bluuebunny/crossref_metadata_2025 huggingface dataset:
Prrx1b directs pro-regenerative fibroblasts during zebrafish heart regeneration
Authors: de Bakker Dennis E.M. , Dronkers Esther , Bouwman Mara , Vink Aryan , Goumans Marie-José , Smits Anke M. , Bakkers Jeroen
Published: June 2020

Rationale

The human heart loses millions of cardiomyocytes after an ischemic injury, but is unable to regenerate the lost tissue. Instead, the injured human heart is repaired by pro-fibrotic fibroblasts that form a large permanent scar. In contrast, the injured zebrafish heart regenerates efficiently without the formation of a permanent scar. While fibroblasts have been shown to be indispensable for zebrafish heart regeneration, very little is known about the mechanisms balancing the fibrotic and regenerative response. A better understanding of these mechanisms could lead to the discovery of novel therapeutic strategies to reduce fibrosis and promote heart regeneration.

Objective

To identify novel mechanisms that regulate the balance between cardiac fibrosis and scar-free regeneration.

Methods and Results

Using a genetic approach, we first show that zebrafishprrx1bloss-of-function mutants display reduced cardiomyocyte proliferation and impaired heart regeneration. Using a lineage tracing approach, we show that Prrx1b is expressed intcf21+ epicardial-derived cells localizing around and inside the injured area. Next, we used a single cell RNA-sequencing approach on sortedtcf21+ cells isolated from injuredprrx1b-/- and wild-type hearts and identified two distinct fibroblast populations. With combined bioinformatic and histological analysis we found thatprrx1b-/- hearts contain an excess of pro-fibrotic fibroblasts that produce TGF-β ligands and collagens, while fewer pro-regenerative Nrg1-expressing fibroblasts are formed. Furthermore, by injecting recombinant NRG1 inprrx1b-/- fish we were able to rescue their cardiomyocyte proliferation defect. Finally, using cultured human fetal epicardial cells and siRNA mediated knock-down of PRRX1 we found that PRRX1 is required for NRG1 induction in human epicardial-derived cells.

Conclusions

Prrx1b in the injured heart restricts fibrosis and stimulates regeneration by directing epicardial-derived cells towards a pro-regenerative Nrg1-producing fibroblast state.
Comparative genomics ofChlamydomonas
Authors: Craig Rory J. , Hasan Ahmed R. , Ness Rob W. , Keightley Peter D.
Published: June 2020

Despite its fundamental role as a model organism in plant sciences, the green algaChlamydomonas reinhardtiientirely lacks genomic resources for any closely related species, obstructing its development as a study system in several fields. We present highly contiguous and well-annotated genome assemblies for the two closest known relatives of the species,Chlamydomonas incertaandChlamydomonas schloesseri, and a third more distantly related species,Edaphochlamys debaryana. We find the threeChlamydomonasgenomes to be highly syntenous with similar gene contents, although the 129.2 MbC. incertaand 130.2 MbC. schloesseriassemblies are more repeat-rich than the 111.1 MbC. reinhardtiigenome. We identify the major centromeric repeat inC. reinhardtiias an L1 LINE transposable element homologous to Zepp (the centromeric repeat inCoccomyxa subellipsoidea) and infer that centromere locations and structure are likely conserved inC. incertaandC. schloesseri. We report extensive rearrangements, but limited gene turnover, between the minus mating-type loci of theChlamydomonasspecies, potentially representing the early stages of mating-type haplotype reformation. We produce an 8-species whole-genome alignment of unicellular and multicellular volvocine algae and identify evolutionarily conserved elements in theC. reinhardtiigenome. We find that short introns (<~100 bp) are extensively overlapped by conserved elements, and likely represent an important functional class of regulatory sequence inC. reinhardtii. In summary, these novel resources enable comparative genomics analyses to be performed forC. reinhardtii, significantly developing the analytical toolkit for this important model system.
Heritable Genetic Background Alters Survival and Phenotype ofMll-AF9-Induced Leukemias
Authors: Young Kira , Loberg Matthew A. , Eudy Elizabeth , Schwartz Logan S. , Mujica Kristina D. , Trowbridge Jennifer J.
Published: June 2020

The MLL-AF9 fusion protein occurring as a result of t(9;11) translocation gives rise to pediatric and adult acute leukemias of distinct lineages, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and mixed phenotype acute leukemia (MPAL). The mechanisms underlying how this same fusion protein results in diverse leukemia phenotypes among different individuals is not well understood. Given emerging evidence from genome-wide association studies (GWAS) that genetic risk factors contribute toMLL-rearranged leukemogenesis, here we tested the impact of genetic background on survival and phenotype of a well-characterizedMll-AF9knockin mouse model. We crossed this model to five distinct inbred strains (129, A/J, C57BL/6, NOD, CAST), and tested their F1 hybrid progeny for dominant genetic effects onMll-AF9phenotypes. We discovered that genetic background altered peripheral blood composition, withMll-AF9CAST F1 demonstrating significantly increased B lymphocyte frequency while the remainder of the strains exhibited myeloid-biased hematopoiesis, similar to the parental line. Genetic background also impacted overall survival, withMll-AF9A/J F1 andMll-AF9129 F1 having significantly shorter survival, andMll-AF9CAST F1 having longer survival, compared to the parental line. Furthermore, we observed a range of hematologic malignancies, withMll-AF9A/J F1,Mll-AF9129 F1 andMll-AF9B6 F1 developing exclusively myeloid cell malignancies (myeloproliferative disorder (MPD) and AML) whereas a subset ofMll-AF9NOD F1 developed MPAL andMll-AF9CAST F1 developed ALL. This study provides a novelin vivoexperimental model to evaluate the underlying mechanisms by whichMLL-AF9results in diverse leukemia phenotypes and provides definitive experimental evidence that genetic risk factors contribute to survival and phenotype ofMLL-rearranged leukemogenesis.
Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons
Authors: Gowrishankar Swetha , Lyons Lila , Rafiq Nisha Mohd , Roczniak-Ferguson Agnes , De Camilli Pietro , Ferguson Shawn M.
Published: June 2020

