bluuebunny/crossref_metadata_2025 huggingface dataset:
Modular representation and control of floppy networks
Authors: Chen Siheng , Giardina Fabio , Choi Gary P. T. , Mahadevan L.
Published: August 2022

Geometric graph models of systems as diverse as proteins, DNA assemblies, architected materials and robot swarms are useful abstract representations of these objects that also unify ways to study their properties and control them in space and time. While much work has been done in the context of characterizing the behaviour of these networks close to critical points associated with bond and rigidity percolation, isostaticity, etc., much less is known about floppy, underconstrained networks that are far more common in nature and technology. Here, we combine geometric rigidity and algebraic sparsity to provide a framework for identifying the zero energy floppy modes via a representation that illuminates the underlying hierarchy and modularity of the network and thence the control of its nestedness and locality. Our framework allows us to demonstrate a range of applications of this approach that include robotic reaching tasks with motion primitives, and predicting the linear and nonlinear response of elastic networks based solely on infinitesimal rigidity and sparsity, which we test using physical experiments. Our approach is thus likely to be of use broadly in dissecting the geometrical properties of floppy networks using algebraic sparsity to optimize their function and performance.
Evolution of the nitric oxide synthase family in vertebrates and novel insights in gill development
Authors: Annona Giovanni , Sato Iori , Pascual-Anaya Juan , Osca David , Braasch Ingo , Voss Randal , Stundl Jan , Soukup Vladimir , Ferrara Allyse , Fontenot Quenton , Kuratani Shigeru , Postlethwait John H. , D'Aniello Salvatore
Published: August 2022

Nitric oxide (NO) is an ancestral key signalling molecule essential for life and has enormous versatility in biological systems, including cardiovascular homeostasis, neurotransmission and immunity. Although our knowledge of NO synthases (Nos), the enzymes that synthesize NO
in vivo
, is substantial, the origin of a large and diversified repertoire of
nos
gene orthologues in fishes with respect to tetrapods remains a puzzle. The recent identification of
nos3
in the ray-finned fish spotted gar, which was considered lost in this lineage, changed this perspective. This finding prompted us to explore
nos
gene evolution, surveying vertebrate species representing key evolutionary nodes. This study provides noteworthy findings: first,
nos2
experienced several lineage-specific gene duplications and losses. Second,
nos3
was found to be lost independently in two different teleost lineages, Elopomorpha and Clupeocephala. Third, the expression of at least one
nos
paralogue in the gills of developing shark, bichir, sturgeon, and gar, but not in lamprey, suggests that
nos
expression in this organ may have arisen in the last common ancestor of gnathostomes. These results provide a framework for continuing research on
nos
genes’ roles, highlighting subfunctionalization and reciprocal loss of function that occurred in different lineages during vertebrate genome duplications.
Behavioural specialization and learning in social networks
Authors: Leimar Olof , Dall Sasha R. X. , Houston Alasdair I. , McNamara John M.
Published: August 2022

Interactions in social groups can promote behavioural specialization. One way this can happen is when individuals engage in activities with two behavioural options and learn which option to choose. We analyse interactions in groups where individuals learn from playing games with two actions and negatively frequency-dependent payoffs, such as producer–scrounger, caller–satellite, or hawk–dove games. Group members are placed in social networks, characterized by the group size and the number of neighbours to interact with, ranging from just a few neighbours to interactions between all group members. The networks we analyse include ring lattices and the much-studied small-world networks. By implementing two basic reinforcement-learning approaches, action–value learning and actor–critic learning, in different games, we find that individuals often show behavioural specialization. Specialization develops more rapidly when there are few neighbours in a network and when learning rates are high. There can be learned specialization also with many neighbours, but we show that, for action–value learning, behavioural consistency over time is higher with a smaller number of neighbours. We conclude that frequency-dependent competition for resources is a main driver of specialization. We discuss our theoretical results in relation to experimental and field observations of behavioural specialization in social situations.
Climate, immigration and speciation shape terrestrial and aquatic biodiversity in the European Alps
Authors: Jardim de Queiroz Luiz , Doenz Carmela J. , Altermatt Florian , Alther Roman , Borko Špela , Brodersen Jakob , Gossner Martin M. , Graham Catherine , Matthews Blake , McFadden Ian R. , Pellissier Loïc , Schmitt Thomas , Selz Oliver M. , Villalba Soraya , Rüber Lukas , Zimmermann Niklaus E. , Seehausen Ole
Published: August 2022

Quaternary climate fluctuations can affect speciation in regional biodiversity assembly in two non-mutually exclusive ways: a glacial species pump, where isolation in glacial refugia accelerates allopatric speciation, and adaptive radiation in underused adaptive zones during ice-free periods. We detected biogeographic and genetic signatures associated with both mechanisms in the assembly of the biota of the European Alps. Age distributions of endemic and widespread species within aquatic and terrestrial taxa (amphipods, fishes, amphibians, butterflies and flowering plants) revealed that endemic fish evolved only in lakes, are highly sympatric, and mainly of Holocene age, consistent with adaptive radiation. Endemic amphipods are ancient, suggesting preglacial radiation with limited range expansion and local Pleistocene survival, perhaps facilitated by a groundwater-dwelling lifestyle. Terrestrial endemics are mostly of Pleistocene age and are thus more consistent with the glacial species pump. The lack of evidence for Holocene adaptive radiation in the terrestrial biome is consistent with faster recolonization through range expansion of these taxa after glacial retreats. More stable and less seasonal ecological conditions in lakes during the Holocene may also have contributed to Holocene speciation in lakes. The high proportion of young, endemic species makes the Alpine biota vulnerable to climate change, but the mechanisms and consequences of species loss will likely differ between biomes because of their distinct evolutionary histories.
Judicial Opinions 112–122
Authors: Arahal David R. , Busse Hans-Jürgen , Bull Carolee T. , Christensen Henrik , Chuvochina Maria , Dedysh Svetlana N. , Fournier Pierre-Edouard , Konstantinidis Konstantinos T. , Parker Charles T. , Rossello-Mora Ramon , Ventosa Antonio , Göker Markus
Published: August 2022

