show that selective sweepstakes likely explain recruitment dynamics in the highly fecund Atlantic cod. We show that the Kingman coalescent (modeling no sweepstakes) and the Xi-Beta coalescent (modeling random sweepstakes), including complex demography and background selection, do not provide an adequate fit for the data. The Durrett-Schweinsberg coalescent, in which selective sweepstakes result from recurrent and pervasive selective sweeps of new mutations, offers greater explanatory power. Our results show that models of sweepstakes reproduction and multiple-merger coalescents are relevant and necessary for understanding genetic diversity in highly fecund natural populations. These findings have fundamental implications for understanding the recruitment variation of fish stocks and general evolutionary genomics of high-fecundity organisms.
2-hydroxyglutarate controls centromere and heterochromatin conformation and function in the male germline
Authors: Mayorek Nina , Schlossberg Miriam , Mansour Yousef , Pillar Nir , Stein Ilan , Mushasha Fatima , Baziza Guy , Medvedev Eleonora , Manevitch Zakhariya , Menzel Julia , Aizenshtein Elina , Sarvin Boris , Sarvin Nikita , Shlomi Tomer , Klutstein Michael , Pikarsky Eli
Published: May 2022

2-hydroxyglutarate (2HG) is recognized as an epigenetic regulator in cancer and some transient biological processes. Of all organs, the testis harbors the highest baseline physiological levels of 2HG, yet it’s putative functions in germ cell biology are unknown. Here we show that 2HG is generated in specific stages of spermatogenesis by the testis specific lactate dehydrogenase C (LDHC), beginning at the last stages of prophase I. Unexpectedly LDHC enters nuclei and concentrates in centromeres. LDHC-generated L-2HG controls centromere condensation and pericentromeric heterochromatin organization through multiple effects including clustering of chromocenters, centromere and chromocenter condensation and expression of satellite RNAs. These effects are rapid and specific to L but not D-2HG.In vivodepletion of L-2HG causes centromere malfunction and activation of the spindle assembly checkpoint. Our findings reveal that 2HG can directly affect centromere and pericentromeric heterochromatin conformation and function and is necessary for licensing chromosome segregation.
Distinct architectural requirements for the parS centromeric sequence of the pSM19035 plasmid partition machinery
Authors: Volante Andrea , Alonso Juan C. , Mizuuchi Kiyoshi
Published: May 2022

Three-component ParABS partition systems ensure stable inheritance of many bacterial chromosomes and low-copy-number plasmids. ParA localizes to the nucleoid through its ATP- dependent non-specific DNA binding activity, whereas centromere-like parS-DNA and ParB form partition complexes that activate ParA-ATPase to drive the system dynamics. The essential parS sequence arrangements vary among ParABS systems, reflecting the architectural diversity of their partition complexes. Here, we focus on the pSM19035 plasmid partition system that uses a ParBpSM of the ribbon-helix-helix (RHH) family. We show that parSpSM with four or more contiguous ParBpSM-binding sequence repeats is required to assemble a stable ParApSM-ParBpSM complex and efficiently activate the ParApSM-ATPase, stimulating complex disassembly. Disruption of the contiguity of the parSpSM sequence array destabilizes the ParApSM-ParBpSM complex and prevents efficient ATPase activation. Our findings reveal the unique architecture of the pSM19035 partition complex and how it interacts with nucleoid-bound ParApSM-ATP.
Two-Stage Multivariate Mendelian Randomization on Multiple Outcomes with Mixed Distributions
Authors: Deng Yangqing , Tu Dongsheng , O’Callaghan Chris J , Liu Geoffrey , Xu Wei
Published: May 2022

