bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural Insight into Mitochondrial β-Barrel Outer Membrane Protein Biogenesis
Authors: Diederichs Kathryn A. , Ni Xiaodan , Rollauer Sarah E. , Botos Istvan , Tan Xiaofeng , King Martin S. , Kunji Edmund R.S. , Jiang Jiansen , Buchanan Susan K. 
Published: April 2020

AbstractIn mitochondria, β-barrel outer membrane proteins mediate protein import, metabolite transport, lipid transport, and biogenesis. The Sorting and Assembly Machinery (SAM) complex consists of three proteins that assemble as a 1:1:1 complex to fold β-barrel proteins and insert them into the mitochondrial outer membrane. We report cryoEM structures of the SAM complex fromMyceliophthora thermophila, which show that Sam50 forms a 16-stranded transmembrane β-barrel with a single polypeptide-transport-associated (POTRA) domain extending into the intermembrane space. Sam35 and Sam37 are located on the cytosolic side of the outer membrane, with Sam35 capping Sam50, and Sam37 interacting extensively with Sam35. Sam35 and Sam37 each adopt a GST-like fold, with no functional, structural, or sequence similarity to their bacterial counterparts. Structural analysis shows how the Sam50 β-barrel opens a lateral gate to accommodate its substrates. The SAM complex structure suggests how it interacts with other mitochondrial outer membrane proteins to create supercomplexes.
Cytoplasmic mRNA decay represses RNA polymerase II transcription during early apoptosis
Authors: Duncan-Lewis Christopher , Hartenian Ella , King Valeria , Glaunsinger Britt A. 
Published: April 2020

ABSTRACTRNA abundance is generally sensitive to perturbations in decay and synthesis rates, but crosstalk between RNA polymerase II transcription and cytoplasmic mRNA degradation often leads to compensatory changes in gene expression. Here, we reveal that widespread mRNA decay during early apoptosis represses RNAPII transcription, indicative of positive (rather than compensatory) feedback. This repression requires active cytoplasmic mRNA degradation, which leads to impaired recruitment of components of the transcription preinitiation complex to promoter DNA. Importin α/β- mediated nuclear import is critical for this feedback signaling, suggesting that proteins translocating between the cytoplasm and nucleus connect mRNA decay to transcription. We also show that an analogous pathway activated by viral nucleases similarly depends on nuclear protein import. Collectively, these data demonstrate that accelerated mRNA decay leads to the repression of mRNA transcription, thereby amplifying the shutdown of gene expression. This highlights a conserved gene regulatory mechanism by which cells respond to threats.IMPACT STATEMENTHuman cells respond to cytoplasmic mRNA depletion during early apoptosis by inhibiting RNA polymerase II transcription, thereby magnifying the gene expression shutdown during stress.
Deaf intermarriage does not increase the prevalence of deafness alleles
Authors: Braun Derek C. , Jain Samir , Epstein Eric , Greenwald Brian H. , Herold Brienna , Gray Margaret 
Published: April 2020

AbstractThe idea that deaf intermarriage increases deafness was forcefully pushed in the late 19th century by Alexander Graham Bell, in proceedings published by the National Academy of Science. Bell’s hypothesis was not supported by a 19th century study by Edward Allen Fay, which was funded by Bell’s own organization, the Volta Bureau. The Fay study showed through an analysis of 4,471 deaf marriages that the chances of having deaf children did not increase significantly when both parents were deaf. In light of an apparent increase in non-complementary pairings when a recent dataset of Gallaudet alumni was compared with the 19th century Fay dataset, Bell’s argument has been resurrected that residential schools for the deaf, which concentrate signing deaf individuals together, have promoted assortative mating and increased the prevalence of both phenotypic deafness and the commonest recessive deafness allele. Because this hypothesis persists, even though it contradicts classical models introduced by R.A. Fisher and Sewell Wright, it is critically important that this hypothesis be thoroughly re-investigated. In this study, we used an established forward-time genetics simulator with parameters and measurements collected from the published literature. Compared to mathematical equations, simulations allowed for more complex modeling, operated without assumptions of parametricity, and captured ending distributions and variances. Our simulation results affirm predictions from classical equations and show that assortative mating only modestly increases the prevalence of phenotypically deaf individuals, with this effect mostly completed by the third generation. Most importantly, our data show that even intense assortative mating does not increase allelic frequency under reported conditions. These results are not locus-specific and are generalizable to other forms of recessive deafness. We offer alternative explanations for the higher rate of non-complementary pairings measured in the contemporary Gallaudet alumni sample as compared to the Fay dataset.
The Molecular Landscape of Asian Breast Cancers Reveals Clinically Relevant Population-Specific Differences
Authors: Pan Jia-Wern , Ahmad Zabidi Muhammad Mamduh , Ng Pei-Sze , Meng Mei-Yee , Hasan Siti Norhidayu , Sandey Bethan , Sammut Stephen-John , Yip Cheng-Har , Rajadurai Pathmanathan , Rueda Oscar M. , Caldas Carlos , Chin Suet-Feung , Teo Soo-Hwang 
Published: April 2020