The dependence of neurons on microtubule-based motors for the movement of lysosomes over long distances raises questions about adaptations that allow neurons to meet these demands. Recently, JIP3/MAPK8IP3, a neuronally enriched putative adaptor between lysosomes and motors, was identified as a critical regulator of axonal lysosome abundance. In this study, we establish a human induced pluripotent stem cell (iPSC)-derived neuron model for the investigation of axonal lysosome transport and maturation and show that loss of JIP3 results in the accumulation of axonal lysosomes and the Alzheimer’s disease-related amyloid precursor protein (APP)-derived Aβ42 peptide. We furthermore reveal an overlapping role of the homologous JIP4 gene in lysosome axonal transport. These results establish a cellular model for investigating the relationship between lysosome axonal transport and amyloidogenic APP processing and more broadly demonstrate the utility of human iPSC-derived neurons for the investigation of neuronal cell biology and pathology.
Redox stress reshapes carbon fluxes ofPseudomonas putidafor cytosolic glucose oxidation and NADPH generation
Authors: Nikel Pablo I. , Fuhrer Tobias , Chavarría Max , Sánchez-Pascuala Alberto , Sauer Uwe , de Lorenzo Víctor
Published: June 2020

The soil bacterium and metabolic engineering platformPseudomonas putidatolerates high levels of endogenous and exogenous oxidative stress, yet the ultimate reason of such property remains unknown. To shed light on this question, NADPH generation routes—the metabolic currency that fuels redox stress responses—were assessed whenP. putidaKT2440 was challenged with H2O2as proxy of oxidative conditions.13C-tracer experiments, metabolomics and flux analysis, together with inspection of physiological parameters and measurement of enzymatic activities, revealed a substantial flux reconfiguration under oxidative stress. In particular, periplasmic glucose processing was rerouted to cytoplasmic oxidation, and cyclic operation of the pentose phosphate pathway led to significant NADPH fluxes, exceeding biosynthetic demands by ~50%. This NADPH surplus, in turn, fuelled the glutathione system for H2O2reduction. These properties not only contribute to the tolerance ofP. putidato environmental stresses, but they also highlight the value of this host for harsh biotransformations.
Coronavirus genomes carry the signatures of their habitats
Authors: Wei Yulong , Silke Jordan R. , Aris Parisa , Xia Xuhua
Published: June 2020

Coronaviruses such as SARS-CoV-2 regularly infect host tissues that express antiviral proteins (AVPs) in abundance. Understanding how they evolve to adapt or evade host immune responses is important in the effort to control the spread of COVID-19. Two AVPs that may shape viral genomes are the zinc finger antiviral protein (ZAP) and the apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3 protein (APOBEC3). The former binds to CpG dinucleotides to facilitate the degradation of viral transcripts while the latter deaminates C into U residues leading to dysfunctional transcripts. We tested the hypothesis that both APOBEC3 and ZAP may act as primary selective pressures that shape the genome of an infecting coronavirus by considering a comprehensive number of publicly available genomes for seven coronaviruses (SARS-CoV-2, SARS-CoV, MERS, Bovine CoV, Murine MHV, Porcine HEV, and Canine CoV). We show that coronaviruses that regularly infect tissues with abundant AVPs have CpG-deficient and U-rich genomes; whereas viruses that do not infect tissues with abundant AVPs do not share these sequence hallmarks. In SARS-CoV-2, CpG is most deficient in the S protein region to evaded ZAP-mediated antiviral defense during cell entry. Furthermore, over four months of SARS-CoV-2 evolutionary history, we observed a marked increase in C to U substitutions in the 5’ UTR and ORF1ab regions. This suggests that the two regions could be under constant C to U deamination by APOBEC3. The evolutionary pressures exerted by host immune systems onto viral genomes may motivate novel strategies for SARS-CoV-2 vaccine development.
Harnessing CRISPR-Cas9 for genome editing inStreptococcus pneumoniae
Authors: Synefiaridou Dimitra , Veening Jan-Willem
Published: June 2020

CRISPR systems provide bacteria and archaea with adaptive immunity against viruses and plasmids by detection and cleavage of invading foreign DNA. Modified versions of this system can be exploited as a biotechnological tool for precise genome editing at a targeted locus. Here, we developed a novel, replicative plasmid that carries the CRISPR-Cas9 system for RNA-programmable, genome editing by counterselection in the opportunistic human pathogenStreptococcus pneumoniae. Specifically, we demonstrate an approach for making targeted, marker-less gene knockouts and large genome deletions. After a precise double-stranded break (DSB) is introduced, the cells’ DNA repair mechanism of homology-directed repair (HDR) pathway is being exploited to select successful transformants. This is achieved through the transformation of a template DNA fragment that will recombine in the genome and eliminate recognition of the target of the Cas9 endonuclease. Next, the newly engineered strain, can be easily cured from the plasmid that is temperature-sensitive for replication, by growing it at the non-permissive temperature. This allows for consecutive rounds of genome editing. Using this system, we engineered a strain with three major virulence factors deleted. The here developed approaches should be readily transportable to other Gram-positive bacteria.

