bluuebunny/crossref_metadata_2025 huggingface dataset:
Mild Adverse Events of Sputnik V Vaccine Extracted from Russian Language Telegram Posts via BERT Deep Learning Model
Authors: Jarynowski Andrzej , Semenov Alexander , Kamiński Mikołaj , Belik Vitaly
Published: June 2021

Background

There is a limited amount of data on the COVID-19 vector vaccine Gam-COVID-Vac (Sputnik V) safety profile. Previous infodemiology studies showed that social media discourse could be analyzed to assess the most concerning adverse events (AE) caused by drugs.

Objective

We aimed to investigate mild AEs of Sputnik V based on a participatory trial conducted on Telegram in the Russian language. We compared AEs extracted from Telegram with other limited databases on Sputnik V and other COVID-19 vaccines. We explored symptom co-occurrence patterns and determined how counts of administered doses, age, gender, and sequence of shots could confound the reporting of AEs.

Materials and Methods

We collected a unique dataset consisting of 11,515 self-reported Sputnik V vaccine AEs posted on the Telegram group, and we utilized natural language processing methods to extract AEs. Specifically, we performed multi-label classifications using the deep neural language model BERT “DeepPavlov”, which we pre-trained on a Russian language corpus and applied to the Telegram messages. The resulting AUC score was 0.991. We chose symptom classes that represented the following AEs: fever, pain, chills, fatigue, nausea/vomiting, headache, insomnia, lymph node enlargement, erythema, pruritus, swelling, and diarrhea.

Results

The results of the retrospective analysis showed that females reported more AEs than males (1.2-fold, P<.001). In addition, there were more AEs from the first dose than from the second dose (1.13-fold, P<.001), and the number of AEs decreased with age (β= .05 per year, P<.001). The results also showed that Sputnik V AEs were more similar to other vector vaccines (132 units) compared with mRNA ones (241 units) according to the average Euclidean distance between the vectors of AE frequencies. Elderly Telegram users reported significantly more (5.6-fold on average) systemic AEs than their peers, according to the results of the phase III clinical trials published inThe Lancet. However, the AEs reported in Telegram posts were consistent (Pearson correlation r=.94, P=.02) with those reported in the Argentinian post-marketing AE registry.

Conclusion

After receiving the Sputnik V vaccination, Telegram users complained about pain (47%), fever (47%), fatigue (34%), and headache (25%). The results showed that the AE profile of Sputnik V was comparable with other COVID-19 vaccines. Examining the sentinel properties of participatory trials (which is subject to self-reporting biases) could still provide meaningful information about pharmaceutics, especially if only a limited amount of information on AEs is provided by producers.
Network meta-analysis and random walks
Authors: Davies Annabel L. , Papakonstantinou Theodoros , Nikolakopoulou Adriani , Rücker Gerta , Galla Tobias
Published: June 2021

Network meta-analysis (NMA) is a central tool for evidence synthesis in clinical research. The results of an NMA depend critically on the quality of evidence being pooled. In assessing the validity of an NMA, it is therefore important to know the proportion contributions of each direct treatment comparison to each network treatment effect. The construction of proportion contributions is based on the observation that each row of the hat matrix represents a so-called ‘evidence flow network’ for each treatment comparison. However, the existing algorithm used to calculate these values is associated with ambiguity according to the selection of paths. In this work we present a novel analogy between NMA and random walks. We use this analogy to derive closed-form expressions for the proportion contributions. A random walk on a graph is a stochastic process that describes a succession of random ‘hops’ between vertices which are connected by an edge. The weight of an edge relates to the probability that the walker moves along that edge. We use the graph representation of NMA to construct the transition matrix for a random walk on the network of evidence. We show that the net number of times a walker crosses each edge of the network is related to the evidence flow network. By then defining a random walk on the directed evidence flow network, we derive analytically the matrix of proportion contributions. The random-walk approach, in addition to being computationally more efficient, has none of the associated ambiguity of the existing algorithm.
Coverage and Effectiveness of mRNA COVID-19 Vaccines among Veterans
Authors: Young-Xu Yinong , Korves Caroline , Roberts Jeff , Powell Ethan I. , Zwain Gabrielle M. , Smith Jeremy , Izurieta Hector S.
Published: June 2021

Importance

The effectiveness of mRNA vaccination in a large and diverse American population, with older age and higher co-morbidity has not been assessed.