ABSTRACTMolecular profiles of breast cancer have contributed to an improved understanding of the disease, enabled development of molecular prognostic signatures to guide treatment decisions and unveiled new or more accurate therapeutic options for breast cancer patients. However, the extent to which differences in genetic, environmental and lifestyle factors influence molecular profiles in different populations remains poorly characterised, as relatively few large-scale molecular studies of breast tumours in non-Caucasian populations have hitherto been reported. Here, we present the molecular profiles of 560 Asian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to the breast tumours in predominantly Caucasian women reported in TCGA and METABRIC, we show an increased prevalence of Her2-enriched molecular subtypes and higher prevalence ofTP53somatic mutations in ER+ Asian breast tumours. Using gene expression and immunohistochemistry, we observed elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst Her2-subtype and enriched immune score are associated with improved survival, presence ofTP53somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil new opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.
Improved synthetic lipidation-based protein translocation system for SNAP-tag fusion proteins
Authors: Yoshii Tatsuyuki , Tahara Kai , Suzuki Sachio , Hatano Yuka , Kuwata Keiko , Tsukiji Shinya 
Published: April 2020

ABSTRACTThe ability to artificially attach lipids to specific intracellular protein targets would be a valuable approach for controlling protein localization and function in cells. We recently devised a chemogenetic method in which a SNAP-tag fusion protein can be translocated from the cytoplasm to the plasma membrane by post-translationally and covalently conjugating a synthetic lipopeptide in cells. However, the first-generation system lacked general applicability. Herein, we present an improved synthetic lipidation system that enables efficient plasma membrane translocation of SNAP-tag fusion proteins in cells. This second-generation system is now applicable to the control of various cell-signaling molecules, offering a new and useful research tool in chemical biology and synthetic biology.
Differential protein phosphorylation affects the localisation of two secretedToxoplasmaproteins and is widespread during stage conversion
Authors: Young Joanna , Broncel Malgorzata , Teague Helena , Russell Matt , McGovern Olivia , Renshaw Matt , Frith David , Snijders Bram , Collinson Lucy , Carruthers Vern , Ewald Sarah , Treeck Moritz 
Published: April 2020

