bluuebunny/crossref_metadata_2025 huggingface dataset:
DOPA pheomelanin is increased in nigral neuromelanin of Parkinson’s disease and it exacerbates alpha-synuclein neurotoxicity
Authors: Cai Waijiao , Wakamatsu Kazumasa , Zucca Fabio A. , Yang Kai , Mohamadzadehhonarvar Niyaz , Srivastava Pranay , Holly Gabriel , Casella Luigi , Ito Shosuke , Zecca Luigi , Chen Xiqun
Published: July 2022

Objective

Neuromelanin (NM) of the human substantia nigra (SN) has long been proposed as a key factor contributing to dopaminergic neuron vulnerability in Parkinson’s disease (PD). NM consists of pheomelanin and eumelanin moieties. Evidence supports that pheomelanin and eumelanin possess distinct chemical and biological characteristics. The present study aimed to investigate the relative composition and specific roles of pheomelanin and eumelanin moieties of NM in PD.

Methods

Pheomelanin and eumelanin components of NM in postmortem SN tissues from patients with PD were assessed by chemical degradation methods and compared with those from control subjects as well as patients with Alzheimer’s disease (AD). Additionally, synthetic pheomelanin and eumelanin were used to investigate their differential impacts on dopaminergic neuronal survival in a mouse model of PD overexpressing alpha-synuclein in the SN.

Results

We identified increased L-3,4-dihydroxyphenylalanine (DOPA) pheomelanin and increased ratios of dopamine (DA) pheomelanin markers to DA in PD SN compared to the controls. Eumelanins derived from both DOPA and DA were reduced in PD group. Melanin markers were unaltered in AD SN compared to the controls. Furthermore, we showed exacerbated dopaminergic neurodegeneration by synthetic DOPA pheomelanin and attenuated DA deficit by synthetic DOPA eumelanin in an alpha-synuclein mouse model of PD.

Conclusion

Our study provides insights into the different roles of pheomelanin and eumelanin moieties in PD pathophysiology. It forms a foundation for further investigations on pheomelanin and eumelanin individually as biomarkers and therapeutic targets for PD.
Pathway Analysis Through Mutual Information
Authors: Jeuken Gustavo S. , Käll Lukas
Published: July 2022

Pathway analysis comes in many forms. Most are seeking to establish a connection between the activity of a certain biological pathway and a difference in phenotype, often relying on an upstream differential expression analysis to establish the difference between case and control. This process usually models this relationship using many assumptions, often of a linear nature, and may also involve statistical tests where the calculation of false discovery rates is not trivial.

Here, we propose a new method for pathway analysis, MIPath, that relies on information theoretical principles, and therefore is absent of a model for the nature of the association between pathway activity and phenotype, resulting on a very minimal set of assumptions. For this, we construct a different graph of samples for each pathway and score the association between the structure of this graph and any phenotype variable using Mutual Information, while adjusting for the effects of random chance in each score.

Our experiments show that this method produces robust and reproducible scores that successfully result in a high rank for target pathways on single cell datasets, outperforming established methods for pathway analysis on these same conditions.
Nitrogen competition is the general mechanism underlying cnidarian-Symbiodiniaceae symbioses
Authors: Cui Guoxin , Mi Jianing , Moret Alessandro , Zhong Huawen , Hung Shiou-Han , Al-Babili Salim , Aranda Manuel
Published: July 2022

Symbiotic associations with Symbiodiniaceae have evolved independently across a diverse range of cnidarian taxa including reef-building corals, anemones and jellyfish, yet the molecular mechanisms underlying their regulation and repeated evolution are still elusive. Here we show that despite their independent evolution, cnidarian hosts employ the same mechanism of symbiont control in which symbiont-derived glucose is used to assimilate nitrogenous waste via amino acid biosynthesis to limit the availability of nitrogen to the symbionts. In this metabolic interaction, glucose significantly reduces symbiont density while ammonium promotes symbiont proliferation. We show that glucose-derived 13C and ammonium-derived 15N are co-incorporated into amino acids by the hosts. Metabolic differences between the hosts further suggest that corals are more susceptible to environmental stress and symbiosis breakdown due to their increased energy demands to satisfy calcification. Our results reveal the general metabolic interaction underlying these symbioses and provide a parsimonious explanation for their repeated evolution.
Photosynthetic-product-dependent Activation of Plasma Membrane H+-ATPase and Nitrate Uptake in Arabidopsis Leaves
Authors: Kinoshita Satoru N. , Suzuki Takamasa , Kiba Takatoshi , Sakakibara Hitoshi , Kinoshita Toshinori
Published: July 2022