Objective

To describe the scope of the mRNA vaccination rollout among the diverse U.S. Veterans population, and to study the mRNA COVID-19 vaccine effectiveness (VE) against infection, symptomatic disease, hospitalization, and death.

Methods

Vaccination histories were obtained from medical records to determine if patients tested for SARS-CoV-2 were unvaccinated, partially vaccinated (first dose of mRNA COVID-19 vaccine), or fully vaccinated (two doses) at time of testing. First, coverage with any COVID-19 vaccination was described for all Veterans enrolled in Veterans Health Administration (VHA). Second, to evaluate VE, a matched test-negative case-control evaluation was conducted utilizing SARS-CoV-2 positive (cases [n=16,690]) and SARS-CoV-2 negative (controls [n=61,610]) tests from Veterans aged ≥18 years old who routinely sought care at a VHA facility and were tested from December 14, 2020, through March 14, 2021. VE was calculated from odds ratios (ORs) with 95% confidence intervals (CI).

Results

By March 7, 2021, among 6,170,750 Veterans, 1,547,045 (23%) received at least one COVID-19 vaccination. mRNA COVID-19 VE against infection, regardless of symptoms, was 94% (95% CI 92-95) and 58% (95%CI 54-62) for full and partial vaccination (vs. no vaccination), respectively. VE against infection was similar across subpopulations, and it was not significantly different from VE against symptomatic disease. VE against COVID-19-related hospitalization and death for full vs. no vaccination was 89% (95%CI 81-93) and 99% (95%CI 87-100), respectively.

Conclusions and Relevance

The VHA’s efficient and equitable distribution of effective vaccines decreased COVID-19 infections, hospitalization, and mortality similarly for all Veterans, including Veterans with low income, homeless Veterans, immunocompromised, the elderly, minorities, and rural Veterans thus reducing health inequalities.
The valuation of outcomes for the temporary and chronic health states associated with Chlamydia trachomatis infection
Authors: Ogwulu Chidubem B.Okeke , Jackson Louise J. , Kinghorn Philip , Roberts Tracy E.
Published: June 2021

Background

Eliciting health-state utility values (HSUVs) for some diseases is complicated by the mix of associated temporary (THSs) and chronic health states (CHSs). This study uses one such disease, chlamydia infection, to explore the challenges. The objectives were to:

Define a set of health-state descriptions related to chlamydia and

Derive HSUVs for these health states (both temporary and chronic).

Methods

HSUVs were elicited for seven health states (five THSs and two CHSs) depicting the symptoms of chlamydia, developed using evidence from the literature and clinical experts. The chained time trade-off (TTO) and visual analogue scale (VAS) were applied to THSs while conventional TTO was applied to the CHSs. Ectopic pregnancy was used as the anchor for the chained TTO approach. The study sampled from three different population groups and the survey was administered face-to-face.

Results

One hundred participants were assessed with an interview completion rate of 100%. Mean TTO utilities were consistently higher than VAS scores. The aggregated mean chained TTO results for the THS ranged from 0.46 (SD, 0.24) for ectopic pregnancy, to 0.77 (SD 0.21) for cervicitis.

Conclusions

Chained TTO was shown to be feasible in this population and the resulting HSUVs could have implications for economic evaluations for chlamydia prevention and control. Methodological challenges included the development of health-state descriptions, the selection, and the duration of appropriate anchor state.
Prognostication for prelabor rupture of membranes and the time of delivery in nationwide insured women: development, validation, and deployment
Authors: Sufriyana Herdiantri , Wu Yu-Wei , Su Emily Chia-Yu
Published: June 2021

Importance

Prognostic predictions of prelabor rupture of membranes lack proper sample sizes and external validation.

