bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimizing testing for COVID-19 in India
Authors: Cherian Philip , Krishna Sandeep , Menon Gautam I.
Published: January 2021

COVID-19 testing across India uses a mix of two types of tests. Rapid Antigen Tests (RATs) are relatively inexpensive point-of-care lateral-flow-assay tests, but they are also less sensitive. The reverse-transcriptase polymerase-chain-reaction (RT-PCR) test has close to 100% sensitivity and specificity in a laboratory setting, but delays in returning results, as well as increased costs relative to RATs, may vitiate this advantage.

India-wide, about 49% of COVID-19 tests are RATs, but some Indian states, including the large states of Uttar Pradesh (pop. 227.9 million) and Bihar (pop. 121.3 million) use a much higher proportion of such tests. Here we show, using simulations based on epidemiological network models, that the judicious use of RATs can yield epidemiological outcomes comparable to those obtained through RT-PCR-based testing and isolation of positives, provided a few conditions are met. These are (a) that RAT test sensitivity is not too low, (b) that a reasonably large fraction of the population, of order 0.5% per day, can be tested, (c) that those testing positive are isolated for a sufficient duration, and that (d) testing is accompanied by other non-pharmaceutical interventions for increased effectiveness. We assess optimal testing regimes, taking into account test sensitivity and specificity, background seroprevalence and current test pricing. We find, surprisingly, that even 100% RAT test regimes should be acceptable, from both an epidemiological as well as a economic standpoint, provided the conditions outlined above are met.

Author summary

Using network models, we study optimal ways of combining low sensitivity, relatively inexpensive point-of-care rapid antigen tests for COVID-19 with higher sensitivity but more expensive laboratory RT-PCR tests. We take into account background seroprevalence and current test pricing for such tests in India, finding that even purely rapid antigen test-based regimes can produce the same reduction in overall infections that pure RT-PCR tests are capable of. This is provided one can test at scale and isolate those testing positive effectively, that the sensitivity of the rapid test is not too low and that non-pharmaceutical interventions proceed in parallel for increased effectiveness.
COVID-19 immunization threshold(s): an analysis
Authors: Bautista Balbás Luis Alfredo , Conesa Mario Gil , Balbás Blanca Bautista , Jiménez Ainhoa Alcaide , Rodríguez Caravaca Gil
Published: January 2021

2

As COVID-19 vaccine research efforts seem to be yielding the first tangible results, the proportion of individuals needed to reap the benefits of herd immunity is a key element from a Public Health programs perspective.

This magnitude, termed the critical immunization threshold (q), can be obtained from the classical SIR model equilibrium equation, equaling (1 − 1/R0)/ ϵ, where R0 is the basic reproduction number and ϵ is the vaccine efficacy. When a significant proportion of the population is already immune, this becomes (n − 1/R0)/ ϵ, where n is the proportion of non-immune individuals. A similar equation can be obtained for short-term immunization thresholds(qt), which are dependent on Rt.

qs for most countries are between 60-75% of the population. Current qt for most countries are between 20-40%.

Therefore, the combination of gradual vaccination and other non-pharmaceutical interventions will mark the transition to the herd immunity, providing that the later turns out to be a feasible objective. Nevertheless, immunization through vaccination is a complex issue and many challenges might appear.
A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and PDAC
Authors: Gopalan Vishaka , Singh Arashdeep , Rashidi Farid , Wang Li , Ruppin Eytan , Arda Efsun , Hannenhalli Sridhar
Published: January 2021

Pancreatic ductal adenocarcinoma (PDAC) tumors can originate either from acinar or ductal cells in the adult pancreas. We re-analyze multiple pancreas and PDAC single-cell RNA-seq datasets and find a subset of non-malignant acinar cells, which we refer to as acinar edge (AE) cells, whose transcriptomes highly diverge from a typical acinar cell in each dataset. Genes up-regulated among AE cells are enriched for transcriptomic signatures of pancreatic progenitors, acinar dedifferentiation, and several oncogenic programs. AE-upregulated genes are up-regulated in human PDAC tumors, and consistently, their promoters are hypo-methylated. High expression of these genes is associated with poor patient survival. The fraction of AE-like cells increases with age in healthy pancreatic tissue, which is not explained by clonal mutations, thus pointing to a non-genetic source of variation. We also find edge-like states in lung and liver tissues, suggesting that sub-populations of healthy cells across tissues can exist in pre-malignant states.
CcLBD25functions as a key regulator of haustorium development inCuscuta campestris
Authors: Jhu Min-Yao , Ichihashi Yasunori , Farhi Moran , Wong Caitlin , Sinha Neelima R.
Published: January 2021

Parasitic plants reduce yield of crops worldwide.Cuscuta campestrisis a stem parasite that attaches to its host, using haustoria to extract nutrients and water. We analyzed the transcriptome of sixC. campestristissues and identified a key gene,CcLBD25, as highly expressed in prehaustoria and haustoria. Our gene co-expression networks (GCN) from different tissue types and laser-capture microdissection (LCM) RNA-Seq data indicate thatCcLBD25could be essential for regulating cell wall loosening and organogenesis. We employed host-induced gene silencing (HIGS) by generating transgenic tomato hosts that express hairpin RNAs to target and down-regulateCcLBD25in the parasite. Our results showed thatC. campestrisgrowing onCcLBD25RNAi transgenic tomatoes transited to the flowering stage earlier and had less biomass compared withC. campestrisgrowing on wild type host. This suggests that the parasites growing on the transgenic plants were stressed due to insufficient nutrient acquisition. Anatomy ofC. campestrishaustoria growing onCcLBD25RNAi tomatoes showed reduced pectin digestion and lack of searching hyphae, which interfered with haustorium penetration and the formation of vascular connections. We developed anin vitrohaustorium (IVH) system to assay the number of prehaustoria produced on strands fromC. campestris. WhenC. campestriswas grown onCcLBD25RNAi tomatoes or wild type tomatoes, the former produce fewer prehaustoria than the latter, indicating that down-regulatingCcLBD25may affect haustorium initiation. The results of this study shed light on the role ofCcLBD25in haustorium development and might help to develop a parasite-resistant system in crops.

