bluuebunny/crossref_metadata_2025 huggingface dataset:
Cochlodiniinecator piscidefendens gen. nov., sp. nov., an algicidal bacterium against the ichthyotoxic dinoflagellate Cochlodinium polykrikoides
Authors: Le Ve Van , Ko So-Ra , Lee Sang-Ah , Jin Long , Blom Jochen , Ahn Chi-Yong , Oh Hee-Mock
Published: November 2021

Harmful algal blooms caused by Cochlodinium polykrikoides result in enormous economic damage to the aquaculture industry. Biological control methods have attracted wide attention due to their environmental-friendliness. In this study, a novel algicidal bacterium, designated strain M26A2MT, was determined for its taxonomic position and was evaluated for its potential to mitigate C. polykrikoides blooms. Strain M26A2MT exhibited the highest 16S rRNA gene sequence similarity to the type strains of

Planktotalea lamellibrachiae

(97.3%),

Halocynthiibacter namhaensis

(97.2%),

Pseudohalocynthiibacter aestuariivivens

(96.8%) and

Halocynthiibacter arcticus

(96.4%) in the family

Rhodobacteraceae

. The predominant fatty acids were C10 : 0 3-OH and summed feature 8 (comprising C18 : 1
ω7c and/or C18 : 1
ω6c). The major polar lipids were phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, one unidentified aminolipid and three unidentified lipids. Q-10 was the respiratory quinone. Strain M26A2MT exerted significant algicidal activity against C. polykrikoides cells by destroying the membrane integrity and the photosynthetic system. Our findings suggest that strain M26A2MT shows a high potential to control outbreaks of C. polykrikoides. Based on the polyphasic characterization, strain M26A2MT is considered to represent a novel species within a novel genus of the family

Rhodobacteraceae

, for which the name Cochlodiniinecator piscidefendens gen. nov., sp. nov. is proposed. The type strain is M26A2MT (=KCTC 82083T=JCM 34119T).
Revisiting dengue virus-mosquito interactions: molecular insights into viral fitness
Authors: Siriphanitchakorn Tanamas , Kini R. Manjunatha , Ooi Eng Eong , Choy Milly M.
Published: November 2021

Dengue virus (DENV), like other viruses, closely interacts with the host cell machinery to complete its life cycle. Over the course of infection, DENV interacts with several host factors with pro-viral activities to support its infection. Meanwhile, it has to evade or counteract host factors with anti-viral activities which inhibit its infection. These molecular virus-host interactions play a crucial role in determining the success of DENV infection. Deciphering such interactions is thus paramount to understanding viral fitness in its natural hosts. While DENV-mammalian host interactions have been extensively studied, not much has been done to characterize DENV-mosquito host interactions despite its importance in controlling DENV transmission. Here, to provide a snapshot of our current understanding of DENV-mosquito interactions, we review the literature that identified host factors and cellular processes related to DENV infection in its mosquito vectors, Aedes aegypti and Aedes albopictus, with a particular focus on DENV-mosquito omics studies. This knowledge provides fundamental insights into the DENV life cycle, and could contribute to the development of novel antiviral strategies.
Molecular epidemiology and phylogenomic analysis of Mycobacterium abscessus clinical isolates in an Asian population
Authors: Chew Ka Lip , Octavia Sophie , Jureen Roland , Ng Oon Tek , Marimuthu Kalisvar , Lin Raymond Tzer Pin , Teo Jeanette W. P.
Published: November 2021

Mycobacterium abscessus

comprises three subspecies: M. abscessus subsp. abscessus
, M. abscessus subsp. bolletii
, and M. abscessus subsp.

massiliense

. These closely related strains are typically multi-drug-resistant and can cause difficult-to-treat infections. Dominant clusters of isolates with increased pathogenic potential have been demonstrated in pulmonary infections in the global cystic fibrosis (CF) population. An investigation was performed on isolates cultured from an Asian, predominantly non-CF population to explore the phylogenomic relationships within our population and compare it to global

M. abscessus

isolates. Whole-genome-sequencing was performed on

M. abscessus

isolates between 2017 and 2019. Bioinformatic analysis was performed to determine multi-locus-sequence-type, to establish the phylogenetic relationships between isolates, and to identify virulence and resistance determinants in these isolates. A total of 210 isolates were included, of which 68.5 % (144/210) were respiratory samples. These isolates consisted of 140 (66.6 %)

M

.

abscessus

subsp.

massiliense

, 67 (31.9 %)

M

.

abscessus

subsp. abscessus, and three (1.4 %)

M

.

abscessus

subsp.

bolletii

. Dominant sequence-types in our population were similar to those of global CF isolates, but SNP differences in our population were comparatively wider despite the isolates being from the same geographical region. ESX (ESAT-6 secretory) cluster three appeared to occur most commonly in ST4 and ST6

M. abscessus

subsp.

massiliense

, but other virulence factors did not demonstrate an association with isolate subspecies or sample source. We demonstrate that although similar predominant sequence-types are seen in our patient population, cross-transmission is absent. The risk of patient-to-patient transmission appears to be largely limited to the vulnerable CF population, indicating infection from environmental sources remains more common than human-to-human transmission. Resistance and virulence factors are largely consistent across the subspecies with the exception of clarithromycin susceptibility and ESX-3.
Increased excursions to functional networks in schizophrenia in the absence of task
Authors: Farinha Miguel , Amado Conceição , Cabral Joana
Published: November 2021