Objective

To develop, validate, and deploy statistical and/or machine learning prediction models using medical histories for prelabor rupture of membranes and the time of delivery.

Design

A retrospective cohort design within 2-year period (2015 to 2016) of a single-payer, government-owned health insurance database covering 75.8% individuals in a country

Setting

Nationwide healthcare providers (n=22,024) at primary, secondary, and tertiary levels

Participants

12-to-55-year-old women that visit healthcare providers using the insurance from ∼1% random sample of insurance holders stratified by healthcare provider and category of family: (1) never visit; (2) visit only primary care; and (3) visit all levels of care

Predictors

Medical histories of diagnosis and procedure (International Classification of Disease version 10) before the latest visit of outcome within the database period

Main Outcomes and Measures

Prelabor rupture of membranes prognostication (area under curve, with sensitivity, specificity, and likelihood ratio), the time of delivery estimation (root mean square error), and inference time (minutes), with 95% confidence interval

Results

We selected 219,272 women aged 33 ± 12 years. The best prognostication achieved area under curve 0.73 (0.72 to 0.75), sensitivity 0.494 (0.489 to 0.500), specificity 0.816 (0.814 to 0.818), and likelihood ratio being positive 2.68 (2.63 to 2.75) and negative 0.62 (0.61 to 0.63). This outperformed models from previous studies according to area under curve of an external validation set, including one using a biomarker (area under curve 0.641; sensitivity 0.419; sensitivity 0.863; positive likelihood ratio 3.06; negative likelihood ratio 0.67;n=1177). Meanwhile, the best estimation achieved ± 2.2 and 2.6 weeks respectively for predicted events and non-events. Our web application only took 5.14 minutes (5.11 to 5.18) per prediction.

Conclusions and Relevance

Prelabor rupture of membranes and the time of delivery were predicted by medical histories; but, an impact study is required before clinical application.

Key Points

Question

Can we use medical histories of diagnosis and procedure in electronic health records to predict prelabor rupture of membranes and the time of delivery before the day in nationwide insured women?

Findings

In this prognostic study applying retrospective cohort paradigm, a significant predictive performance was achieved and validated. The area under receiver operating characteristics curve was 0.73 with the estimation errors of ± 2.2 and 2.6 weeks for the time of delivery.

Meaning

Preliminary prediction can be conducted in a wide population of insured women to predict prelabor rupture of membranes and estimate the time of delivery.
The evolution of knowledge on genes associated with human diseases
Authors: Lüscher-Dias Thomaz , Dalmolin Rodrigo Juliani Siqueira , de Paiva Amaral Paulo , Alves Tiago Lubiana , Schuch Viviane , Franco Glória Regina , Nakaya Helder I
Published: June 2021

Thousands of scientific articles describing genes associated with human diseases are published every week. Computational methods such as text mining and machine learning algorithms are now able to automatically detect these associations. In this study, we used a cognitive computing text-mining application to construct a knowledge network comprised of 3,723 genes and 99 diseases. We then tracked the yearly changes on these networks to analyze how our knowledge has evolved in the past 30 years. Our approach helped to unravel the molecular bases of diseases over time, and to detect shared mechanisms between clinically distinct diseases. It also revealed that multi-purpose therapeutic drugs target genes which are commonly associated with several psychiatric, inflammatory, or infectious disorders. By navigating in this knowledge tsunami, we were able to extract relevant biological information and insights about human diseases.
ADESSO: a rapid, adaptable and sensitive Cas13-based COVID-19 diagnostic platform
Authors: Casati Beatrice , Verdi Joseph Peter , Hempelmann Alexander , Kittel Maximilian , Klaebisch Andrea Gutierrez , Meister Bianca , Welker Sybille , Asthana Sonal , Boskovic Pavle , Man Ka Hou , Schopp Meike , Ginno Paul , Radlwimmer Bernhard , Stebbins Charles Erec , Miethke Thomas , Papavasiliou Fotini Nina , Pecori Riccardo
Published: June 2021