One-sentence summary

CcLBD25plays a pivotal role in haustorium initiation, regulating pectin digestion, and searching hyphae development during the haustorium penetration process.
All-Flesh Tomato Regulated by Reduced Dosage ofAFFProvides New Insights into Berry Fruit Evolution
Authors: Liu Lei , Zhang Kang , Bai JinRui , Lu Jinghua , Lu Xiaoxiao , Hu Junling , Pan Chunyang , He Shumin , Yuan Jiale , Zhang Yiyue , Zhang Min , Guo Yanmei , Wang Xiaoxuan , Huang Zejun , Du Yongchen , Cheng Feng , Li Junming
Published: January 2021

The formation of locule gel is not only an important developmental process in tomato but also a typical characteristic of berry fruit. In this study, we collected a tomato material that produces all-flesh fruits (AFF), whose locule tissue remains in a solid state during fruit development. We built genetic populations to fine map the causal gene of AFF trait, investigate the function ofAFFgene, and identified it as the causal locus conferring the locule gel formation. We determined the causal mutation as a 416-bp deletion that occurred in the promoter region ofAFF, which reduces the expression dosage ofAFF. The 416-bp deleted sequence has a high level of conservation among closely related Solanaceae species, as well as in the tomato population. The activity of the 416-bp deletion in down-regulating gene expression was further verified by the relative activity in a luciferase experiment. Furthermore, with the BC6 NIL materials, we reveal that the reduced expression dosage ofAFFdoes not impact the normal development of seeds, while produces non-liquefied locule tissue, which is distinct from that of the normal tomatoes in terms of metabolic components. Based on these findings, we propose that theAFFgene is the core node in locule tissue liquefaction, whose function cannot be compensated by its paralogsTAG1, TAGL1, orTAGL11. Our findings provide clues to investigate fruit type differentiation among Solanaceae crops, and also contributes to the breeding application of all flesh fruit tomatoes for the tomato processing industry.

One Sentence Summary

The sequence deletion that occurred in the cis-regulatory region ofAFF—the core node of locule tissue liquefaction determined here—reduced its expression dosage, and produced all flesh fruit tomato.
debar, a sequence-by-sequence denoiser for COI-5P DNA barcode data
Authors: Nugent Cameron M. , Elliott Tyler A. , Ratnasingham Sujeevan , Hebert Paul D. N. , Adamowicz Sarah J.
Published: January 2021

DNA barcoding and metabarcoding are now widely used to advance species discovery and biodiversity assessments. High-throughput sequencing (HTS) has expanded the volume and scope of these analyses, but elevated error rates introduce noise into sequence records that can inflate estimates of biodiversity. Denoising —the separation of biological signal from instrument (technical) noise—of barcode and metabarcode data currently employs abundance-based methods which do not capitalize on the highly conserved structure of the cytochromecoxidase subunit I (COI) region employed as the animal barcode. This manuscript introduces debar, an R package that utilizes a profile hidden Markov model to denoise indel errors in COI sequences introduced by instrument error. In silico studies demonstrated that debar recognized 95% of artificially introduced indels in COI sequences. When applied to real-world data, debar reduced indel errors in circular consensus sequences obtained with the Sequel platform by 75%, and those generated on the Ion Torrent S5 by 94%. The false correction rate was less than 0.1%, indicating that debar is receptive to the majority of true COI variation in the animal kingdom. In conclusion, the debar package improves DNA barcode and metabarcode workflows by aiding the generation of more accurate sequences aiding the characterization of species diversity.
Trial and error: a hierarchical modeling approach to test-retest assessment
Authors: Chen Gang , Pine Daniel S. , Brotman Melissa A. , Smith Ashley R. , Cox Robert W. , Haller Simone P.
Published: January 2021

The concept oftest-retest reliabilityindexes the consistency of a measurement across time. High reliability is critical for any scientific study, but specifically for the study of individual differences. Evidence of poor reliability of commonly used behavioral and functional neuroimaging tasks is mounting. Reports on low reliability of task-based fMRI have called into question the adequacy of using even the most common, well-characterized cognitive tasks with robust population-level effects, to measure individual differences. Here, we lay out a hierarchical framework that estimates reliability as a correlation divorced from trial-level variability, and show that reliability estimates tend to be higher compared to the conventional framework that adopts condition-level modeling and ignores across-trial variability. We examine how estimates from the two frameworks diverge and assess how different factors (e.g., trial and subject sample sizes, relative magnitude of cross-trial variability) impact reliability estimates. We also show that, under specific circumstances, the two statistical frameworks converge. Results from the two approaches are approximately equivalent if (a) the trial sample size is sufficiently large, or (b) cross-trial variability is in the same order of magnitude as, or less than, cross-subject variability. As empirical data indicate that cross-trial variability is large in most tasks, this work highlights that a large number of trials (e.g., greater than 100) may be required to achieve precise reliability estimates. We reference the toolsTRRand3dLMErfor the community to apply trial-level models to behavior and neuroimaging data and discuss how to make these new measurements most useful for current studies.
HIV modifies the m6A and m5C epitranscriptomic landscape of the host cell
Authors: Cristinelli Sara , Angelino Paolo , Janowczyk Andrew , Delorenzi Mauro , Ciuffi Angela
Published: January 2021

