bluuebunny/crossref_metadata_2025 huggingface dataset:
Change points in the spread of COVID-19 question the effectiveness of nonpharmaceutical interventions in Germany
Authors: Wieland Thomas
Published: July 2020

Aims

Nonpharmaceutical interventions against the spread of SARS-CoV-2 in Germany included the cancellation of mass events (from March 8), closures of schools and child day care facilities (from March 16) as well as a “lockdown” (from March 23). This study attempts to assess the effectiveness of these interventions in terms of revealing their impact on infections over time.

Methods

Dates of infections were estimated from official German case data by incorporating the incubation period and an empirical reporting delay. Exponential growth models for infections and reproduction numbers were estimated and investigated with respect to change points in the time series.

Results

A significant decline of daily and cumulative infections as well as reproduction numbers is found at March 8 (CI [7, 9]), March 10 (CI [9, 11] and March 3 (CI [2, 4]), respectively. Further declines and stabilizations are found in the end of March. There is also a change point in new infections at April 19 (CI [18, 20]), but daily infections still show a negative growth. From March 19 (CI [18, 20]), the reproduction numbers fluctuate on a level below one.

Conclusions

The decline of infections in early March 2020 can be attributed to relatively small interventions and voluntary behavioural changes. Additional effects of later interventions cannot be detected clearly. Liberalizations of measures did not induce a re-increase of infections. Thus, the effectiveness of most German interventions remains questionable. Moreover, assessing of interventions is impeded by the estimation of true infection dates and the influence of test volume.
The human oral phageome is highly diverse and rich in jumbo phages
Authors: Carr Victoria R. , Shkoporov Andrey , Gomez-Cabrero David , Mullany Peter , Hill Colin , Moyes David L.
Published: July 2020

Until recently, the contribution of bacteriophages to the composition and function of the human microbiome has been largely overlooked. Recent developments in discovering novel bacteriophages from human metagenomes have been mostly focused on the gut. Here we profile and compare the phageome of 633 human oral sites and 221 paired gut phageomes acquired from countries worldwide. Phageome profiles are specific to oral sites and the gut across individuals, with the largest separation between the oral cavity and the gut. The differences in phage genotypes is bolstered by distinct phage host compositions between these sites. The greatest diversity of phages is found on the tongue and in dental plaque. Notably, 37 unique circular jumbo phage genomes were identified in oral sites, particularly on the dorsum of the tongue, whilst none were found in the gut. Oral sites provide conducive environments, such as robust biofilms, that can harbour genetically diverse phages.
Network analysis reveals how lipids and other cofactors influence membrane protein allostery
Authors: Westerlund Annie M. , Fleetwood Oliver , Perez-Conesa Sergio , Delemotte Lucie
Published: July 2020

Many membrane proteins are modulated by external stimuli, such as small molecule binding or change in pH, transmembrane voltage or temperature. This modulation typically occurs at sites that are structurally distant from the functional site. Revealing the communication, known as allostery, between these two sites is key to understanding the mechanistic details of these proteins. Residue interaction networks of isolated proteins are commonly used to this end. Membrane proteins, however, are embedded in a lipid bilayer which may contribute to allosteric communication. The fast diffusion of lipids hinders direct use of standard residue interaction networks. Here, we present an extension which includes cofactors such as lipids and small molecules in the network. The novel framework is applied to three membrane proteins: a voltage-gated ion channel (KCNQ1), a G-protein coupled receptor (GPCR -β2 adrenergic receptor) and a pH-gated ion channel (KcsA). Through systematic analysis of the obtained networks and their components, we demonstrate the importance of lipids for membrane protein allostery. Finally, we reveal how small molecules may stabilize different protein states by allosterically coupling and decoupling the protein from the membrane.
The role of icIL-1RA type 1 in oral keratinocyte senescence and the development of the senescence associated secretory phenotype
Authors: Niklander Sven E , Crane Hannah L , Darda Lav , Lambert Daniel W , Hunter Keith D
Published: July 2020

There is compelling evidence that senescent cells, through the senescence-associated secretory phenotype (SASP), can promote malignant transformation and invasion. IL-1 is a key mediator of this cytokine network, but the control of its activity in the senescence program has not been elucidated. IL-1 signalling is regulated by IL-1RA, which has four variants. Here, we show that expression of intracellular IL-1RA type 1 (icIL-1RA1), which competitively inhibits binding of IL-1 to its receptor, is progressively lost during oral carcinogenesisex vivoand that the pattern of expression is associated with keratinocyte replicative fatein vitro. We demonstrate icIL-1RA1 is an important regulator of the SASP in mortal cells, as CRISPR-CAS9 mediated icIL-1RA1 knockdown in normal and mortal dysplastic oral keratinocytes is followed by increased IL-6 and IL-8 secretion, and rapid senescence following release from ROCK inhibition. Thus, we suggest that downregulation of icIL-1RA1 in early stages of the carcinogenesis process can enable the development of a premature and de-regulated SASP, creating a pro-inflammatory state in which cancer is more likely to arise.
De novo formation of an early endosome during Rab5 to Rab7 transition
Authors: Skjeldal Frode Miltzow , Haugen Linda Hofstad , Mateus Duarte , Frei Dominik , Bakke Oddmund
Published: July 2020