Brain activity during rest has been demonstrated to evolve through a repertoire of functional connectivity (FC) patterns, whose alterations may provide biomarkers of schizophrenia - a psychotic disorder characterized by dysfunctional brain connectivity. In this study, differences between the dynamic exploration of resting-state networks using functional magnetic resonance imaging (fMRI) data from 71 schizophrenia patients and 74 healthy controls were investigated using a method focusing on the dominant fMRI signal phase coherence pattern at each time point. Through the lens of dynamical systems theory, brain activity in the form of temporal FC state trajectories was examined for intergroup differences by calculating the fractional occupancy, dwell time, limiting probability of each state and the transition probabilities between states. Results showed reduced fractional occupancy of a globally synchronized state in schizophrenia. Conversely, FC states overlapping with canonical functional subsystems exhibited increased fractional occupancy and limiting probability in schizophrenia. Furthermore, state-to-state transition probabilities were altered in schizophrenia. This revealed a reduced probability of remaining in a global integrative state, increased probability of switching from this state to functionally meaningful networks and reduced probability of remaining in a state related to the Default Mode network. These results revealed medium to large effect sizes. Finally, this study showed that using K-medoids clustering did not influence the observed intergroup differences - highlighting the utility of dynamical systems theory to better understand brain activity. Combined, these findings expose pronounced differences between schizophrenia patients and healthy controls - supporting and extending current knowledge regarding disrupted brain dynamics in schizophrenia.
Problems with comparative analyses of avian brain size
Authors: Hooper Rebecca , Brett Becky , Thornton Alex
Published: November 2021

There are multiple hypotheses for the evolution of cognition. The most prominent hypotheses are the Social Intelligence Hypothesis (SIH) and the Ecological Intelligence Hypothesis (EIH), which are often pitted against one another. These hypotheses tend to be tested using broad-scale comparative studies of brain size, where brain size is used as a proxy of cognitive ability, and various social and/or ecological variables are included as predictors. Here, we test how methodologically robust such analyses are. First, we investigate variation in brain and body size measurements across >1000 species of bird. We demonstrate that there is substantial variation in brain and body size estimates across datasets, indicating that conclusions drawn from comparative brain size models are likely to differ depending on the source of the data. Following this, we subset our data to the Corvides infraorder and interrogate how modelling decisions impact results. We show that model results change substantially depending on variable inclusion, source and classification. Indeed, we could have drawn multiple contradictory conclusions about the principal drivers of brain size evolution. These results reflect recent concerns that current methods in comparative brain size studies are not robust. We add our voices to a growing community of researchers suggesting that we move on from using such methods to investigate cognitive evolution. We suggest that a more fruitful way forward is to instead use direct measures of cognitive performance to interrogate why variation in cognition arises within species and between closely related taxa.
Potent neutralizing anti-SARS-CoV-2 human antibodies cure infection with SARS-CoV-2 variants in hamster model
Authors: Imbrechts Maya , Maes Wim , Ampofo Louanne , Van den Berghe Nathalie , Calcoen Bas , Van Looveren Dominique , Noppen Sam , Hollevoet Kevin , Vercruysse Thomas , Zhang Xin , Abdelnabi Rana , Foo Caroline , Jan Thibaut Hendrik , Jochmans Dirk , Ven Karen , Lammertyn Jeroen , Vanhoorelbeke Karen , Callewaert Nico , De Munter Paul , Schols Dominique , Neyts Johan , Declerck Paul , Geukens Nick
Published: November 2021

Treatment with neutralizing monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contributes to COVID-19 management. Unfortunately, SARS-CoV-2 variants can escape several of these recently approved mAbs, highlighting the need for additional discovery and development. In a convalescent COVID-19 patient, we identified six mAbs, classified in four epitope groups, that potently neutralized SARS-CoV-2 Wuhan, alpha, beta, gamma and delta infection in vitro. In hamsters, mAbs 3E6 and 3B8 potently cured infection with SARS-CoV-2 Wuhan, beta and delta when administered post-viral infection at 5 mg/kg. Even at 0.2 mg/kg, 3B8 still reduced viral titers. Intramuscular delivery of DNA-encoded 3B8 resulted in in vivo mAb production of median serum levels up to 90 μg/ml, and protected hamsters against delta infection. Overall, our data mark 3B8 as a promising candidate against COVID-19, and highlight advances in both the identification and gene-based delivery of potent human mAbs.
Interactions of host defense and hyper-keratinization in psoriasis
Authors: Deng Jingwen , Leijten Emmerik , Nordkamp Michel Olde , Hartgring Sarita , Tao Weiyang , Pouw Juliette , Balak Deepak , Rijken Rianne , Huang Runyue , Radstake Timothy , Lu Chuanjian , Pandit Aridaman
Published: November 2021

Objectives

To understand the crosstalk between the host and microbiota in psoriatic skin, using a systems biology approach based on transcriptomics and microbiome profiling.

Methods

We collected the skin tissue biopsies and swabs in both lesion and non-lesion skin of 13 patients with psoriasis (PsO), 15 patients with psoriatic arthritis (PsA), and healthy skin from 12 patients with ankylosing spondylitis (AS). We performed transcriptome sequencing and metagenomics profiling on the local skin sites to study the similarities and differences in the molecular profiles between the three conditions, and the associations between the host defense and microbiota dynamic.