Importance

Streptococcus pneumoniae(the pneumococcus) is an important opportunistic human pathogen killing over a million people each year. Having the availability of a system capable of easy genome editing would significantly facilitate drug discovery and vaccine candidate efforts. Here, we introduced an easy to use system to perform multiple rounds of genome editing in the pneumococcus by putting the CRISPR-Cas9 system on a temperature-sensitive replicative plasmid. The here used approaches will advance genome editing projects in this important human pathogen.
Multi-epitope Based Peptide Vaccine Design Using Three Structural Proteins (S, E, and M) of SARS-CoV-2: AnIn SilicoApproach
Authors: Roy Arpita Singha , Tonmoy Mahafujul Islam Quadery , Fariha Atqiya , Hami Ithmam , Afif Ibrahim Khalil , Munim Md. Adnan , Alam Mohammad Rahanur , Hossain Md. Shahadat
Published: June 2020

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the novel coronavirus responsible for the ongoing pandemic of coronavirus disease (COVID-19). No sustainable treatment option is available so far to tackle such a public health threat. Therefore, designing a suitable vaccine to overcome this hurdle asks for immediate attention. In this study, we targeted for a design of multi-epitope based vaccine using immunoinformatics tools. We considered the structural proteins S, E and, M of SARS-CoV-2, since they facilitate the infection of the virus into host cell and using different bioinformatics tools and servers, we predicted multiple B-cell and T-cell epitopes having potential for the required vaccine design. Phylogenetic analysis provided insight on ancestral molecular changes and molecular evolutionary relationship of S, E, and M proteins. Based on the antigenicity and surface accessibility of these proteins, eight epitopes were selected by various B cell and T cell epitope prediction tools. Molecular docking was executed to interpret the binding interactions of these epitopes and three potential epitopes WTAGAAAYY, YVYSRVKNL, and GTITVEELK were selected for their noticeable higher binding affinity scores −9.1, −7.4, and −7.0 kcal/mol, respectively. Targeted epitopes had 91.09% population coverage worldwide. In summary, we identified three epitopes having the most significant properties of designing the peptide-based vaccine against SARS-CoV-2.
Microglial activation results in neuron-type-specific increase in mPFC GABAergic transmission and abnormal behavior in mice
Authors: Tang Binliang , Jiang Jinxiang , Wang Lei , Misrani Afzal , Huo Qingwei , Han Yuanyuan , Long Cheng , Yang Li
Published: June 2020

Neuroinflammation and synaptic dysfunction are two early symptoms of most neurological diseases. However, the mechanisms underlying microglia-associated neuroinflammation in the regulation of synaptic activity remain obscure. We report here that acute neuroinflammation induced by a single-dose proinflammatory cytokine inducer, lipopolysaccharide (LPS), results in enhanced inhibitory postsynaptic currents (IPSCs) of glutamatergic neurons, upregulated levels of GABAAR subunits, glutamine synthetase (GS) and vGAT, and downregulated BDNF and pTrkB levels, due to enhanced activation of microglia in the medial prefrontal cortex (mPFC). Blockage of microglial activation by minocycline ameliorated LPS-induced aberrant mIPSCs and associated aberrant protein expression and behavior. Exogenous application of BDNF prior to LPS challenge also ameliorated LPS-induced abnormal mIPSCs. Thus, this study elucidates a critical role for microglia in the neurobiology of GABAergic synaptic dysfunction induced by neuroinflammation, revealing a novel GABAergic signaling pathway that might be targeted therapeutically to treat neuroinflammation-induced abnormal synaptic activity and associated aberrant behavior.
CDC6 regulates mitotic CDK1 via cyclin B and not cyclin A and acts through abona fideCDK inhibitor Xic1
Authors: El Dika Mohammed , Wechselberger Lisa , Djeghout Bilal , Benouareth Djamel Eddine , Jęderka Krystyna , Lewicki Sławomir , Prigent Claude , Kloc Malgorzata , Kubiak Jacek Z.
Published: June 2020

The timing of the M-phase entry and its progression are precisely controlled by a CDC6-dependent mechanism that inhibits the major mitotic kinase CDK1, and, thus, regulates the dynamic of CDK1 during the M-phase. In this paper, we describe the differential regulation of the mitotic CDK1 dynamics by exogenous cyclin A or a non-degradable cyclin B added to theXenopus laevisembryo cycling extracts. We showed that the variations in the level of cyclin B modify both CDK1 activity and the timing of the M-phase progression, while the cyclin A levels modify only CDK1 activity without changing the timing of the M-phase events. In consequence, CDC6 regulates the M-phase through endogenous cyclin B, but not cyclin A, which we demonstrated directly by the depletion of cyclin A, and the addition of CDC6 to the cycling extracts. Further, we showed, by p9 precipitation (p9 protein associates with Cyclin-Dependent Kinases, CDK), followed by the Western blotting that CDC6, and thebona fideCDK1 inhibitor Xic1, associate with CDK1 and/or another CDK present in Xenopus embryos, the CDK2. Finally, we demonstrated that the Xic1 temoprarily separates from the mitotic CDK complexes during the peak of CDK1 activity. These data show the differential coordination of the M-phase progression by CDK1/cyclin A and CDK1/cyclin B, confirm the critical role of the CDC6-dependent CDK1 inhibition in this process and show that CDC6 acts through the cyclin B- and not cyclin A/CDK complexes. This CDC6- and cyclin B-dependent mechanism may also depend on the precisely regulated association of Xic1 with the CDK complexes. We postulate that the dissociation of Xic1 from the CDK complexes allows the maximal activation of CDK1 during the M-phase.
Microbial Diversity of Deep-Sea Ferromanganese Crust Field in the Rio Grande Rise, Southwestern Atlantic Ocean
Authors: Bergo Natascha Menezes , Bendia Amanda Gonçalves , Ferreira Juliana Correa Neiva , Murton Bramley , Brandini Frederico Pereira , Pellizari Vivian Helena
Published: June 2020