Summary

In clinical research, it is of importance to study whether certain clinical factors or exposures have causal effects on clinical and patient reported outcomes like toxicities, quality of life, and self-reported symptoms, which can help improve patient care. Usually, such outcomes are recorded as multiple variables with different distributions. Mendelian randomization is a commonly used technique for causal inference with the help of genetic instrumental variables to deal with observed and unobserved confounders. Nevertheless, the current methodology of Mendelian randomization on multiple outcomes only focuses on one outcome at a time, meaning that it does not consider the correlation structure of multiple outcomes, which may lead to loss of statistical power. In situations with multiple outcomes of interest, especially when there are mixed correlated outcomes with multiple distributions, it is much more desirable to jointly analyze them with a multivariate approach. Some multivariate methods have been proposed to model mixed outcomes, however, they do not incorporate instrumental variables and cannot handle unmeasured confounders. To overcome the above challenges, we propose a two-stage multivariate Mendelian Randomization Method (MRMO), that can perform multivariate analysis on mixed outcomes using instrumental variables. We demonstrate that our proposed MRMO algorithm can gain power over the existing univariate method through simulation studies and a clinical application on a randomized Phase III clinical trial study on colorectal cancer patients.
Chemical genetic screening identifies nalacin as an inhibitor of GH3 amido synthetase for auxin conjugation
Authors: Xie Yinpeng , Zhu Ying , Wang Na , Luo Min , Ohta Tsuyoshi , Guo Ruipan , Yu Zongjun , Aizezi Yalikunjiang , Zhang Linlin , Yan Yan , Zhang Yujie , Bao Hongyu , Wang Yichuan , Zhu Ziqiang , Huang Ancheng , Zhao Yunde , Asami Tadao , Huang Hongda , Guo Hongwei , Jiang Kai
Published: May 2022

Root system is critical for plant growth and development. To develop plant growth regulators functioning in root development, we performed a phenotype-based chemical screen in Arabidopsis and identified a chemical, nalacin, that mimicked the effects of auxin on root development. Genetic, pharmacological and biochemical approaches demonstrated that nalacin exerts its auxin-like activities by inhibiting indole-3-acetic acid (IAA) conjugation that is mediated by Gretchen Hagen 3 (GH3) acyl acid amido synthetases. The crystal structure of Arabidopsis GH3.6 in complex with D4 (a derivative of nalacin) together with docking simulation analysis revealed the molecular basis of the inhibition of group II GH3 by nalacin. Sequence alignment analysis indicated broad bioactivities of nalacin and D4 as inhibitors of GH3s in vascular plants, which were confirmed, at least, in tomato and rice. In summary, our work identifies nalacin as a potent inhibitor of IAA conjugation mediated by group II GH3 that plays versatile roles in hormone-regulated plant development and has potential applications in both basic research and agriculture.
Cytokinins induce prehaustoria coordinately with quinone and phenolic signals in the parasitic plant Striga hermonthica
Authors: Aoki Natsumi , Cui Songkui , Yoshida Satoko
Published: May 2022

Orobanchaceae parasitic plants are major threats to global food security, causing severe agricultural damage worldwide. Parasitic plants derive water and nutrients from their host plants through multicellular organs called haustoria. The formation of a prehaustorium, a primitive haustorial structure, is provoked by host-derived haustorium-inducing factors (HIFs). Quinones, including 2,6-dimethoxy-p-benzoquinone (DMBQ), and phenolics, including syringic acid, are of most potent HIFs for various species in Orobanchaceae, but except non-photosynthetic holoparasites, Phelipanche and Orobanche spp. On the other hand, cytokinin phytohormones was reported to induce prehaustoria in Phelipanche ramosa. However, little is known about whether cytokinins act as HIFs in the other parasitic species. Moreover, the signaling pathways for quinones, phenolics and cytokinins in prehaustorium induction are not well understood. This study showed that cytokinins act as HIFs in Striga hermonthica but not in Phtheirospermum japonicum. Using chemical inhibitors for each type of HIF, we demonstrated that cytokinins activate prehaustorium formation through a signaling pathway that overlaps with the quinone and phenolic HIF pathways in S. hermonthica. Host root exudates activated S. hermonthica cytokinin biosynthesis and signaling genes, and inhibitors blocking any of three types of HIFs perturbed the prehaustorium-inducing activity of exudates, indicating that host root exudates include a mixture of HIFs. Our study reveals the importance of cytokinins for prehaustorium formation in obligate parasitic plants.
A Genetically Encodable and Chemically Disruptable System for Synthetic Post-Translational Modification Dependent Signaling
Authors: McMahan Jeffrey B. , Ngo John T.
Published: May 2022