Rab5 and Rab7a are the main determinants of early and late endosomes and are important regulators of endosomal progression. The transport from early endosomes to late endosome seems to be regulated through an endosomal maturation switch where Rab5 is exchanged with Rab7a on the same endosome. Here we provide new insight into the mechanism of endosomal maturation where we have discovered a stepwise Rab5 detachment, sequentially regulated by Rab7a. The initial detachment of Rab5 is Rab7a independent and demonstrate a diffusion-like exchange between cytosol and endosomal membrane, and the second phase is slower where Rab5 converges into a specific domain that specifically detaches as a Rab5 indigenous endosome. Consequently, we show that early endosomal maturation regulated through the Rab5 to Rab7a switch induce the formation of a new fully functional early endosome. Progression through a stepwise early endosomal maturation regulates the direction of the transport and concomitantly regulates the homeostasis of early endosomes.
Strategic stakeholders’ typology and mapping using stakeholder network analyses on integrated crops-livestock farming systems in West New Guinea
Authors: Iyai Deny Anjelus , Widayati Isti , Fatem Hendrik , Nurhayati Dwi , Arim Maria , Monim Hanike , Ronsumbre Adolof , Baaka Alnita , Orisu Lily , Saragih Desni T.R. , Syufi Yafet , Nuhuyanan Lambertus E. , Woran Djonly , Mofu Wolfram , Randa Sangle Y. , Sonbait Lukas Y. , Arizona Rizki , Baransano Michael , Seseray Daniel , Pattiselanno Freddy , Yaku Alexander , Koibur Johan
Published: July 2020

Stakeholders and its network play prominent roles in development particularly agriculture sector. The involvement of many stakeholders and other parties shaped how farms can sustain in terms of economic, social and environment indicators. Exploring the importance and roles of actors become strategic and vital to recognize. Study was done in Manokwari using focus group discussion towards twenty various represented individuals, groups and mass institutions. The queries discussed concerning background, resources delivery, interconnectivity amongst actors, intervention and innovation. The finding is that the stakeholders in mixed crop-livestock are dominated by individuals’ actors who privately manage the farms officially has laws. These actors are commonly act like stakeholders who are positively important ruled the farms. The threats are real and exist and should be lowering as much as possible to mitigate the turn-back effect. The top five shared resources are access, satisfaction, power, knowledge and time allocation. Those resources will stay longer to sustain strong needs of the farms. The relationship of actors is dominated by positive similarity and the ranges of correlation are varying in between negative, neutral to positive. This is due to actors reluctant to deliver the intervention and innovation. Actors with low interest and low power should then be promote to high interest and power by using aids, guidance and services from each actor in mixed crop-livestock farms business.
Toxoplasma gondiiPPM3C, a secreted protein phosphatase, affects parasitophorous vacuole effector export
Authors: Mayoral Joshua A. , Tomita Tadakimi , Tu Vincent , Aguilan Jennifer T. , Sidoli Simone , Weiss Louis M.
Published: July 2020

Toxoplasma gondiiis a highly successful parasite that infects a significant portion of the human population. As an intracellular parasite,T. gondiithrives within many different cell types due to its residence in the parasitophorous vacuole, a specialized and heavily modified compartment in which parasites divide. Within this vacuole, numerous secreted proteins facilitate functions that optimize intracellular survival. We characterized one such protein, TgPPM3C, which is predicted to contain a domain belonging to the PP2C class of serine/threonine phosphatases and is secreted by both tachyzoites and differentiating bradyzoites into the vacuolar lumen. Genetic deletion of TgPPM3C established that parasites lacking this predicted phosphatase exhibit a minor growth defectin vitro, are avirulent during acute infection in mice, and form fewer cysts in mouse brain during chronic infection. A label-free phosphoproteomic approach was utilized to identify putative TgPPM3C substrates and demonstrated several secreted proteins with altered phosphorylation status in the absence of TgPPM3C. Altered phosphorylation status was seen in MYR1, a protein essential to the process of protein effector export from the parasitophorous vacuole into the host cell, and in GRA16 and GRA28, two exported effector proteins. Defects were seen in the export of GRA16 and GRA28, but not the effector TgIST, in the TgPPM3C knockout strain. Parasites lacking TgPPM3C also exhibited defects in host c-Myc induction, a process influenced by effector export. Phosphomimetic mutations of GRA16 serine residues recapitulated export defects, implicating de-phosphorylation as an important process in facilitating the export of GRA16. These findings provide an example of the emerging critical role that phosphatases play in regulating the complex environment of theT. gondiiparasitophorous vacuole.
Identification of a conserved virion-stabilizing network inside the interprotomer pocket of enteroviruses
Authors: Flatt Justin W. , Domanska Aušra , Seppälä Alma L. , Butcher Sarah J.
Published: July 2020