SARS-CoV-2 is the causative agent for a pandemic that has had immense consequences for the health and economic sectors worldwide. While PCR testing and later antigen tests have proven critical for helping to stem the spread of the virus, these methods suffer from general applicability and sensitivity, respectively. Moreover, the emergence of variant strains creates the need for flexibility to correctly and efficiently diagnose the presence of substrains in the population. To address these needs we have developed the diagnostic test ADESSO (Accurate Detection of Evolving SARS-CoV-2 through SHERLOCK Optimization) which employs the Cas13 system to diagnose patients in as little as 1 hour without sophisticated equipment. Using an extensive panel of clinical samples, we demonstrate that ADESSO correctly identifies COVID-19 positive samples at a sensitivity and specificity comparable to RT-qPCR on extracted RNA and higher than antigen tests for unextracted samples. Taken together, ADESSO is a fast, sensitive and cheap method that can be applied in a point of care (POC) setting to diagnose COVID-19 and can be quickly adjusted to detect new variants.
Mucosal-Associated Invariant T (MAIT) Cells are Highly Activated in Duodenal Tissue of Humans with Vibrio cholerae O1 Infection
Authors: Bhuiyan Taufiqur R. , Rahman M. Arifur , Trivedi Shubhanshi , Afroz Taliman , Banna Hasan Al , Hoq Mohammad Rubel , Pop Ioana , Jensen Owen , Rashu Rasheduzzaman , Uddin Muhammad Ikhtear , Hossain Motaher , Khan Ashraful I. , Chowdhury Fahima , Harris Jason B. , Calderwood Stephen B. , Ryan Edward T. , Qadri Firdausi , Leung Daniel T.
Published: June 2021

Mucosal-associated invariant T (MAIT) cells are unconventional T lymphocytes with a semi-conserved TCRα, activated by the presentation of vitamin B metabolites by the MHC-I related protein, MR1, and with diverse innate and adaptive effector functions. The role of MAIT cells in acute intestinal infections, especially at the mucosal level, is not well known. Here, we analyzed the presence and phenotype of MAIT cells in duodenal biopsies and paired peripheral blood samples, in patients during and after culture-confirmed Vibrio cholerae O1 infection. Immunohistochemical staining of duodenal biopsies from cholera patients identified MAIT cells in the lamina propria, but not in the lining of villous and crypt epithelia. We observed significantly higher frequencies of duodenal MAIT cells at the acute stage (day 2) of V. cholerae infection as compared to late convalescence (day 30, p = 0.0049). By flow cytometry, we showed that duodenal MAIT cells are more activated than peripheral MAIT cells (p < 0.01 across time points), although there were no significant differences between duodenal MAITs at day 2 and day 30. We found fecal markers of intestinal permeability and inflammation to be correlated with the loss of duodenal (but not peripheral) MAIT cells, and single-cell sequencing revealed differing T cell receptor usage between the duodenal and peripheral blood MAIT cells. In summary, we show that MAIT cells are present and highly activated in the lamina propria of the duodenum during V. cholerae infection. Future work into the trafficking and tissue-resident function of MAIT cells is warranted.
Continuous Positive Airway Pressure (CPAP) for Moderate to Severe Covid19 Acute Respiratory Distress Syndrome (CARDS) in a Resource limited setting
Authors: Hoole Anbesan , Qamar Sahar , Khan Ayesha , Ejaz Mariam
Published: June 2021

Introduction

Covid19 Acute Respiratory Distress Syndrome (CARDS) poses a challenge in management particularly due to limited capacity of ventilated intensive care beds and staffing, and this is exacerbated in resource poor settings with poor patient outcomes. Within this context CPAP has been trialled for CARDS although mainly in resource rich settings.

Methods

This study retrospectively analyses the survival outcomes and characteristics of a cohort of patients with moderate to severe CARDS were treated exclusively with CPAP in a rural secondary level hospital in Pakistan with limited previous critical care expertise.

Results

32 out of the 41 patients (78%) who were treated with CPAP survived overall (30/37 (81%) who were treated according to protocol).