Results

We found that lesion and non-lesional samples were remarkably different in terms of their transcriptome profiles. Functional annotation of differentially expressed genes (DEGs) showed a major enrichment in neutrophil activation. By using coexpression gene networks, we identified a gene module that was associated with local psoriasis severity at the site of biopsy. From this module, we extracted a “core” set of genes that were functionally involved in neutrophil activation, epidermal cell differentiation and response to bacteria. Skin microbiome analysis revealed that the abundance of Enhydrobacter, Micrococcus and Leptotrichia were significantly correlated with the “core network” of genes.

Conclusions

We identified a core network that regulates inflammation and hyper-keratinization in psoriatic skin, and is associated with local disease severity and microbiome composition.
A large-scale systematic survey of SARS-CoV-2 antibodies reveals recurring molecular features
Authors: Wang Yiquan , Yuan Meng , Peng Jian , Wilson Ian A. , Wu Nicholas C.
Published: November 2021

In the past two years, the global research in combating COVID-19 pandemic has led to isolation and characterization of numerous human antibodies to the SARS-CoV-2 spike. This enormous collection of antibodies provides an unprecedented opportunity to study the antibody response to a single antigen. From mining information derived from 88 research publications and 13 patents, we have assembled a dataset of ∼8,000 human antibodies to the SARS-CoV-2 spike from >200 donors. Analysis of antibody targeting of different domains of the spike protein reveals a number of common (public) responses to SARS-CoV-2, exemplified via recurring IGHV/IGK(L)V pairs, CDR H3 sequences, IGHD usage, and somatic hypermutation. We further present a proof-of-concept for prediction of antigen specificity using deep learning to differentiate sequences of antibodies to SARS-CoV-2 spike and to influenza hemagglutinin. Overall, this study not only provides an informative resource for antibody and vaccine research, but fundamentally advances our molecular understanding of public antibody responses to a viral pathogen.
Effectiveness of a third dose of BNT162b2 or mRNA-1273 vaccine for preventing post-vaccination COVID-19 infection: an observational study
Authors: Sharma Aditya , Oda Gina , Holodniy Mark
Published: November 2021

Background

BNT162b2 and mRNA-1273 vaccines are highly protective against COVID-19. Concern about waning immunity and reduced effectiveness against SARS-COV-2 variants led to use of a third dose six months after completing the primary series. We used data from the Veterans Health Administration to evaluate the effectiveness of a third dose of BNT162b2 or mRNA-1273 compared to the primary series in preventing post-vaccination COVID-19.

Methods

During January 1 - November 25, 2021, third dose recipients were matched (1:1) to demographically similar controls who did not receive a third dose. Eligible participants had completed the primary series at least six months (180 days) before recruitment date and had received at least one SARS-CoV-2 PCR test. Long-term care residents were excluded. Primary outcomes were documented SARS-CoV-2 infection and COVID-19 hospitalization. Effectiveness was estimated as 1-incidence rate ratio.

Findings

Following matching, the BNT162b2 group included 74,032 pairs and the mRNA-1273 group included 55,098 pairs. In BNT162b2 and mRNA-1273 groups, median age was 72 (interquartile range [IQR]: 64-75) and 72 (IQR: 66-77) years, 69,426 (93.8%) and 52,241 (94.8%) were male, and 43,039 (58.1%) and 37,218 (67.5%) were non-Hispanic White, respectively. Effectiveness of a third dose of BNT162b2 or mRNA-1273 compared to the primary series was 45.7% (95% confidence interval [CI]: 37.9-52.5%) and 46.6% (95% CI: 36.4-55.3%) for documented SARS-CoV-2 infection and 44.8% (95% CI: 26.6-58.4%) and 50.0% (95% CI: 26.2-66.1%) for COVID-19 hospitalization, respectively.

Interpretation

A third dose of BNT162b2 or mRNA-1273 is moderately effective against post-vaccination COVID-19 infection compared to the primary series.

Funding

None.
SARS-CoV-2 genomic monitoring in the São Paulo State unveils new sublineages of the AY.43 strain
Authors: Lima Alex Ranieri Jerônimo , Ribeiro Gabriela , Viala Vincent Louis , de Lima Loyze Paola Oliveira , Martins Antonio Jorge , Santos Barros Claudia Renata dos , Marqueze Elaine Cristina , de Souza Todao Bernardino Jardelina , Moretti Debora Botequio , Rodrigues Evandra Strazza , Santos Elaine Vieira , Brassaloti Ricardo Augusto , de Lello Rocha Campos Cassano Raquel , Mariani Pilar Drummond Sampaio Corrêa , Clemente Luan Gaspar , Assato Patricia Akemi , Silva da Costa Felipe Allan da , Poleti Mirele Daiana , Lesbon Jessika Cristina Chagas , Mattos Elisangela Chicaroni , Banho Cecilia Artico , Sacchetto Lívia , Moraes Marília Mazzi , Palmieri Melissa , da Silva Fabiana Erica Vilanova , Grotto Rejane Maria Tommasini , Souza-Neto Jayme A. , Giovanetti Marta , de Alcantara Luiz Carlos Junior , Nogueira Maurício Lacerda , Fukumasu Heidge , Coutinho Luiz Lehmann , Kashima Simone , Neto Raul Machado , Covas Dimas Tadeu , Slavov Svetoslav Nanev , Elias Maria Carolina , Sampaio Sandra Coccuzzo
Published: November 2021

