bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutralizing activity of broadly neutralizing anti-HIV-1 antibodies against primary African isolates
Authors: Lorenzi Julio C.C. , Mendoza Pilar , Cohen Yehuda Z. , Nogueira Lilian , Lavine Christy , Sapiente Joseph , Seaman Michael S. , Wiatr Marie , Mugo Nelly R. , Mujugira Andrew , Delany Sinead , Lingappa Jairam , Celum Connie , Caskey Marina , Nussenzweig Michel C.
Published: September 2020

Novel therapeutic and preventive strategies are needed to contain the HIV-1 epidemic. Broadly neutralizing human antibodies (bNAbs) with exceptional activity against HIV-1 are currently being tested in HIV-1 prevention trials. The selection of anti-HIV-1 bNAbs for clinical development was primarily guided by theirin vitroneutralizing activity against HIV-1 Env pseudotyped viruses. Here we report on the neutralizing activity of 9 anti-HIV-1 bNAbs now in clinical development against 126 Clade A, C, D PBMC-derived primary African isolates. The neutralizing potency and breadth of the bNAbs tested was significantly reduced compared to pseudotyped viruses panels. The difference in sensitivity between pseudotyped viruses and primary isolates varied from 3-to nearly 100-fold depending on the bNAb and the HIV-1 clade. Thus, the neutralizing activity of bNAbs against primary African isolates differs and cannot be predicted from their activity against pseudovirus panels. The data have significant implications for interpreting the results of ongoing HIV-1 prevention trials.
Within-host competition modulates pneumococcal antibiotic resistance in the pre-vaccination era
Authors: Lourenço José , Daon Yair , Gori Andrea , Obolski Uri
Published: September 2020

Background

Antibiotic treatment is a key tool in the fight against pneumococcal infections. However, the ongoing emergence of antibiotic resistant strains and high frequencies of antibiotic resistance of pneumococci pose a major public health challenge. How and which ecological and evolutionary mechanisms help maintain the coexistence of strains susceptible and resistant to antibiotic treatment remains largely an open question.

Methods/results

Expanding on aStreptococcus pneumoniaemodelling framework, we here explore how both between- and within-host mechanisms of transmission can sustain observed levels of pneumococcal resistance to antibiotics in the pre-vaccination era using a stochastic, individual-based model. Our framework considers that within-host competition for co-colonization between resistant and susceptible strains can arise via pre-existing immunity (immunological competition) or intrinsic fitness differences due to resistance costs (ecological competition). We find that beyond stochasticity, host-population structure or movement at the between-host level, competition at the within-host level can explain observed variation in resistance frequencies.

Conclusion

In a series of simulated scenarios informed by observed pneumococcal data in the European region, we demonstrate that ecological competition for co-colonization can explain much of the variation in co-existence observed at the country level in the pre-vaccination era. This work expands our understanding of how within-host pneumococcal competition facilitates the maintenance of antibiotic resistance in the pre-vaccination era. The demonstration of the effects of such underlying, often unmeasured competition-related components of pneumococcal dynamics improves our understanding of the mechanistic drivers for the emergence and maintenance of antibiotic resistance.
Associations between ADHD symptom remission and white matter microstructure: a longitudinal analysis
Authors: Leenders A.E.M. , Damatac C.G. , Soheili-Nezhad S. , Chauvin R.J.M. , Mennes M.J.J. , Zwiers M.P. , vanRooij D. , Akkermans S.E.A. , Naaijen J. , Franke B. , Buitelaar J.K. , Beckmann C.F. , Sprooten E.
Published: September 2020

Background

Attention-deficit hyperactivity disorder (ADHD) is associated with white matter (WM) microstructure. Our objective was to investigate how WM microstructure is longitudinally related to symptom remission in adolescents and young adults with ADHD.

Methods

We obtained diffusion-weighted imaging (DWI) data from 99 participants at two time points (mean age baseline: 16.91 years, mean age follow-up: 20.57 years). We used voxel-wise Tract-Based Spatial Statistics (TBSS) with permutation-based inference to investigate associations of inattention (IA) and hyperactivity-impulsivity (HI) symptom change with fractional anisotropy (FA) at baseline, follow-up, and change between time points.

Results

Remission of combined HI and IA symptoms was significantly associated with reduced FA at follow-up in the left superior longitudinal fasciculus and the left corticospinal tract (CST) (PFWE=0.038 andPFWE=0.044, respectively), mainly driven by an association between HI remission and follow-up CST FA (PFWE=0.049). There was no significant association of combined symptom decrease with FA at baseline or with changes in FA between the two assessments.