Major efforts have been underway to develop broad-spectrum high potency capsid binders that inhibit the life cycle of enteroviruses, a large group (familyPicornaviridae) whose members include poliovirus, coxsackieviruses, echoviruses, numbered enteroviruses, and rhinoviruses. These diverse viruses cause a wide variety of illnesses, ranging from the mild common cold to hand-foot-and-mouth disease, myocarditis, pancreatitis, aseptic meningitis, and encephalitis. So-called classical capsid binders target a surface exposed hydrophobic pocket in one of the viral coat proteins (VP1) to prevent the genome uncoating process. However, efficacy, toxicity, emergence of drug-resistant viruses, and existence of certain enteroviral species that lack the VP1 pocket limit their clinical benefit. Recently, we identified a new druggable site at a conserved interface formed by multiple capsid proteins, the VP1-VP3 interprotomer pocket. To further study the properties that confer druggability at this site, we have determined high-resolution cryo-electron microscopy structures of two enteroviruses, coxsackieviruses B3 and B4, complexed with interprotomer-targeting compounds, CP17 and CP48 respectively. Until now, there has been no structure available for Coxsackievirus B4 despite the fact that the virus has long been implicated in the development of insulin-dependent diabetes mellitus. At better than 3 Å resolution, we could identify the detailed interactions that facilitate ligand binding. Both compounds target the same three conserved residues, each from a different polypeptide chain, to form a virion-stabilizing network inside the pocket. We measured the in silico binding energy for both inhibitors when anchored to the network and found a global stabilizing effect on the order of thousands of kcal/mol under saturating conditions (60 total sites per virion). Intriguingly, a recent X-ray structure has revealed that glutathione targets the same network within the interprotomer site of bovine enterovirus F3, where it is thought to facilitate virus assembly. In summary, our findings provide the structural basis for how a newly designed class of capsid binders target and stabilize enteroviruses. Future efforts to chemically optimize drugs for enhanced targeting to the interprotomer pocket is a promising endeavor in the fight against enteroviruses, especially given the possibility of synergistic effects when used in combination with classical VP1 binders like pleconaril.
Identification of VIMP as a gene inhibiting cytokine production in human CD4+ effector T cells
Authors: Capelle Christophe , Zeng Ni , Danileviciute Egle , Rodrigues Sabrina Freitas , Ollert Markus , Balling Rudi , He Feng Q.
Published: July 2020

Many players regulating the CD4+T cell-mediated inflammatory response have already been identified. However, the critical nodes that constitute the regulatory and signalling networks underlying CD4 T cell responses are still missing. Using a correlation network-guided strategy based on time-series transcriptome data of human CD4+CD25-effector T cells (Teffs), here we identifiedVIMP(VCP-interacting membrane protein), one of the 25 genes encoding selenocysteine in humans, as a gene regulating the effector functions of human CD4 T cells. Knocking-downVIMPin Teffs enhanced their proliferation and expression of several cytokines, including IL-2 and CSF2. We identified VIMP as an endogenous inhibitor of cytokine production in Teffs via both, the E2F5 transcription regulatory pathway and the Ca2+/NFATC2 signalling pathway. Our work not only indicates that VIMP might be a promising therapeutic target for various diseases involving CD4 T cells, but also shows that our network-guided approach might be generally applicable to different types of cells and can significantly aid in predicting new functions of the genes of interest.

One-sentence summary

Using a network-guided approach, we identified that Selenoprotein S (SELS or VIMP) negatively regulates cytokine expression of human CD4+ effector T cells via the E2F5 and calcium Ca2+/NFATC2 pathways.
Global analysis of transcription start sites in the new ovine reference genome (Oar rambouillet v1.0)
Authors: Salavati Mazdak , Caulton Alex , Clark Richard , Gazova Iveta , Smith Timothy P. L. , Worley Kim C. , Cockett Noelle E. , Archibald Alan L. , Clarke Shannon M. , Murdoch Brenda M. , Clark Emily L. ,   on behalf of The Ovine FAANG Project Consortium
Published: July 2020

The overall aim of the Ovine FAANG project is to provide a comprehensive annotation of the new highly contiguous sheep reference genome sequence (Oar rambouillet v1.0). Mapping of transcription start sites (TSS) is a key first step in understanding transcript regulation and diversity. Using 56 tissue samples collected from the reference ewe Benz2616 we have performed a global analysis of TSS and TSS- Enhancer clusters using Cap Analysis Gene Expression (CAGE) sequencing. CAGE measures RNA expression by 5’ cap-trapping and has been specifically designed to allow the characterization of TSS within promoters to single-nucleotide resolution. We have adapted an analysis pipeline that uses TagDust2 for clean-up and trimming, Bowtie2 for mapping, CAGEfightR for clustering and the Integrative Genomics Viewer (IGV) for visualization. Mapping of CAGE tags indicated that the expression levels of CAGE tag clusters varied across tissues. Expression profiles across tissues were validated using corresponding polyA+ mRNA-Seq data from the same samples. After removal of CAGE tags with < 10 read counts, 39.3% of TSS overlapped with 5’ ends of 31,113 transcripts that had been previously annotated by NCBI (out of a total of 56,308 from the NCBI annotation). For 25,195 of the transcripts, previously annotated by NCBI, no TSS meeting stringent criteria were identified. A further 14.7% of TSS mapped to within 50bp of annotated promoter regions. Intersecting these predicted TSS regions with annotated promoter regions (±50bp) revealed 46% of the predicted TSS were ‘novel’ and previously un-annotated. Using whole genome bisulphite sequencing data from the same tissues we were able to determine that a proportion of these ‘novel’ TSS were hypo-methylated (32.2%) indicating that they are likely to be reproducible rather than ‘noise’. This global analysis of TSS in sheep will significantly enhance the annotation of gene models in the new ovine reference assembly. Our analyses provide one of the highest resolution annotations of transcript regulation and diversity in a livestock species to date.
Single cell analysis of FOXP3 deficiencies in humans and mice unmasks intrinsic and extrinsic CD4+T cell perturbations
Authors: Zemmour David , Charbonnier Louis-Marie , Leon Juliette , Six Emmanuelle , Keles Sevgi , Delville Marianne , Baris Safa , Zuber Julien , Chen Karin , Neven Benedicte , Garcia-Lloret Maria I , Ruemmele Franck , Brugnara Carlo , Cerf-Bensussan Nadine , Rieux-Laucat Frederic , Cavazzana Marina , André Isabelle , Chatila Talal A. , Mathis Diane , Benoist Christophe
Published: July 2020