Plasma membrane (PM) H+-ATPase is a pivotal enzyme for plant growth and development that acts as a primary transporter and is activated by phosphorylation of the penultimate residue, threonine, at the C-terminus. Photosynthetically active radiation activates PM H+-ATPase via phosphorylation in mesophyll cells ofArabidopsis thaliana, and phosphorylation of PM H+-ATPase depends on photosynthesis and photosynthesis-related sugar supplementation, such as sucrose, fructose and glucose. However, the molecular mechanism and the physiological role of photosynthesis-dependent PM H+-ATPase activation are still unknown. Analysis using sugar analogues, such as palatinose, turanose, and 2-deoxy glucose, revealed that sucrose metabolites and products of glycolysis such as pyruvate induce phosphorylation of PM H+-ATPase. Transcriptome analysis showed that novel isoform of theSmall Auxin Up RNAgenes,SAUR30, is upregulated in a light- and sucrose-dependent manner. Time course analyzes of sucrose supplementation showed that phosphorylation level of PM H+-ATPase increased within 10 min, but expression level ofSAUR30increased later than 10 min. The results suggest two temporal regulations may participate in the regulation of PM H+-ATPase. Interestingly, a15NO3-uptake assay in leaves showed that light increases15NO3-uptake, and that increment of15NO3-uptake depends on PM H+-ATPase activity. The results opened the possibility of physiological role of photosynthesis-dependent PM H+-ATPase activation in the uptake of NO3-. We speculate that PM H+-ATPase may connect photosynthesis and nitrogen metabolism in leaves.
Formate-induced CO tolerance and innovative methanogenesis inhibition in co-fermentation of syngas and plant biomass for carboxylate production
Authors: Baleeiro Flávio C. F. , Varchmin Lukas , Kleinsteuber Sabine , Sträuber Heike , Neumann Anke
Published: July 2022

Production of monocarboxylates using microbial communities is highly dependent on local and degradable biomass feedstocks. Syngas or different mixtures of H2, CO, and CO2can be co-fed to a fermenter to alleviate this dependence. To understand the effects of adding these gases during anaerobic fermentation of plant biomass, a series of batch experiments was carried out with different syngas compositions and corn silage (pH 6.0, 32°C). Co-fermentation of syngas with corn silage increased the overall carboxylate yield per gram of volatile solids (VS) by up to 44% (0.36 ± 0.07 g gVS-1; in comparison to 0.23 ± 0.04 g gVS-1with a N2/CO2headspace), despite slowing down biomass degradation. Ethylene and CO exerted a synergistic effect in preventing methanogenesis, leading to net carbon fixation. Less than 12% of the electrons were misrouted to CH4when either 15 kPa CO or 5 kPa CO + 1.5 kPa ethylene was used. CO increased the selectivity to acetate and propionate, which accounted for 86% (electron equivalents) of all products at 49 kPa CO, by favoring lactic acid bacteria and actinobacteria overn-butyrate andn-caproate producers. This happened even when an inoculum pre-acclimatized to syngas and lactate was used. Intriguingly, the effect of CO onn-butyrate andn-caproate production was reversed when formate was present in the broth. The concept of co-fermenting syngas and plant biomass shows promise in two aspects: by making anaerobic fermentation a carbon-fixing process and by increasing the production of propionate and acetate. Testing the concept in a continuous process could improve selectivity ton-butyrate andn-caproate by enriching chain-elongating bacteria adapted to CO and complex biomass.
Metformin protects trabecular meshwork against oxidative injury via activating integrin/ROCK signals
Authors: Xu Lijuan , Zhang Xinyao , Zhao Yin , Cao Yang , Liang Yuanbo
Published: July 2022

Background

This study aimed to investigate the protective effect of metformin on the trabecular meshwork (TM) and explore its molecular mechanisms in vivo and in vitro.

Methods

Ocular hypertension (OHT) mouse models were induced with dexamethasone (DEX) and further treated with metformin to determine its IOP lowering effect. Cultured human TM cells (HTMC) were pre-stimulated with tert-butyl hydroperoxide (tBHP) to induce oxidative damage and then supplemented with metformin for another 24 h. The expression of fibrotic markers and integrin/ROCK signals, including α-SMA, TGF-β, fibronectin, F-actin, integrin beta 1, Rho-associated kinase (ROCK)1/2, AMP-activated protein kinase (AMPK), myosin light chain 1 (MLC 1), and F-actin were determined by western blotting (WB) and immunofluorescence (IF). Reactive oxygen species (ROS) content was analysed using flow cytometry (FCM).

Results

Administration of metformin reduced the elevated IOP and alleviated the fibrotic activity of aqueous humour outflow in OHT models. Additionally, metformin rearranged the disordered cytoskeleton in the TM both in vivo and in vitro. Furthermore, metformin significantly inhibited ROS production and activated integrin/ROCK signalling induced by tBHP in HTMC.

Conclusion

Metformin reduced the elevated IOP in steroid-induced OHT mouse models and exerted its protective effects against oxidative injury by regulating cytoskeleton remodelling through the integrin/ROCK pathway. This study provides new insights into metformin use and preclinical evidence for the potential treatment of primary open-angle glaucoma.
A DARPin-based molecular toolset to probe gephyrin and inhibitory synapse biology
Authors: Campbell Benjamin F. N. , Dittmann Antje , Dreier Birgit , Plückthun Andreas , Tyagarajan Shiva K.
Published: July 2022

Neuroscience currently requires the use of antibodies to study synaptic proteins, where antibody binding is used as a correlate to define the presence, plasticity, and regulation of synapses. Gephyrin is an inhibitory synaptic scaffolding protein used to mark GABAergic and glycinergic postsynaptic sites. Despite the importance of gephyrin in modulating inhibitory transmission, its study is currently limited by the tractability of available reagents. Designed Ankyrin Repeat Proteins (DARPins) are a class of synthetic protein binder derived from diverse libraries by in vitro selection, and tested by high-throughput screening to produce specific binders. In order to generate a functionally diverse toolset for studying inhibitory synapses, we screened a DARPin library against gephyrin mutants representing both phosphorylated and dephosphorylated states. We validated the robust use of anti-gephyrin DARPin clones for morphological identification of gephyrin clusters in rodent neuron culture and brain tissue, discovering previously overlooked clusters. This DARPin-based toolset includes clones with heterogenous gephyrin binding modes that allowed for identification of the most extensive gephyrin interactome to date, and defined novel classes of putative interactors, creating a framework for understanding gephyrin’s non-synaptic functions. This study demonstrates anti-gephyrin DARPins as a versatile platform for studying inhibitory synapses in an unprecedented manner.
In-depth study of tomato and weed viromes reveals undiscovered plant virus diversity in an agroecosystem
Authors: Rivarez Mark Paul Selda , Pecman Anja , Bačnik Katarina , Maksimović Carvalho Ferreira Olivera , Vučurović Ana , Seljak Gabrijel , Mehle Nataša , Gutiérrez-Aguirre Ion , Ravnikar Maja , Kutnjak Denis
Published: July 2022