Seamounts are often covered with Fe and Mn oxides, known as ferromanganese (Fe-Mn) crusts. Future mining of these crusts is predicted to have significant effects on biodiversity in mined areas. Although microorganisms have been reported on Fe–Mn crusts, little is known about the role of crusts in shaping microbial communities. Here, we investigated microbial community based on 16S rRNA gene sequences retrieved from Fe-Mn crusts, coral skeleton, calcarenite and biofilm at crusts of the Rio Grande Rise (RGR). RGR is a prominent topographic feature in the deep southwestern Atlantic Ocean with Fe-Mn crusts. Our results revealed that crust field of the RGR harbors a usual deep-sea microbiome. We observed differences of microbial structure according to the sampling location and depth, suggesting an influence of water circulation and availability of particulate organic matter. Bacterial and archaeal groups related to oxidation of nitrogen compounds, such as Nitrospirae, Nitrospinae phyla, Nitrosopumilus within Thaumarchaeota group were present on those substrates. Additionally, we detected abundant assemblages belonging to methane oxidation, i. e. Ca. Methylomirabilales (NC10) and SAR324 (Deltaproteobacteria). The chemolithoautotrophs associated with ammonia-oxidizing archaea and nitrite-oxidizing bacteria potentially play an important role as primary producers in the Fe-Mn substrates from RGR. These results provide the first insights into the microbial diversity and potential ecological processes in Fe-Mn substrates from the Atlantic Ocean. This may also support draft regulations for deep-sea mining in the region.
Dendritic cell actin dynamics controls T cell priming efficiency at the immunological synapse
Authors: Leithner Alexander , Altenburger Lukas M. , Hauschild Robert , Assen Frank , Rottner Klemens , Stradal Theresia E.B. , Stein Jens V. , Sixt Michael
Published: June 2020

Dendritic cells (DCs) are crucial for the priming of naïve T cells and the initiation of adaptive immunity. Priming is initiated at a heterologous cell-cell contact, the immunological synapse (IS). While it is established that actin dynamics regulates signalling at the T cell side of the contact, little is known about the cytoskeletal contribution on the DC side. We show that that the DC cytoskeleton is decisive for the formation of a multifocal synaptic structure, which correlates with T cell priming efficiency. We demonstrate that DC actin appears in transient foci at the IS and that these foci are dynamized by the WAVE complex. Absence of WAVE in DCs leads to stabilized contacts with T cells, caused by an increase in ICAM1-integrin mediated cell-cell adhesions. This results in a lower number of activated and proliferating T cells. Our results reveal an important role of DC actin in the regulation of synaptic contacts with crucial relevance for full T cell expansion.
Sex differences in vocalizations to familiar or unfamiliar females in mice
Authors: Sasaki Eri , Tomita Yuiri , Kanno Kouta
Published: June 2020

Mice, both wild and laboratory strains, emit ultrasound to communicate. The sex differences between male to female (male–female) and female to female (female– female) ultrasonic vocalizations (USVs) have been discussed for decades. In the present study, we compared the number of USVs emitted to familiar and unfamiliar females by both males (male–female USVs) and females (female–female USVs). We found that females vocalized more to unfamiliar than to familiar females. In contrast, males exhibited more USVs to familiar partners. This sexually dimorphic behavior suggests that mice change their vocal behavior in response to the social context, and their perception of the context is based on social cognition and memory. In addition, because males vocalized more to familiar females, USVs appear to be not just a response to novel things or individuals, but also to be a social response.
Steady-State Regulation of COPII-Dependent Secretory Cargo Sorting by Inositol Trisphosphate Receptors, Calcium, and Penta EF Hand Proteins
Authors: Held Aaron , Lapka Jacob , Sargeant John , Hojanazarova Jennet , Madreiter-Sokolowski Corina , Malli Roland , Graier Wolfgang F. , Hay Jesse C.
Published: June 2020