The study of RNA modifications, today known as epitranscriptomics, is of growing interest. The N6-methyladenosine (m6A) and 5-methylcytosine (m5C) RNA modifications are abundantly present on mRNA molecules, and impact RNA interactions with other proteins or molecules, thereby affecting cellular processes, such as RNA splicing, export, stability and translation. Recently m6A and m5C marks were found to be present on human immunodeficiency (HIV) transcripts as well and affect viral replication. Therefore, the discovery of RNA methylation provides a new layer of regulation of HIV expression and replication, and thus offers novel array of opportunities to inhibit replication. However, no study has been performed to date to investigate the impact of HIV replication on the transcript methylation level in the infected cell. We used a productive HIV infection model, consisting of the CD4+ SupT1 T cell line infected with a VSV-G pseudotyped HIVeGFP-based vector, to explore the temporal landscape of m6A and m5C epitranscriptomic marks upon HIV infection, and compare it to mock-treated cells. Cells were collected at 12, 24 and 36h post-infection for mRNA extraction and FACS analysis. M6A RNA modifications were investigated by methylated RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-Seq). M5C RNA modifications were investigated using a bisulfite conversion approach followed by high-throughput sequencing (BS-Seq).

Our data suggest that HIV Infection impacted the methylation landscape of HIV-infected cells, inducing mostly increased methylation of cellular transcripts upon infection. Indeed, differential methylation (DM) analysis identified 59 m6A hypermethylated and only 2 hypomethylated transcripts and 14 m5C hypermethylated transcripts and 7 hypomethylated ones. All data and analyses are also freely accessible on an interactive web resource (http://sib-pc17.unil.ch/HIVmain.html). Furthermore, both m6A and m5C methylations were detected on viral transcripts and viral particle RNA genomes, as previously described, but additional patterns were identified.

This work used differential epitranscriptomic analysis to identify novel players involved in HIV life cycle, thereby providing innovative opportunities for HIV regulation.
Role of the N- and C-terminal regions of FliF, the MS ring component inVibrioflagellar basal body
Authors: Kojima Seiji , Kajino Hiroki , Hirano Keiichi , Inoue Yuna , Terashima Hiroyuki , Homma Michio
Published: January 2021

The MS ring is a part of the flagellar basal body and formed by 34 subunits of FliF, which consists of a large periplasmic region and two transmembrane segments connected to the N- and C-terminal regions facing the cytoplasm. A cytoplasmic protein, FlhF, which determines the position and number of the basal body, supports MS ring formation in the membrane. In this study, we constructed FliF deletion mutants that lack 30 or 50 residues at the N-terminus (ΔN30 and ΔN50), and 83 (ΔC83) or 110 residues (ΔC110) at the C-terminus. The N-terminal deletions were functional and conferred motility ofVibriocells, whereas the C-terminal deletions were nonfunctional. The mutants were expressed inEscherichia colito determine whether an MS ring could still be assembled. When co-expressing ΔN30FliF or ΔN50FliF with FlhF, fewer MS rings were observed than with the expression of wild-type FliF, in the MS ring fraction, suggesting that the N-terminus interacts with FlhF. MS ring formation is probably inefficient without an additional factor or FlhF. The deletion of the C-terminal cytoplasmic region did not affect the ability of FliF to form an MS ring because a similar number of MS rings were observed for ΔC83FliF as with wild-type FliF, although further deletion of the second transmembrane segment (ΔC110FliF) abolished it. These results suggest that the terminal regions of FliF have distinct roles; the N-terminal region for efficient MS ring formation and the C-terminal region for MS ring function. The second transmembrane segment is indispensable for MS ring assembly.

Importance

The bacterial flagellum is a supramolecular architecture involved in cell motility. At the base of the flagella, a rotary motor that begins to construct an MS ring in the cytoplasmic membrane comprises 34 transmembrane proteins (FliF). Here, we investigated the roles of the N and C terminal regions of FliF, which are MS rings. Unexpectedly, the cytoplasmic regions of FliF are not indispensable for the formation of the MS ring, but the N-terminus appears to assist in ring formation through recruitment of FlhF, which is essential for flagellar formation. The C-terminus is essential for motor formation or function.
SARS-CoV-2 seroprevalence in the urban population of Qatar: An analysis of antibody testing on a sample of 112,941 individuals
Authors: Coyle Peter V. , Chemaitelly Hiam , Hadj Kacem Mohamed Ali Ben , Al Molawi Naema Hassan Abdulla , Kahlout Reham Awni El , Gilliani Imtiaz , Younes Nourah , Kanaani Zaina Al , Khal Abdullatif Al , Kuwari Einas Al , Butt Adeel A. , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Rahim Hanan F. Abdul , Nasrallah Gheyath K. , Yassine Hadi M. , Kuwari Mohamed G. Al , Romaihi Hamad Eid Al , Al-Thani Mohamed H. , Bertollini Roberto , Abu-Raddad Laith J.
Published: January 2021

Background

Qatar has experienced a large SARS-CoV-2 epidemic. Our first objective was to assess the proportion of the urban population that has been infected with SARS-CoV-2, by measuring the prevalence of detectable antibodies. Our second objective was to identify predictors for infection and for having higher antibody titers.