Delta VOC is highly diverse and more than 120 sublineages have been identified in Pango lineages with the continuous description of emerging ones. Brazil is now one of the most vaccinated countries against SARS-CoV-2 in the world which can enhance the emergence of viral mutations related to improved viral fitness. In this study, we identified two novel sublineages of the AY.43 lineage which were classified as AY.43.1 and AY.43.2 as observed on the specific clustering on the obtained phylogenetic tree. The novel sublineages were defined by the following characteristic nonsynonymous mutations ORF1ab:A4133V and ORF3a:T14I for AY.43.1 and ORF1ab:G1155C for AY.43.2. The majority of the analyzed sequences of both lineages were Brazilian, which shows that probably these two emerging sublineages have Brazilian origin. It is still unknown how these two sublineages are disseminated in São Paulo State and Brazil and their potential impact on the ongoing vaccination process. However, the performed study reinforces the importance of the SARS-CoV-2 genome monitoring for timely identification of emerging SARS-CoV-2 variants which can impact the ongoing SARS-CoV-2 vaccination and public health policies.
Population level impact of a pulse oximetry remote monitoring programme on mortality and healthcare utilisation in the people with covid-19 in England: a national analysis using a stepped wedge design
Authors: Beaney T , Clarke J , Alboksmaty A , Flott K , Fowler A , Benger JR , Aylin P , Elkin S , Neves AL , Darzi A
Published: November 2021

Objectives

To identify the population level impact of a national pulse oximetry remote monitoring programme for covid-19 (COVID Oximetry @home; CO@h) in England on mortality and health service use.

Design

Retrospective cohort study using a stepped wedge pre- and post-implementation design.

Setting

All Clinical Commissioning Groups (CCGs) in England implementing a local CO@h programme.

Participants

217,650 people with a positive covid-19 polymerase chain reaction test result and symptomatic, from 1st October 2020 to 3rd May 2021, aged ≥65 years or identified as clinically extremely vulnerable. Care home residents were excluded.

Interventions

A pre-intervention period before implementation of the CO@h programme in each CCG was compared to a post-intervention period after implementation.

Main outcome measures

Five outcome measures within 28 days of a positive covid-19 test: i) death from any cause; ii) any A&E attendance; iii) any emergency hospital admission; iv) critical care admission; and v) total length of hospital stay.

Results

Implementation of the programme was not associated with mortality or length of hospital stay. Implementation was associated with increased health service utilisation with a 12% increase in the odds of A&E attendance (95% CI: 6%-18%) and emergency hospital admission (95% CI: 5%-20%) and a 24% increase in the odds of critical care admission in those admitted (95% CI: 5%-47%). In a secondary analysis of CO@h sites with at least 10% or 20% of eligible people enrolled, there was no significant association with any outcome measure. However, uptake of the programme was low, with enrolment data received for only 5,527 (2.5%) of the eligible population.

Conclusions

At a population level, there was no association with mortality following implementation of the CO@h programme, and small increases in health service utilisation were observed. Low enrolment of eligible people may have diluted the effects of the programme at a population level.
SARS-CoV-2 Delta variant saliva viral load is 15-fold higher than wild-type strains
Authors: Imai Kenichi , Ikeno Ryo , Tanaka Hajime , Takada Norio
Published: November 2021

The emergence of SARS-CoV-2 Delta variants has escalated COVID-19 cases globally due to their high transmissibility. Since saliva is crucial for SARS-CoV-2 transmission, we hypothesized that a higher viral load of Delta variants in saliva than their parental wild-type strains contributed to the high transmissibility in the first place. However, studies have not reported this particular comparison done with viral copy numbers. Twenty-two genetically confirmed -positive saliva samples for wild-type strain and 32 Delta variants were statistically compared for viral copy number per milliliter determined by real-time qPCR combined with synthesized viral RNA and Poisson’s null distribution equation between the groups of wild and variant strains and between whole saliva and centrifugal supernatant in each group. We found that the copy number of the Delta variants was 15.1 times higher than wild-type strains of the whole saliva. In addition, the viral load of both strains in the whole saliva was higher than the pertinent supernatant, indicating that most viruses in the whole saliva are associated with host cells. Meanwhile, more than a million virions per milliliter of the viral load of the variants in the supernatants were 4.0 times higher but not significant than wild-type strains. Humanity must share our findings; the simple but concrete note that Delta variant viral load is abundant in the saliva is critical for preventing the spread of infection.
Donor Age and Time in Culture Affect Dermal Fibroblast Contraction in a Hydrogel Skin Graft Model
Authors: Detwiler Amber , Polkoff Kathryn , Gaffney Lewis , Freytes Donald , Piedrahita Jorge
Published: November 2021