Conclusions

In this longitudinal DWI study of ADHD using dimensional symptom scores, we show that greater symptom decrease is associated with lower follow-up FA in specific WM tracts. Altered FA thus may appear to follow, rather than precede, changes in symptom remission. Our findings indicate divergent WM developmental trajectories between individuals with persistent and remittent ADHD, and support the role of prefrontal and sensorimotor tracts in the remission of ADHD.
NEBULA: a fast negative binomial mixed model for differential expression and co-expression analyses of large-scale multi-subject single-cell data
Authors: He Liang , Kulminski Alexander M.
Published: September 2020

The growing availability of large-scale single-cell data revolutionizes our understanding of biological mechanisms at a finer resolution. In differential expression and co-expression analyses of multi-subject single-cell data, it is important to take into account both subject-level and cell-level overdispersions through negative binomial mixed models (NBMMs). However, the application of NBMMs to large-scale single-cell data is computationally demanding. In this work, we propose an efficient NEgative Binomial mixed model Using a Large-sample Approximation (NEBULA)), which analytically solves the high-dimensional integral in the marginal likelihood instead of using the Laplace approximation. Our benchmarks show that NEBULA dramatically reduces the running time by orders of magnitude compared to existing tools. We showed that NEBULA controlled false positives in identifying marker genes, while a simple negative binomial model produced spurious associations. Leveraging NEBULA, we decomposed between-subject and within-subject overdispersions of an snRNA-seq data set in the frontal cortex comprising ∼80,000 cells from a cohort of 48 individuals for Alzheimer’s diseases (AD). We observed that subpopulations and known subject-level covariates contributed substantially to the overdispersions. We carried out cell-type-specific transcriptome-wide within-subject co-expression analysis ofAPOE. The results revealed thatAPOEwas most co-expressed with multiple AD-related genes, includingCLUandCST3in astrocytes,TREM2and C1q genes in microglia, andITM2B, an inhibitor of the amyloid-beta peptide aggregation, in both cell types. We found that the co-expression patterns were different inAPOE2+andAPOE4+cells in microglia, which suggest an isoform-dependent regulatory role in the immune system through the complement system in microglia. NEBULA opens up a new avenue for the broad application of NBMMs in the analysis of large-scale multi-subject single-cell data.
Population variability in social brain morphology: links to socioeconomic status and health disparity
Authors: Suryoputri Nathania , Kiesow Hannah , Bzdok Danilo
Published: September 2020

Health disparity across layers of society involves reasons beyond the healthcare system. Socioeconomic status (SES) shapes people’s daily interaction with their social environment, and is known to impact various health outcomes. Using generative probabilistic modeling, we investigated health satisfaction and complementary indicators of socioeconomic lifestyle in the human social brain. In a population cohort of ~10,000 UK Biobank participants, our first analysis probed the relationship between health status and subjective social standing (i.e., financial satisfaction). We identified volume effects in participants unhappy with their health in regions of the higher associative cortex, especially the dorsomedial prefrontal cortex (dmPFC) and bilateral temporo-parietal junction (TPJ). Specifically, participants in poor subjective health showed deviations in dmPFC and TPJ volume as a function of financial satisfaction. The second analysis on health status and objective social standing (i.e., household income) revealed volume deviations in regions of the limbic system for individuals feeling unhealthy. In particular, low-SES participants dissatisfied with their health showed deviations in volume distributions in the amygdala and hippocampus bilaterally. Thus, our population-level evidence speaks to the possibility that health status and socioeconomic position have characteristic imprints in social brain differentiation.
Novel Competition test for food rewards reveals stable dominance status in adult male rats
Authors: Costa Diana F , Moita Marta A , Márquez Cristina
Published: September 2020

Social hierarchy is a potent modulator of behavior, that is typically established through overt agonistic interactions between individuals in the group. Once established, social ranks are maintained through subtler interactions allowing the redirection of energy away from agonistic interactions towards other needs. The available tasks for assessing social rank in rats allow the study of the mechanisms by which social hierarches are formed in early phases but fail to assess the maintenance of established hierarchies between stable pairs of animals, which might rely on distinct neurobiological mechanisms. Here we present and validate a novel trial-based dominancy assay, the modified Food Competition test, where established social hierarchies can be identified in the home cage of non-food deprived pairs of male rats. In this task, we introduce a small conflict in the home cage, where access to a new feeder containing palatable pellets can only be gained by one animal at a time. We found that this subtle conflict triggered asymmetric social interactions and resulted in higher consumption of food by one of the animals in the pair, which reliably predicted hierarchy in other tests. Our findings reveal stable dominance status in pair-housed rats and provide a novel tool for the evaluation of established social hierarchies, the modified Food Competition test, that is robust and easy to implement.
Distinct recruitment of feed-forward and recurrent pathways across higher-order areas of mouse visual cortex
Authors: Li Jennifer Y. , Hass Charles A. , Matthews Ian , Kristl Amy C. , Glickfeld Lindsey L.
Published: September 2020

Cortical visual processing transforms features of the external world into increasingly complex and specialized neuronal representations. These transformations arise in part through target-specific routing of information; however, within-area computations may also contribute to area-specific function. Here, we sought to determine whether higher-order visual cortical areas LM, AL, PM, and AM have specialized anatomical and physiological properties by using a combination of whole-cell recordings and optogenetic stimulation of V1 axons in vitro. We discovered area-specific differences in the strength of recruitment of interneurons through feed-forward and recurrent pathways, as well as differences in cell-intrinsic properties and interneuron densities. These differences were most striking when comparing across medial and lateral areas, suggesting that these areas have distinct profiles for net excitability and integration of V1 inputs. Thus, cortical areas are not defined simply by the information they receive, but also by area-specific circuit properties that enable specialized filtering of these inputs.
Muilla lordsburgana(Asparagaceae: Brodiaeoideae), a new species found north of Lordsburg, southwestern New Mexico
Authors: Alexander Patrick J.
Published: September 2020