Methods

Residual blood specimens from individuals receiving routine and other clinical care between May 12-September 9, 2020 were tested for anti-SARS-CoV-2 antibodies. Associations with seropositivity and higher antibody titers were identified through regression analyses. Probability weights were applied in deriving the epidemiological measures.

Results

We tested 112,941 individuals (∼10% of Qatar’s urban population), of whom 51.6% were men and 66.0% were 20-49 years of age. Seropositivity was 13.3% (95% CI: 13.1-13.6%) and was significantly associated with sex, age, nationality, clinical-care type, and testing date. The proportion with higher antibody titers varied by age, nationality, clinical-care type, and testing date. There was a strong correlation between higher antibody titers and seroprevalence in each nationality, with a Pearson correlation coefficient of 0.85 (95% CI: 0.47-0.96), suggesting that higher antibody titers may indicate repeated exposure to the virus. The percentage of antibody-positive persons with prior PCR-confirmed diagnosis was 47.1% (95% CI: 46.1-48.2%), severity rate was 3.9% (95% CI: 3.7-4.2%), criticality rate was 1.3% (95% CI: 1.1-1.4%), and fatality rate was 0.3% (95% CI: 0.2-0.3%).

Conclusions

Fewer than two in every 10 individuals in Qatar’s urban population had detectable antibodies against SARS-CoV-2 between May 12-September 9, 2020, suggesting that this population is still far from the herd immunity threshold and at risk from a subsequent epidemic wave.
Leveraging mathematical models of disease dynamics and machine learning to improve development of novel malaria interventions
Authors: Golumbeanu Monica , Yang Guojing , Camponovo Flavia , Stuckey Erin M. , Hamon Nicholas , Mondy Mathias , Rees Sarah , Chitnis Nakul , Cameron Ewan , Penny Melissa A.
Published: January 2021

Background

Substantial research is underway to develop next-generation interventions that address current malaria control challenges. As there is limited testing in their early development, it is difficult to predefine intervention properties such as efficacy that achieve target health goals, and therefore challenging to prioritize selection of novel candidate interventions. Here, we present a quantitative approach to guide intervention development using mathematical models of malaria dynamics coupled with machine learning. Our analysis identifies requirements of efficacy, coverage, and duration of effect for five novel malaria interventions to achieve targeted reductions in malaria prevalence. This study highlights the role of mathematical models to support intervention development.

Methods

A mathematical model of malaria transmission dynamics is used to simulate deployment and predict potential impact of new malaria interventions by considering operational, health-system, population, and disease characteristics. Our method relies on consultation with product development stakeholders to define the putative space of novel intervention specifications. We couple the disease model with machine learning to search this multi-dimensional space and efficiently identify optimal intervention properties that achieve specified health goals. We demonstrate the power of our approach by application to five malaria interventions in development.

Results

Aiming for malaria prevalence reduction, we identify and quantify key determinants of intervention impact along with their minimal properties required to achieve the desired health goals. While coverage is generally identified as the largest driver of impact, higher efficacy, longer protection duration or multiple deployments per year are needed to increase prevalence reduction. We show that the efficacy and duration needs depend on the biological action of the interventions. Interventions on multiple parasite or vector targets, as well as combinations the new interventions with drug treatment, lead to significant burden reductions and lower efficacy or duration requirements.

Conclusions

Our approach uses disease dynamic models and machine learning to support decision-making and resource investment, facilitating development of new malaria interventions. By evaluating the intervention capabilities in relation to the targeted health goal, our analysis allows prioritization of interventions and of their specifications from an early stage in development, and subsequent investments to be channeled cost-effectively towards impact maximization. Although we focus on five malaria interventions, the analysis is generalizable to other new malaria interventions.
Latitudinal patterns in intertidal ecosystem structure in West Greenland suggest resilience to climate change
Authors: Thyrring Jakob , Wegeberg Susse , Blicher Martin E , Krause-Jensen Dorte , Høgslund Signe , Olesen Birgit , Wiktor Jozef , Mouritsen Kim N , Peck Lloyd S , Sejr Mikael K
Published: January 2021