Regenerating functional skin without the formation of scar tissue remains an important goal for Tissue Engineering. Current hydrogel-based grafts minimize contraction of full-thickness skin wounds and support skin regeneration using adult or neonatal foreskin dermal fibroblasts, which are often expanded in vitro and used after multiple passages. Based on the known effects of 2D tissue culture expansion on cellular proliferation and gene expression, we hypothesized that differences in donor age and time in culture may also influence the functionality of 3D skin constructs by affecting fibroblast-mediated graft contraction. To validate these predicted differences in fibroblast phenotype and resulting 3D graft model contraction, we isolated porcine dermal fibroblasts of varying donor age for use in a 2D proliferation assay and a 3D cell-populated collagen matrix contractility assay. In 2D cell culture, doubling time remained relatively consistent between all age groups from passage 1 to 6. In the contractility assays, fetal and neonatal groups contracted faster and generated more contractile force than the adult group at passage 1. However, after 5 passages in culture, there was no difference in contractility between groups. These results show how cellular responses differ based on donor age and time in culture, which could account for important differences in biomanufacturing of 3D hydrogel-based skin grafts. Future research and therapies using bioengineered skin grafts should consider how results may vary based on donor age and time in culture before seeding.

IMPACT STATEMENT

Little is known about the impact of donor age and time in culture on the contraction of the 3D hydrogel-based graft. These results show how cellular phenotypes differ based on donor age and time in culture, which could account for important inconsistencies in biomanufacturing of skin grafts and in vitro models. These findings are relevant to research and therapies using bioengineered skin graft models and the results can be used to increase reproducibility and consistency during the production of bioengineered skin constructs. Future in vivo studies could help determine the best donor age and time in culture for improved wound healing outcomes or more reproducible in vitro testing constructs.
Asymmetrical dose-responses shape the evolutionary trade-off between antifungal resistance and nutrient use
Authors: Després Philippe C , Cisneros Angel F , Alexander Emilie MM , Sonigara Ria , Gagné-Thivierge Cynthia , Dubé Alexandre K , Landry Christian R
Published: November 2021

Antimicrobial resistance is an emerging threat for public health. The success of resistance mutations depends on the trade-off between the benefits and costs they incur. This trade-off is largely unknown and uncharacterized for antifungals. Here, we systematically measure the effect of all amino acid substitutions in the yeast cytosine deaminase Fcy1, the target of the antifungal 5-FC (flucytosine). We identify over 900 missense mutations granting resistance to 5-FC, a large fraction of which appear to act through destabilisation of the protein. The relationship between 5-FC resistance and growth sustained by cytosine deamination is characterized by a sharp trade-off, such that small gains in resistance universally lead to large losses in canonical enzyme function. We show that this steep relationship can be explained by differences in the dose-response functions of 5-FC and cytosine. Finally, we observe the same trade-off shape for the ortholog ofFCY1inCryptoccocus neoformans, a human pathogen. Our results provide a powerful resource and platform for interpreting drug target variants in fungal pathogens as well as unprecedented insights into resistance-function trade-offs.
Regulation of the macrolide resistance ABC-F translation factor MsrD
Authors: Fostier Corentin R. , Ousalem Farès , Leroy Elodie C. , Ngo Saravuth , Soufari Heddy , Innis C. Axel , Hashem Yaser , Boёl Grégory
Published: November 2021

Antibiotic resistance ABC-Fs (ARE ABC-Fs) are translation factors currently proliferating among human pathogens that provide resistance against clinically important ribosome-targeting antibiotics. Here, we combine genetic and structural approaches to determine the regulation of streptococcal ARE ABC-F gene msrD in response to macrolide exposure and also demonstrate that MsrD twin-ATPase sites work asymmetrically to mediate the dynamic of MsrD interaction with the ribosome. We show that cladinose-containing macrolides lead to insertion of MsrDL leader peptide into an undocumented conserved crevice of the ribosomal exit tunnel concomitantly with 23S rRNA rearrangements that prevent peptide bond formation and preclude accommodation of release factors. The stalled ribosome obstructs formation of a Rho-independent terminator which prevents msrD transcriptional attenuation. This stalled ribosome is rescued by MsrD, but not by MsrD mutants which do not provide antibiotic resistance, showing evidence of equivalence between MsrD function in antibiotic resistance and its action on this complex.
Similarities Between Bacterial GAD and Human GAD65: Implications in Gut Mediated Autoimmune Type 1 Diabetes
Authors: Bedi Suhana , Richardson Tiffany M. , Jia Baofeng , Saab Hadeel , Brinkman Fiona S.L. , Westley Monica
Published: November 2021

A variety of islet autoantibodies (AAbs) can predict and possibly dictate eventual type 1 diabetes (T1D) diagnosis. Upwards of 75% of those with T1D are positive for AAbs against glutamic acid decarboxylase (GAD65), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells. Interestingly, bacterial populations within the human gut also express GAD65 and produce GABA. Evidence suggests that dysbiosis of the microbiome may correlate with T1D pathogenesis and physiology. Therefore, autoimmune linkages between the gut microbiome and islets susceptible to autoimmune attack need to be further elucidated. Utilizing silico analyses, we show here that 25 GAD sequences from different human gut bacterial sources show sequence and motif similarities to human beta cell GAD65. Our motif analyses determined that a majority of gut GAD sequences contain the pyroxical dependent decarboxylase domain of human GAD65 which is important for its enzymatic activity. Additionally, we showed overlap with known human GAD65 T-cell receptor epitopes which may implicate the immune destruction of beta cells. Thus, we propose a physiological hypothesis in which changes in the gut microbiome in those with T1D result in a release of bacterial GAD, thus causing miseducation of the host immune system. Due to the notable similarities, we found between humans and bacterial GAD, these deputized immune cells may then go on to target human beta cells leading to the development of T1D.
Salmonella Typhimurium infection drives NK cell loss and conversion to ILC1-like cells, and CIS inhibition enhances antibacterial immunity
Authors: McCulloch Timothy R. , Rossi Gustavo R. , Wells Timothy J. , Souza-Fonseca-Guimaraes Fernando
Published: November 2021