Abstract

Muilla lordsburganaP.J.Alexander sp. nov. is described from eastern Lordsburg Mesa in the northwestern fringe of the Chihuahuan Desert, southwestern New Mexico. It is very similar toMuilla coronata, a species known in the Mojave Desert of California and a small area of adjacent Nevada. Compared toMuilla coronata, the style and stigma combined are longer, the anthers are longer, the fruits are larger, and the seeds are larger. It has a short flowering period in March, and is difficult or impossible to find at other times of the year. It is narrowly distributed, limited to a band of deep, coarse, sandy soils derived primarily from granite. Several species that are otherwise uncommon in the area also occur in this habitat, includingLogfia depressa, Pectocarya platycarpa, andPlagiobothrys arizonicus. Invasive species, especiallyErodium cicutariumin the winter annual flora, are generally dominant.Muilla lordsburganahas probably been overlooked until now because it is not easy to observe and occurs in habitats that are not attractive to botanists.
Evidence that an HDAC2-targeted ASO persistently upregulates cortical acetylcholine and dopamine signaling via a CREB | Gs positive feedback loop
Authors: Sanders Teresa H.
Published: September 2020

Epigenetic modulation of neural circuits facilitates learning and memory. Here, we examined specific inhibition of histone deacetylase 2 (HDAC2) expression in rats receiving a single intracerebroventricular injection ofHDAC2-targeted anti-sense oligonucleotides (ASOs) one month prior to cognitive testing. TheHDAC2ASO-injected rats displayed increased novelty preference, decreased cortical and hippocampalHDAC2mRNA and protein, and upregulated gene expression that persisted 1-month post-injection. Cortical RNA-seq revealed strongly increased transcription of a subset of cyclic adenosine monophosphate (cAMP)-response element binding (CREB) genes known to influence synaptic plasticity, along with dopamine (DRD1, DRD2) and adenosine (ADORA2A) G-protein-coupled receptors (GPCRs). Our analysis identified evidence of a positive-feedback loop that amplified expression of CREB-regulated Gs GPCRs and genes in cAMP/Gs/Gi signaling pathways. Additionally, we found differential expression of enzymes that shift neurotransmitter biosynthesis away from norepinephrine and toward dopamine and acetylcholine (DBH, CHAT). We also observed increased expression of genes important for neurotransmitter packaging (SV2C, VMAT) and release (SYT9). The data indicate that persistent inhibition ofHDAC2expression enables long-lived enhancement of aspects of cognition through increased cortical transcription of a subset of CREB-regulated genes amplified by a positive-feedback mechanism that increases synaptic plasticity and shifts neurotransmitter balance toward increased dopaminergic and cholinergic signaling.
Fungal symbionts of Arctic zooplankton induce mortality and reduce swimming activity
Authors: Hassett BT , Ershova E , Berge J
Published: September 2020

Zooplankton are key intermediaries between microbes and higher trophic levels. Elevated temperatures in the Arctic are expected to increase metabolic rates, which in turn will result in increased rates of zooplankton production and foraging. We postulate that this may also be tied to elevated incidence of fungi parasitism in key zooplankton species. We present data ofin-situfungal parasitism in the key Arctic zooplankton species complexCalanusspp. We found that >10% ofCalanusspecimens were internally parasitized by fungi that had 100% molecular identity toPenicillium chrysogenum. Experimental studies with two strains ofP. chrysogenumandCalanusspp. revealed an increased mortality effect suggesting that fungi decrease the survival of overwintering zooplankton, which may have cascading effects on higher trophic levels that feed onCalanus. Moreover,Calanusdemonstrated reduced swimming activity in the presence ofP. chyrsogenum, indicating that fungi could affect predator avoidance and vertical migration patterns of zooplankton. Semi-thin sectioning of live zooplankton incubated withP. chrysogenumrevealed the presence of hyphae throughout the body, underscoring the parasitic nature ofP. chrysogenuminCalanus. We hypothesize that as the Arctic warms, the balance between host and pathogen could shift in favor of pathogen reproduction, resulting in a greater effect of fungal pathogens on zooplankton.
Molecular mechanisms for environmentally induced plasticity in the positioning of meiotic recombination at hotspots
Authors: Mukiza Tresor O. , Protacio Reine U. , Davidson Mari K. , Wahls Wayne P.
Published: September 2020

In meiosis, Spo11/Rec12-initiated homologous recombination is clustered at hotspots that regulate its frequency and distribution across the genome. Intriguingly, the intensities and positions of recombination hotspots can change dramatically in response to intracellular and extracellular conditions, and can display epigenetic memory. Here, using the fission yeastSchizosaccharomyces pombe, we reveal mechanisms for hotspot plasticity. We show that each of six hotspot-activating proteins (transcription factors Atf1, Pcr1, Php2, Php3, Php5, Rst2) is rate-limiting for promoting recombination at its own DNA binding site, allowing each class of hotspot to be regulated independently by agonistic and antagonistic signals. We also discovered that the regulatory protein-DNA complexes can establish a recombinationally poised epigenetic state before meiosis. Notably, Atf1 and Pcr1 controlled the activation of DNA sequence-dependent hotspots to which they do not bind; and they do so by regulating the expression of other hotspot-activating proteins. Thus, while each transcription factor activates its own class of DNA sequence-dependent hotspots directly incis, cross-talk between regulatory networks modulates intransthe frequency and positioning of recombination at other classes of DNA sequence-dependent hotspots. We posit that such mechanisms allow cells to alter the frequency distribution of meiotic recombination in response to metabolic states and environmental cues.
The energetics of social signaling during roost location in Spix’s disc-winged bats
Authors: Chaverri Gloriana , Iturralde-Pólit Paula , Sandoval-Herrera Natalia Ivone , Romero-Vásquez Adarli , Cháves-Ramírez Silvia , Sagot Maria
Published: September 2020