Opinion 112 denies the request to place

Seliberia

Aristovskaya and Parinkina 1963 (Approved Lists 1980) on the list of rejected names because the information provided is insufficient. For the same reason, Opinion 113 denies the request to reject

Shewanella irciniae

Lee et al. 2006 and Opinion 114 denies the request to reject the name

Enterobacter siamensis

Khunthongpan et al. 2014. Opinion 115 rejects the epithet of

Moorella thermoautotrophica

(Wiegel et al. 1981) Collins et al. 1994, which is regarded as a nomen confusum. To assess the consequences of Rule 8, Opinion 116 revisits names of taxa above the rank of genus which should comprise the stem of the name of a nomenclatural type and a category-specific ending but fail to do so. Such names should be orthographically corrected if the sole error is the inadvertent usage of an incorrect stem or be regarded as illegitimate if otherwise. The necessary corrections are made for a number of names. In Opinion 117, the request to designate

Methylothermus subterraneus

Hirayama et al. 2011 as the type species of the genus

Methylothermus

is denied because an equivalent action compatible with the Code was already conducted. In Opinion 118, the possible orthographical correction of the name

Flaviaesturariibacter

is treated, as are the analogous cases of

Fredinandcohnia

and

Hydrogeniiclostidium

. The genus names are corrected to Flaviaestuariibacter, Ferdinandcohnia and

Hydrogeniiclostridium

, respectively. Opinion 119 concludes that assigning

Actinomycetales

Buchanan 1917 (Approved Lists 1980) as nomenclatural type of the class

Actinobacteria

Stackebrandt et al. 1997 would not render that name legitimate if Rule 8 remained retroactive. The request is granted but

Actinomycetales

is also assigned as type of

Actinomycetes

Krassilnikov 1949 (Approved Lists 1980). In Opinion 120, the possible orthographical correction of the name

Amycolatopsis albidoflavus

is treated. It is grammatically corrected to Amycolatopsis albidoflava. Six names which could according to Rule 61 be grammatically corrected by anyone are also corrected. Opinion 121 denies the request to revise Opinion 69 and notes that Opinion 69 does not have the undesirable consequences emphasized in the request. In Opinion 122, the request to reject various taxon names of

Mollicutes

proposed in 2018 is denied because it is based on misinterpretations of the Code, which are clarified. Alternative ways to solve the perceived problems are outlined. These Opinions were ratified by the voting members of the International Committee on Systematics of Prokaryotes.
Cap-snatching as a possible contributor to photosynthesis shut-off
Authors: Xu Min , Risse Judith , Kormelink Richard
Published: August 2022

Cap-snatching is a mechanism applied by segmented, negative strand (-) RNA viruses (NSVs) to initiate genome transcription. So far, the cap donor source of cytoplasmic-replicating NSVs has remained elusive. Recently, studies pointed to processing body (P body, PB) as the potential source for providing capped RNAs but conclusive evidence is still lacking. To attempt identifying these sources, here the 5′ non-viral leader sequences of Tomato spotted wilt virus (TSWV) N mRNAs were analysed by high-throughput sequencing (HTS) from plants subjected to normal and heat-stress conditions, and subsequently mapped on host donor transcripts. The majority of non-viral heterogenous, host-derived leader sequences ranged in size between ~10–20 nt and contained A or AG residues at the cleavage site and the presence of certain sequence motifs. Mapping the capped-leader sequences to the 5’ UTR region of genes encoded by the Nicotiana tabacum genome, identified 348 donor genes and which were specifically enriched in cellular photosynthesis pathway. Nineteen of those were clearly expressed differentially at normal condition versus heat-stress conditions. Although the results did not point towards snatching of capped-RNA leader sequences from certain cytoplasmic RNA granules in particular, they indicated photosynthesis downregulation (and development of disease symptoms) partially result from cap-snatching.
A KLHL40 3’ UTR splice-altering variant causes milder NEM8, an under-appreciated disease mechanism
Authors: Dofash Lein N.H. , Monahan Gavin , Servián-Morilla Emilia , Rivas Eloy , Faiz Fathimath , Sullivan Patricia , Oates Emily , Clayton Joshua , Taylor Rhonda L. , Davis Mark R. , Beilharz Traude , Laing Nigel G. , Cabrera-Serrano Macarena , Ravenscroft Gianina
Published: August 2022