FOXP3deficiency in humans with IPEX syndrome and mice results in fatal systemic autoimmunity by altering regulatory T cell (Treg) physiology, but actual cellular and molecular mechanisms of disease are unclear, part because Treg surface markers may be unreliable in disease states. We used deep profiling by flow cytometry, population and single-cell RNAseq to analyze Tregs and conventional (Tconv) CD4+ T lymphocytes in cohorts of IPEX patients with a range of genetic lesions, and inFoxp3-deficient mice. In all patients and mice, heterogeneous Treg-like cells with an activeFOXP3locus were observed, some differing very little from normal Tregs, others more distant. Tconv showed no widespread activation or Th bias. The dominant mark was a monomorphic signature equally affecting all CD4+T cells, unexpectedly dampening tumor-Treg and cytokine-signaling modules. In mixed bone marrow chimeras, WT Tregs exerted dominant suppression, normalizing the states of mutant Treg and Tconv, extinguishing the disease signature, and revealing a small gene cluster truly regulated, cell-intrinsically, by FOXP3. These results suggest a two-step pathogenesis model, with therapeutic implications: limited downregulation of a few core Treg genes de-represses a systemic mediator(s), which imprints the disease signature on all T cells, and further dampens Treg function.
Can the occipital alpha-phase speed up visual detection through a real-time EEG-based brain-computer interface (BCI)?
Authors: Vigué-Guix Irene , Fernández Luis Morís , Cuello Mireia Torralba , Ruzzoli Manuela , Soto-Faraco Salvador
Published: July 2020

Electrical brain oscillations reflect fluctuations in neural excitability. Fluctuations in the alpha band (α, 8-12 Hz) in the occipito-parietal cortex are thought to regulate sensory responses, leading to cyclic variations in visual perception. Inspired by this theory, some past and recent studies have addressed the relationship between α-phase from extra-cranial EEG and behavioural responses to visual stimuli in humans. The latest studies have usedofflineapproaches to confirm α-gated cyclic patterns. However, a particularly relevant implication is the possibility to use this principleonlinefor real-time neurotechnology, whereby stimuli are time-locked to specific α-phases leading to predictable outcomes in performance. Here we aimed at providing a proof-of-concept for such real-time neurotechnology. Participants performed a speeded response task to visual targets that were presented upon a real-time estimation of the α-phase via an EEG closed-loop brain-computer interface (BCI). We predicted, according to the theory, a modulation of reaction times (RTs) along the α-cycle. Our BCI system achieved reliable trial-to-trial phase-locking of stimuli to the phase of individual occipito-parietal α-oscillations. Yet, the behavioural results did not support a consistent relation between RTs and the phase of the α-cycle neither at group nor single participant levels. We must conclude that although the α-phase might play a role in perceptual decisions from a theoretical perspective, its impact on EEG-based BCI application appears negligible.
Insights into gene expression changes under conditions that facilitate horizontal gene transfer (mating) of a model Archaeon
Authors: Makkay Andrea M. , Louyakis Artemis S. , Ram-Mohan Nikhil , Gophna Uri , Gogarten J. Peter , Papke R. Thane
Published: July 2020

Horizontal gene transfer is a means by which bacteria, archaea, and eukaryotes are able to trade DNA within and between species. While there are a variety of mechanisms through which this genetic exchange can take place, one means prevalent in the archaeonHaloferax volcaniiinvolves the transient formation of cytoplasmic bridges between cells and is referred to as mating. This process can result in the exchange of very large fragments of DNA between the participating cells. Genes governing the process of mating, including triggers to initiate mating, mechanisms of cell fusion, and DNA exchange, have yet to be characterized. We used a transcriptomic approach to gain a more detailed knowledge of how mating might transpire. By examining the differential expression of genes expressed in cells harvested from mating conditions on a filter over time and comparing them to those expressed in a shaking culture, we were able to identify genes and pathways potentially associated with mating. These analyses provide new insights into both the mechanisms and barriers of mating inHfx. volcanii.
Comparison of three TaqMan Real-Time Reverse Transcription-PCR assays in detecting SARS-CoV-2
Authors: Xiao Yan , Li Zhen , Wang Xinming , Wang Yingying , Wang Ying , Wang Geng , Ren Lili , Li Jianguo
Published: July 2020