Long-term social aggregations are maintained by multiple mechanisms, including the use of acoustic signals, which may nonetheless entail significant energetic costs. To date, however, no studies have gauged whether there are significant energetic costs to social call production in bats, which heavily rely on acoustic communication for a diversity of social tasks. We measure energetic expenditure during acoustic signaling in Spix’s disc-winged bats (Thyroptera tricolor), a species that commonly uses contact calls to locate the ephemeral furled leaves that they use for roosting. To determine the cost of sound production, we measured oxygen consumption using intermittent-flow respirometry methods, with and without social signaling. Our results show that the emission of contact calls significantly increases oxygen consumption; vocal individuals spent, on average, 12.42 kJ more during social signaling trials than they spent during silent trials. Furthermore, production of contact calls during longer periods increased oxygen consumption for males but not for females. We also found that as resting metabolic rates increased in males, there was a decreasing probability that they would emit response calls. These results provide support to the “allocation model”, which predicts that only individuals with lower self-maintenance costs can afford to spend energy in additional activities. Our results provide a step forward in our understanding of how physiology modulates behavior, specifically how the costs of call production and resting metabolic rates may explain the differences in vocal behavior among individuals.

Summary Statement

Spix’s disc-winged bats constantly produce contact calls while searching for roosts, which we show significantly increases an individual’s metabolic rate.
Untargeted LC-MS metabolomics for the analysis of micro-scaled extracellular metabolites fromhepatocytes
Authors: Abdalkader Rodi , Chaleckis Romanas , Meister Isabel , Zhang Pei , Wheelock Craig , Kamei Ken-ichrio
Published: September 2020

Metabolome analysis in micro physiological models is a challenge due to the low volume of cell culture medium (CCM). Here, we report a LC-MS-based untargeted metabolomics protocol for the detection of hepatocyte extracellular metabolites from micro-scale samples of CCM. Using a single LC-MS method we have detected 57 metabolites of which 27 showed >2-fold shifts after 72-hours incubation. We demonstrate that micro-scale CCM samples can be used for modelling micro-physiological temporal dynamics in metabolite intensities.

Graphical Abstract
Emergence of irregular activity in networks of strongly coupled conductance-based neurons
Authors: Sanzeni A. , Histed M.H. , Brunel N.
Published: September 2020

Cortical neurons are characterized by irregular firing and a broad distribution of rates. The balanced state model explains these observations with a cancellation of mean excitatory and inhibitory currents, which makes fluctuations drive firing. In networks of neurons with current-based synapses, the balanced state emerges dynamically if coupling is strong, i.e. if the mean number of synapses per neuronKis large and synaptic efficacy is of order. When synapses are conductance-based, current fluctuations are suppressed when coupling is strong, questioning the applicability of the balanced state idea to biological neural networks. We analyze networks of strongly coupled conductance-based neurons and show that asynchronous irregular activity and broad distributions of rates emerge if synaptic efficacy is of order 1/log(K). In such networks, unlike in the standard balanced state model, current fluctuations are small and firing is maintained by a drift-diffusion balance. This balance emerges dynamically, without fine tuning, if inputs are smaller than a critical value, which depends on synaptic time constants and coupling strength, and is significantly more robust to connection heterogeneities than the classical balanced state model. Our analysis makes experimentally testable predictions of how the network response properties should evolve as input increases.
Temperature and elemental sulfur shape microbial communities in two extremely acidic aquatic volcanic environments
Authors: Rojas-Gätjens Diego , Arce-Rodríguez Alejandro , Puente-Sánchez Fernando , Avendaño Roberto , Libby Eduardo , Mora-Amador Raúl , Rojas-Jimenez Keilor , Fuentes-Schweizer Paola , Pieper Dietmar H , Chavarría Max
Published: September 2020