Immunotherapy has revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes. More recently, immunotherapy has emerged to restore immunity against infectious agents, including bacterial infections. Immunotherapy primarily targets inhibitory pathways in tumor-resident T cells, however interest in other effector populations, such as natural killer (NK) cells, is growing. We have previously discovered that NK cell metabolism, proliferation, and activation can be neutralized through the TGF-β immunosuppressive pathway by inducing plasticity of NK cells and differentiation into ILC1-like subsets. NK cells are also regulated through cytokine-inducible SH2-containing protein (CIS), which is induced by IL-15 and is a potent intracellular checkpoint suppressing NK cell survival and function. Targeting these two distinct pathways to restore NK cell function has shown promise is cancer models, but their application in bacterial infection remains unknown. Here, we investigate whether enhancement of NK cell function can improve anti-bacterial immunity, using Salmonella Typhimurium as a model. We identified conversion of NK cells to ILC1-like for the first time in the context of bacterial infection, however TGF-β signaling was curiously redundant in this plasticity. Future work should focus on identifying drivers of ILC1 plasticity and its functional implication in bacterial infection models. We further describe that CIS-deficient mice displayed enhanced pro-inflammatory function and dramatically enhanced anti-infection immunity. Inhibition of CIS may present as a viable therapeutic option to enhance immunity towards bacterial infection.
Structure of Dunaliella Photosystem II reveals conformational flexibility of stacked and unstacked supercomplexes
Authors: Caspy Ido , Fadeeva Maria , Mazor Yuval , Nelson Nathan
Published: November 2021

Photosystem II (PSII) generates an oxidant whose redox potential is high enough to enable water oxidation1,2, a substrate so abundant that it assures a practically unlimited electron source for life on earth3. Our knowledge on the mechanism of water photooxidation was greatly advanced by high-resolution structures of prokaryotic PSII4–6. Here we show high-resolution structures of eukaryotic PSII from the green algae Dunaliella salina at two distinct conformations. The conformers are also present in stacked PSII, exhibiting flexibility that is relevant to the grana formation in chloroplasts of the green lineage. CP29, one of PSII associated light harvesting antennae, plays a major role in distinguishing the two conformations of the supercomplex. We also show that the stacked PSII dimer, a form suggested to support the organization of thylakoid membranes7,8, can appear in many different orientations providing a flexible stacking mechanism for the arrangement of grana stacks in thylakoids. Our findings provide a structural basis for the heterogenous nature of the eukaryotic PSII on multiple levels.
Nrf1 is not a direct target gene of SREBP1, albeit both are integrated into the rapamycin-responsive regulatory network in human hepatoma cells
Authors: Liu Keli , Hu Shaofan , Qiu Lu , Wang Meng , Zhang Zhengwen , Sun Guiyin , Zhang Yiguo
Published: November 2021

It is questionable why no further experimental evidence confirming those findings, since being reported by Manning’s group in 2014’s Nature (doi: 10.1038/nature13492), has been provided in the hitherto known literature. They found that ‘Growth factors stimulate an increase in Nrf1 through mTORC1, which induces NRF1 transcription in an SREBP1-dependent manner’ and asserted that Nrf1 is directly regulated by SREBP1. Thereby, a key issue arising from their work is of particular concern about whether the mTORC1 signaling to upregulation of Nrf1-targeted proteasomal expression profiles occurs directly by SREBP1. In this study, our experiment evidence revealed that Nrf1 is not a direct target of SREBP1, although both are involved in the rapamycin-responsive regulatory networks. Closely scrutinizing two distinct transcriptomic datasets unraveled no significant changes in transcriptional expression of Nrf1 and almost all proteasomal subunits in either siSREBP2-silencing cells or SREBP1–/– MEFs, when compared to equivalent controls. However, distinct upstream signaling to Nrf1 dislocation by p97 and its processing by DDI1/2, along with downstream proteasomal expression, may be monitored by mTOR signaling, to various certain extents, depending on distinct experimental settings in different types of cells. Our further evidence has been obtained from DDI1–/–(DDI2insC) cells, demonstrating that putative effects of mTOR on the rapamycin-responsive signaling to Nrf1 and proteasomes may also be executed partially through a DDI1/2-independent mechanism, albeit the detailed regulatory events remain to be determined.
Cross-modal Semantic Relationships Guide Spontaneous Orienting in Real-life Scenes
Authors: Kvasova Daria , Stewart Travis , Soto-Faraco Salvador
Published: November 2021