Discussion

Results suggest non inferiority to CARDS outcomes of critical care units employing Intubation and Mechanical Ventilation (IMV) in resource rich settings. CPAP should be promoted as an efficacious and cost-effective method for treating CARDS within the context of the pandemic surge of Covid19 in resource poor settings.

Key Messages

What is the key question?

Is Continuous Positive Airway Pressure (CPAP) an effective treatment for Covid19 Acute Respiratory Distress Syndrome (CARDS) in a resource poor setting in a pandemic surge context?

What is the bottom line?

Survival rate for CARDS on CPAP in our single centre retrospective cohort study is 78% which is similar to outcomes from critical care centres in resource rich settings employing Intubation and Mechanical Ventilation (IMV) and better than outcomes in many critical care centres in resource poor settings. This suggests CPAP should be promoted as an efficacious and cost-effective method for managing the pandemic surge of CARDS in resource poor settings.

Why read on?

The current surge of Covid19 CARDS in resource poor settings poses a significant challenge in terms of effective management given cost and resource restraints, reflected by poor outcomes in overwhelmed critical care centres employing IMV. This is the largest study so far documenting the survival outcomes and characteristics of patients with CARDS treated exclusively with CPAP within a resource poor setting.
The polarity and specificity of SARS-CoV2-specific T lymphocyte responses determine disease susceptibility
Authors: Fahrner Jean-Eudes , Carrier Agathe ,   Lyon COVID study group, De Sousa Eric , Drubay Damien , Dubuisson Agathe , Geraud Arthur , Goubet Anne-Gaëlle , Ferrere Gladys , Haddad Yacine , Lahmar Imran , Mazzenga Marine , Melenotte Cléa , Picard Marion , Thelemaque Cassandra , Cerbone Luigi , Lérias Joana R. , Laparra Ariane , Bernard Alice , Kloeckner Benoît , Gazzano Marianne , Danlos François-Xavier , Terrisse Safae , Alves Costa Silva Carolina , Pizzato Eugenie , Flament Caroline , Ly Pierre , Tartour Eric , Meziani Lydia , Ahmed-Belkacem Abdelhakim , Miyara Makoto , Gorochov Guy , Barlesi Fabrice , Pradon Caroline , Gallois Emmanuelle , Pommeret Fanny , Colomba Emeline , Lavaud Pernelle , Deutsch Eric , Gachot Bertrand , Spano Jean-Philippe , Merad Mansouria , Scotte Florian , Marabelle Aurélien , Griscelli Frank , Blay Jean-Yves , Soria Jean-Charles , Andre Fabrice , Chevalier Mathieu , Caillat-Zucman Sophie , Fenollar Florence , La Scola Bernard , Kroemer Guido , Maeurer Markus , Derosa Lisa , Zitvogel Laurence
Published: June 2021

Optimal vaccination and immunotherapy against coronavirus disease COVID-19 relies on the in-depth comprehension of immune responses determining the individual susceptibility to be infected by SARS-CoV-2 and to develop severe disease. We characterized the polarity and specificity of circulating SARS-CoV-2-specific T cell responses against whole virus lysates or 186 unique peptides derived from the SARS-CoV-2 or SARS-CoV-1 ORFeome on 296 cancer-bearing and 86 cancer-free individuals who were either from the pre-COVID-19 era (67 individuals) or contemporary COVID-19-free (237 individuals) or who developed COVID-19 (78 individuals) in 2020/21. The ratio between the prototypic T helper 1 (TH1) cytokine, interleukin-2, and the prototypic T helper 2 (TH2) cytokine, interleukin-5 (IL-5), released from SARS-CoV-2-specific memory T cells measured in early 2020, among SARS-CoV-2-negative persons, was associated with the susceptibility of these individuals to develop PCR-detectable SARS-CoV-2 infection in late 2020 or 2021. Of note, T cells from individuals who recovered after SARS-CoV-2 re-infection spontaneously produced elevated levels of IL-5 and secreted the immunosuppressive TH2 cytokine interleukin-10 in response to SARS-CoV-2 lysate, suggesting that TH2 responses to SARS-CoV-2 are inadequate. Moreover, individuals susceptible to SARS-CoV-2 infection exhibited a deficit in the TH1 peptide repertoire affecting the highly mutated receptor binding domain (RBD) amino acids (331-525) of the spike protein. Finally, current vaccines successfully triggered anti-RBD specific TH1 responses in 88% healthy subjects that were negative prior to immunization. These findings indicate that COVID-19 protection relies on TH1 cell immunity against SARS-CoV-2 S1-RBD which in turn likely drives the phylogenetic escape of the virus. The next generation of COVID-19 vaccines should elicit high-avidity TH1 (rather than TH2)-like T cell responses against the RBD domain of current and emerging viral variants.
Recovery of deleted deep sequencing data sheds more light on the early Wuhan SARS-CoV-2 epidemic
Authors: Bloom Jesse D.
Published: June 2021