Aquatic environments of volcanic origin provide an exceptional opportunity to study the adaptations of microbial communities to early planet life conditions such as high temperatures, high metal concentrations, and low pH. Here, we characterized the prokaryotic communities and physicochemical properties of seepage sites at the bottom of the Poas Volcano crater and the Agrio River, two geologically related extremely acidic environments located in the Central Volcanic mountain range of Costa Rica. Both locations hold a very low pH (pH 1.79−2.20) and have high sulfate and iron concentrations (Fe = 47−206 mg/L, SO42- = 1170-2460 mg/L measured as S), but significant differences in their temperature (90.0−95.0°C in the seepages at Poas Volcano versus 19.1−26.6 °C in Agrio River) and in the abundance of elemental sulfur. Based on the analysis of 16S rRNA gene sequences, we determined that Sulfobacillus spp., sulfur-oxidizing bacteria, represented more than half (58.4−78.4%) of the sequences in Poas Volcano seepage sites, while Agrio River was dominated by the iron− and sulfur−oxidizing Leptospirillum (7.4−55.5%) and members of the archeal order Thermoplasmatales (16.0−58.2%). Both environments share some chemical characteristics and part of their microbiota, however the temperature and the presence of reduced sulfur are likely the main distinguishing feature ultimately shaping their microbial communities. Our data suggest that in the Poas Volcano-Agrio River system there is a common metabolism but with specialization of species that adapt to the physicochemical conditions of each environment.
Cyclooxgenase-2 is induced by SARS-CoV-2 infection but does not affect viral entry or replication
Authors: Chen Jennifer S. , Alfajaro Mia Madel , Wei Jin , Chow Ryan D. , Filler Renata B. , Eisenbarth Stephanie C. , Wilen Craig B.
Published: September 2020

Identifying drugs that regulate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its symptoms has been a pressing area of investigation during the coronavirus disease 2019 (COVID-19) pandemic. Nonsteroidal anti-inflammatory drugs (NSAIDs), which are frequently used for the relief of pain and inflammation, could modulate both SARS-CoV-2 infection and the host response to the virus. NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which mediate the production of prostaglandins (PGs). PGE2, one of the most abundant PGs, has diverse biological roles in homeostasis and inflammatory responses. Previous studies have shown that NSAID treatment or inhibition of PGE2receptor signaling leads to upregulation of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2, thus raising concerns that NSAIDs could increase susceptibility to infection. COX/PGE2signaling has also been shown to regulate the replication of many viruses, but it is not yet known whether it plays a role in SARS-CoV-2 replication. The purpose of this study was to dissect the effect of NSAIDs on COVID-19 in terms of SARS-CoV-2 entry and replication. We found that SARS-CoV-2 infection induced COX-2 upregulation in diverse human cell culture and mouse systems. However, suppression of COX-2/PGE2signaling by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect onACE2expression, viral entry, or viral replication. Our findings suggest that COX-2 signaling driven by SARS-CoV-2 may instead play a role in regulating the lung inflammation and injury observed in COVID-19 patients.

Importance

Public health officials have raised concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating symptoms of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). NSAIDs function by inhibiting the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). These enzymes are critical for the generation of prostaglandins, lipid molecules with diverse roles in maintaining homeostasis as well as regulating the inflammatory response. While COX-1/COX-2 signaling pathways have been shown to affect the replication of many viruses, their effect on SARS-CoV-2 infection remains unknown. We found that SARS-CoV-2 infection induced COX-2 expression in both human cell culture systems and mouse models. However, inhibition of COX-2 activity with NSAIDs did not affect SARS-CoV-2 entry or replication. Our findings suggest that COX-2 signaling may instead regulate the lung inflammation observed in COVID-19 patients, which is an important area for future studies.
CARD8 inflammasome mediates pyroptosis of HIV-1-infected cells by sensing viral protease activity
Authors: Wang Qiankun , Gao Hongbo , Clark Kolin M. , Tang Pengfei , Harlan Gray H. , Kutluay Sebla B. , DeSelm Carl J. , Presti Rachel M. , Shan Liang
Published: September 2020

HIV-1 has high mutation rates and exists as mutant swarms in the host. Rapid evolution of HIV-1 allows the virus to outpace host immune system, leading to viral persistence. Novel approaches to target immutable components are needed to clear HIV-1 infection. Here we report a pattern-recognition receptor CARD8 that senses enzymatic activity of the HIV-1 protease, which is indispensable for the virus. All subtypes of HIV-1 can be sensed by CARD8 despite substantial viral diversity. HIV-1 evades CARD8 sensing because the viral protease remains inactive in infected cells prior to viral budding. Induction of premature intracellular activation of the viral protease triggers CARD8 inflammasome-mediated pyroptosis of HIV-1-infected cells. This strategy leads to clearance of latent HIV-1 in patient CD4+T cells after virus reactivation. Taken together, our study identifies CARD8 as an inflammasome sensor of HIV-1 that holds promise as a strategy for clearance of persistent HIV-1 infection.
Virus-Like Particle Based-Vaccines Elicit Neutralizing Antibodies against the HIV-1 Fusion Peptide
Authors: Mogus Alemu Tekewe , Liu Lihong , Jia Manxue , Ajayi Diane T. , Xu Kai , Kong Rui , Huang Jing , Yu Jian ,   VRC Production Program, Kwong Peter D. , Mascola John R. , Ho David D. , Tsuji Moriya , Chackerian Bryce
Published: September 2020