We describe an engineered “writer/reader” framework for programming post-translational control into synthetic mammalian signaling proteins. In this approach, a bacterially-derived biotin protein ligase (BirA) was used as a “writer” element for the modification of artificial receptors and transcription factors containing a biotin acceptor peptide (AP) fusion tag. To enable modification events to transmit biochemical information, we designed encodable “reader” modules using sequences from a biotinamide-binding antibody. Proteins fused to reader domains were able to interact with AP-tagged polypeptides in a biotinylation-dependent manner, and control over the timing and extent of these interactions could be modulated through both genetic and chemically-based strategies. Genetic and cell-specific control over AP-reader module interactions was achieved via regulated BirA expression, and the interaction states of both intra-and inter-cellular complexes could be modulated with biotinamide-based and bioorthogonally-functionalized compounds. The utility of this approach was demonstrated by installing post-translational and chemogenetic control into synthetic Notch (“SynNotch”)-based systems.
MATTE: anti-noise module alignment for phenotype-gene-related analysis
Authors: Cai Guoxin , Zhou Zhan , Gu Xun
Published: May 2022

Purpose

Although many transcriptome analysis methods find fundamental interactions or markers of some phenotypes, preservation of module or network is still a challenge.

Methods

The study developed a method to directly compare the transcriptome data of phenotypes and present the differences modularly, called Module Alignment of TranscripTomE(MATTE).

Results

MATTE performs better under high noise than differential co-expression(DC) clustering in the simulation experiments but still detects differential expression(DE) and DC genes. After subsequent annotation of cell types in single-cell data, MATTE obtained the best scores in both supervised and unsupervised learning, i. e. MATTE found meaningful markers. Finally, we apply MATTE in analyzing the transcriptome of Breast Cancer(BRCA). We have found five BRCA subtypes, and the characteristic of one subtype is detected in the form of a module network.

Conclusion

MATTE can find meaningful genes and modules, thus facilitating the downstream analysis task to obtain insight into biology.
Knowledge, attitude, and practice towards lymphatic filariasis among inhabitants of an endemic town in Oyo State, Nigeria
Authors: Jaiyeola Taiwo Mofadeke , Udoh Ekerette Emmanuel , Adebambo Abiola Basirat
Published: May 2022

Introduction

The burden of lymphatic Filariasis (LF) popularly called Ina orun in southwest Nigeria is of serious concern and it calls for urgent attention. The study aimed at assessing the knowledge attitude and practice of inhabitants of two communities endemic with LF in Ibadan south-west Local Government Area (IBSWLGA) of Oyo State, Nigeria.

Materials and methods

A cross-sectional study was carried out using a semi-structured questionnaire.

Results

Out of 243 participants comprising of both male and female with a mean age of 35.01± 8.53 years, 35% reported ever hearing about LF. The majority (73.3%) of the participants had an overall poor knowledge of the disease, while only 26.7% have good knowledge of the disease. 26.3% of the participants knew the main cause of LF while 74.9% did not know the disease is communicable. About half (50.6%) and 42.4% of the participants did not know the symptoms and the prevention practices respectively. Only 27.2% knew that mosquitoes play a major role in LF transmission. 85.6% of the respondents were not aware of the Mass Drug Administration (MDA) program in the study area while 36.6% of participants did not know the role of MDA in preventing and controlling LF.

Conclusion

These results indicate poor community knowledge, inadequate prevention practices, and a lack of awareness of available programmatic efforts that the population can benefit from to tackle continuous transmission of the lymphatic filariasis disease. In conclusion, with the present low status on the disease awareness and response, increased sensitization and community interventions on LF are necessary and this calls for urgent attention.
Immunomodulatory effects of Simvastatin in Toll-like receptor-2 stimulated Rheumatoid arthritis synoviocytes
Authors: Saeed Mohammad , Al-Karakooly Zeiyad , Ali Nawab , Ortmann Robert A.
Published: May 2022