Quick and accurate detection of SARS-CoV-2 is critical for COVID-19 control. Dozens of real-time reverse transcription PCR (qRT-PCR) assays have been developed to meet the urgent need of COVID-19 control. However, methodological comparisons among the developed qRT-PCR assays are limited. In the present study, we evaluated the sensitivity, specificity, amplification efficiency, and linear detection ranges of three qRT-PCR assays, including the assays developed by our group (IPBCAMS), and the assays recommended by WHO and China CDC (CCDC). The three qRT-PCR assays exhibited similar sensitivities, with the limit of detection (LOD) at about 10 copies per reaction (except the ORF 1b gene assay in CCDC assays with a LOD at about 100 copies per reaction). No cross reaction with other respiratory viruses were observed in all of the three qRT-PCR assays. Wide linear detection ranges from 106to 101copies per reaction and acceptable reproducibility were obtained. By using 25 clinical specimens, the N gene assay of IPBCAMS assays and CCDC assays performed better (with detection rates of 92% and 100%, respectively) than that of the WHO assays (with a detection rate of 60%), and the ORF 1b gene assay in IPBCAMS assays performed better (with a detection rate of 64%) than those of the WHO assays and the CCDC assays (with detection rates of 48% and 20%, respectively). In conclusion, the N gene assays of CCDC assays and IPBCAMS assays and the ORF 1b gene assay of IPBCAMS assays were recommended for qRT-PCR screening of SARS-CoV-2.
Role of sex and high fat diet in metabolic and hypothalamic disturbances in the 3xTg-AD mouse model of Alzheimer’s disease
Authors: Robison Lisa. S. , Gannon Olivia J. , Thomas Melissa A. , Salinero Abigail E. , Abi-Ghanem Charly , Poitelon Yannick , Belin Sophie , Zuloaga Kristen L.
Published: July 2020

Hypothalamic dysfunction occurs early in the clinical course of Alzheimer’s disease (AD), likely contributing to disturbances in feeding behavior and metabolic function that are often observable years prior to the onset of cognitive symptoms. Late-life weight loss and low BMI are associated with increased risk of dementia and faster progression of disease. However, high fat diet and metabolic disease (e.g. obesity, type 2 diabetes), particularly in mid-life, are associated with increased risk of AD, as well as exacerbated AD pathology and behavioral deficits in animal models. In the current study, we explored possible relationships between hypothalamic function, diet/metabolic status, and AD. Considering the sex bias in AD, with women representing two-thirds of AD patients, we sought to determine whether these relationships vary by sex. WT and 3xTg-AD male and female mice were fed a control (10% fat) or high fat (HF; 60% diet) diet from ~3-7 months of age, then tested for metabolic and hypothalamic disturbances. On control diet, male 3xTg-AD mice displayed decreased body weight, reduced fat mass, hypoleptinemia, and mild systemic inflammation, as well as increased expression of gliosis- and inflammation-related genes in the hypothalamus (Iba1, GFAP, TNF-α, IL-1β). In contrast, female 3xTg-AD mice on control diet displayed metabolic disturbances opposite that of 3xTg-AD males (increased body and fat mass, impaired glucose tolerance). HF diet resulted in expected metabolic alterations across groups (increased body and fat mass; glucose intolerance; increased plasma insulin and leptin, decreased ghrelin; nonalcoholic fatty liver disease-related pathology). HF diet resulted in the greatest weight gain, adiposity, and glucose intolerance in 3xTg-AD females, which were associated with markedly increased hypothalamic expression of GFAP and IL-1β, as well as GFAP labeling in several hypothalamic nuclei that regulate energy balance. In contrast, HF diet increased diabetes markers and systemic inflammation preferentially in AD males but did not exacerbate hypothalamic inflammation in this group. These findings provide further evidence for the roles of hypothalamic and metabolic dysfunction in AD, which in the 3xTg-AD mouse model appears to be dependent on both sex and diet.
Multiple genetic pathways regulating lifespan extension are neuroprotective in a G2019S LRRK2 nematode model of Parkinson’s disease
Authors: Senchuk Megan M. , Van Raamsdonk Jeremy M. , Moore Darren J.
Published: July 2020

Background

Mutations in theleucine-rich repeat kinase 2(LRRK2) gene are the most frequent cause of late-onset, familial Parkinson’s disease (PD), andLRRK2variants are associated with increased risk for sporadic PD. While advanced age represents the strongest risk factor for disease development, it remains unclear how different age-related pathways interact to regulateLRRK2-driven late-onset PD.

Findings

In this study, we employ aC.elegansmodel expressing PD-linked G2019S LRRK2 to examine the interplay between age-related pathways and LRRK2-induced dopaminergic neurodegeneration. We find that multiple genetic pathways that regulate lifespan extension can provide robust neuroprotection against mutant LRRK2. However, the level of neuroprotection does not strictly correlate with the magnitude of lifespan extension, suggesting that lifespan can be experimentally dissociated from neuroprotection. Using tissue-specific RNAi, we demonstrate that lifespan-regulating pathways, including insulin/IGF-1 signaling, TOR, and mitochondrial respiration, can be directly manipulated in neurons to mediate neuroprotection. We extend this finding for AGE-1/PI3K, where pan-neuronal versus dopaminergic neuronal restoration of AGE-1 reveals both cell-autonomous and non-cell-autonomous neuroprotective mechanisms downstream of insulin signaling.