ABSTRACTThe intracellular parasiteToxoplasma gondiiresides within a membrane bound parasitophorous vacuole (PV) and secretes an array of proteins to establish this replicative niche. It has been shown previously thatToxoplasmaboth secretes kinases and that numerous proteins are phosphorylated after secretion. Here we assess the role of phosphorylation of SFP1 and the related GRA29, two secreted proteins with unknown function. We show that both proteins form stranded structures in the PV that are independent of the previously described intravacuolar network or actin. GRA29 likely acts as a seed for SFP1 strand formation, and these structures can form independently of otherToxoplasmasecreted proteins. We show that an unstructured region at the C-terminus of SFP1 and GRA29 is required for the formation of strands and that mimicking phosphorylation of this domain negatively regulates strand development. When tachyzoites convert to chronic stage bradyzoites, both proteins show a dispersed localisation throughout the cyst matrix. Many secreted proteins are reported to dynamically redistribute as the cyst forms and secreted kinases are known to play a role in cyst formation. Using quantitative phosphoproteome and proteome analysis comparing tachyzoite and early bradyzoite stages, we reveal widespread differential phosphorylation of secreted proteins. These data support a model in which secreted kinases and phosphatases are important to dynamically regulate parasite secreted proteins during stage conversion.IMPORTANCEToxoplasma gondiiis a common parasite that infects up to one third of the human population. Initially the parasite grows rapidly, infecting and destroying cells of the host, but subsequently switches to a slow-growing form and establishes chronic infection. In both stages the parasite lives within a membrane bound vacuole within the host cell, but in the chronic stage a durable cyst wall is synthesized that provides protection to the parasite during transmission to a new host.Toxoplasmasecretes proteins into the vacuole to build its replicative niche and previous studies identified many of these proteins as phosphorylated. We investigate two secreted proteins and show that phosphorylation plays an important role in their regulation. We also observed widespread phosphorylation of secreted proteins when parasites convert from acute to chronic stages, providing new insight into how the cyst wall may be dynamically regulated.
Characterization of Oral bacteriome dysbiosis in type 2 diabetic patients
Authors: Kori Junaid Ahmed , Saleem Faizan , Ullah Saeed , Azim M. Kamran 
Published: April 2020

AbstractWe aimed to characterize the relationship of the oral microbiome with diabetes in Pakistan. Saliva samples were collected from diabetic patients (n = 49) and healthy individuals (n = 55). 16S metagenomics saliva was carried out by NGS technology. We observed that the phylum Firmicutes (p-value = 0.024 at 95% confidence interval) was significantly more abundant among diabetic patients than among the controls. We found that the abundance of phylum Actinobacteria did not significantly vary among both groups in contrast to a similar report from the USA (Long et al., 2017). On genus level, acidogenic bacteria Prevotella (p-value = 0.024) and Leptotrichia (p-value = 1.5 × 10−3); and aciduric bacteria Veillonella (p-value = 0.013) were found to be in higher abundance in diabetic patients. These bacteria are found in dental biofilm and involved in the metabolism of fermentable carbohydrates. Stratified analysis by gender revealed healthy and diabetic females to be more divergent. Abundance of Prevotella (p-value = 4.4 × 10-3) and Leptotrichia (p-value = 0.015) was significantly associated with male patients. A comparison of oral bacteriome between two groups revealed the dominance of acidogenic and aciduric bacteria in diabetics which suggested the involvement of these eubacteria in oral dysbacteriosis in diabetes mellitus.
Population age structure only partially explains the large number of COVID-19 deaths at the oldest ages
Authors: Medford Anthony , Trias-Llimós Sergi 
Published: April 2020

AbstractTo date any attention paid to the age shape of COVID-19 deaths has been mostly in relation to attempts to understand the differences in case fatality rates between countries. The aim of this paper is to explore differences in age distribution of deaths from COVID-19 among European countries which have old age structures. We do this by way of a cross-country comparison and put forward some reasons for potential differences.
AutoTriage - An Open Source Edge Computing Raspberry Pi-based Clinical Screening System
Authors: Hegde Chaitra , Jiang Zifan , Suresha Pradyumna Byappanahalli , Zelko Jacob , Seyedi Salman , Smith Monique A. , Wright David W. , Kamaleswaran Rishikesan , Reyna Matt A. , Clifford Gari D. 
Published: April 2020