Nemaline myopathy 8 (NEM8) is typically a severe autosomal recessive disorder associated with variants in the kelch-like family member 40 gene (KLHL40). Common features include fetal akinesia, fractures, contractures, dysphagia, respiratory failure, and neonatal death. Here, we describe a man in his 20s with relatively mild NEM8. He presented with hypotonia and bilateral femur fractures at birth, later developing bilateral Achilles’ contractures, scoliosis, and elbow and knee contractures. He had walking difficulties throughout childhood and became wheelchair bound during adolescence after prolonged immobilisation. Muscle MRI during adolescence indicated prominent fat replacement in his pelvic girdle, posterior compartments of thighs, and vastus intermedius. Muscle biopsy revealed nemaline bodies and intranuclear rods. RNA sequencing and western blotting of patient skeletal muscle indicated significant reduction in KLHL40 mRNA and protein respectively. Using gene panel screening, exome sequencing and RNA sequencing, we identified compound heterozygous variants in KLHL40; a truncating 10.9 kb deletion in trans with a likely pathogenic variant (c.*152G>T) in the 3’ untranslated region (UTR). Computational tools SpliceAI and Introme predicted the c.*152G>T variant created a cryptic donor splice site. RNA-seq and in vitro analyses indicated that the c.*152G>T variant induces multiple de novo splicing events that likely provoke nonsense mediated decay of KLHL40 mRNA explaining the loss of mRNA expression and protein abundance in the patient. Analysis of 3’ UTR variants in ClinVar suggests SNPs that introduce aberrant 3’ UTR splicing may be underrecognised in Mendelian disease. We encourage consideration of this mechanism during variant curation.
Impact of age and SARS-CoV-2 breakthrough infection on humoral immune responses after three doses of COVID-19 mRNA vaccine
Authors: Mwimanzi Francis , Lapointe Hope R. , Cheung Peter K. , Sang Yurou , Yaseen Fatima , Kalikawe Rebecca , Datwani Sneha , Burns Laura , Young Landon , Leung Victor , Ennis Siobhan , Brumme Chanson J. , Montaner Julio S.G. , Dong Winnie , Prystajecky Natalie , Lowe Christopher F. , DeMarco Mari L. , Holmes Daniel T. , Simons Janet , Niikura Masahiro , Romney Marc G. , Brumme Zabrina L. , Brockman Mark A.
Published: August 2022

Background

Longer-term immune response data after three doses of COVID-19 mRNA vaccine remain limited, particularly among older adults and following Omicron breakthrough infection.

Methods

We quantified wild-type- and Omicron-specific serum IgG levels, ACE2 displacement activities and live virus neutralization up to six months post-third dose in 116 adults aged 24-98 years who remained COVID-19-naïve or experienced their first SARS-CoV-2 infection during this time.

Results

Among 78 participants who remained COVID-19-naïve throughout follow-up, wild-type- and Omicron BA.1-specific IgG concentrations were comparable between younger and older adults, though BA.1-specific responses were consistently significantly lower than wild-type-specific responses in both groups. Wild-type- and BA.1-specific IgG concentrations declined at similar rates among COVID-19-naïve younger and older adults, with median half-lives ranging from 69-78 days. Antiviral antibody function declined substantially over time in COVID-19-naïve individuals, particularly older adults: by six months, BA.1-specific neutralization was undetectable in 96% of older adults, versus 56% of younger adults. SARS-CoV-2 infection, experienced by 38 participants, boosted IgG levels and neutralization above those induced by vaccination alone. Nevertheless, BA.1-specific neutralization remained significantly lower than wild-type, with BA.5-specific neutralization lower still.

Conclusions

Our findings underscore the immune benefits of third COVID-19 mRNA vaccine doses in adults of all ages, but rapid decline of Omicron-specific neutralization activity in COVID-19-naïve individuals, particularly among older adults, demonstrates the need for fourth doses within 3-6 months to maintain systemic responses. Individuals who experienced SARS-CoV-2 breakthrough infection post-third vaccine dose however can likely delay a fourth dose beyond this timeframe.
Laboratory Validation and Clinical Implementation of Human Monkeypox Saliva-Based Tests
Authors: Allan-Blitz Lao-Tzu , Carragher Kevin , Sukhija-Cohen Adam , Li Hong , Klausner Jeffrey D.
Published: August 2022

Background

Improved diagnostic capabilities and accessibility are essential for controlling the outbreak of Human Monkeypox.

Methods

We describe a saliva-based polymerase chain reaction (PCR) assay for Human Monkeypox, in vitro test performance, and clinical implementation of that assay at three testing sites in Los Angeles. Finally, using pre-specified search terms, we conducted a systematic rapid review of PubMed and Web of Science online databases of studies reporting the performance of oral pharyngeal or saliva-based tests for Human Monkeypox.

Results

Laboratory evaluation of the assay showed in silico inclusivity of 100% for 97 strains of Human Monkeypox, with an analytic sensitivity of 250 copies/mL, and 100% agreement compared to known positive and negative specimens. Clinical testing identified 22 cases of Human Monkeypox among 132 individuals (16.7%). Of those 22 cases, 16 (72.7%) reported symptoms, 4 (18.2%) without a rash at the time of testing. Our systematic rapid review identified 6 studies; 23 patients had tests performed on oropharyngeal specimens 100% agreed with the PCR test result of a lesion swab.

Conclusion

Saliva-based PCR tests are potential tools for outbreak control, and further evaluation of the performance of such tests is warranted.
Post-acute sequelae of SARS-CoV-2 (PASC) impact quality of life at 6, 12 and 18 months post-infection
Authors: Demko Zoe O , Yu Tong , Mullapudi Sarika K. , Varela Heslin M. Gabriela , Dorsey Chamia A. , Payton Christine B. , Tornheim Jeffrey A. , Blair Paul W. , Mehta Shruti H. , Thomas David L. , Manabe Yukari C. , Antar Annukka A.R. ,   the OutSMART Study Team
Published: August 2022