Conclusions

Our data demonstrate the importance of distinct lifespan-regulating pathways in the pathogenesis ofLRRK2-linked PD, and suggest that extended longevity is broadly neuroprotective via the actions of these pathways at least in part within neurons. This study further highlights the complex interplay that occurs between cells and tissues during organismal aging and disease manifestation.
Increasing growth temperature alters the within-host competition of viral strains and influences virus genetic variation
Authors: Alcaide Cristina , Sardanyés Josep , Elena Santiago F. , Gómez Pedro
Published: July 2020

The emergence of viral diseases in plant crops hamper the sustainability of food production, and this may be boosted by global warming. Concurrently, mixed viral infections are becoming common in plants, of which epidemiology are unpredictable due to within-host virus-virus interactions. However, the extent in which the combined effect of variations in the abiotic components of the plant ecological niche (e.g., temperature) and the prevalence of mixed infections (i.e., within-host interactions among viruses) affect the evolutionary dynamics of viral populations is not well understood. Here, we explore the interplay between ecological and evolutionary factors during viral infections, and show that two individual strains of pepino mosaic virus (PepMV) coexisted in a temperature-dependent continuum between neutral and antagonistic interactions in tomato plants. After a long-term infection, the mutational analysis of the evolved viral genomes revealed strain-specific single-nucleotide polymorphisms that were modulated by the interaction between the type of infection and temperature. Mathematical modeling allowed us to asses a thermal reaction norm for both strains, which indicated that viral replication rates were increased along with increasing temperature in mixed infections, with a remarkable strain-dependent effect. These results suggest that the growth temperature is an ecological driver of virus-virus interactions, with an effect on the genetic diversity of individual viruses co-infecting a host. This research provides insights into the effect that climate change will have on the evolutionary dynamics of viral populations.
Novel tunable spatio-temporal patterns from a simple genetic oscillator circuit
Authors: Yáñez Feliú Guillermo , Vidal Gonzalo , Muñoz Silva Macarena , Rudge Timothy J.
Published: July 2020

Multicellularity, the coordinated collective behaviour of cell populations, gives rise to the emergence of self-organized phenomena at many different spatio-temporal scales. At the genetic scale, oscillators are ubiquitous in regulation of multicellular systems, including during their development and regeneration. Synthetic biologists have successfully created simple synthetic genetic circuits that produce oscillations in single cells. Studying and engineering synthetic oscillators in a multicellular chassis can therefore give us valuable insights into how simple genetic circuits can encode complex multicellular behaviours at different scales. Here we develop a study of the coupling between the repressilator synthetic genetic ring oscillator and constraints on cell growth in colonies. We show in silico how mechanical constraints generate characteristic patterns of growth rate inhomogeneity in growing cell colonies. Next, we develop a simple one-dimensional model which predicts that coupling the repressilator to this pattern of growth rate via protein dilution generates travelling waves of gene expression. We show that the dynamics of these spatio-temporal patterns are determined by two parameters; the protein degradation and maximum expression rates of the repressors. We derive simple relations between these parameters and the key characteristics of the travelling wave patterns: firstly, wave speed is determined by protein degradation and secondly, wavelength is determined by maximum gene expression rate. Our analytical predictions and numerical results were in close quantitative agreement with detailed individual based simulations of growing cell colonies. Confirming published experimental results we also found that static ring patterns occur when protein stability is high. Our results show that this pattern can be induced simply by growth rate dilution and does not require transition to stationary phase as previously suggested. Our method generalizes easily to other genetic circuit architectures thus providing a framework for multi-scale rational design of spatio-temporal patterns from genetic circuits. We use this method to generate testable predictions for the synthetic biology design-build-test-learn cycle.
The fragile X mental retardation protein promotes adjustments in cocaine self-administration that preserve reinforcement level
Authors: Huebschman Jessica L. , Davis Megan C. , Pensa Catherina Tovar , Guo Yuhong , Smith Laura N.
Published: July 2020

The fragile X mental retardation protein (FMRP), an RNA-binding protein, regulates cocaine-induced neuronal plasticity and is critical for the normal development of drug-induced locomotor sensitization, as well as reward-related learning in the conditioned place preference assay. However, it is unknown whether FMRP impacts behaviors that are used to more closely model substance use disorders. Utilizing an intravenous cocaine self-administration (IVSA) assay inFmr1knockout (KO) and wild type (WT) littermate mice, we find that, despite normal acquisition and extinction learning,Fmr1KO mice fail to make a normal upward shift in responding during dose-response testing. Later, with access to the original acquisition dose under increasing schedules of reinforcement (FR1, FR3, FR5),Fmr1KO mice earn significantly fewer cocaine infusions than WT mice. Importantly, operant conditioning with a palatable food reinforcer does not show similar deficits, indicating that our results do not stem from broad learning or reward-related deficits inFmr1KO mice. Additionally, we find an FMRP target, the activity-regulated cytoskeleton-associated protein (Arc), to be significantly reduced inFmr1KO mouse synaptic fractions from the nucleus accumbens following cocaine IVSA. Overall, our findings suggest that FMRP facilitates adjustments in drug self-administration behavior that generally serve to preserve reinforcement level, and combined with our similar IVSA findings inArcKO mice, suggest Arc as a target of FMRP to investigate in behavioral shifts that occur when drug availability is altered.
Adherence to Pakistan dietary guidelines – Findings from major cities of Pakistan
Authors: Rafique Ibrar , Muhammad Arif Nadeem Saqib , Murad Nighat , Munir Muhammad Kashif , Khan Aftab , Irshad Rabia , Rahat Tayyaba , Naz Saima
Published: July 2020

Background

Pakistan dietary guidelines for better nutrition were developed to cater the local need and prevent nutritional deficiency by providing information to public about healthy eating practices.

Aims

To assess the level of adherence to Pakistan Dietary Guidelines for Better Nutrition (PDGN)

Methods

It was a community based study conducted in five cities with two stage stratified sampling approach. Total of 448 participants were interviewed using Food frequency questionnaire adapted to local context. Five food groups (proteins, cereals, dairy, vegetables and fruits) were taken as per country guidelines. A score point of 1 was given to each food group making a total of 5 scores. Data were analyzed using SPSS.