Broadly neutralizing antibodies (bnAbs) isolated from HIV-infected individuals delineate vulnerable sites on the HIV envelope glycoprotein that are potential vaccine targets. A linear epitope at the N-terminal region of the HIV-1 fusion peptide (FP8) is the primary target of VRC34.01, a bnAb that neutralizes ~50% of primary HIV isolates. FP8 has attracted attention as a potential HIV vaccine target because it is a simple linear epitope. Here, we used platform technologies based on RNA bacteriophage virus-like particles (VLPs) to develop multivalent vaccines targeting the FP8 epitope. We produced recombinant MS2 VLPs displaying the FP8 peptide and we chemically conjugated synthetic FP8 peptides to Qβ VLPs. Both recombinant and conjugated FP8-VLPs induced high titers of FP8-specific antibodies in mice. A heterologous prime-boost-boost regimen employing the two FP8-VLP vaccines and native envelope trimer was the most effective approach for eliciting HIV-1 neutralizing antibodies. Given the potent immunogenicity of VLP-based vaccines, this vaccination strategy – inspired by bnAb-guided epitope mapping, VLP bioengineering, and optimal prime-boost immunization strategies – may be an effective strategy for eliciting bnAb responses against HIV.
METTL3 inhibitors for epitranscriptomic modulation of cellular processes
Authors: Moroz-Omori Elena V. , Huang Danzhi , Bedi Rajiv Kumar , Cheriyamkunnel Sherry J. , Bochenkova Elena , Dolbois Aymeric , Rzeczkowski Maciej D. , Wiedmer Lars , Caflisch Amedeo
Published: September 2020

The methylase METTL3 is the writer enzyme of the N6-methyladenosine (m6A) modification of RNA. Using a structure-based drug discovery approach, we identified a METTL3 inhibitor (UZH1a) with potency in a biochemical assay of 280 nM, while its enantiomerUZH1bis 100 times less active. The crystal structure of the complex of METTL3 withUZH1aillustrates the interactions that make it selective against protein methyltransferases. We observed a dose-dependent reduction in m6A methylation level of mRNA in several cell lines treated withUZH1aalready after 16 h of exposure, as determined by triple-quadrupole LC mass spectrometry, while its enantiomerUZH1bwas essentially inactive at concentrations up to 100 μM. Interestingly, the kinetics of m6A level reduction in mRNAs followed a first-order reaction model, with a half-decay time τ of 1.8 h and a maximum m6A inhibition level of 70%, which is in line with the previously observed shorter half-life of m6A-modified mRNAs. Notably, treatment with the compounds did not alter cellular METTL3 levels, ruling out indirect effects on m6A levels. The effect of the m6A level depletion byUZH1adirectly translated into growth inhibition of MOLM-13 leukemia cells, under short-term and long-term culture. Incubation of the MOLM-13 cells withUZH1a, but not withUZH1b, resulted in increased cell apoptosis and cell cycle arrest already after 16 h of incubation. Interestingly, other cell lines sensitive to METTL3 level (U2Os, HEK293T) did not reveal statistically significant differences betweenUZH1aandUZH1bin a cell viability assay, confirming that the degree of reliance on m6A signalling for survival can vary between cancers/cell types.
The impact of second language immersion: Evidence from a bi-directional longitudinal cross-linguistic study
Authors: Brice Henry , Frost Stephen , Bick Atira S. , Molfese Peter J. , Rueckl Jay G. , Pugh Kenneth R. , Frost Ram
Published: September 2020

Brice et al. (2019) presented data from the first epoch of a longitudinal study of the neurobiological underpinnings of first-language (L1) and second-language (L2) processing. Results showed a similar network of activation for reading across L1 and L2, as well as significant convergence of print and speech processing across a network of left-hemisphere regions in both L1 and L2 with greater activation and convergence for L2 in anterior regions, and greater activation and convergence for L1 in posterior regions of the reading network. Here, we present the first look at longitudinal changes in these effects. L2 showed relatively few changes in activation, with some shifts in the weighting between ventral and dorsal processing. L1, however, showed more widespread differences in processing, suggesting that the neurobiological footprint of reading is dynamic, with both L1 and L2 impacting each other. Print/speech convergence showed very little longitudinal change, suggesting that it is a stable marker of the differences in L1 and L2 processing.
Reduced competence to arboviruses following the sustainable invasion ofWolbachiainto nativeAedes aegyptifrom Niterói, Southeastern Brazil
Authors: Gesto João Silveira Moledo , Ribeiro Gabriel Sylvestre , Rocha Marcele Neves , Dias Fernando Braga Stehling , Peixoto Julia , Carvalho Fabiano Duarte , Pereira Thiago Nunes , Moreira Luciano Andrade
Published: September 2020

Field release ofWolbachia-infectedAedes aegyptihas emerged as a promising solution to manage the transmission of dengue, Zika and chikungunya in endemic areas across the globe. Through an efficient self-dispersing mechanism, and the ability to induce virus-blocking properties,Wolbachiaoffers an unmatched potential to gradually modify wildAe. aegyptipopulations turning them unsuitable disease vectors. Here in this work, a proof-of-concept field trial was carried out in a small community of Niterói, greater Rio de Janeiro. Following the release ofWolbachia-infected eggs, we reported a successful invasion and long-term establishment of the bacterium across the territory, as denoted by stable high-infection indexes (>80%). We have also demonstrated that refractoriness to dengue and Zika viruses, either thorough oral-feeding or intra-thoracic saliva challenging assays, were maintained over the adaptation to the natural environment of Southeastern Brazil. These findings further supportWolbachia’s ability to invade localAe. aegyptipopulations and impair disease transmission, and shall pave the way for future epidemiological and economic impact assessments.
Intrinsic and extrinsic noise are distinguishable in a synthesis – export – degradation model of mRNA production
Authors: Gorin Gennady , Pachter Lior
Published: September 2020