Background

In agroecosystems, viruses are well known to influence crop health and a few cause phytosanitary and economic problems, but their diversity in non-crop plants and role outside the disease perspective is less known. An extensive virome exploration that includes both crop and diverse weed plants is therefore needed to better understand roles of viruses in agroecosystems. Such unbiased exploration is possible through viromics, which could generate biological and ecological insights from immense high-throughput sequencing (HTS) data.

Results

Here, we implemented HTS-based viromics to explore viral diversity in tomatoes and weeds in farming areas at a nation-wide scale. We detected 125 viruses, including 79 novel species, wherein 65 were found exclusively in weeds. This spanned 21 higher-level plant virus taxa dominated by Potyviridae, Rhabdoviridae, and Tombusviridae, and four non-plant virus families. We detected viruses of non-plant hosts and viroid-like sequences, and demonstrated infectivity of a novel tobamovirus in plants of Solanaceae family. Diversities of predominant tomato viruses were variable, in some cases, comparable to that of global isolates of same species. We phylogenetically classified novel viruses, and showed links between a subgroup of phylogenetically-related rhabdoviruses to their taxonomically-related host plants. Ten classified viruses detected in tomatoes were also detected in weeds, which might indicate possible role of weeds as their reservoirs, and that these viruses could be exchanged between the two compartments.

Conclusions

We showed that even in relatively well studied agroecosystems, such as tomato farms, a large part of very diverse plant viromes can still be unknown and is mostly present in understudied non-crop plants. The overlapping presence of viruses in tomatoes and weeds implicate possible presence of virus reservoir and possible exchange between the weed and crop compartments, which may influence weed management decisions. The observed variability and widespread presence of predominant tomato viruses and the infectivity of a novel tobamovirus in solanaceous plants, provided foundation for further investigation of virus disease dynamics and their effect on tomato health. The extensive insights we generated from such in-depth agroecosystem virome exploration will be valuable in anticipating possible emergences of plant virus diseases, and would serve as baseline for further post-discovery characterization studies.
High Frequency Oscillations (250-500Hz) in Animal Models of Alzheimer’s Disease and Two Animal Models of Epilepsy
Authors: Lisgaras Christos Panagiotis , Scharfman Helen E.
Published: July 2022

Objective

To test the hypothesis that high frequency oscillations (HFOs) between 250 and 500Hz occur in mouse models of Alzheimer’s disease (AD) and thus are not unique to epilepsy.

Methods

Experiments were conducted in three mouse models of AD: Tg2576 mice that simulate a form of familial AD, presenilin 2 knock-out (PS2KO) mice, and the Ts65Dn model of Down’s syndrome. We recorded HFOs using wideband (0.1-500Hz, 2kHz) intra-hippocampal and cortical surface EEG at 1month until 24months-old during wakefulness, slow wave sleep (SWS) and rapid eye movement (REM) sleep. Interictal spikes (IIS) and seizures were also analyzed for the possible presence of HFOs. Comparisons were made to the intra-hippocampal kainic acid and pilocarpine models of epilepsy.

Results

We describe for the first time that hippocampal and cortical HFOs are a new EEG abnormality in AD mouse models. HFOs occurred in all transgenic mice but no controls. They were also detectable as early as 1month of age and prior to amyloid-β plaque neuropathology. HFOs were most frequent during SWS (vs. REM or wakefulness). Notably, HFOs in the AD and epilepsy models were indistinguishable in both spectral frequency and duration. HFOs also occurred during IIS and seizures in the AD models, although with altered spectral properties compared to isolated HFOs.

Significance

Our data demonstrate that HFOs, an epilepsy biomarker with high translational value, are not unique to epilepsy and thus not disease specific. Our findings also strengthen the idea of hyperexcitability in AD and its significant overlap with epilepsy. HFOs in AD mouse models may serve as an EEG biomarker which is detectable from the scalp and thus amenable to non-invasive detection in people at risk for AD.