Little data exist on long COVID outcomes beyond one year. In a cohort enrolled with mild-moderate acute COVID-19, a wide range of symptoms manifest at 6, 12, and 18 months. Endorsing over 3 symptoms associates with poorer quality of life in 5 domains: physical, social, fatigue, pain, and general health.
Adjusted booster schedules disperse age-dependent differences in antibody titers benefitting risk populations
Authors: Müller Lisa , Andrée Marcel , Moskorz Wiebke , Drexler Ingo , Hauka Sandra , Ptok Johannes , Walotka Lara , Grothmann Ramona , Hillebrandt Jonas , Ritchie Anastasia , Peter Laura , Walker Andreas , Timm Jörg , Adams Ortwin , Schaal Heiner
Published: August 2022

We provide follow-up data on the humoral immune response after COVID-19 vaccinations of a cohort aged below 60 and over 80 years. While anti-SARS-CoV-2 spike-specific IgG and neutralization capacity waned rapidly after initial vaccination, additional boosters highly benefitted humoral immune responses including neutralization of Omikron variants in the elderly cohort.
Developing a video expert panel as a reference standard to evaluate respiratory rate counting in paediatric pneumonia diagnosis: protocol for a cross-sectional study
Authors: Khan Ahad Mahmud , Ahmed Salahuddin , Chowdhury Nabidul Haque , Islam Md Shafiqul , McCollum Eric D , King Carina , Shi Ting , Nahar Kamrun , Simpson Robynne , Ahmed Ayaz , Rahman Md Mozibur , Baqui Abdullah H , Cunningham Steven , Campbell Harry ,   RESPIRE Collaboration
Published: August 2022

Introduction

Manual counting of respiratory rate (RR) in children is challenging for health workers and can result in misdiagnosis of pneumonia. Some novel RR counting devices automate the counting of RR and classification of fast breathing. The absence of an appropriate reference standard to evaluate the performance of these devices is a challenge. If good quality videos could be captured, with RR interpretation from these videos systematically conducted by an expert panel, it could act as a reference standard. This study is designed to develop a video expert panel (VEP) as a reference standard to evaluate RR counting for identifying pneumonia in children.

Methods and analysis

Using a cross-sectional design, we will enrol children aged 0-59 months presenting with suspected pneumonia at different levels of health facilities in Dhaka and Sylhet, Bangladesh. We will video record a physician/health worker counting RR manually and also using an automated RR counter (ChARM) from each child. We will establish a standard operating procedure for capturing quality videos, make a set of reference videos, and train and standardise the VEP members using the reference videos. After that, we will assess the performance of the VEP as a reference standard to evaluate RR counting. We will calculate the mean difference and proportions of agreement within ±2 breaths per minute and create Bland-Altman plots with limits of agreement between VEP members.

Ethics and dissemination

The study protocol was approved by the National Research Ethics Committee of Bangladesh Medical Research Council (BMRC), Bangladesh (registration number: 39315022021) and Edinburgh Medical School Research Ethics Committee (EMREC), Edinburgh, UK (REC Reference: 21-EMREC-040). Dissemination of the study findings will be through conference presentations and publications in peer-reviewed scientific journals.

Strengths and limitations of this study

Expert paediatricians will provide feedback to develop a standard operating procedure for videography of child chest movements.

The video expert panel will be trained and standardized using the expert paediatrician-interpreted reference videos.

Video expert panel members will be masked to respiratory rate counted by each other and to respiratory rate manual counts, and with the automated counter.

Children with varying severity of illness will be enrolled from different levels of health facilities in Bangladesh.

Despite the availability of multiple respiratory rate counters, only the ChARM device will be used in this study.
Estimating COVID-19 Vaccine Protection Rates via Dynamic Epidemiological Models–A Study of Ten Countries
Authors: Zhu Yuru , Gu Jia , Qiu Yumou , Chen Song Xi
Published: August 2022

The real-world performance of vaccines against COVID-19 infections is critically important to counter the pandemics. We propose a varying coefficient stochastic epidemic model to estimate the vaccine protection rates based on the publicly available epidemiological and vaccination data. To tackle the challenges posed by the unobserved state variables, we develop a multi-step decentralized estimation procedure that uses different data segments to estimate different parameters. A B-spline structure is used to approximate the underlying infection rates and to facilitate model simulation in obtaining an objective function between the imputed and the simulation-based estimates of the latent state variables, leading to simulation-based estimation of the diagnosis rate using data in the pre-vaccine period and the vaccine effect parameters using data in the post-vaccine periods. And the time-varying infection, recovery and death rates are estimated by kernel regressions. We apply the proposed method to analyze the data in ten countries which collectively used 8 vaccines. The analysis reveals that the average protection rate of the full vaccination was at least 22% higher than that of the partial vaccination and was largely above the WHO recognized level of 50% before November 20, 2021, including the Delta variant dominated period. The protection rates for the booster vaccine in the Omicron period were also provided.
Distinctive features of lipoprotein profiles in stroke patients
Authors: Konishi Tomokazu , Hayashi Yurie , Fujiwara Risako , Kawata Shinpei , Ishikawa Tatsuya
Published: August 2022

Classes of lipoproteins solubilize lipids in the blood, and their profiles are important for preventing atherosclerotic diseases. These can be identified by gel filtration HPLC, which has been analyzed in a manner that yields the same values as the de facto standard method, i.e., ultracentrifugation; however, previous studies have found that ultracentrifugation and its simplified alternatives, enzymatic methods, yield incorrect values. Here HPLC data of stroke patients and the controls were compared using data-driven analyses, without consideration for ultracentrifugation. The data well-separated patients from controls. In many patients, the level of HDL1 (a cholesterol scavenger) was low. The TG/cholesterol ratio of chylomicrons was found to be low in patients and high in the healthy elderly; the lower level may indicate a larger intake of animal fats. High levels of free glycerol in the elderly were hazardous, suggesting more dependence on lipids as an energy source. Statins had minimal effect on these factors. LDL cholesterol, the commonly-used risk indicator, was not a risk factor actually. Enzymatic methods failed to separate the patients from the control; hence, the existing guidelines for screening methods and medical treatment need to be revised. As an immediate step, glycerol would be an adaptable indicator.
Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation
Authors: Zeppillo Tommaso , Ali Heba , Wenger Sally , Lopez Murcia Francisco J. , Gideons Erinn , Signorelli Janetti , Schmeisser Michael J. , Wiltfang Jens , Rhee JeongSeop , Brose Nils , Taschenberger Holger , Krueger-Burg Dilja
Published: August 2022