Intrinsic and extrinsic noise sources in gene expression, originating respectively from transcriptional stochasticity and from differences between cells, complicate the determination of transcriptional models. In particularly degenerate cases, the two noise sources are altogether impossible to distinguish. However, the incorporation of downstream processing, such as the mRNA splicing and export implicated in gene expression buffering, recovers the ability to identify the relevant source of noise. We report analytical copy-number distributions, discuss the noise sources’ qualitative effects on lower moments, and provide simulation routines for both models.
Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C
Authors: Posada-Céspedes Susana , Van Zyl Gert , Montazeri Hesam , Kuipers Jack , Rhee Soo-Yon , Kouyos Roger , Günthard Huldrych F. , Beerenwinkel Niko
Published: September 2020

Although combination antiretoviral therapies seem to be effective at controlling HIV-1 infections regardless of the viral subtype, there is increasing evidence for subtype-specific drug resistance mutations. The order and rates at which resistance mutations accumulate in different subtypes also remain poorly understood. Here, we present a methodology for the comparison of mutational pathways in different HIV-1 subtypes, based on Hidden Conjunctive Bayesian Networks (H-CBN), a probabilistic model for inferring mutational pathways from cross-sectional genotype data. We introduce a Monte Carlo sampling scheme for learning H-CBN models on a large number of resistance mutations and develop a statistical test to assess differences in the inferred mutational pathways between two groups. We apply this method to the temporal progression of mutations conferring resistance to the protease inhibitor lopinavir in a large cross-sectional data set of South African individuals living with HIV-1 subtype C, as well as a genotype data set of subtype B infections derived from the Stanford HIV Drug Resistance Database and the Swiss HIV Cohort Study. We find strong support for different initial mutational events in the protease, namely at residue 46 in subtype B and at residue 82 in subtype C. Our results also show that mutations can accumulate along various alternative paths within subtypes, as opposed to a unique total temporal ordering. Furthermore, the maximum likelihood mutational networks for subtypes B and C share only 7 edges (Jaccard distance 0.802) and imply many different evolutionary pathways. Beyond HIV drug resistance, the statistical methodology is applicable more generally for the comparison of inferred mutational pathways between any two groups.

Author summary

There is a disparity in the distribution of infections by HIV-1 subtype in the world. Subtype B is predominant in America, Western Europe and Australia, and most therapeutic strategies are based on research and clinical studies on this subtype. However, non-B subtypes represent the majority of global HIV-1 infections; e.g., subtype C alone accounts for nearly half of all HIV-1 infections. We present a statistical framework enabling the comparison of patterns of accumulating mutations in different HIV-1 subtypes. Specifically, we study lopinavir resistance pathways in HIV-1 subtypes B versus C, but the methodology can be generally applied to compare the temporal ordering of genetic events in different subgroups.
Modulation of metabolic hormone signalingviaa circadian hormone and a biogenic amine inDrosophila melanogaster
Authors: Braco Jason T. , Saunders Cecil J. , Nelson Jonathan M. , Johnson Erik C.
Published: September 2020

In insects, Adipokinetic hormone is the primary hormone responsible for the mobilization of stored energy. While a growing body of evidence has solidified AKH’s role in modulating the physiological and behavioral responses to metabolic stress, little is known about the upstream endocrine circuit that directly regulates AKH release. We evaluated the AKH-expressing cell transcriptome to identify potential regulatory elements controlling AKH cell activity, and found that a number of receptors show consistent expression levels, including all known dopamine receptors, dopamine ecdysone receptor (DopEcR), Dopamine 2-like receptor (D2R), Dopamine 1-like receptor 2 (DopR2), DopR, and the Pigment Dispersing Factor (PDFR). We tested the consequences of targeted genetic knockdown and found that RNAi elements targeting each dopamine receptor caused a significant reduction in survival under starvation. In contrast, PDFR knockdown significantly extended lifespan under starvation whereas expression of a tethered PDF in AKH cells resulted in a significantly shorter lifespan during starvation. These manipulations also caused various changes in locomotor activity under starvation. Specifically, there were higher amounts of locomotor activity in dopamine receptor knockdowns, in both replete and starved states. PDFR knockdown resulted in increased locomotion during replete conditions and locomotion levels that were comparable to wild-type during starvation. Expression of a membrane-tethered PDF led to decreased locomotion under baseline and starvation. Next, we used live-cell imaging to evaluate the acute effects of the ligands for these receptors (dopamine, ecdysone, and Pigment Dispersing Factor) on AKH cell activation. Dopamine application led to a transient increase in intracellular calcium in a sugar-dependent manner. Furthermore, we found that co-application of dopamine and ecdysone led to a complete loss of this response, suggesting that these two hormones are acting antagonistically. We also found that PDF application directly led to an increase in cAMP in AKH cells, and that this response was dependent on expression of the PDFR in AKH cells. Together these results suggest a complex circuit in which multiple hormones act on AKH cells to modulate metabolic state.
Bacterial profiles and their antimicrobial susceptibility pattern of Isolates from inanimate hospital environments at Tikur Anbessa Specialized Teaching Hospital, Addis Ababa, Ethiopia
Authors: Sebre Shemse , Erku Woldaregay , Seman Aminu , Awoke Tewachw , Desalegn Zelalem , Mihret Wude , Mihret Adane , Abebe Tamrat
Published: September 2020