Climate change has ecosystem-wide cascading effects. Little is known, however, about the resilience of Arctic marine ecosystems to environmental change. Here we quantify and compare large-scale patterns in rocky intertidal biomass, coverage and zonation in six regions along a north-south gradient of temperature and ice conditions in West Greenland (60-72°N). We related the level and variation in assemblage composition, biomass and coverage to latitudinal-scale environmental drivers. Across all latitudes, the intertidal assemblage was dominated by a core of stress-tolerant foundation species that constituted >95% of the biomass. Hence, canopy-forming macroalgae, represented by Fucus distichus subsp. evanescens and F. vesiculosus and, up to 69 °N, also Ascophyllum nodosum, together with Semibalanus balanoides, occupied >70% of the vertical tidal range in all regions. Thus, a similar functional assemblage composition occurred across regions, and no latitudinal depression was observed. The most conspicuous difference in species composition from south to north was that three common species (the macroalgae Ascophyllum nodosum, the amphipod Gammarus setosus and the gastropod Littorina obtusata) disappeared from the mid-intertidal, although at different latitudes. There were no significant relationships between assemblage metrics and air temperature or sea ice coverage as obtained from weather stations and satellites, respectively. Although the mean biomass decreased >50% from south to north, local biomass in excess of 10 000 g ww m-2 was found even at the northernmost site, demonstrating the patchiness of this habitat and the effect of small-scale variation in environmental characteristics. Hence, using the latitudinal gradient in a space-for-time substitution, our results suggest that while climate modification may lead to an overall increase in the intertidal biomass in north Greenland, it is unlikely to drive dramatic functional changes in ecosystem structure in the near future. Our dataset provides an important baseline for future studies to verify these predictions for Greenlands intertidal zone.
Cholesteryl Hemiazelate Induces Lysosome Dysfunction and Exocytosis in Macrophages
Authors: Domingues Neuza , Almeida Calado Rita Diogo , Brito Patrícia H. , Matthiesen Rune , Ramalho José , Soares Maria I. L. , Pereira Telmo , Oliveira Luis , Vicente José R. , Wong Louise H. , Cho Soo Min , Simões Ines C. M. , Sampaio Julio , Klose Christian , Surma Michal A. , Almeida Manuel S. , Rodrigues Gustavo , Araújo-Gonçalves Pedro , Ferreira Jorge , Simons Kai , Pinho e Melo Teresa M. V. D. , Peden Andrew , Almeida Claudia Guimas , Futter Clare E. , Futerman Anthony H. , Vaz Winchil L.C. , Vieira Otilia V.
Published: January 2021

OBJECTIVE

A key event in atherogenesis is the formation of lipid-loaded macrophages, lipidotic cells, which exhibit irreversible accumulation of undigested modified low-density lipoproteins in lysosomes. This event culminates with the loss of cell homeostasis, inflammation and cell death. In this study we propose to identify the chemical etiological factors and understanding the molecular and cellular mechanisms responsible for the impairment of lysosome function in macrophages.

APPROACH AND RESULTS

Using shotgun lipidomics we have discovered that a family of oxidized lipids (cholesteryl hemiesters, ChE), end products of oxidation of polyunsaturated cholesteryl esters, occurs at higher concentrations in the plasma of two cohorts of cardiovascular disease patients than in the plasma of a control cohort. Macrophages exposed to the most prevalent ChE, cholesteryl hemiazelate (ChA) exhibit lysosome enlargement, peripheral lysosomal positioning, lysosome dysfunction and lipidosis which are irreversible. The transcriptomic profile of macrophages exposed to ChA indicates that the lysosome pathway is deeply affected and is well correlated with lysosome phenotypic and functional changes. Interestingly, the dysfunctional peripheral lysosomes are more prone to fuse with the plasma membrane, secreting their undigested luminal content into the extracellular milieu with potential consequences to the pathology.

CONCLUSION

We identify ChA not only as one of the molecules involved in the etiology of irreversible lysosome dysfunction culminating with lipidosis but also as a promoter of exocytosis of the dysfunctional lysosomes. The latter event is a new mechanism that may be important in the pathogenesis of atherosclerosis.
Cell migration driven by long-lived spatial memory
Authors: d’Alessandro Joseph , Barbier-Chebbah Alex , Cellerin Victor , Bénichou Olivier , Mège René-Marc , Voituriez Raphaël , Ladoux Benoît
Published: January 2021

Many living cells actively migrate in their environment to perform key biological functions – from unicellular organisms looking for food to single cells such as fibroblasts, leukocytes or cancer cells that can shape, patrol or invade tissues. Cell migration results from complex intracellular processes that enable cell self-propulsion1,2, and has been shown to also integrate various chemical or physical extracellular signals3,4,5. While it is established that cells can modify their environment by depositing biochemical signals or mechanically remodeling the extracellular matrix, the impact of such self-induced environmental perturbations on cell trajectories at various scales remains unexplored. Here, we show that cells remember their path: by confining cells on 1D and 2D micropatterned surfaces, we demonstrate that motile cells leave long-lived physicochemical footprints along their way, which determine their future path. On this basis, we argue that cell trajectories belong to the general class of self-interacting random walks, and show that self-interactions can rule large scale exploration by inducing long-lived ageing, subdiffusion and anomalous first-passage statistics. Altogether, our joint experimental and theoretical approach points to a generic coupling between motile cells and their environment, which endows cells with a spatial memory of their path and can dramatically change their space exploration.
Single-molecule super-resolution imaging of T-cell plasma membrane CD4 redistribution upon HIV-1 binding
Authors: Yuan Yue , Jacobs Caron , Garcia Isabel Llorente , Pereira Pedro M. , Lawrence Scott P. , Laine Romain F. , Marsh Mark , Henriques Ricardo
Published: January 2021

The first step of cellular entry for the human immunodeficiency virus type-1 (HIV-1) occurs through the binding of its envelope protein (Env) with the plasma membrane receptor CD4 and co-receptor CCR5 or CXCR4 on susceptible cells, primarily CD4+T cells and macrophages. Although there is considerable knowledge of the molecular interactions between Env and host cell receptors that lead to successful fusion, the precise way in which HIV-1 receptors redistribute to sites of virus binding at the nanoscale remains unknown. Here, we quantitatively examine changes in the nanoscale organisation of CD4 on the surface of CD4+T cells following HIV-1 binding. Using single-molecule super-resolution imaging, we show that CD4 molecules are distributed mostly as either individual molecules or small clusters of up to 4 molecules. Following virus binding, we observe a local 3-to-10-fold increase in cluster diameter and molecule number for virus-associated CD4 clusters. Moreover, a similar but smaller magnitude reorganisation of CD4 was also observed with recombinant gp120. For the first time, our results quantify the nanoscale CD4 reorganisation triggered by HIV-1 on host cells. Our quantitative approach provides a robust methodology for characterising the nanoscale organisation of plasma membrane receptors in general with the potential to link spatial organisation to function.
EMS-based mutants are useful for enhancing drought tolerance in spring wheat
Authors: Zahra Sadaf , Zulfiqar Sana , Hussain Momina , Akhtar Muhammad , Shaheen Tayyaba , Mehboob-ur-Rahman
Published: January 2021