KEY POINTS

High frequency oscillations (HFOs, 250-500Hz) occur in mouse models of Alzheimer’s disease

HFOs are detectable from the hippocampus and overlying cortex

HFOs are most frequent during slow wave sleep

HFOs in AD mouse models resemble HFOs in two animal models of epilepsy

HFOs can be detected during interictal spikes and seizures in the AD models
Intestinal Epithelial Heat Shock Protein 25/27 integrates host and microbial drivers of mucosal restitution following inflammatory injury
Authors: Cham Candace M. , Messer Jeannette S. , Lake Joash , Zhu Xiaorong , Tao Yun , He Lei , Weber Christopher R. , Lin Fanfei , Dai Zhanghan , Tong Jinlu , Temelkova Sara , Rubin David T. , Liu Cambrian , Chang Eugene B.
Published: July 2022

Mucosal healing following inflammatory injury is poorly understood and often neglected, despite being the best indicator of long-term outcomes in inflammatory bowel diseases. We report here that the enigmatic small molecular weight heat shock protein, Hsp25 (the human form is Hsp27), plays a vital role in converging microbial and host factors to promote pSTAT3-mediated mucosal healing. In wild type mice, the proximal-to-distal gradient of intestinal epithelial cell (IEC) Hsp25 expression is dependent on microbial cues. Patients with left-sided ulcerative colitis, however, show reduced levels of Hsp27 expression in both uninvolved and involved areas compared to normal colons of non-IBD patients. In mice with global or IEC-specific Hsp25 gene-targeted deletion, impaired mucosal healing with development of hallmarks of chronic disease are observed following DSS-induced or TNBS-induced colitis, whereas mucosal restitution is accelerated in IEC-specific overexpressing Hsp25 transgenic mice. In colonic IECs derived from these murine lines, Hsp25 binds and stabilizes a phospho-STAT3/YAP nuclear complex stimulated by IL-22 to sustain its wound healing gene programming. Thus, our findings provide insight into the mechanism of action of IEC Hsp25/27 in integrating host and microbial drivers of mucosal restitution, which can be leveraged to develop novel approaches for achieving and maintaining remission in complex immune disorders like IBD.
Odd-Even Oddball Task: Evaluating Event-Related Potentials (ERPs) during Word Discrimination Compared to Speech-Token and Tone Discrimination
Authors: Voola Marcus , Nguyen An T. , Marinovic Welber , Rajan Gunesh , Tavora-Vieira Dayse
Published: July 2022

The use of tonal and speech token auditory oddball tasks has been used abundantly in past literature; however, it has been argued that tasks using non-word sounds fail to capture the higher-level ability to interpret and discriminate stimuli based on meaning which are critical to language comprehension. As such this study aims to examine how neural signals associated with discrimination and evaluation-processes (P3b) from semantic stimuli compare with those elicited by pure tones and speech tokens.

This study comprises of two experiments, both containing thirteen adults (Exp 1: (Mean(SD)age = 25.20(3.89) years and Exp 2: Mean(SD)age = 25.3(3.79) years) with normal hearing in both ears (PTA ≤ 20dB HL). Scalp electroencephalography and auditory event related potentials was recorded in free field whilst they completed three different oddball tasks: 1) Tones, 2) Speech tokens and 3) Odd/Even numbers. In experiment two, the duration of each stimulus was the same.

P3b peak latency was significantly different between all three tasks, in both experiments. P3b amplitude was identified to be sensitive to reaction time, with tasks that have a large reaction time variability resulting in the P3b amplitude to be smeared out, thereby reducing the amplitude size.

The findings from this study highlight the need to take into consideration all factors of the task before attributing any effects to any additional process such as semantic processing and mental effort. Furthermore, it highlights the need for more cautious interpretation of P3b results in auditory oddball tasks.
Event-Related Potentials of Single Sided Deaf Cochlear Implant Users – Using a Semantic Oddball Paradigm in Noise
Authors: Voola Marcus , Wedekind Andre , Nguyen An T. , Marinovic Welber , Rajan Gunesh , Tavora-Vieira Dayse
Published: July 2022

Objective

In individuals with single sided deafness (SSD), which is characterised by a profound hearing loss in one ear and normal hearing in the contralateral ear, binaural input is no longer present. A cochlear implant (CI) is the only way to restore functional hearing in the profoundly deaf ear, with previous literature demonstrating improvements in speech in noise intelligibility with the provision of a CI. However, we currently have a limited understanding of the neural processes involved (e.g., how the brain integrates the electrical signal produced by the CI with the acoustic signal produced by the normal hearing ear) and how the modulation of these processes with CI contributes to improved speech in noise intelligibility. Using a semantic oddball paradigm presented in the presence of background noise, this study aims to investigate how the provision of CI impacts speech in noise perception of SSD CI users.

Method

High density electroencephalography (EEG) from twelve SSD-CI participants was recorded whilst they completed a semantic acoustic oddball task. All participants completed the oddball task in three different free field conditions with the speech and noise coming from different speakers. The three tasks were 1) with the CI-On in background noise, 2) with the CI-Off in background noise and 3) with the CI-On without background noise (Control). We examined task-performance (RT, subjective listening effort, and accuracy) and measured N2N4 and P3b event-related brain potentials (ERPs) linked to the discrimination and evaluation of task relevant stimuli. Speech in noise and sound localisation abilities was also measured.

Results

Reaction time was significantly different between all tasks with CI-On (M(SE) = 809(39.9) ms) having faster RTs than CI-Off (M(SE) = 845(39.9) ms) and Control (M(SE) = 785(39.9) ms) being the fastest condition. The Control condition exhibited a significantly shorter N2N4 and P3b area latency when compared to the other two conditions. However, despite these differences noticed in RTs and area latency, we observed similar results between all three conditions for N2N4 and P3b difference area.