Abstract

The function of GABAergic synapses is critically shaped by cell adhesion proteins that recruit GABAARs to synapses and mediate transsynaptic signalling, but the synapse-type-specific function of such synaptic adhesion proteins and their mutual interaction remain incompletely understood. A ubiquitous cell adhesion protein at GABAergic synapses is Neuroligin-2 (Nlgn2), which recruits synaptic GABAARs by promoting the assembly of the postsynaptic gephyrin scaffold. While Nlgn2 is present at virtually all GABAergic synapses throughout the forebrain, its loss affects different GABAergic synapse subtypes with different severity, indicating that synapse-specific interactors and synapse-organizer-redundancies define the function of Nlgn2 for a given synapse type. Here we investigated how Nlgn2 function at GABAergic synapses in mouse hippocampal area CA1 is modulated by two recently identified interaction partners, MDGA1 and MDGA2. We show that Nlgn2 and MDGA1 colocalize most prominently in the stratum radiatum (S.R.) of area CA1, and that combined Nlgn2 and MDGA1 deletion causes a layer-specific exacerbation of the loss of gephyrin puncta in layer S.R. seen following Nlgn2 deletion. Intriguingly, combined Nlgn2 and MDGA1 deletion concurrently ameliorates the abnormal cytosolic gephyrin aggregation, the reduction in inhibitory synaptic transmission and the exacerbated anxiety-related behavior seen in Nlgn2 knockout (KO) mice. In contrast, heterozygous deletion of MDGA2 in Nlgn2 KO mice has only minor effects on gephyrin and GABAAR puncta and does not normalize cytosolic gephyrin aggregates, inhibitory synaptic transmission or anxiety-related behavior. Our data indicate that MDGA1, but not MDGA2, modulates Nlgn2 function, primarily by regulating the formation of cytosolic gephyrin aggregates. Given that both Nlgn2 and the MDGA family of proteins have been linked to psychiatric disorders, such as autism and schizophrenia, our data lead to the notion that abnormal gephyrin aggregation may contribute to the pathophysiology of these disorders, and that intervention with gephyrin aggregation could present a novel therapeutic strategy.
Emergence of Erythromycin Resistant Invasive Group A Streptococcus in West Virginia, United States
Authors: Powell Lillie , Choi Soo Jeon , Chipman Chloe , Grund Megan , LaSala P. Rocco , Lukomski Slawomir
Published: August 2022

Combination therapy with penicillin and clindamycin has been a mainstay for treatment of invasive group A Streptococcus (iGAS) infections yet increasing macrolide resistance may limit such treatment for strains displaying MLSB phenotypes. The CDC recently reported erythromycin and clindamycin resistance rates for iGAS exceeding 20% in 2017. Here, we investigated 76 iGAS isolates from 66 patients identified at J.W. Ruby Memorial Hospital in West Virginia from 2020-2021. emm typing was performed using the CDC protocol and database. Resistance genes were detected by PCR and sequencing, whereas antimicrobial susceptibility testing was performed in clinical and research laboratories with standard techniques. Median patient age was 42 years (23-86 range). 76% (n=50) of isolates were simultaneously resistant to erythromycin and clindamycin, which included both inducible (n=40) and constitutive (n=9) resistance. All emm92 (n=35) and emm11 (n=8) isolates were erythromycin resistant, while the remaining 11% (n=7) of resistant isolates comprised 5 emm types. Susceptible isolates primarily included emm89 (n=6) iGAS. Macrolide resistance was conferred by the plasmid-borne ermT gene in all emm92 isolates and by chromosomally-encoded ermA (n=7), ermB (n=7), and mefA (n=1) in other emm types. Macrolide-resistant iGAS were typically resistant to tetracycline and aminoglycoside antibiotics. Here, we characterized iGAS infections affecting non-pediatric residents across West Virginia. We showed a shift in emm-type distribution compared to historical and national reports, and dominance of macrolide-resistant isolates which raises concern for emerging resistance to commonly-prescribed antibiotics used in treatment of iGAS infections.
Common and rare variants in SLCO1B1 are associated with statin intolerance
Authors: Bigossi Margherita , Maroteau Cyrielle , Dawed Adem Y , Taylor Alasdair , Srinivasan Sundararajan , Melhem Alaa’ Lufti , Pearson Ewan R , Pola Roberto , Palmer Colin N A , Siddiqui Moneeza K
Published: August 2022

Background and Aims

The efficacy of statin therapy is hindered by adverse drug reactions, most frequently musculoskeletal symptoms. Variants in SLCO1B1, which encodes the hepatic transporter OATB1B1, influence statin pharmacokinetics, resulting in altered plasma concentration of the drug and its metabolites. While pharmacogenetic testing of the loss-of-function Val174Ala (rs4149056T>C) is recommended to reduce risk of statin intolerance, current guidelines acknowledge the potential role of gain-of-function variants. This study tests the hypothesis that accounting for gain-of-function variants in SLCO1B1, in addition to Val174Ala, will provide more reliable estimates of statin intolerance.