In real-world scenes, the different objects and events available to our senses are interconnected within a rich web of semantic associations. These semantic links help parse information and make sense of the environment. For example, during goal-directed attention, characteristic everyday life object sounds help speed up visual search for these objects in natural and dynamic environments. However, it is not known whether semantic correspondences also play a role under spontaneous observation. Here, we investigated this question addressing whether crossmodal semantic congruence can drive spontaneous, overt visual attention in free-viewing conditions. We used eye-tracking whilst participants (N=45) viewed video clips of realistic complex scenes presented alongside sounds of varying semantic congruency with objects within the videos. We found that characteristic sounds increased the probability of looking, the number of fixations, and the total dwell time on the semantically corresponding visual objects, in comparison to when the same scenes were presented with semantically neutral sounds or just with background noise only. Our results suggest that crossmodal semantic congruence has an impact on spontaneous gaze and eye movements, and therefore on how attention samples information in a free viewing paradigm. Our findings extend beyond known effects of object-based crossmodal interactions with simple stimuli and shed new light upon how audio-visual semantically congruent relationships play out in everyday life scenarios.
Translational suppression via IFG-1/eIF4G confers resistance to stress-induced RNA alternative splicing in Caenorhabditis elegans
Authors: Chomyshen Samantha C. , Wu Cheng-Wei
Published: November 2021

Splicing of pre-mRNA is an essential process for dividing cells and splicing defects have been linked to aging and various chronic diseases. Environmental stress has recently been shown to alter splicing fidelity and molecular mechanisms that protect against splicing disruption remains unclear. Using an in vivo RNA splicing reporter, we performed a genome-wide RNAi screen in Caenorhabditis elegans and found that protein translation suppression via silencing of the conserved initiation factor 4G (IFG-1/eIF4G) protects against cadmium-induced splicing disruption. Transcriptome analysis of an ifg-1 deficient mutant revealed an overall increase in splicing fidelity and resistance towards cadmium-induced alternative splicing compared to the wild-type. We found that the ifg-1 mutant up-regulates >80 RNA splicing regulatory genes that are controlled by the TGF-β transcription factor SMA-2. The extended lifespan of the ifg-1 mutant is partially reduced upon sma-2 depletion and completely nullified when core spliceosome genes including snr-1, snr-2, and uaf-2 are knocked down. Together, these data describe a molecular mechanism that provides resistance towards stress-induced alternative splicing and demonstrate an essential role for RNA homeostasis in promoting longevity in a translation-compromised mutant.
KymoMerge: a new tool for analysis of multichannel kymographs
Authors: McMahon Lloyd P. , Digilio Laura , Duston Alois , Yap Chan Choo , Winckler Bettina
Published: November 2021

Kymograph analysis is commonly used by researchers to study dynamic processes in cells. Current tools widely available only allow for analysis of one channel kymographs. Here we provide a python-coded, open source program to use as a plug-in for ImageJ which creates one kymograph from the kymographs of two separate channels of one time-lapse movie. This add-in, which we call KymoMerge, therefore allows for analysis of only the co-located tracks in multi-channel movies.
Systems genetics uncovers microbe-lipid-host connections in the murine gut
Authors: Zhang Q , Linke V , Overmyer KA , Traeger LL , Kasahara K , Miller IJ , Manson DE , Polaske TJ , Kerby RL , Kemis JH , Trujillo EA , Reddy TR , Russell JD , Schueler KL , Stapleton DS , Rabaglia ME , Seldin M , Gatti DM , Keele GR , Pham DT , Gerdt JP , Vivas EI , Lusis AJ , Keller MP , Churchill GA , Blackwell HE , Broman KW , Attie AD , Coon JJ , Rey FE
Published: November 2021

The molecular bases of how host genetic variation impact gut microbiome remain largely unknown. Here, we used a genetically diverse mouse population and systems genetics strategies to identify interactions between molecular phenotypes, including microbial functions, intestinal transcripts and cecal lipids that influence microbe-host dynamics. Quantitative trait loci (QTL) analysis identified genomic regions associated with variations in bacterial taxa, bacterial functions, including motility, sporulation and lipopolysaccharide production, and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and cecal levels of ornithine lipids (OL). Follow-up studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that OL have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits. Collectively, these results suggest that OL are key players in A. muciniphila-host interactions and support the role of host genetics as a determinant of responses to gut microbes.
Carbon Dot-based Fluorescent Antibody Nanoprobes as Brain Tumour Glioblastoma Diagnostics
Authors: Ghirardello Mattia , Shyam Radhe , Liu Xia , Garcia-Millan Teodoro , Sittel Imke , Ramos-Soriano F. Javier , Kurian Kathreena , Galan M. Carmen
Published: November 2021

The development of efficient and sensitive tools for the detection of brain cancer in patients is of the utmost importance particularly because many of these tumours go undiagnosed until the disease has advanced and when treatment is less effective. Current strategies employ antibodies (Abs) to detect Glial Fibrillary Acid Protein (GFAP) in tissue samples, since GFAP is unique to the brain and not present in normal peripheral blood, and it relies on fluorescent reporters.