Sustainable wheat production in drought prone areas can be achieved by developing resilient wheat varieties. In the present study, chemical mutagenesis was used to induce mutations in a cultivated wheat variety ‘NN-Gandum-1’. In total, 44 mutants were selected based on their high yield potential for exposing to well-watered (W1) and rainfed (W2) conditions for one season. Then 24 mutants were selected, and were exposed to W1and W2regimes. On the basis of least relative reduction in physiological parameters under W2regime, five mutants were selected for conducting exome capturing assays. In total, 184 SNPs were identified in nine genes (ABC transporter type 1, Aspartic peptidase, Cytochrome P450, transmembrane domain, Heavy metal-associated domain, HMA, NAC domain, NAD (P)-binding domain, S-type anion channel, Ubiquitin-conjugating enzyme E2 and UDP-glucuronosyl/UDP-glucosyltransferase). Maximum number of mutations were observed in chr.2D, which contained mutations in three genes i.e. ABC transporter type 1, NAD (P)-binding domain and UDP-glucuronosyl/UDP-glucosyltransferase which may have a role in conferring drought tolerance. The selected mutants were further tested for studying their biochemical responses under both the regimes for two years. The extent of membrane damage was estimated through malondialdehydeand hydrogen per oxidase and tolerance to drought stress was assessed via antioxidant enzymes in leaves. The selected mutants under drought stress increased the accumulation of proline content, total soluble sugars, total free amino acids, while decreased total chlorophyll content, carotenoids and total soluble protein. Finally, the procedure of narrowing down the number of developed mutants from a large mutation population (>4000) is found useful for exploring the complex trait like drought without compromising yield potential. These mutants can further be explored to understand the genetic circuits of drought tolerance in wheat which will pave the way towards improving livelihood of resource poor farming community mostly relying on cereal food.
Plasmodium falciparumK13 mutations in Africa and Asia present varying degrees of artemisinin resistance and an elevated fitness cost in African parasites
Authors: Stokes Barbara H. , Rubiano Kelly , Dhingra Satish K. , Mok Sachel , Straimer Judith , Gnädig Nina F. , Bath Jade R. , Deni Ioanna , Ward Kurt E. , Striepen Josefine , Yeo Tomas , Ross Leila S. , Legrand Eric , Ariey Frédéric , Cunningham Clark H. , Souleymane Issa M. , Gansané Adama , Nzoumbou-Boko Romaric , Ndayikunda Claudette , Kabanywanyi Abdunoor M. , Uwimana Aline , Smith Samuel J. , Kolley Olimatou , Ndounga Mathieu , Warsame Marian , Leang Rithea , Nosten François , Anderson Timothy J.C. , Rosenthal Philip J. , Ménard Didier , Fidock David A.
Published: January 2021

The emergence of artemisinin (ART) resistance inPlasmodium falciparumparasites has led to increasing rates of treatment failure with first-line ART-based combination therapies (ACTs) in Southeast Asia. In this region, select mutations in K13 can result in delayed parasite clearance ratesin vivoand enhanced survival in the ring-stage survival assay (RSA)in vitro. Our genotyping of 3,299P. falciparumisolates across 11 sub-Saharan countries reveals the continuing dominance of wild-type K13 and confirms the emergence of a K13 R561H variant in Rwanda. Using gene editing, we provide definitive evidence that this mutation, along with M579I and C580Y, can confer variable degrees ofin vitroART resistance in AfricanP. falciparumstrains. C580Y and M579I were both associated with substantial fitness costs in African parasites, which may counter-select against their dissemination in high-transmission settings. We also report the impact of multiple K13 mutations, including the predominant variant C580Y, on RSA survival rates and fitness in multiple Southeast Asian strains. No change in ART susceptibility was observed upon editing point mutations in ferrodoxin or mdr2, earlier associated with ART resistance in Southeast Asia. These data point to the lack of an evident biological barrier to mutant K13 mediating ART resistance in Africa, while identifying their detrimental impact on parasite growth.
Mapping the dynamic transfer functions of epigenome editing
Authors: Lee Jessica B. , Caywood Leandra M. , Lo Jennifer Y. , Levering Nicholas , Keung Albert J.
Published: January 2021

Biological information can be encoded in the dynamics of signaling components which has been implicated in a broad range of physiological processes including stress response, oncogenesis, and stem cell differentiation. To study the complexity of information transfer across the eukaryotic promoter, we screened 119 dynamic conditions—modulating the frequency, intensity, and pulse width of light—regulating the binding of an epigenome editor to a fluorescent reporter. This system revealed highly tunable gene expression and filtering behaviors and provided the most comprehensive quantification to date of the maximum amount of information that can be reliably transferred across a promoter as ∼1.7 bits. Using a library of over 100 orthogonal epigenome editors, we further determined that chromatin state could be used to tune mutual information and expression levels, as well as completely alter the input-output transfer function of the promoter. This system unlocks the information-rich content of eukaryotic epigenome editing.
Detecting origin fraud with trade data: the case of U.S. honey imports*
Authors: Ferrier Peyton Michael
Published: January 2021