Methods and Results

High-risk haplotypes were derived from Val174Ala and three common gain-of-function SLCO1B1 variants and compared to low-risk haplotypes. In statin users from Tayside Scotland, UK, those with high-risk haplotypes had increased odds across three phenotypes of statin intolerance (general statin intolerance: ORGSI 2.42[95%CI:1.29, 4.31], p=0.003; statin-related myopathy ORSRM 2.51[95%CI:1.28, 4.53],p=0.004; statin-related suspected rhabdomyolysis: ORSRSR 2.85[95%CI:1.03, 6.65],p=0.02). In contrast, using the Val174Ala genotype alone produced weaker results. A meta-analysis with results from adjudicated cases of statin-induced myopathy in the PREDICTION-ADR Consortium confirmed these findings (ORVal174Ala 1.99 [95%CI:1.01, 3.95],p=0.048; ORrisk-haplotypes 1.76 [95%CI:1.16, 2.69],p=0.008). For those requiring high-dose statin therapy, high-risk haplotypes were more consistently associated with the time to onset of statin intolerance amongst the three phenotypes compared to Val174Ala (general statin intolerance: HRVal174Ala 2.49 [95%CI:1.09, 5.68],p=0.03; HRrisk-haplotypes 2.44 [95%CI:1.46, 4.08],p<0.001). Exome-sequenced rare variants were found to be associated with the risk of intolerance (p=0.02).

Conclusions

We demonstrate that accounting for gain-of-function variants in SLCO1B1, in addition to Val174Ala, provides more reliable estimates of statin intolerance.
Rigorous hepatitis B surface antigen analyses and identification of hepatitis B chronicity amongst South Africans attending public health facilities over a five-year period: 2015 to 2019
Authors: Moonsamy Shelina , Pillay Pavitra , Prabdial-Sing Nishi
Published: August 2022

Hepatitis B, a potentially life-threatening viral infection of the liver, remains a global public health concern despite the availability of effective vaccines for over three decades. Given that most HBsAg studies targeted distinct cohorts, we aimed to provide HBsAg data nationally in the public health sector of South Africa.

We conducted a cross-sectional study on HBsAg tests obtained from the National Health Laboratory Service Central Data Warehouse for tests performed nationally during the period 2015 to 2019. Annual data were cleaned and appended prior to data interrogation to determine and analyse the total number of cases who tested positive for HBsAg and the number of chronic HBV infections.

We identified 176,530 cases who tested positive for HBsAg at least once during the 5-year period, with a test positivity rate of 9%. Chronic infections were identified in 6.4% of HBsAg positive cases. Clearance of HBsAg was observed in 5,571 cases, inclusive of clearance in 135 chronic cases. Significantly more males tested positive for HBsAg and were chronically infected (p < 0.0001). Amongst individuals who were vaccine-eligible as infants (0 to 19 years old), 4,980 tested HBsAg positive, of which 22.7% (1,131) were under 5 years old, with a HBsAg population positivity rate of 0.02% and test positivity rate of 4.83%.

HBsAg positivity amongst vaccine-eligible individuals is likely due to suboptimal vaccine coverage rates reported for South Africa. Without a birth dose of the HBV vaccine and lack of routine HBsAg screening at antenatal care, it is likely that the majority of HBsAg positive cases under 5 years old were vertically infected. Optimal HBV vaccine coverage, inclusive of a birth dose, is key to eliminating horizontal and vertical transmission of HBV. Early identification of HBV chronicity is fundamental in reducing the risk of liver cirrhosis and hepatocellular carcinoma.
Abrupt permafrost thaw triggers microbial bloom and grazer succession
Authors: Scheel Maria , Zervas Athanasios , Rijkers Ruud , Tveit Alexander Tøsdal , Ekelund Flemming , Jiménez Francisco Campuzano , Jacobsen Carsten Suhr , Christensen Torben Røjle
Published: August 2022

Permafrost soils store a substantial part of the global soil carbon and nitrogen. However global warming causes abrupt erosion and gradual thaw, which make these stocks vulnerable to microbial decomposition into greenhouse gases. Here, we investigated the microbial response to abruptin situpermafrost thaw. We sequenced the total RNA of a 1 m deep soil core consisting of up to 26’500-year-old permafrost material from an active abrupt erosion site. We analysed the microbial community in the active layer soil, the recently thawed, and the intact permafrost and found maximum RNA:DNA ratios indicating a microbial bloom in recently thawed permafrost. Several fast-growing prokaryotic taxa dominated thawed permafrost, including Sphingobacteriales, Burkholderiales, and Nitrosomonadales. Overall, the thaw state and soil moisture consistently explained changes in community composition, with especially the permafrost community being significantly distinct from thawed soils. Predation correlated with changes in prokaryotic composition. Bacterial grazers were dominated by Myxococcales and abundant in the active layer. In contrast, protozoa, especially Cercozoa and Ciliophora, doubled in relative abundance in thawed layers. Our findings highlight the ecological importance of a rapid development of microbial blooms as well as the successive predation as biological control mechanism in abruptly thawing permafrost.

One sentence summary

Using total RNA from an up to 26’500-year-old abruptly eroding permafrost site in Greenland, we described a microbial bloom and its controls, including bacterial and microeukaryotic predators.