Recently, we demonstrated that agonist-stimulated Ca2+signaling involving IP3 receptors modulates ER export rates through activation of the penta-EF Hand (PEF) proteins apoptosis-linked gene-2 (ALG-2) and peflin. It is unknown, however, whether IP3Rs and PEF proteins regulate ER export rates at steady state. Here we tested this idea in normal rat kidney (NRK) epithelial cells by manipulation of IP3R isoform expression. Under standard growth conditions, spontaneous cytosolic Ca2+oscillations occurred simultaneously in successive groups of contiguous cells, generating intercellular Ca2+waves (ICWs) that moved across the monolayer periodically. Depletion of IP3R-3, typically the least promiscuous IP3R isoform, caused increased cell participation in ICWs in unstimulated cells. The increased spontaneous signaling was sufficient to cause increased ALG-2 and Sec31A, and decreased peflin localization at ER exit sites (ERES), resulting in increased ER-to-Golgi transport of the COPII client cargo VSV-G. The elevated ER-to-Golgi transport caused greater concentration of VSV-G at ERES and had reciprocal effects on transport of VSV-G and a bulk-flow cargo, though both cargos equally required Sec31A. Inactivation of client cargo sorting using 4-phenylbutyrate (4-PBA) had opposing reciprocal effects on client and bulk-flow cargo and neutralized any effect of ALG-2 activation on transport. This work extends our knowledge of ALG-2 mechanisms and indicates that in NRK cells, IP3R isoforms regulate homeostatic Ca2+signaling that helps determine the basal secretion rate and stringency of COPII-dependent cargo sorting.
Visual processing and fold-change detection by the larva of the simple chordateCiona
Authors: Borba Cezar , Kourakis Matthew J. , Schwennicke Shea , Brasnic Lorena , Smith William C.
Published: June 2020

Visual processing transforms the complex visual world into useful information.Ciona, a close relative of vertebrates, has one of the simplest nervous systems known, yet has a range of visuomotor behaviors. Among them are negative phototaxis and a looming-shadow response. These two behaviors are mediated by separate photoreceptor groups acting via distinct, but overlapping, neural circuits. We show here that processing circuits underlying both behaviors transform visual inputs to generate fold-change detection (FCD) outputs. In FCD, the response scales with the relative fold changes in input, but is invariant to the overall magnitude of the stimulus. Several different circuit architectures can generate FCD responses. Both the behavioral outputs and the putative circuitry for the two visuomotor behaviors point to them using different FCD circuits. Pharmacological treatment points to circuits in the posterior brain vesicle ofCiona, a region we speculate shares homology with the vertebrate midbrain, as important for FCD.
The BCG dilemma: linear versus non-linear correlation models over the time of the COVID-19 pandemic
Authors: Lopez-Campos Guillermo , Hawthorne Christopher , Valvano Miguel A.
Published: June 2020

In this work we have analysed the use of two different correlation metrics and two different datasets, detecting differences in the extent and directionality of the correlation between COVID-19 infection and BCG immunization. Correlation between COVID-19 infection, death rates and BCG immunization is strongly affected by the correlation metrics and so will be their biological interpretation.
Sentinel surveillance of SARS-CoV-2 in wastewater anticipates the occurrence of COVID-19 cases
Authors: Chavarria-Miró Gemma , Anfruns-Estrada Eduard , Guix Susana , Paraira Miquel , Galofré Belén , Sánchez Gloria , Pintó Rosa M. , Bosch Albert
Published: June 2020

SARS-CoV-2 was detected in Barcelona sewage long before the declaration of the first COVID-19 case, indicating that the infection was present in the population before the first imported case was reported. Sentinel surveillance of SARS-CoV-2 in wastewater would enable adoption of immediate measures in the event of future COVID-19 waves.

Article Summary Line

SARS-CoV-2 genomes occur in sewage long before the declaration of COVID-19 cases among the population.
Impacts of regional climate on the COVID-19 fatality in 88 countries
Authors: Wen Minneng , Chen Liyuan
Published: June 2020

The COVID-19 pandemic had led to 500000 confirmed death by June 30, 2020. We combined the number of monthly confirmed new cases and deaths with latitude, temperature, humidity, rainfall, and sunshine ultraviolet (UV) to explore the climate impacts on COVID-19 fatality in 88 countries. There was a significant decrease in overall case-fatality rate in May and June (from 8.17% to 4.99% and 3.22%). The fatality in temperate marine regions was the highest (11.13%). The fatality was 5.71% in high latitudes (≥30°) but only 3.73% in low latitudes (<30°). The fatality was 6.76% in cold regions (<20°C) but only 3.90% in hot regions (≥20°C). The fatality was 5.87% in rainy regions (≥40mm) but only 3.33% in rainless regions (<40mm). The fatality was 6.57% in cloudy regions (<50) but only 3.86% in sunny regions (≥50). Traveling to hot sunny regions without pollution is a strategy for risk reduction.
Short‐term change in water availability influences thermoregulation behaviours in a dry‐skinned ectotherm
Authors: Rozen‐Rechels David , Farigoule Pauline , Agostini Simon , Badiane Arnaud , Meylan Sandrine , Le Galliard Jean‐François
Published: June 2020

Mechanistic models of terrestrial ectotherms predict that climate warming will induce activity restriction due to heat stress and loss of shade, leading to the extinction of numerous populations. Such models rely on the assumption that activity patterns are dictated by simple temperature thresholds independent of changes in water availability. However, changes in water availability may further influence thermoregulation behaviour of ectotherms through dehydration risk perception, changes in water balance or changes in microclimatic conditions.

Here, we experimentally assess the interactive effects of thermal conditions and water availability on activity patterns, shade selection and thermoregulation efficiency in a model ectothermic species.

Thermoregulation behaviour of adult common lizards Zootoca vivipara was monitored in outdoor mesocosms as we manipulated water availability, providing water as mist in the morning and free‐standing water during the daytime. We recorded operative temperatures and micro‐meteorological conditions to infer thermal constraints and dehydration risk.

Activity and shade selection were better predicted by continuous changes in thermal conditions and dehydration risk, respectively, than by threshold functions. In addition, water supplementation increased activity in males and reduced shade selection in both sexes, most probably as a behavioural response to the perception of a stronger dehydration risk. Water supplementation also influenced the thermal quality of the environment, which in turn altered daily activity patterns and thermoregulation statistics.