Results

Overall adherence to PDGN was poor as none of the participants had 05 score while only 1% achieved score 04. However, adherence was more in females (B = 0.45, 95%CI = 0.24; 0.66), graduates (B = 0.45, 95% CI = 0.25; 0.64), unmarried (B = 0.30, 95% CI = 0.18; 0.43), unemployed (B = 0.22, 95% CI = 0.01-0.43) and aged >50 years (B = 0.34, 95% CI = 0.08; 0.60) as compared to others. Among food groups, mean intake of cereals (carbohydrates) was high (3.38±1.39) followed by other items with fruits was least (0.76±0.91). Overall, at least one serving of discretionary food was taken by participants which was more female gender (p= 0.001), graduates (p= 0.003), high socio-economic group (p=0.001) and employed persons (p= 0.04).

Conclusion

The adherence to PDGN was poor and there is a need to bring behavior change by information education and communication to the society.
COVID-19-related Fake News in Social Media
Authors: Al-Zaman Md. Sayeed
Published: July 2020

This study analyzes N=125 prominent fake news related to the COVID-19 pandemic spread in social media from 29 January to 11 April 2020. The five parameters of the analysis are themes, content types, sources, coverage, and intentions. First, the six major themes of fake news are health, religiopolitical, political, crime, entertainment, religious, and miscellaneous. Health-related fake news (67.2%) dominates the others. Second, the seven types of fake news contents have four main types: text, photo, audio and video, and three combined types: text & photo; text & video; and text & photo & video. More fake news takes the forms of text & video (47.2%), while the main types of content are less popular. Third, the two main sources of fake news are online media and mainstream media, where online-produced fake news (94.4%) prevails. Fourth, the main two types of coverages are international and national, and more fake news has an international connection (54.4%). Fifth, the intention of fake news has three types: positive, negative, and unknown. Most of the COVID-19-related fake news is negative (63.2%). Although fake news cases are unevenly distributed and repeatedly fluctuates during the period, a slow decrease of daily cases is noticed toward the end.
Does sub-Saharan Africa truly defy the forecasts of the COVID-19 pandemic? Response from population data
Authors: Fokoua-Maxime Dongmo Christophe , Amor-Ndjabo Monique , Ankobil Amandus , Victor-Kiyung Momah , Franck-Metomb Steve , Choukem Simeon Pierre
Published: July 2020

Introduction

Since its identification, the COVID-19 infection has caused substantial mortality and morbidity worldwide, but sub-Saharan Africa seems to defy the predictions. We aimed to verify this hypothesis using strong statistical methods.

Methods

We conducted a cross-sectional study comparing the projected and actual numbers as well as population proportions of COVID-19 cases in the 46 sub-Saharan African countries on May 1st, May 29th (4 weeks later) and June 26th (8 weeks later). The source of the projected number of cases was a publication by scientists from the Center for Mathematical Modeling of Infectious Diseases of the London School of Hygiene & Tropical Medicine, whereas the actual number of cases was obtained from the WHO situation reports. We calculated the percentage difference between the projected and actual numbers of cases per country. Further, “N-1” chi-square tests with Bonferroni correction were used to compare the projected and actual population proportion of COVID-19 cases, along with the 95% confidence interval of the difference between these population proportions. All statistical tests were 2-sided, with 0.05 used as threshold for statistical significance.

Results

On May 1st, May 29th and June 26th, respectively 40 (86.95%), 45 (97.82%) and 41 (89.13%) of the sub-Saharan African countries reported a number of confirmed cases that was lower than the predicted number of 1000 cases for May 1st and 10000 for both May 29th and June 26th. At these dates, the population proportions of confirmed Covid-19 cases were significantly lower (p-value <0.05) than the projected proportions of cases. Across all these dates, South-Africa always exceeded the predicted number and population proportion of COVID-19 infections.

Conclusion

Sub-Saharan African countries did defy the dire predictions of the COVID-19 burden. Preventive measures should be further enforced to preserve this positive outcome.
Predicting the second wave of COVID-19 in Washtenaw County, MI
Authors: Renardy Marissa , Kirschner Denise
Published: July 2020

The COVID-19 pandemic has highlighted the patchwork nature of disease epidemics, with infection spread dynamics varying wildly across countries and across states within the US. These heterogeneous patterns are also observed within individual states, with patches of concentrated outbreaks. Data is being generated daily at all of these spatial scales, and answers to questions regarded reopening strategies are desperately needed. Mathematical modeling is useful in exactly these cases, and using modeling at a county scale may be valuable to further predict disease dynamics for the purposes of public health interventions. To explore this issue, we study and predict the spread of COVID-19 in Washtenaw County, MI, the home to University of Michigan, Eastern Michigan University, and Google, as well as serving as a sister city to Detroit, MI where there has been a serious outbreak. Here, we apply a discrete and stochastic network-based modeling framework allowing us to track every individual in the county. In this framework, we construct contact networks based on synthetic population datasets specific for Washtenaw County that are derived from US Census datasets. We assign individuals to households, workplaces, schools, and group quarters (such as prisons). In addition, we assign casual contacts to each individual at random. Using this framework, we explicitly simulate Michigan-specific government-mandated workplace and school closures as well as social distancing measures. We also perform sensitivity analyses to identify key model parameters and mechanisms contributing to the observed disease burden in the three months following the first observed cases on COVID-19 in Michigan. We then consider several scenarios for relaxing restrictions and reopening workplaces to predict what actions would be most prudent. In particular, we consider the effects of 1) different timings for reopening, and 2) different levels of workplace vs. casual contact re-engagement. Through simulations and sensitivity analyses, we explore mechanisms driving magnitude and timing of a second wave of infections upon re-opening. This model can be adapted to other US counties using synthetic population databases and data specific to those regions.
Finding Rare Disease Patients in EHR Databases via Lightly-Supervised Learning
Authors: Colbaugh Rich , Glass Kristin
Published: July 2020