Microbial contamination of hospital environment plays an important role in the spread of health care-associated infections (HCAIs). This study was conducted to determine bacterial contamination, bacterial profiles and antimicrobial susceptibility pattern of bacterial isolates from environmental surfaces and medical equipment. A cross-sectional study was conducted at Tikur Anbessa Specialized Hospital (TASH) from June to September, 2018. A total of 164 inanimate surfaces located at intensive care units (ICUs) and operation theaters (OTs) were swabbed. All isolates were identified by using routine bacterial culture, Gram staining and a panel of biochemical tests. For each identified bacteria, antibiogram profiles were determined by the Kirby Bauer disk diffusion method according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI). Out of the 164 swabbed samples, 141 (86%) were positive for bacterial growth. The predominant bacteria identified from OTs and ICUs wereS. aureus(23% vs 11.5%),Acinetobacterspp (3.8% vs 17.5%) and Coagulase negativeStaphylococcus(CONS) (12.6% vs 2.7%) respectively. Linens were the most contaminated materials among items studied at the hospital (14.8%). The proportions of resistance among Gram-positive bacteria (GPB) were high for penicillin (92.8%), cefoxitin (83.5%) and erythromycin (54.1%). However, the most effective antibiotics were clindamycin with only 10.4% and 16.5% resistance rates, respectively. The antimicrobial susceptibility profiles of Gram-negative bacteria (GNB) revealed that the most effective antibiotics were amikacin, ciprofloxacin, and gentamicin with resistance rate of 25%, 37.5%, and 46.3%, respectively. However, the highest resistance was recorded against ampicillin (97.5%), ceftazidime (91.3%), ceftriaxone (91.3%) and aztreonam (90%). The inanimate surfaces near immediate patient environment and commonly touched medical equipment within OTs and ICUs are reservoirs of potential pathogenic bacteria that could predispose critically ill patients to acquire HCAIs. The proportions of antimicrobial resistance profile of the isolates are much higher from studied clean inanimate environments.
SARS-CoV-2 and Malayan pangolin coronavirus infect human endoderm, ectoderm and induced lung progenitor cells
Authors: Hong Bixia , Lai Xinyuan , Chen Yangzhen , Luo Tianming , An Xiaoping , Song Lihua , Zhuang Hui , Fan Huahao , Li Tong , Xiang Kuanhui , Tong Yigang
Published: September 2020

Since the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in several somatic cells, little is known about the infection of SASRS-CoV-2 and its related pangolin coronavirus (GX_P2V). Here we present for the first time that SARS-CoV-2 pseudovirus and GX_P2V could infect lung progenitor and even anterior foregut endoderm cells causing these cells death, which differentiated from human embryonic stem cells (hESCs). The infection and replication of SARS-CoV-2 and GX_P2V were inhibited when treated with whey protein of breastmilk and Remdesivir, confirming that these two viruses could infect lung progenitor and even anterior foregut endoderm. Moreover, we found that SARS-CoV-2 pseudovirus could infect endoderm and ectoderm. We found that whey protein blocked SARS-CoV-2 infecting these cells. In line with the SARS-CoV-2 results, GX_P2V could also infected endoderm and ectoderm, and also was inhibited by Remdesivir treatment. Although expressing coronavirus related receptor such as ACE2 and TMPRSS2, mesoderm cells are not permissive for SARS-CoV-2 and GX_P2V infection, which needed further to study the mechanisms. Interestingly, we also found that hESCs, which also express ACE2 and TMPRSS2 markers, are permissive for GX_P2V but not SARS-CoV-2 pseudovirus infection and replication, indicating the widespread cell types for GX_P2V infection. Heparin treatment blocked efficiently viral infection. These results provided insight that these stem cells maybe provided a stable repository of coronavirus function or genome. The potential consequence of SARS-CoV-2 and animal coronavirus such as GX_P2V infection in hESCs, germ layer and induced progenitors should be closely monitored.
Microbial map of the world’s vineyards: Applying the concept of microbialterroiron a global scale
Authors: Gobbi A. , Acedo A. , Imam N. , Santini R.G. , Ortiz-Álvarez R. , Ellegaard-Jensen L. , Belda I. , Hansen L.H.
Published: September 2020

The specific microbial biodiversity linked to a particular vineyard location is reported to be a crucial aspect, in conjunction with edaphic, climatic and human factors, in the concept of wineterroir. These biogeographical patterns are known as microbialterroirs.

This study applied an HTS amplicon library approach in order to conduct a global survey of vineyards’ soil microbial communities. In all, soil samples from 200 vineyards on four continents were analysed in an attempt to establish the basis for the development of a vineyard soil microbiome map to represent microbial wineterroirson a global scale.

This study established links between vineyard locations and microbial biodiversity on different scales: between continents and countries, and between different wine regions within the same country. Geography had a strong effect on the composition of microbial communities on a global scale, which was also maintained on a country scale. Furthermore, a predictive model was developed, based on random forest analyses, to discriminate between microbial patterns in order to identify the geographical source of the samples with reasonable precision. Finally this study is the first to describe the microbial community of new and northern wine-producing regions, such as Denmark, that could be of great interest for viticulture adaptation in a context of climate change.