This demonstrates that dual effects of heat and water stress on activity patterns may lead to stronger activity restriction as a result of climate change than currently predicted.
Impacts of selective logging on the oxidative status of tropical understorey birds
Authors: Messina Simone , Edwards David P. , AbdElgawad Hamada , Beemster Gerrit T. S. , Tomassi Suzanne , Benedick Suzan , Eens Marcel , Costantini David
Published: June 2020

Selective logging is the dominant form of human disturbance in tropical forests, driving changes in the abundance of vertebrate and invertebrate populations relative to undisturbed old‐growth forests.

A key unresolved question is understanding which physiological mechanisms underlie different responses of species and functional groups to selective logging. Regulation of oxidative status is thought to be one major physiological mechanism underlying the capability of species to cope with environmental changes.

Using a correlational cross‐sectional approach, we compared a number of oxidative status markers among 15 understorey bird species in unlogged and selectively logged forest in Borneo in relation to their feeding guild. We then tested how variation of markers between forest types was associated with that in population abundance.

Birds living in logged forests had a higher activity of the antioxidant enzyme superoxide dismutase and a different regulation of the glutathione cycle compared to conspecific birds in unlogged forest. However, neither oxidative damage nor oxidized glutathione differed between forest types. We also found that omnivores and insectivores differed significantly in all markers related to the key cellular antioxidant glutathione irrespective of the forest type. Species with higher levels of certain antioxidant markers in a given type of forest were less abundant in that forest type compared to the other.

Our results suggest that there was little long‐term effect of logging (last logging rotation occurred ~15 years prior to the study) on the oxidative status of understorey bird species. However, it is unclear if this was owing to plasticity or evolutionary change. Our correlative results also point to a potential negative association between some antioxidants and population abundance irrespective of the forest type.
Vaginal compared with intramuscular progestogen for preventing preterm birth in high‐risk pregnant women (VICTORIA study): a multicentre, open‐label randomised trial and meta‐analysis
Authors: Choi S‐J , Kwak DW , Kil K , Kim S‐C , Kwon J‐Y , Kim YH , Na S , Bae J‐G , Cha H‐H , Shim J‐Y , Oh KY , Lee KA , Kim SM , Cho IA , Lee SM , Cho GJ , Jo YS , Choi GY , Choi SK , Hur SE , Hwang HS , Kim YJ ,   from The Preterm Birth Research Committee of the Korean Society of Maternal Fetal Medicine
Published: June 2020

Objective

To compare the efficacy of two types of progestogen therapy for preventing preterm birth (PTB) and to review the relevant literature.

Design

A multicentre, randomised, open‐label, equivalence trial and a meta‐analysis.

Setting

Tertiary referral hospitals in South Korea.

Population

Pregnant women with a history of spontaneous PTB or short cervical length (<25 mm).

Methods

Eligible women were screened and randomised at 16‒22 weeks of gestation to receive either 200 mg of vaginal micronised progesterone daily (vaginal group) or an intramuscular injection of 250 mg 17α‐hydroxyprogesterone caproate weekly (IM group). Stratified randomisation was carried out according to participating centres and indications for progestogen therapy. This trial was registered at ClinicalTrials.gov (NCT02304237).

Main outcome measure

Preterm birth (PTB) before 37 weeks of gestation.

Results

A total of 266 women were randomly assigned and a total of 247 women (119 and 128 women in the vaginal and IM groups, respectively) were available for the intention‐to‐treat analysis. Risks of PTB before 37 weeks of gestation did not significantly differ between the two groups (22.7 versus 25.8%, P = 0.571). The difference in PTB risk between the two groups was 3.1% (95% CI −7.6 to 13.8%), which was within the equivalence margin of 15%. The meta‐analysis results showed no significant differences in the risk of PTB between the vaginal and IM progestogen treatments.

Conclusion

Compared with vaginal progesterone, treatment with intramuscular progestin might increase the risk of PTB before 37 weeks of gestation by as much as 13.8%, or reduce the risk by as much as 7.6%, in women with a history of spontaneous PTB or with short cervical length.

Tweetable abstract

Vaginal and intramuscular progestogen showed equivalent efficacy for preventing preterm birth before 37 weeks of gestation.
Phenotyping peach‐allergic patients sensitized to lipid transfer protein and analysing severity biomarkers
Authors: Bogas Gador , Muñoz‐Cano Rosa , Mayorga Cristobalina , Casas Rocio , Bartra Joan , Pérez Natalia , Pascal Mariona , Palomares Francisca , Torres María José , Gómez Francisca
Published: June 2020

Background

Patients with peach allergy due to nsLTP sensitization constitute a heterogeneous group in terms of sensitization profile and severity. This could be due to the presence of additional allergies to pollens. The aim of this study was to analyse the clinical characteristics, sensitization profile and severity of reactions in peach‐allergic patients sensitized to nsLTP from two Mediterranean areas with different pollen exposure.

Methods

Patients with diagnosis of LTP allergy from the Allergy Unit of Hospital Regional Universitario de Malaga (HRUM) and Hospital Clinic de Barcelona (HCB) were prospectively included and classified into two groups; (a) LTP‐monoallergic: those that presented reaction only with peach and (b) LTP‐Allergy: those that presented reaction with peach and at least another plant‐food containing LTP.