Conclusion

The inconsistency between the behavioural and neural results suggest that EEG may not be a reliable measure of cognitive effort. This rationale is further supported by the different explanations used in past studies to explain N2N4 and P3b effects. Future studies should look to alternative measures of auditory processing (e.g., pupillometry) to get a deeper understanding of the underlying auditory processes that facilitate speech in noise intelligibility.
An improved graph representation learning method for drug-target interaction prediction over heterogeneous biological information graph
Authors: Zhao Bo-Wei , Su Xiao-Rui , You Zhu-Hong , Hu Peng-Wei , Hu Lun
Published: July 2022

The prediction task of the relationships between drugs and targets plays a significant role in the process of new drug discovery. Computational-based strategies for predicting drug-target interactions (DTIs) are regarded as a high-efficiency way. Moreover, recent studies adopted a graph neural network (GNN) to discover underlying DTIs and achieved better performance. Although these inductive methods can straightway learn biomolecules’ latent representations, they have an over-smoothing phenomenon in the course of obtaining the rich neighborhood information of each node in the biological information network, which further leads to a consistent feature representation of each node. To address the above issues, a novel model, called iGRLDTI, is proposed to precisely identify new DTIs based on an improved graph representation learning strategy. Specifically, iGRLDTI first constructs a biological information graph (BIG) by calculating the biological knowledge of drugs and targets with the relationships between them. Then, an improved graph representation learning strategy is designed to capture the enriched feature representations of drugs and targets. Finally, the Gradient Boosting Decision Tree classifier is applied to predict potential DTIs. Experimental results demonstrate that iGRLDTI yields better performance by comparing it with other state-of-the-art models on the benchmark dataset. Besides, our case studies denote that iGRLDTI can successfully identify unknown DTIs according to the improved feature representations of drugs and targets.
KIPEs3: Automatic annotation of biosynthesis pathways
Authors: Rempel Andreas , Choudhary Nancy , Pucker Boas
Published: July 2022

Flavonoids and carotenoids are pigments involved in stress mitigation and numerous other processes. Both pigment classes can contribute to flower and fruit coloration. Flavonoid aglycones and carotenoids are produced by a pathway that is largely conserved across land plants. Glycosylations, acylations, and methylations of the flavonoid aglycones can be species-specific and lead to a plethora of biochemically diverse flavonoids. We previously developed KIPEs for the automatic annotation of biosynthesis pathways and presented an application on the flavonoid aglycone biosynthesis.

KIPEs3 is an improved version with additional features and the potential to identify not just the core biosynthesis players, but also candidates involved in the decoration steps and in the transport of flavonoids. Functionality of KIPEs3 is demonstrated through the analysis of the flavonoid biosynthesis inArabidopsis thalianaNd-1,Capsella grandiflora, andDioscorea dumetorum. We demonstrate the applicability of KIPEs to other pathways by adding the carotenoid biosynthesis to the repertoire. As a technical proof of concept, the carotenoid biosynthesis was analyzed in the same species andDaucus carota. KIPEs3 is available as an online service to enable access without prior bioinformatics experience.

KIPEs3 facilitates the automatic annotation and analysis of biosynthesis pathways with a consistent and high quality in a large number of plant species. Numerous genome sequencing projects are generating a huge amount of data sets that can be analyzed to identify evolutionary patterns and promising candidate genes for biotechnological and breeding applications.
The circadian clock controls temporal and spatial patterns of floral development in sunflower
Authors: Marshall Carine M. , Thompson Veronica L. , Creux Nicky M. , Harmer Stacey L.
Published: July 2022

Biological rhythms are ubiquitous. They can be generated by circadian oscillators, which produce daily rhythms in physiology and behavior, as well as by developmental oscillators such as the segmentation clock, which produces modular developmental units in a periodic fashion. Here, we show that the circadian clock controls the timing of late-stage floret development, or anthesis, in domesticated sunflower. In these plants, what appears to be a single inflorescence consists of up to thousands of individual florets tightly packed onto a capitulum disk. While early floret development occurs continuously across capitula to generate iconic spiral phyllotaxy, during anthesis floret development occurs in discrete ring-like pseudowhorls with up to hundreds of florets undergoing simultaneous maturation. We demonstrate circadian regulation of floral organ growth and show that the effects of light on this process are time-of-day dependent. Disruption of circadian rhythms in floral organ development causes loss of pseudowhorl formation. Thus, we show that the sunflower circadian clock acts in concert with environmental response pathways to tightly synchronize the anthesis of hundreds of florets each day, generating spatial patterns on the developing capitulum disk. This coordinated mass release of floral rewards at predictable times of day likely promotes pollinator visits and plant reproductive success.
Ocean acidification increases susceptibility to sub-zero air temperatures in ecosystem engineers (Mytilus sp.): a limit to poleward range shifts
Authors: Thyrring Jakob , MacLeod Colin D. , Marshall Katie E. , Kennedy Jessica , Tremblay Réjean , Harley Christopher D. G.
Published: July 2022