AbstractWith the recent COVID-19 pandemic, healthcare systems all over the world are struggling to manage the massive increase in emergency department (ED) visits. This has put an enormous demand on medical professionals. Increased wait times in the ED increases the risk of infection transmission. In this work we present an open-source, low cost, off-body system to assist in the automatic triage of patients in the ED based on widely available hardware. The system initially focuses on two symptoms of the infection fever and cyanosis. The use of visible and far-infrared cameras allows for rapid assessment at a 1m distance, thus reducing the load on medical staff and lowering the risk of spreading the infection within hospitals. Its utility can be extended to a general clinical setting in non-emergency times as well to reduce wait time, channel the time and effort of healthcare professionals to more critical tasks and also prioritize severe cases.Our system consists of a Raspberry Pi 4, a Google Coral USB accelerator, a Raspberry Pi Camera v2 and a FLIR Lepton 3.5 Radiometry Long-Wave Infrared Camera with an associated IO module. Algorithms running in real-time detect the presence and body parts of individual(s) in view, and segments out the forehead and lip regions using PoseNet. The temperature of the forehead-eye area is estimated from the infrared camera image and cyanosis is assessed from the image of the lips in the visible spectrum. In our preliminary experiments, an accuracy of 97% was achieved for detecting fever and 77% for the detection of cyanosis, with a sensitivity of 91% and area under the receiver operating characteristic curve of 0.91. Heart rate and respiratory effort are also estimated from the visible camera.Although preliminary results are promising, we note that the entire system needs to be optimized before use and assessed for efficacy. The use of low-cost instrumentation will not produce temperature readings and identification of cyanosis that is acceptable in many situations. For this reason, we are releasing the full code stack and system design to allow others to rapidly iterate and improve the system. This may be of particular benefit in low-resource settings, and low-to-middle income countries in particular, which are just beginning to be affected by COVID-19.
A new tool for 3D segmentation of computed tomography data:Drishti Paintand its applications
Authors: Hu Yuzhi , Limaye Ajay , Lu Jing 
Published: April 2020

AbstractComputational tomography is more and more widely used in many fields for its non-destructive and high-resolution in detecting internal structures of the samples. 3D segmentation of computed tomography data, which sheds light into internal features of target objects, is increasingly gaining in importance. However, how to efficiently and precisely reconstruct computed tomography data and better represent the data remains a hassle. Here, using a set of scan data of a fossil fish as a case study, we present a new release of open-source volume exploration, rendering, and 3D segmentation software,Drishtiv2.6.6, and its protocol for performing 3D segmentation and other advanced applications. We provide new toolsets and workflow to segment computed tomography data thus benefit the scientific community with more accurate and precise digital reconstruction, 3D modelling and 3D printing results. Our procedure is widely applicable not only in palaeontology, but also in biological, medical, and industrial researches, and can be used as a framework to segment computed tomography and other forms of volumetric data from any research field.
Potential host range of multiple SARS-like coronaviruses and an improved ACE2-Fc variant that is potent against both SARS-CoV-2 and SARS-CoV-1
Authors: Li Yujun , Wang Haimin , Tang Xiaojuan , Ma Danting , Du Chengzhi , Wang Yifei , Pan Hong , Zou Qing , Zheng Jie , Xu Liangde , Farzan Michael , Zhong Guocai 
Published: April 2020

SUMMARYThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a currently uncontrolled pandemic and the etiological agent of coronavirus disease 2019 (COVID-19). It is important to study the host range of SARS-CoV-2 because some domestic species might harbor the virus and transmit it back to humans. In addition, insight into the ability of SARS-CoV-2 and SARS-like viruses to utilize animal orthologs of the SARS-CoV-2 receptor ACE2 might provide structural insight into improving ACE2-based viral entry inhibitors. Here we show that ACE2 orthologs of a wide range of domestic and wild animals support entry of SARS-CoV-2, as well as that of SARS-CoV-1, bat coronavirus RaTG13, and a coronavirus isolated from pangolins. Some of these species, including camels, cattle, horses, goats, sheep, pigs, cats, and rabbits may serve as potential intermediate hosts for new human transmission, and rabbits in particular may serve as a useful experimental model of COVID-19. We show that SARS-CoV-2 and SARS-CoV-1 entry could be potently blocked by recombinant IgG Fc-fusion proteins of viral spike protein receptor-binding domains (RBD-Fc) and soluble ACE2 (ACE2-Fc). Moreover, an ACE2-Fc variant, which carries a D30E mutation and has ACE2 truncated at its residue 740 but not 615, outperforms all the other ACE2-Fc variants on blocking entry of both viruses. Our data suggest that RBD-Fc and ACE2-Fc could be used to treat and prevent infection of SARS-CoV-2 and any new viral variants that emerge over the course of the pandemic.
Towards a probiotic approach for building plumbing – nutrient-based selection during initial biofilm formation on flexible polymeric materials
Authors: Lisa Neu , Laura Cossu , Hammes Frederik 
Published: April 2020