There is considerable interest in developing computational models capable of detecting rare disease patients in population-scale databases such as electronic health records (EHRs). Deriving these models is challenging for several reasons, perhaps the most daunting being the limited number of already-diagnosed, ‘labeled’ patients from which to learn. We overcome this obstacle with a novel lightly-supervised algorithm that leverages unlabeled and/or unreliably-labeled patient data – which is typically plentiful – to facilitate model induction. Importantly, we prove the algorithm issafe:adding unlabeled/unreliably-labeled data to the learning procedure produces models which are usually more accurate, and guaranteed never to be less accurate, than models learned from reliably-labeled data alone. The proposed method is shown to substantially outperform state-of-the-art models in patient-finding experiments involving two different rare diseases and a country-scale EHR database. Additionally, we demonstrate feasibility of transforming high-performance models generated through light supervision into simpler models which, while still accurate, are readily-interpretable by non-experts.
Impact of Congestive Heart Failure and Role of Cardiac Biomarkers in COVID-19 patients: A Systematic Review and Meta-Analysis
Authors: Dalia Tarun , Lahan Shubham , Ranka Sagar , Acharya Prakash , Gautam Archana , Mastoris Ioannis , Sauer Andrew , Shah Zubair
Published: July 2020

Importance

Coronavirus disease 2019 (COVID-19) has been reported to cause worse outcomes in patients with underlying cardiovascular disease, especially in patients with acute cardiac injury, which is determined by elevated levels of high-sensitivity troponin. There is paucity of data on the impact of congestive heart failure (CHF) on outcomes in COVID-19 patients.

Objective

To evaluate the occurrence of acute cardiac injury and arrhythmias and to assess the impact of pre-existing CHF and hypertension (HTN) in COVID-19 patients.

Data Sources

We conducted a literature search of PubMed/Medline, EMBASE, and Google Scholar databases from 11/1/2019 till 06/07/2020. databases using following search terms or keywords: “(COVID) AND (Clinical); ((heart) OR (myocard*)) AND (COVID); (COVID) AND (Troponin); (Coronavirus) AND (Heart).”

Study Selection

We identified all relevant studies reporting cardiovascular comorbidities, cardiac biomarkers, disease severity, and survival in COVID-19 patients.

Data Extraction and Synthesis

We followed preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines for abstracting data. Pooled data was meta-analyzed using random-effects model and between-study heterogeneity was calculated with Higgins I2 statistic.

Main outcome and measures

To assess the impact of HTN and CHF and to evaluate different cardiac biomarkers in COVID-19 patients based on their disease severity.

Results

We collected pooled data on 5,967 COVID-19 patients from 20 individual studies. We found that both non-survivors and those with severe disease had an increased risk of acute cardiac injury and cardiac arrhythmias, our pooled relative risk (RR) was — 8.52 (95% CI 3.63– 19.98) (p<0.001); and 3.61 (95% CI 2.03–6.43) (p=0.001), respectively. Mean difference in the levels of Troponin-I, CK-MB, and NT-proBNP was higher in deceased and severely infected patients. The RR of in-hospital mortality was 2.35 (95% CI 1.18–4.70) (p=0.022) and 1.52 (95% CI 1.12–2.05) (p=0.008) among patients who had pre-existing CHF and hypertension, respectively.

Conclusion and Relevance

Cardiac involvement in COVID-19 infection appears to significantly adversely impact patient prognosis and survival. Pre-existence of CHF, and high cardiac biomarkers like NT-pro BNP and CK-MB levels in COVID-19 patients correlates with worse outcomes.
Modelling interventions to control COVID-19 outbreaks in a refugee camp
Authors: Gilman R. Tucker , Mahroof-Shaffi Siyana , Harkensee Christian , Chamberlain Andrew T.
Published: July 2020

Refugee camp populations are expected to be vulnerable to COVID-19 due to overcrowding, unsanitary conditions, and inadequate medical facilities. Because there has been no COVID-19 outbreak in a refugee camp to date, the potential for nonpharmaceutical interventions to slow the spread of COVID-19 in refugee camps remains untested. We used an agent-based model to simulate COVID-19 outbreaks in the Moria refugee camp, and we studied the effects of feasible interventions. Subdividing the camp (’sectoring’) “flattened the curve,” reducing peak infection by up to 70% and delaying peak infection by up to several months. The use of face masks coupled with efficient isolation of infected individuals reduced the overall incidence of infection and sometimes averted epidemics altogether. These interventions must be implemented quickly to be effective. Lockdowns had little effect on COVID-19 dynamics. Our findings provide an evidence base for camp managers planning intervention strategies against COVID-19 or future epidemics.