Ongoing climate change has caused rapidly increasing temperatures, and an unprecedented decline in seawater pH, known as ocean acidification. Increasing temperatures are redistributing species towards higher and cooler latitudes which are most affected by ocean acidification. Whilst the persistence of intertidal species in cold environments is related to their capacity to resist sub-zero air temperatures, studies have never considered the interacting impacts of ocean acidification and freeze stress on species survival and distribution. A full-factorial experiment was used to study whether ocean acidification increases mortality in Mytilus spp. following sub-zero air temperature exposure. We examined physiological processes behind variation in freeze tolerance using 1H NMR metabolomics, analyses of fatty acids, and amino acid composition. We show that low pH conditions (pH = 7.5) significantly decrease freeze tolerance in both intertidal and subtidal populations of Mytilus spp. Under current day pH conditions (pH = 7.9), intertidal M. trossulus were more freeze tolerant than subtidal M. trossulus and M. galloprovincialis. Opposite, under low pH conditions, subtidal M. trossulus was more freeze tolerant than the other groups. We observed a marked shift from negative to positive metabolite-metabolite correlations across species under low pH conditions, but there was no evidence that the concentration of individual metabolites or amino acids affected freeze tolerance. Finally, pH-induced changes in the composition of cell membrane phospholipid fatty acids had no effect on survival. These results suggest that ocean acidification can offset the poleward expanding facilitated by warming, and that reduced freeze tolerance could result in a niche squeeze if temperatures become lethal at the equatorward edge.
The changing landscape of respiratory viruses contributing to respiratory hospitalisations: results from a hospital-based surveillance in Quebec, Canada, 2012-13 to 2021-22
Authors: Gilca Rodica , Amini Rachid , Carazo Sara , Frenette Charles , Boivin Guy , Charest Hugues , Dumaresq Jeannot
Published: July 2022

Background

A comprehensive description of the combined effect of SARS-CoV-2 and respiratory viruses (RV) other than SARS-CoV-2 (ORV) on hospitalisations is lacking.

Aim

To compare viral etiology of acute respiratory infections (ARI) hospitalisations before and during two pandemic years from a surveillance network in Quebec, Canada.

Method

We compared detection of ORV and SARS-CoV-2 during 2020-21 and 2021-22 to 8 pre-pandemic influenza seasons in patients hospitalised with ARI who were tested systematically by a multiplex PCR.

Results

During pre-pandemic influenza seasons, overall RV detection was 92.7% (1,493) (48.3% respiratory syncytial virus (RSV)) in children and 62.8% (4,339) (40.1% influenza) in adults. Overall RV detection in 2020-21 was 58.6% (29) in children (all ORV) and 43.7% (333) in adults (3.4% ORV, 40.3% SARS-CoV2, both including coinfections). In 2021-22 overall RV detection was 91.0% (201) in children (82.8% ORV, 8.1% SARS-CoV-2, both including coinfections) and 55.5% (527) in adults (14.1% ORV, 41.4% SARS-CoV-2, both including coinfections).

Virtually no influenza was detected in 2020-21 and in 2021-22 up to epi-week 2022-9 presented here; no RSV was detected in 2020-21. In 2021-22, detection of RSV was comparable to pre-pandemic years but with an unusually early season. There were significant differences in ORV and SARS-CoV-2 detection between time periods and age groups.

Conclusion

Significant continuous shifts in age distribution and viral etiology of ARI hospitalisations occurred during two pandemic years. This reflects evolving RV epidemiology and underscores the need for increased scrutiny of ARI hospitalisation etiology to inform tailored public health recommendations.
Glycolysis-enhancing α1-adrenergic antagonists modify cognitive symptoms related to Parkinson’s disease
Authors: Weber Matthew A. , Sivakumar Kartik , Tabakovic Ervina E. , Oya Mayu , Aldridge Georgina M. , Zhang Qiang , Simmering Jacob E. , Narayanan Nandakumar S.
Published: July 2022

Terazosin is an α1-adrenergic receptor antagonist that enhances glycolysis and increases cellular ATP by binding to the enzyme phosphoglycerate kinase 1 (PGK1). Recent work has shown that terazosin is protective against motor dysfunction in rodent models of Parkinson’s disease (PD) and is associated with slowed motor symptom progression in PD patients. However, PD is also characterized by profound cognitive symptoms. We tested the hypothesis that terazosin protects against cognitive symptoms associated with PD. We report two main results. First, in rodents with ventral tegmental area (VTA) dopamine depletion modeling aspects of PD-related cognitive dysfunction, we found that terazosin preserved cognitive function and produced a non-statistically significant trend towards protected VTA tyrosine hydroxylase levels. Second, we found that after matching for demographics, comorbidities, and disease duration, PD patients newly started on terazosin, alfuzosin, or doxazosin had a lower hazard of being diagnosed with dementia compared to tamsulosin, an α1-adrenergic receptor antagonist that does not enhance glycolysis. Together, these findings suggest that in addition to slowing motor symptom progression, glycolysis-enhancing drugs protect against cognitive symptoms of PD.
Comparative effectiveness of fenfluramine versus cannabidiol in their licensed indications for the treatment of seizures in Dravet Syndrome: a systematic review and network meta-analysis
Authors: Linley Warren , Schwenkglenks Matthias , Hawkins Neil , Toward Toby
Published: July 2022