AbstractUpon entering building plumbing systems, drinking water bacteria experience considerable changes in environmental conditions. For example, some flexible polymeric materials leach organic carbon, which increases bacterial growth and reduces diversity. Here we show that the carbon supply by a flexible polymeric material drives nutrient-based selection within establishing biofilm communities. We found that migrating carbon from EPDM coupons resulted in considerable growth for different drinking water communities (0.2 – 3.3 × 108cells/cm2). All established biofilm communities showed low diversity (29 – 50 taxa/biofilm), with communities dominated by even viewer taxa (e.g., 5 taxa accounting for 94 ± 5 % relative abundance, n = 15). Interestingly, biofilm communities shared some taxa (e.g.,Methylobacteriumspp.) and families (e.g., Comamonadaceae), despite the difference in starting communities. Moreover, selected biofilm communities performed better than their original communities regarding maximum attachment (91 ± 5 vs. 69 ± 23 %, n = 15) and attachment rate (5.0 ± 1.7 × 104vs. 2.4 ± 1.2 × 104cells/cm2/h, n = 15) when exposed to new EPDM coupons. Our results demonstrate nutrient-based selection during initial biofilm formation on a flexible polymeric material and a resulting benefit to selected communities. We anticipate our findings to help connecting observational microbiological findings with their underlying ecological principles. Regarding initial biofilm formation, attachment dynamics, growth, and selection thereof are important for the management of microbial communities. In fact, managing initial colonization by supplying specific carbon and/or introducing consciously chosen/designed communities potentially paves the way for a probiotic approach for building plumbing materials.
Temporal patterns in electrical nerve stimulation: burst gap code shapes tactile frequency perception
Authors: Ng Kevin K. W. , Olausson Christoffer , Vickery Richard M. , Birznieks Ingvars 
Published: April 2020

AbstractWe have previously described a novel temporal encoding mechanism in the somatosensory system, where mechanical pulses grouped into periodic bursts create a perceived tactile frequency based on the duration of the silent gap between bursts, rather than the mean rate or the periodicity. This coding strategy may offer new opportunities for transmitting information to the brain using various sensory neural prostheses and haptic interfaces. However, it was not known whether the same coding mechanisms apply when using electrical stimulation, which recruits a different spectrum of afferents. Here, we demonstrate that the predictions of the burst gap coding model for frequency perception apply to burst stimuli delivered with electrical pulses, re-emphasising the importance of the temporal structure of spike patterns in neural processing and perception of tactile stimuli. Reciprocally, the electrical stimulation data confirm that the results observed with mechanical stimulation do indeed depend on neural processing mechanisms in the central nervous system, and are not due to skin mechanical factors and resulting patterns of afferent activation.
Development of fluorescence polarization-based competition assay for nicotinamideN-methyltransferase
Authors: Iyamu Iredia D. , Huang Rong 
Published: April 2020

AbstractMethylation-mediated pathways play an important role in the progression of cancer. Inhibitors of several key methyltransferases including DNA methyltransferases and histone methyltransferases have proven to be instrumental for both understanding the function of the respective enzymes activites and translational applications in cancer epigenetic therapy. NicotinamideN-methyltransferase (NNMT) is a major metabolic enzyme involved in epigenetic regulation through catalysis of methyl transfer from the cofactorS-adenosyl-L-methionine, onto nicotinamide and other pyridines, to form S-adenosyl homocysteine and 1-methyl-nicotinamide or the corresponding pyridinium ions. Accumulating evidence infers that NNMT is a novel therapeutic target for a variety of diseases such as cancer, diabetes, obesity, cardiovascular and neurodegenerative diseases. Therefore, there is an urgent need to discover potent and specific inhibitors for NNMT. Herein, we reported the design and synthesis of a fluorescent probeII138, and established a fluorescence polarization (FP)-based competition assay for evaluation of NNMT inhibitors. Importantly, the unique feature of this FP competition assay is its capability to identify inhibitors that interfere with the interaction of the NNMT active site directly or allosterically. In addition, this assay performane is robust with a Z factor of 0.76, and applicable in high-throughput screening for inhibitors for NNMT.