Following the 2001 U.S. imposition of antidumping tariffs on imported honey from China and Argentina, industry press noted patterns of trade suggesting that honey was being transshipped to circumvent tariffs, origin fraud that was later uncovered in criminal cases. This article presents three approaches that use trade and production data to flag countries for possible instances of origin fraud and then compares these countries with those implicated in criminal cases and media reports. In our preferred empirical method, we also find that countries with higher corruption scores are more likely to show increases in suspicious trade patterns following the tariffs.
Facility‐specific ‘house’ microbiome ensures the maintenance of functional microbial communities into coffee beans fermentation: implications for source tracking
Authors: da Silva Vale Alexander , de Melo Pereira Gilberto Vinícius , de Carvalho Neto Dão Pedro , Sorto Ruben Dario , Goés‐Neto Aristóteles , Kato Rodrigo , Soccol Carlos Ricardo
Published: January 2021

This work aimed at studying the unconfirmed hypothesis predicting the existence of a connection between coffee farm microbiome and the resulting spontaneous fermentation process. Using Illumina‐based amplicon sequencing, 360 prokaryotes and 397 eukaryotes were identified from coffee fruits and leaves, over‐ripe fruits, water used for coffee de‐pulping, depulped coffee beans, soil, and temporal fermentation samples at an experimental farm in Honduras. Coffee fruits and leaves were mainly associated with high incidence of Enterobacteriaceae, Pseudomonas, Colletotrichum, and Cladosporium. The proportion of Enterobacteriaceae was increased when leaves and fruits were collected on the ground compared to those from the coffee tree. Coffee farm soil showed the richest microbial diversity with marked presence of Bacillus. Following the fermentation process, microorganisms present in depulped coffee beans (Leuconostoc, Gluconobater, Pichia, Hanseniaspora, and Candida) represented more than 90% of the total microbial community, which produced lactic acid, ethanol, and several volatile compounds. The community ecology connections described in this study showed that coffee fruit provides beneficial microorganisms for the fermentation process. Enterobacteria, Colletotrichum, and other microbial groups present in leaves, fruit surface, over‐ripe fruits, and soil may transfer unwanted aromas to coffee beans, so they should be avoided from having access to the fermentation tank.
Alarming decline of bovids in Kasanka National Park, Zambia: A case study of the puku antelope (Kobus vardonii)
Authors: Rduch Vera , Jentke Thalia
Published: January 2021

Knowledge about antelope populations and their status is a key for conservation. In November 2019, we used distance sampling to perform a re‐survey of the bovid species in Kasanka National Park, Zambia, with a focus on the puku (Kobus vardonii). Data collection and subsequent analyses were of the same design as in a previous survey in 2009–2010. This allowed for the direct comparison between survey periods, especially for the data collected in November 2010 and 2019. The estimated puku population size decreased from 5,038 (range 3,268–7,238) animals in 2009–2010 to 819 (range 250–2,708) animals in 2019, representing an 84% decline. Smaller group sizes were observed. Changes in population structure (decline in male abundance, fewer male groups) and spatial distribution (decline in population density, especially along the park boundaries) of puku showed signs of increased poaching activities in Kasanka National Park. Also, puku became more vigilant and demonstrated significantly longer flight distances in 2019 in comparison with 2010. A strong decline in puku in combination with clear signs of poaching, as well as the reduced species richness and sightings of other bovids, should become an agenda for long‐term conservation of Kasanka National Park.
Children’s Use of Testimony to Determine Reality Status
Authors: Woolley Jacqueline D. , Nissel Jenny , Gilpin Ansley T.
Published: January 2021

Verbal testimony about reality status is critical but often contradictory. These studies address whom children consider reliable sources of information about reality and how they evaluate conflicting testimony. In Study 1, seventy 4‐ to 8‐year‐olds heard an adult or child provide testimony about how to cook food and use toys, and about the reality of unfamiliar entities. Children selected the adult for food and the child for toys. Six‐ and 8‐year‐olds also selected the adult regarding reality. In Study 2, ninety 4‐ to 8‐year‐olds heard conflicting reality information from children and adults. Six‐ to 8‐year‐olds endorsed adult and child claims differentially and stated that adults knew more. By age 6, children favor adult testimony about reality over that of children.
Ultraviolet filters in sunscreens and cosmetic products—A market survey
Authors: Chaiyabutr Chayada , Sukakul Thanisorn , Kumpangsin Titinun , Bunyavaree Monthatip , Charoenpipatsin Norramon , Wongdama Supisara , Boonchai Waranya
Published: January 2021

Background

As several reports have raised a variety of environmental, health, and safety issues related to ultraviolet (UV) filters, it is crucial to understand the trends in the exposure of the population to UV filters.

Objective

To determine the frequency of UV filter usage in sunscreens and other cosmetic products in Thai market.

Methods

We surveyed the UV filter labelling on sunscreens and cosmetic products sold in the Thai market. In all, 312 sunscreens and 1350 other cosmetic products were investigated.

Results

Titanium dioxide was the most frequently used UV filter in both sunscreens (66.7%) and other cosmetic products (68.4%). Ethylhexyl methoxycinnamate was the most common organic UVB filter, whereas butyl methoxydibenzoylmethane was the most common organic UVA filter. In sunscreens aimed at children, bis‐ethylhexyloxyphenol methoxyphenyl triazine was the most commonly used UV filter. The most frequent co‐occurrence of UV filters was titanium dioxide and ethylhexyl methoxycinnamate.