Purpose: Fenfluramine and cannabidiol are licensed as add-on therapies for the treatment of seizures in Dravet syndrome (DS); however, there are no comparative trials of these therapies. We assessed the comparative effectiveness of fenfluramine (with/without concomitant stiripentol) versus cannabidiol (with/irrespective of concomitant clobazam, using robust indirect comparison methods.
Methods: We systematically searched for randomised controlled trials (RCTs) of licensed regimens published up to 30 November 2021. Outcomes of interest were placebo-adjusted reductions from baseline in monthly convulsive seizure frequency (MCSF), the odds of achieving >25%, >50%, >75% and 100% reductions from baseline in MCSF, and the odds of experiencing serious treatment-emergent adverse events (TEAEs). Comparative efficacy and safety were assessed using Bayesian network meta-analysis (NMA). PROSPERO registration: CRD42021296141.
Results: We identified five relevant placebo-controlled RCTs (three for fenfluramine; two for cannabidiol; N=667). All licensed regimens of fenfluramine and cannabidiol significantly reduced MCSF compared with standard of care. When indirectly comparing fenfluramine 0.7mg/kg/day (without concomitant stiripentol) and fenfluramine 0.4mg/kg/day (with concomitant stiripentol) versus cannabidiol 10mg/kg/day, irrespective of clobazam use, the mean differences in placebo-adjusted reduction from baseline in MCSF were 47.3% (95%CrI: 18.9, 64.7) and 35.1% (1.0, 57.5), respectively, and versus cannabidiol 10mg/kg/day plus clobazam were 37.2% (2.0, 59.7) and 23.5% (-20.2, 51.3), respectively. For these outcomes, and for the proportion of patients achieving >25%, >50% and >75% reductions in MCSF, Bayesian treatment ranking indicated >99% probability that fenfluramine is the most effective therapy versus <1% probability for cannabidiol 10 or 20mg/kg/day (maximum recommended dose), with/irrespective of concomitant clobazam. Fenfluramine regimens had lower odds of serious TEAEs.
Conclusion: NMA using RCT data indicates fenfluramine provides superior convulsive seizure control compared to cannabidiol across all licensed dose regimens and is comparatively well-tolerated. Fenfluramine may meet the need for a highly effective and tolerable add-on therapy to control seizures in DS.
Pre-existing population immunity and SARS-CoV-2 variant establishment and dominance dynamics in the United States: An ecological study
Authors: Ankomah Pierre O. , Siedner Mark J. , Bhattacharyya Roby P.
Published: July 2022

We conducted an ecological analysis of the dynamics of Delta and Omicron establishment and dominance in U.S. states. Omicron became the dominant circulating variant later in states with higher population-level immunity. By contrast, population immunity did not impact the rates of transition from prior variants to either Delta or Omicron.
DIFFERENTIAL SARS-COV-2 ANTIGEN SPECIFICITY OF THE HUMORAL RESPONSE IN INACTIVATED VIRUS-VACCINATED, CONVALESCENT, AND BREAKTHROUGH SUBJECTS
Authors: Duarte Luisa F. , Vázquez Yaneisi , Diethelm-Varela Benjamín , Pavez Valentina , Berríos-Rojas Roslye , White Jessica A. , Kalergis Alexis M. , Bueno Susan M. , González Pablo A.
Published: July 2022

Analytical methods for the differential determination between natural infection with SARS- CoV-2 vs. immunity elicited by vaccination or infection after immunization (breakthrough cases) represent attractive new research venues in the context of the ongoing COVID-19 pandemic caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Herein, we set out to compare humoral responses against several SARS-CoV-2 structural and non-structural proteins in infected unvaccinated (convalescent), vaccinated, as well as vaccinated and infected (breakthrough) individuals. Our results indicate that immunization with an inactivated SARS-CoV-2 vaccine (CoronaVac) induces significantly higher levels of IgG antibodies against the membrane (M) protein of SARS-CoV-2 as compared to convalescent subjects both, after the primary vaccination schedule and after a booster dose. Moreover, we found that CoronaVac-immunized individuals, after receiving a third vaccine shot, display equivalent levels of N-specific IgG antibodies as convalescents subjects. Regarding non-structural viral proteins, for the two viral proteins ORF3a and NSP8, IgG antibodies were produced in more than 50% of the convalescent subjects. Finally, a logistic regression model and a receiver operating characteristic (ROC) analysis show that combined detection of M and N proteins may be useful as a biomarker to differentiate breakthrough cases from vaccinated and convalescent individuals that did not receive prior vaccination. Taken together, these results suggest that multiple SARS-CoV-2 antigens may be used as differential biomarkers for distinguishing natural infection from vaccination.
Speech-In-Noise Comprehension is Improved When Viewing a Deep-Neural-Network-Generated Talking Face
Authors: Shan Tong , Xu Chenliang , Duan Zhiyao , Maddox Ross K.
Published: July 2022

Listening in a noisy environment is challenging, but many previous studies have demonstrated that comprehension of speech can be substantially improved by looking at the talker’s face. We recently developed a deep neural network (DNN) based system that generates movies of a talking face from speech audio and a single face image. In this study, we aimed to quantify the benefits that such a system can bring to speech comprehension, especially in noise. The target speech audio was masked with signal to noise ratios of −9, −6, −3, and 0 dB and was presented to subjects in three audio-visual (AV) stimulus conditions: 1) synthesized AV: audio with the synthesized talking face movie; 2) natural AV: audio with the original movie from the corpus; and 3) audio-only: audio with a static image of the talker. Subjects were asked to type the sentences they heard in each trial and keyword recognition was quantified for each condition. Overall, performance in the synthesized AV condition fell approximately halfway between the other two conditions, showing a marked improvement over the audio-only control but still falling short of the natural AV condition. Every subject showed some benefit from the synthetic AV stimulus. The results of this study support the idea that a DNN-based model that generates a talking face from speech audio can meaningfully enhance comprehension in noisy environments, and has the potential to be used as a “visual hearing aid.”
Clonal breeding strategies to harness heterosis: insights from stochastic simulation
Authors: Labroo Marlee R. , Endelman Jeffrey B. , Gemenet Dorcus C. , Werner Christian R. , Gaynor R. Chris , Covarrubias-Pazaran Giovanny E.
Published: July 2022