Results

A total of 252 patients were included, 235 (93.2%) had LTP‐syndrome and 17 (6.8%) were LTP‐monoallergic. We found a higher percentage of anaphylaxis and delayed onset of symptoms in the LTP‐monoallergic group (P = .02 and P = .04, respectively). Moreover, anaphylaxis was less frequent in patients with profilin sensitization (P = .03). The comparison of patients' data from HRUM with data from HCB showed differences in sensitization to olive tree pollen and profilin (P = .01 and P = .001, respectively).

Conclusion

This study was undertaken to characterize two large group of subjects from to two regions with differing exposures to pollen. We found that more than 90% of peach‐allergic patients in both populations evolved to LTP‐Allergy and showed an early onset. Profilin sensitization could be more useful as a severity biomarker than the number of nsLTP, aeroallergen sensitizations or sIgE levels. This could provide clues regarding sensitization and severity patterns that might be relevant in other geographical areas.
A compendium answering 150 questions on COVID‐19 and SARS‐CoV‐2
Authors: Riggioni Carmen , Comberiati Pasquale , Giovannini Mattia , Agache Ioana , Akdis Mübeccel , Alves‐Correia Magna , Antó Josep M. , Arcolaci Alessandra , Azkur Ahmet Kursat , Azkur Dilek , Beken Burcin , Boccabella Cristina , Bousquet Jean , Breiteneder Heimo , Carvalho Daniela , De las Vecillas Leticia , Diamant Zuzana , Eguiluz‐Gracia Ibon , Eiwegger Thomas , Eyerich Stefanie , Fokkens Wytske , Gao Ya‐dong , Hannachi Farah , Johnston Sebastian L. , Jutel Marek , Karavelia Aspasia , Klimek Ludger , Moya Beatriz , Nadeau Kari C. , O'Hehir Robyn , O'Mahony Liam , Pfaar Oliver , Sanak Marek , Schwarze Jürgen , Sokolowska Milena , Torres María J. , van de Veen Willem , van Zelm Menno C. , Wang De Yun , Zhang Luo , Jiménez‐Saiz Rodrigo , Akdis Cezmi A.
Published: June 2020

In December 2019, China reported the first cases of the coronavirus disease 2019 (COVID‐19). This disease, caused by the severe acute respiratory syndrome–related coronavirus 2 (SARS‐CoV‐2), has developed into a pandemic. To date, it has resulted in ~9 million confirmed cases and caused almost 500 000 related deaths worldwide. Unequivocally, the COVID‐19 pandemic is the gravest health and socioeconomic crisis of our time. In this context, numerous questions have emerged in demand of basic scientific information and evidence‐based medical advice on SARS‐CoV‐2 and COVID‐19. Although the majority of the patients show a very mild, self‐limiting viral respiratory disease, many clinical manifestations in severe patients are unique to COVID‐19, such as severe lymphopenia and eosinopenia, extensive pneumonia, a “cytokine storm” leading to acute respiratory distress syndrome, endothelitis, thromboembolic complications, and multiorgan failure. The epidemiologic features of COVID‐19 are distinctive and have changed throughout the pandemic. Vaccine and drug development studies and clinical trials are rapidly growing at an unprecedented speed. However, basic and clinical research on COVID‐19–related topics should be based on more coordinated high‐quality studies. This paper answers pressing questions, formulated by young clinicians and scientists, on SARS‐CoV‐2, COVID‐19, and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development, and epidemiology. A total of 150 questions were answered by experts in the field providing a comprehensive and practical overview of COVID‐19 and allergic disease.
Inhibition of mite‐induced dermatitis, pruritus, and nerve sprouting in mice by the endothelin receptor antagonist bosentan
Authors: Kido‐Nakahara Makiko , Wang Bing , Ohno Fumitaka , Tsuji Gaku , Ulzii Dugarmaa , Takemura Masaki , Furue Masutaka , Nakahara Takeshi
Published: June 2020

Background

Endothelin‐1 (EDN1) can evoke histamine‐independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL‐25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model.

Methods

We analyzed the mite‐induced AD‐like NC/Nga murine model, which was topically applied with bosentan or ethanol control every day for 3 weeks. We also subjected in vitro primary sensory neuron culture systems to nerve elongation and branching assays after EDN1 stimulation.

Results

Topical application of bosentan significantly attenuated the development of mite‐induced AD‐like skin inflammation, dermatitis scores, ear thickness, scratching bouts, and serum level of thymus and activation‐regulated chemokine in NC/Nga mice. Bosentan application also significantly reduced the gene expression of Il13, Il17, and Ifng in the treated lesions. Histologically, the number of infiltrated dermal cells, the epidermal EDN1 expression, and the number of intraepidermal nerve fibers were significantly inhibited upon bosentan application. While EDN1 significantly elongated the neurites of dorsal root ganglion cells in a dose‐ and time‐dependent manner, bosentan treatment attenuated this.

Conclusions

EDN1 plays a significant role in mite‐induced inflammation and itch. Topical bosentan is a potential protective candidate for AD.
High incidence of radiolucent lines at the implant–cement interface of a new total knee replacement
Authors: Hoskins Wayne , Gorup Peter , Claireaux Harry , Stokes Chris , Bingham Roger
Published: June 2020

Background

Recently introduced total knee arthroplasty (TKA) implants have been linked with the early development of periprosthetic radiolucency (PPRL). The aim of this study was to carry out a retrospective clinical and radiographical analysis of a consecutive series of a new TKA, and to assess the incidence and distribution of PPRL.