Herein we describe a low cost, practical and general method for the labelling of proteins and antibodies with fluorescent carbon dots (CD) to generate diagnostic probes that are robust, photostable and applicable to the clinical setting. The two-step protocol relies on the conjugation of a dibenzocyclooctyne (DBCO)-functionalised CD with azide functionalised proteins by combining amide conjugation and strain promoted alkyne-azide cycloaddition (SPAAC) ligation chemistry. The new class of Ab-CD conjugates developed using this strategy was successfully used for the immunohistochemical staining of human brain tissues of patients with glioblastoma (GBM) validating the approach. Overall, these novel fluorescent probes offer a promising and versatile strategy in terms of costs, photostability and applicability which can be extended to other Abs and protein systems.
Pancreatic cancer ductal cell of origin drives CD73-dependent generation of immunosuppressive adenosine
Authors: Singh Kanchan , Faraoni Erika Y. , Dai Yulin , Chandra Vidhi , Vucic Emily , Mills Tingting , Pruski Melissa , Clark Trent , Van Buren George , Thosani Nirav C. , Bynon John S. , Wray Curtis J. , Bar-Sagi Dafna , Poulsen Kyle L. , Vornik Lana A. , Savage Michelle I. , Sei Shizuko , Mohammed Altaf , Zhao Zhongming , Eltzschig Holger K. , Brown Powel H. , McAllister Florencia , Bailey-Lundberg Jennifer
Published: November 2021

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding initial triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing novel targets for effective prevention and therapy. Here, we interrogate the differential molecular mechanisms dependent on cell of origin and pathology subtype that determine immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell of origin dependent-epithelial gene signatures revealed that Nt5e/CD73, a cell surface enzyme that is the pacemaker for extracellular adenosine generation, is one of the top 10% of genes over-expressed in murine tumors arising from ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by Imaging Mass Cytometry and High-Performance Liquid Chromatography. Our data indicate that ductal activation of oncogenic mutant Kras results in loss of PTEN and elevated AKT signaling which ultimately releases CD73 suppression. Delivery of CD73 small molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. Analysis in human PDAC subtypes indicates that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC Squamous and Basal Subtypes, considered to have the highest immunosuppression and worst prognosis. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment which is dependent on ductal cell of origin, linking biology with pathological subtype classification, critical components to personalized approaches for PDAC prevention and immunotherapeutic intervention.

Abstract Figure
Positive feedback promotes terrestrial emergence behaviour in an amphibious fish
Authors: Tigert Liam , Turko Andy J. , Wright Patricia A.
Published: November 2021

Major ecological transitions such as the invasion of land by aquatic vertebrates have been hypothesised to be facilitated by positive feedback between habitat choice and phenotypic plasticity. We tested whether aquatic hypoxia, emergence behaviour, and plastic changes in gill surface area could create such a positive feedback loop and drive an amphibious fish to spend increasing amounts of time out of water. We found that terrestrially acclimated amphibious mangrove rivulus Kryptolebias marmoratus were more sensitive to, and less tolerant of, aquatic hypoxia relative to water-acclimated fish, which are necessary trade-offs for positive feedback to occur. Next, we acclimated fish to normoxic or hypoxic water with the opportunity to emerge for 7d to test the predictions that fish in hypoxic conditions should regularly leave water, reduce gill surface area, and become less hypoxia tolerant. Consistent with these predictions, fish in severe hypoxia spent almost 50% of the time out of water and coverage of the gill lamellae by an inter-lamellar cell mass almost doubled. Hypoxia acclimated fish were also more sensitive to acute aquatic hypoxia (emergence at higher oxygen levels), and lost equilibrium faster in hypoxic water compared to control fish. Thus, we show that a positive feedback loop develops in amphibious fish where emergence behaviour begets further emergence behaviour, driven by gill remodelling which reduces aquatic respiratory function. Such a scenario may explain how amphibious behaviour has repeatedly evolved in fishes that occupy hypoxic aquatic habitats despite the associated challenges of life on land.
OxPhos Dysfunction Causes Hypermetabolism and Reduces Lifespan in Cells and in Patients with Mitochondrial Diseases
Authors: Sturm Gabriel , Karan Kalpita R , Monzel Anna , Santhanam Balaji S , Taivassalo Tanja , Bris Céline , Ware Sarah A , Cross Marissa , Towheed Atif , Higgins-Chen Albert , McManus Meagan J , Cardenas Andres , Lin Jue , Epel Elissa S , Rahman Shamima , Vissing John , Grassi Bruno , Levine Morgan , Horvath Steve , Haller Ronald G , Lenaers Guy , Wallace Douglas C , St-Onge Marie-Pierre , Tavazoie Saeed , Procaccio Vincent , Kaufman Brett A , Seifert Erin L , Hirano Michio , Picard Martin
Published: November 2021

Patients with primary mitochondrial diseases present with fatigue and multi-system disease, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. Integrating data from 17 cohorts of patients with mitochondrial diseases (n=690), we find that clinical mitochondrial disorders increase resting energy expenditure, a state termed hypermetabolism. In a longitudinal cellular model of primary patient-derived fibroblasts from multiple donors, we show that genetic and pharmacological disruptions of oxidative phosphorylation (OxPhos) similarly trigger increased energy consumption in a cell-autonomous manner, despite near-normal OxPhos coupling efficiency. Hypermetabolism is associated with mtDNA instability, activation of the integrated stress response, increased extracellular secretion of age-related cytokines and metabokines including GDF15, as well as an accelerated rate of telomere erosion and epigenetic aging, and a reduced Hayflick limit. Together with these dynamic measures, we have generated a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations in response to OxPhos dysfunction. The increased energetic cost of living, or hypermetabolism, in cells and organisms with OxPhos defects has important biological and clinical implications.