Fibroblast-like synoviocytes (FLS) are major effector cells in Rheumatoid arthritis (RA). Toll-like receptor-2 (TLR2) activation of FLS plays a key role in RA pathogenesis. Recently, statins have been shown to modulate RA. We investigated the immunomodulatory effects of simvastatin (SMV) in vitro, in FLS cell lines from control and RA subjects, in the presence of TLR2 activation. Normal and RA FLS cultures (1×105 cells/well) were treated with SMV then activated with TLR2 ligand (Pam3CSK4 100μg/ml) for 24-hours. SMV caused dose-dependent cytotoxicity in both cell lines as assessed by Alamar-blue assay and increased ROS production measured by flow cytometry. Gene expression of anti-oxidants including GSR, TXNRD1, PRDX1, SOD2 and MT3 was upregulated. BNIP3 expression was increased 2200-fold in RA-FLS after SMV/TLR2 treatment pointing to apoptosis as a cause of observed cytotoxicity. Apoptosis increased in both cell lines with SMV to 25%. Akt decreased dose-dependently in RA FLS assessed by western blots. IP-1, IP-2 and IP3 decreased with SMV/TLR2 treatment indicating cell survival while IL-6 increased dose-dependently. Thus, SMV induces apoptosis in FLS by upregulating BNIP3 and inhibiting Akt. FLS react to survive by increasing IL-6, decreasing IP-1 and IP-2 and upregulating anti-oxidant genes. SMV has immunomodulatory properties and may be used in RA as adjunctive therapy in combination with other more potent disease-modifying medications.
A Bioinformatics Approach To Reveal Common Genes And Molecular Pathways Shared By Cutaneous Melanoma and Uveal Melanoma
Authors: Jayaraj Dr. Perumal , Sen Seema , Kaur Khushneet , Gupta Kritika , Taluja Shreya
Published: May 2022

Background

Melanomas are highly aggressive in nature and are known for metastasis and death. Melanocytes that give rise to melanomas are neural crest progenitor-cells. Our research is primarily concerned with Uveal Melanoma (UM) and Cutaneous Melanoma (CM). Although they both share same melanocytic origin, but the biology of their respective is different.

Aim

The aim of our study is to recognize the common differentially expressed genes (DEGs) between UM and CM.

Methodology

The gene expression profile was downloaded from the GEO and analyzed by GEO2R for identification of DEGs. By applying DAVID, GO and KEGG, pathway enrichment analysis was performed. PPI of these DEGs was analyzed using STRING and visualized through Cytoscape and MCODE. Further, we utilized HPA and GEPIA to obtain Kaplan-Meier Graph for survival analysis in order to assess the prognostic value of hub genes.

Results

We examined the UM and CM datasets and discovered three common upregulated and eight common downregulated DEGs for both the melanomas based on computational analysis. HMGCS1 and ELOVL5 were shown to be enriched in a variety of altered molecular pathways and pathways in cancer. Overexpression of HMGCS1 and ELOVL5 were linked to poor prognosis in CM.

Conclusion

On computational evaluation, we found that HMGCS1 and ELOVL5 were upregulated in both of these melanomas. Enrichment analysis showed that these genes are involved in cancer metabolism pathway and associated with poor prognosis in CM. However, the molecular study of these genes in UM is limited. Therefore, a better understanding of the cancer metabolism pathways should be carried to pave the way for clinical benefits.
Chemical degradation of BTK/TEC as a novel approach to inhibit platelet function and thrombosis
Authors: Trory Justin S. , Munkacsi Attila , Śledź Kamila M. , Goudswaard Lucy J. , Heesom Kate J. , Moore Samantha F. , Nabet Behnam , Aggarwal Varinder K. , Hers Ingeborg
Published: May 2022

The tyrosine kinase BTK plays an important role in platelet function downstream of GPVI and CLEC2 receptors and has been proposed as a novel target to prevent thrombosis in patients that are at increased risk. However, current clinically approved BTK inhibitors have off target effects and are associated with an increased bleeding risk. In this study, we therefore explored whether BTK can be targeted for degradation in human platelets by using recently developed heterobifunctional molecules that employ the proteasomal system to break down BTK. Here we confirm that human platelets are highly susceptible to BTK degraders with the generic tyrosine kinase degrader TL12-186, and the BTK degraders DD-04-15 and DD-03-171 leading to breakdown of BTK and its closely related kinase TEC, an effect that was prevented by proteasomal inhibitors. Tandem Mass Tag proteomic analysis confirmed high selectivity with TL12-186 degrading BTK/TEC, FAK/PYK2 and FER, whereas DD-04-15 and DD-03-171 degraded BTK/TEC only. GPVI-mediated platelet integrin αIIbβ3 activation, P-selectin expression, and phosphatidyl-serine exposure were largely impaired upon BTK/TEC degradation, with PAR-1-mediated responses left intact. This is the first study to demonstrate that chemical protein degraders can be successfully employed in anucleate human platelets to modulate their function.