Abstract Figure
The asthma gut microbiota influences lung inflammation in gnotobiotic mice
Authors: Wilson Naomi G. , Hernandez-Leyva Ariel , Rosen Anne L. , Jaeger Natalia , McDonough Ryan T. , Santiago-Borges Jesus , Lint Michael A. , Rosen Thomas R. , Tomera Christopher P. , Bacharier Leonard B. , Swamidass S. Joshua , Kau Andrew L.
Published: August 2022

The composition of the gut microbiota in early childhood is linked to asthma risk but the role of the gut microbiota in older patients with established asthma is less clear. Here, we used a cohort of 38 school-aged children (19 with asthma) and 57 adults (17 with asthma) to develop a model that aids in the design of mechanistic experiments in gnotobiotic mice. These experiments show that enterotoxigenic Bacteroides fragilis (ETBF) is associated with increased gut permeability, oxidative stress, and markers of Th17-mediated inflammation in the lungs of mice following ovalbumin sensitization and challenge (OSC). Further, ETBF is enriched in a human population with asthma compared to healthy controls. Our results provide evidence that ETBF has the potential to alter the phenotype of airway inflammation in a subset of patients with asthma outside of early childhood which suggests that therapies targeting the gut microbiota may be helpful tools for asthma control.
Dystroglycan N-terminal domain enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy
Authors: Okuma Hidehiko , Hord Jeffrey M. , Chandel Ishita , Venzke David , Anderson Mary E. , Walimbe Ameya S. , Joseph Soumya , Gastel Zeita , Hara Yuji , Saito Fumiaki , Matsumura Kiichiro , Campbell Kevin P.
Published: August 2022

Dystroglycan (DG) requires extensive post-translational processing to function as a receptor for extracellular matrix proteins containing laminin-G-like (LG) domains. Matriglycan is an elongated polysaccharide of alternating xylose and glucuronic acid that is uniquely synthesized on α-dystroglycan (α-DG) by like-acetylglucosaminyltransferase-1 (LARGE1) and binds with high affinity to matrix proteins like laminin. Defects in the post-translational processing of α-DG that result in a shorter form of matriglycan reduce the size of α-DG and decrease laminin binding, leading to various forms of muscular dystrophy. However, little is known regarding mechanisms that generate full-length matriglycan on α-DG (~150-250 kDa). Here, we show that LARGE1 can only synthesize a short, non-elongated form of matriglycan in mouse skeletal muscle that lacks the DG N-terminus (α-DGN), resulting in a ~100-125 kDa α-DG. This smaller form of α-DG binds laminin and maintains specific force but does not prevent muscle pathophysiology, including reduced force induced by eccentric contractions and abnormalities in neuromuscular junctions. Collectively, our study demonstrates that α-DGN is required for LARGE1 to extend matriglycan to its full mature length on α-DG and thus prevent muscle pathophysiology.
Ex vivomidgut cultures ofAedes aegyptiare efficiently infected by mosquito-borne alpha- and flaviviruses
Authors: Rosales Rosas Ana Lucia , Wang Lanjiao , Goossens Sara , Cuvry Arno , Li Li-Hsin , Santos-Ferreira Nanci , Soto Alina , Dallmeier Kai , Rocha-Pereira Joana , Delang Leen
Published: August 2022

Aedes aegyptimosquitoes can transmit several arboviruses, including chikungunya virus (CHIKV), dengue virus (DENV), and Zika virus (ZIKV). When blood-feeding on a virus-infected human, the mosquito ingests the virus into the midgut (stomach), where it replicates and must overcome the midgut barrier to disseminate to other organs and ultimately be transmitted via the saliva. Current tools to study mosquito-borne viruses (MBVs) include 2D-cell culture systems andin vivomosquito infection models, which offer great advantages, yet have some limitations.

Here, we describe a long-termex vivoculture ofAe. aegyptimidguts. Cultured midguts were metabolically active for 7 days in a 96-well plate at 28°C and were permissive to ZIKV, DENV, Ross River virus (RRV) and CHIKV.Ex vivomidguts fromCulex pipiensmosquitoes were found to be permissive to Usutu virus (USUV). Immunofluorescence staining confirmed viral protein synthesis in CHIKV-infected midguts ofAe. aegypti. Furthermore, fluorescence microscopy revealed replication and spread of a reporter DENV in specific regions of the midgut. In addition, two known antiviral molecules, β-D-N4-hydroxycytidine (NHC) and 7-deaza-2’-C-methyladenosine (7DMA), were able to inhibit CHIKV and ZIKV replication, respectively, in theex vivomodel.

Together, our results show thatex vivomidguts can be efficiently infected with mosquito-borne alpha- and flaviviruses and employed to evaluate antiviral drugs. Furthermore, the setup can be extended to other mosquito species.Ex vivomidgut cultures could thus be a new model to study MBVs, offering the advantage of reduced biosafety measures compared to infecting living mosquitoes.

Importance

Mosquito-borne viruses (MBVs) are a significant global health threat since they can cause severe diseases in humans, such as hemorrhagic fever, encephalitis, and chronic arthritis. MBVs rely on the mosquito vector to infect new hosts and perpetuate virus transmission. No therapeutics are currently available. The study of arbovirus infection in the mosquito vector can greatly contribute to elucidating strategies for controlling arbovirus transmission. This work investigated the infection of midguts fromAedes aegyptimosquitoes in anex vivoplatform. We found several MBVs capable of replicating in the midgut tissue, including viruses of major health importance, such as dengue, chikungunya, and Zika viruses. Additionally, antiviral compounds reduced arbovirus infection in the cultured midgut tissue. Overall, the midgut model emerges as a useful tool for diverse applications such as studying tissue-specific responses to virus infection and screening potential anti-arboviral molecules.
Disabling of ARC1 through CRISPR/CAS9 leads to a complete breakdown of self-incompatibility responses in Brassica napus
Authors: Abhinandan Kumar , Hickerson Neil M.N. , Lan Xingguo , Samuel Marcus A.
Published: August 2022