Methods

A retrospective review of all new TKA implants performed by a single surgeon at a single hospital between March 2013 and October 2017 was performed. The minimum follow‐up period was 3 months, with ongoing patient review at 6, 12 and 36 months. Sequential post‐operative radiographs were performed to determine the presence of PPRL.

Results

A total of 122 TKAs were identified in 112 patients over the 4.5‐year study period. The average follow‐up time was 21 months (range 3–51 months). PPRL was noted in 29 TKAs (23.8%). When comparing the PPRL group to those without PPRL, there was a difference in body mass index, with body mass index associated with an increased likelihood of PPRL (P = 0.003). There was no difference in constraint of implant (P = 0.818), cement type (P = 0.340), patella resurfacing (P = 0.286), age (P = 0.984) gender (P = 0.376) or initial mechanical axis deviation (P = 0.054) between groups. PPRL were most commonly seen in tibial anterior‐posterior (AP) zone 1 and zone 2 (96.6%), followed by femoral lateral zone 5 (58.6%), tibia lateral zone 1 (55.2%) and tibial lateral zone 2 (53.2%). No patients have required revision surgery.

Conclusion

A high incidence of early PPRL is seen in patients undergoing primary TKA using a new implant system, mainly involving the tibial component. Ongoing clinical and radiological assessment for patients seems warranted based on these findings.
Two‐group Poisson‐Dirichlet mixtures for multiple testing
Authors: Denti Francesco , Guindani Michele , Leisen Fabrizio , Lijoi Antonio , Wadsworth William Duncan , Vannucci Marina
Published: June 2020

The simultaneous testing of multiple hypotheses is common to the analysis of high‐dimensional data sets. The two‐group model, first proposed by Efron, identifies significant comparisons by allocating observations to a mixture of an empirical null and an alternative distribution. In the Bayesian nonparametrics literature, many approaches have suggested using mixtures of Dirichlet Processes in the two‐group model framework. Here, we investigate employing mixtures of two‐parameter Poisson‐Dirichlet Processes instead, and show how they provide a more flexible and effective tool for large‐scale hypothesis testing. Our model further employs nonlocal prior densities to allow separation between the two mixture components. We obtain a closed‐form expression for the exchangeable partition probability function of the two‐group model, which leads to a straightforward Markov Chain Monte Carlo implementation. We compare the performance of our method for large‐scale inference in a simulation study and illustrate its use on both a prostate cancer data set and a case‐control microbiome study of the gastrointestinal tracts in children from underdeveloped countries who have been recently diagnosed with moderate‐to‐severe diarrhea.
Optimality of testing procedures for survival data in the nonproportional hazards setting
Authors: Arfè Andrea , Alexander Brian , Trippa Lorenzo
Published: June 2020

Most statistical tests for treatment effects used in randomized clinical trials with survival outcomes are based on the proportional hazards assumption, which often fails in practice. Data from early exploratory studies may provide evidence of nonproportional hazards, which can guide the choice of alternative tests in the design of practice‐changing confirmatory trials. We developed a test to detect treatment effects in a late‐stage trial, which accounts for the deviations from proportional hazards suggested by early‐stage data. Conditional on early‐stage data, among all tests that control the frequentist Type I error rate at a fixed α level, our testing procedure maximizes the Bayesian predictive probability that the study will demonstrate the efficacy of the experimental treatment. Hence, the proposed test provides a useful benchmark for other tests commonly used in the presence of nonproportional hazards, for example, weighted log‐rank tests. We illustrate this approach in simulations based on data from a published cancer immunotherapy phase III trial.
Gut microbiome, diet, and conservation of endangered langurs in Sri Lanka
Authors: Amato Katherine R. , Kuthyar Sahana , Ekanayake‐Weber Marcy , Salmi Roberta , Snyder‐Mackler Noah , Wijayathunga Lasanthi , Vandercone Rajnish , Lu Amy
Published: June 2020

Understanding the mechanisms by which organisms respond to environmental change is critical to conservation biology. Recent research indicates that the gut microbiome may mediate mammalian responses to the environment and can be used as a biomarker to understand host ecological strategies. Here, we explore the relationship between the gut microbiome, host dietary niche, and potential resilience to habitat alteration using two closely related, sympatric non‐human primate species: the tufted gray langur (Semnopithecus priam) and the purple‐faced langur (Semnopithecus vetulus). The gray langur is suspected to be a habitat generalist less perturbed by anthropogenic disturbance, while the purple‐faced langur is suspected to be a specialist more sensitive to disturbance. To test these characterizations, we assessed the gut microbiome using 16S rRNA gene amplicon sequencing of fecal samples collected from Kaludiyapokuna Forest Reserve, Sri Lanka (gray langur n = 50 samples, purple‐faced langur n = 7 samples). Our results demonstrate that despite strong gut microbial similarities, gray langurs had a more diverse gut microbiome that harbored Prevotella and Akkermansia, taxa involved in starch degradation, while the purple‐faced langur gut microbiome harbored Roseburia, Clostridium, and Ruminococcus, taxa involved in processing plant structural carbohydrates. Compared to related species in other locations, both Sri Lankan langurs harbored more pathogenic bacteria. These differences suggest that gray langurs have more generalist diets, making them more resilient to anthropogenic change, but also indicate that they are not impervious to human encroachment. Our findings suggest that microbiome analyses are an important tool for langur ecology and conservation, and should be integrated into ongoing studies.