To produce genetic gain, hybrid crop breeding can change the additive as well as dominance genetic value of populations, which can lead to utilization of heterosis. A common hybrid breeding strategy is reciprocal recurrent selection (RRS), in which parents of hybrids are typically recycled within pools based on general combining ability (GCA). However, the relative performance of RRS and other possible breeding strategies have not been thoroughly compared. RRS can have relatively increased costs and longer cycle lengths which reduce genetic gain, but these are sometimes outweighed by its ability to harness heterosis due to dominance and increase genetic gain. Here, we used stochastic simulation to compare gain per unit cost of various clonal breeding strategies with different amounts of population inbreeding depression and heterosis due to dominance, relative cycle lengths, time horizons, estimation methods, selection intensities, and ploidy levels. In diploids with phenotypic selection at high intensity, whether RRS was the optimal breeding strategy depended on the initial population heterosis. However, in diploids with rapid cycling genomic selection at high intensity, RRS was the optimal breeding strategy after 50 years over almost all amounts of initial population heterosis under the study assumptions. RRS required more population heterosis to outperform other strategies as its relative cycle length increased and as selection intensity decreased. Use of diploid fully inbred parents vs. outbred parents with RRS typically did not affect genetic gain. In autopolyploids, RRS typically was not beneficial regardless of the amount of population inbreeding depression.

Key Message

Reciprocal recurrent selection sometimes increases genetic gain per unit cost in clonal diploids with heterosis due to dominance, but it typically does not benefit autopolyploids.
Longitudinal, multi-platform metagenomics yields a high-quality genomic catalog and guides an in vitro model for cheese communities
Authors: Saak Christina C. , Pierce Emily C. , Dinh Cong B. , Portik Daniel , Hall Richard , Ashby Meredith , Dutton Rachel J.
Published: July 2022

Microbiomes are intricately intertwined with human health, geochemical cycles and food production. While many microbiomes of interest are highly complex and experimentally intractable, cheese rind microbiomes have proven powerful model systems for the study of microbial interactions. To provide a more comprehensive view of the genomic potential and temporal dynamics of cheese rind communities, we combine longitudinal, multi-platform metagenomics of three ripening washed-rind cheeses with whole genome sequencing of community isolates. Sequencing-based approaches revealed a highly reproducible microbial succession in each cheese, co-existence of closely related Psychrobacter species, and enabled the prediction of plasmid and phage diversity and their host associations. Combined with culture-based approaches, we established a genomic catalog and a paired 16-member in vitro washed rind cheese system. The combination of multi-platform metagenomic time-series data and an in vitro model provides a rich resource for further investigation of cheese rind microbiomes both computationally and experimentally.

Importance

Metagenome sequencing can provide great insights into microbiome composition and function and help researchers develop testable hypotheses. Model microbiomes, such as those composed of cheese rind bacteria and fungi, then allow the testing of these hypotheses in a controlled manner. Here, we first generate an extensive longitudinal metagenomic dataset. This dataset reveals successional dynamics, yields a phyla-spanning bacterial genomic catalog, associates mobile genetic elements with their hosts and provides insights into functional enrichment of Psychrobacter in the cheese environment. Next, we show that members of the washed-rind cheese microbiome lend themselves to in vitro community reconstruction. This paired metagenomic data and in vitro system can thus be used as a platform for generating and testing hypotheses related to the dynamics within, and functions associated with, cheese rind microbiomes.
Identification of a Broadly Fibrogenic Macrophage Subset Induced by Type 3 Inflammation in Human and Murine Liver and Lung Fibrosis
Authors: Fabre Thomas , Barron Alexander M. S. , Christensen Stephen M. , Asano Shoh , Wadsworth Marc H. , Chen Xiao , Wang Ju , McMahon James , Schlerman Frank , White Alexis , Kravarik Kellie , Fisher Andrew J. , Borthwick Lee A. , Hart Kevin M. , Henderson Neil C. , Wynn Thomas A. , Dower Ken
Published: July 2022

Macrophages are central orchestrators of the tissue response to injury, with distinct macrophage activation states playing key roles in the progression and resolution of fibrosis. Identifying the unique fibrogenic macrophages that are found in human fibrotic tissues could lead to new and more effective treatments for fibrosis. Here we used human liver and lung single cell RNA sequencing datasets to identify a unique subset of CD9+ TREM2+ macrophages expressing SPP1, GPNMB, FABP5, and CD63 with strong pro-fibrotic activity. This population was validated across orthogonal techniques, species and tissues. These macrophages were enriched at the outside edges of scarring adjacent to activated mesenchymal cells, and in the fibrotic niche across species and organs. Neutrophils producing the type 3 cytokines GM-CSF and IL-17A, and expressing MMP9, which participates in the activation of TGF-β1, clustered with these scar-associated macrophages. Using in vitro primary human cell assays, we determined that GM-CSF, IL-17A and TGF-β1 drive the differentiation of these scar-associated macrophages, and that co-culture of monocyte-derived macrophages with hepatic stellate cells and TGF-β1 augmented type 1 collagen deposition. In vivo blockade of GM-CSF, IL-17A or TGF-β1 with small or large molecules reduced scar-associated macrophage expansion and fibrosis in multiple models of hepatic and pulmonary fibrosis. Our work demonstrates that a specific scar-associated macrophage population is linked with fibrosis across species and tissues. It further provides a strategy for unbiased discovery, triage and preclinical validation of therapeutic targets within this fibrogenic macrophage population.