Self-incompatibility (SI) is a genetic mechanism utilized by many flowering plants to promote outcrossing by recognizing and rejecting self-pollen. While the molecular mechanisms controlling SI can differ in various families, plants in the Brassicaceae family have been found to regulate SI through a S-haplotype-specific receptor-ligand interaction. The recognition of self-pollen leads to the activation of ARMADILLO-REPEAT-CONTAINING1 (ARC1), an E3 ligase which is thought to degrade the compatibility factors required for pollen germination, thus resulting in SI. However, the role of ARC1 in SI in the Brassicaceae family has been disputed within the scientific community. While various studies demonstrate that the manipulation of ARC1 and its downstream targets can break-down the SI response, others show that the SI phenotype can be imparted to self-compatible cultivars without the ARC1 gene. This study investigated the involvement of ARC1 in SI through the generation of loss-of-function ARC1 mutants using CRISPR-Cas9 in B. napus. Loss of ARC1 resulted in complete breakdown of SI in two different S-haplotypes providing strong evidence for the essential nature of ARC1 for mounting a successful SI response.
Semi-Self-Supervised Learning for Semantic Segmentation in Images with Dense Patterns
Authors: Najafian Keyhan , Ghanbari Alireza , Kish Mahdi Sabet , Eramian Mark , Shirdel Gholam Hassan , Stavness Ian , Jin Lingling , Maleki Farhad
Published: August 2022

Deep learning has shown potential in domains where large-scale annotated datasets are available. However, manual annotation is expensive, time-consuming, and tedious. Pixel-level annotations are particularly costly for semantic segmentation in images with dense irregular patterns of object instances, such as in plant images. In this work, we propose a method for developing high-performing deep learning models for semantic segmentation of wheat heads utilizing little manual annotation. We simulate a computationally-annotated dataset using a few annotated images, a short unannotated video clip of a wheat field, and several video clips from fields with no wheat. This dataset is then used to train a customized U-Net model for wheat head segmentation. Considering the distribution shift between the simulated and real data, we apply three domain adaptation steps to gradually bridge the domain gap. Only using two annotated images, we achieved a Dice score of 0.89 on the internal test set, i.e., images extracted from the wheat field video. The model trained using only two annotated images was evaluated on a diverse external dataset collected from 18 different domains across five countries and achieved a Dice score of 0.73. To further expose the model to images from different growth stages and environmental conditions, we incorporated two annotated images from each of the 18 domains and further fine-tuned the model. This resulted in improving the Dice score to 0.91. These promising results highlight the utility of the proposed approach in the absence of large-annotated datasets. Although the utility of the proposed method is shown on a wheat head dataset, it can be extended to other segmentation tasks with similar characteristics of irregularly repeating patterns of object instances.
Six states of Enterococcus hirae V-type ATPase reveals non-uniform rotor rotation during turnover
Authors: Burton-Smith Raymond N. , Song Chihong , Ueno Hiroshi , Murata Takeshi , Iino Ryota , Murata Kazuyoshi
Published: August 2022

The vacuolar-type ATPase from Enterococcus hirae (EhV-ATPase) is a thus-far unique adaptation of V-ATPases, as it performs Na+ transport and demonstrates an off-axis rotor assembly. Recent single molecular studies of the isolated V1 domain have indicated that there are subpauses within the three major states of the pseudo three-fold symmetric rotary enzyme. However, there was no structural evidence for these. Herein we activated the EhV-ATPase complex with ATP and identified multiple structures consisting of a total of six states of this complex by using cryo-electron microscopy. The orientations of the rotor complex during turnover, especially in the intermediates, were not as perfectly uniform as expected. The densities in the nucleotide binding pockets in the V1 domain indicated the different catalytic conditions for the six conformations. The off-axis rotor and its’ interactions with the stator a-subunit during rotation suggests that this non-uniform rotor rotation is performed through the entire complex.
Long-lasting impact of chito-oligosaccharide application on strigolactone biosynthesis and fungal accommodation promotes arbuscular mycorrhiza inMedicago truncatula
Authors: Volpe Veronica , Chialva Matteo , Mazzarella Teresa , Crosino Andrea , Capitanio Serena , Costamagna Lorenzo , Kohlen Wouter , Genre Andrea
Published: August 2022

The establishment of arbuscular mycorrhiza (AM) between plants and Glomeromycotina fungi is preceded by the exchange of chemical signals: fungal released Myc-factors, including chitoligosaccharides (CO) and lipo-chitooligosaccharides (LCO), activate plant symbiotic responses, while root exuded strigolactones stimulate hyphal branching and boost CO release.

Furthermore, fungal signaling reinforcement through CO application was shown to promote AM development inMedicago truncatula, but the cellular and molecular bases of this effect remained unclear.

Here we focused on long-termM. truncatularesponses to CO treatment, demonstrating its impact on the transcriptome of both mycorrhizal and non-mycorrhizal roots over several weeks and providing a novel insight into the mechanistic bases of the CO-dependent promotion of AM colonization.

CO treatment caused the long-lasting regulation of strigolactone biosynthesis and fungal accommodation related genes. This was mirrored by an increase in root didehydro-orobanchol content, and the promotion of accommodation responses to AM fungi in root epidermal cells. Lastly, an advanced down-regulation of AM symbiosis marker genes was observed at the latest time point in CO-treated plants, in line with an increased number of senescent arbuscules.

Overall, CO treatment triggered molecular, metabolic and cellular responses underpinning a protracted acceleration of AM development.