Conclusions

Titanium dioxide was the most commonly used UV filter, which differs from the findings of previous surveys. Knowing the availability and frequency of each UV filter provides valuable information about consumer exposure levels, facilitates refinements of the allergen series in patch testing, and enhances the monitoring of adverse effects of UV filters.
Persistence of both reversible airway obstruction and higher blood eosinophils may predict lung function decline in severe asthma
Authors: Sposato Bruno , Scalese Marco , Ricci Alberto , Rogliani Paola , Paggiaro Pierluigi ,   The Omalizumab Italian Study Group
Published: January 2021

Objective

This study analysed whether the persistence of both reversible airway obstruction (RAO) and elevated BE counts was associated to reduced asthma control and accelerated lung function decline in treated severe asthmatics.

Methods

About 202 severe asthmatics were studied after 12–120 months of step‐5 treatment associated to anti‐IgE therapy. Following treatments, reversibility tests, after inhaling 400 mcg of Salbutamol, were performed. FEV1 > 12% or ≤12% changes differentiated RAO+ from RAO− subjects. Blood eosinophil (BE) counts after treatment were considered.

Results

Pre‐/post‐treatment bronchodilator FEV1% and ACT were lower (61% [50–71], 74.4% [62.5–83.7] and 20[18–22]), whereas BE were higher (380 cells/µl [170–590]) in RAO+ compared to RAO− subjects (77% [64–88], p = 0.0001, 81.8% [66.1–94.3], p = 0.0001, 21[18–23], p = 0.045 and 230 cells/µl [80–360], p = 0.003). A negative relationship between SABA‐induced FEV1% changes and pre‐bronchodilator FEV1% (β = −0.551%; p = 0.0001) and ACT (β = −0.059; p = 0.038) was found. Conversely, post‐treatment BE levels were positively related (β = 145.565 cells/µl; p = 0.003) to FEV1 > 12% increases. A rising trend of pre‐/post‐bronchodilator FEV1% in time was observed in RAO− subjects with BE < 300 cells/µl. Conversely, we highlighted significant declining tendencies of pre/post‐bronchodilator FEV1% in RAO+ patients with BE > 300 cells/µl reaching lower values after more than 36 months of step‐5 treatment (59.6% [39.9–72.1] vs 74[66.5–89.2] of RAO+ individuals with BE < 300 cells/µl [p = 0.026] and 81.6% [66.1–91.8] of RAO‐subjects with BE > 300 cells/µl [p = 0.009]).

Conclusion

Persistent SABA‐induced FEV1 > 12%, especially when associated to BE > 300 cells/ml, may be a marker of accelerated lung function decline in severe asthmatics despite maximal step‐5 treatment. The highest bronchodilation associated to the lowest BE levels should be the main goal of asthma treatment to prevent such decline.
CDKL5 deficiency in forebrain glutamatergic neurons results in recurrent spontaneous seizures
Authors: Wang Hong‐Tao , Zhu Zi‐Ai , Li Yi‐Yan , Lou Sen‐Sen , Yang Guang , Feng Xue , Xu Wei , Huang Zhi‐Li , Cheng Xuewen , Xiong Zhi‐Qi
Published: January 2021

Objective

Mutations of the cyclin‐dependent kinase‐like 5 (CDKL5) gene cause severe neurodevelopmental disorders characterized by intractable epilepsy, intellectual disability, and autism. Multiple mouse models generated for mechanistic studies have exhibited phenotypes similar to some human pathological features, but none of the models has developed one of the major symptoms affecting CDKL5 deficiency disorder (CDD) patients: intractable recurrent seizures. As disrupted neuronal excitation/inhibition balance is closely associated with the activity of glutamatergic and γ‐aminobutyric acidergic (GABAergic) neurons, our aim was to study the effect of the loss of CDKL5 in different types of neurons on epilepsy.

Methods

Using the Cre‐LoxP system, we generated conditional knockout (cKO) mouse lines allowing CDKL5 deficiency in glutamatergic or GABAergic neurons. We employed noninvasive video recording and in vivo electrophysiological approaches to study seizure activity in these Cdkl5 cKO mice. Furthermore, we conducted Timm staining to confirm a morphological alteration, mossy fiber sprouting, which occurs with limbic epilepsy in both human and mouse brains. Finally, we performed whole‐cell patch clamp in dentate granule cells to investigate cell‐intrinsic properties and synaptic excitatory activity.

Results

We demonstrate that Emx1‐ or CamK2α‐derived Cdkl5 cKO mice manifest high‐frequency spontaneous seizure activities recapitulating the epilepsy of CDD patients, which ultimately led to sudden death in mice. However, Cdkl5 deficiency in GABAergic neurons does not generate such seizures. The seizures were accompanied by typical epileptic features including higher amplitude spikes for epileptiform discharges and abnormal hippocampal mossy fiber sprouting. We also found an increase in spontaneous and miniature excitatory postsynaptic current frequencies but no change in amplitudes in the dentate granule cells of Emx1‐cKO mice, indicating enhanced excitatory synaptic activity.

Significance

Our study demonstrates that Cdkl5 cKO mice, serving as an animal model to study recurrent spontaneous seizures, have potential value for the pathological study of CDD‐related seizures and for therapeutic innovation.