The origin and early spread of SARS-CoV-2 remains shrouded in mystery. Here I identify a data set containing SARS-CoV-2 sequences from early in the Wuhan epidemic that has been deleted from the NIH’s Sequence Read Archive. I recover the deleted files from the Google Cloud, and reconstruct partial sequences of 13 early epidemic viruses. Phylogenetic analysis of these sequences in the context of carefully annotated existing data further supports the idea that the Huanan Seafood Market sequences are not fully representative of the viruses in Wuhan early in the epidemic. Instead, the progenitor of currently known SARS-CoV-2 sequences likely contained three mutations relative to the market viruses that made it more similar to SARS-CoV-2’s bat coronavirus relatives.
Fluid administration guided by inferior vena cava ultrasound before spinal anaesthesia may reduce post procedural hypotension rate
Authors: Favre Mathieu , Ceruti Samuele , Biggiogero Maira , Musiari Michele , Glotta Andrea , Gimigliano Isabella , Aguirre José , Borgeat Alain , Saporito Andrea
Published: June 2021

PURPOSE

This study was conducted to estimate the incidence of hypotension after spinal anaesthesia after inferior vena cava ultrasound (IVCUS) guided volaemic optimization compared with a control group in patients undergoing elective surgery. According to ESICM guidelines, hypotension was defined as two systolic arterial pressure (SAP) measurements < 80 mmHg and / or a mean arterial pressure (MAP) < 60 mmHg, or a drop in SAP of more than 50 mmHg or more than 25% from baseline, or a decrease in MAP by more than 30% from baseline and / or clinical signs/symptoms of inadequate perfusion.

MATERIALS AND METHODS

From May 2014 to February 2019, a prospective, controlled, randomised, three-arm, parallel-group trial was performed in our tertiary hospital. In the IVCUS group (I, 132 patients) and passive leg raising test group (L, 148 patients), a pre-anaesthesia volume optimization was achieved following a fluid response protocol. In control group (C, 149 patients), no specific intervention was performed.

RESULTS

474 patients were collected. In group I, hypotension rate was 35%. In group L hypotension rate was 44%. In group C hypotension rate was 46%. An 11% reduction rate in hypotension (95% CI -1 to -24%, P=0.047) was observed between the group I and the group C. A 2% reduction rate in hypotension (95% CI -3 to -5%, P=0.428) was observed between group L and the group C. Total fluid amount administered was greater in the I group I than in the group C (593 ml versus 453 ml, P=0.015) and greater in the group L than the group C (511 ml versus 453 ml, P=0.11).

CONCLUSION

IVCUS guided fluid optimisation decrease the incidence of arterial hypotension after spinal anaesthesia.
Impacts of Mycoplasma agalactiae restriction-modification systems on pan-epigenome dynamics and genome plasticity
Authors: Dordet-Frisoni Emilie , Vandecasteele Céline , Contarin Rachel , Sagné Eveline , Baranowski Eric , Klopp Christophe , Nouvel Laurent Xavier , Citti Christine
Published: June 2021

DNA methylation plays an important role in the biology of bacteria. Often associated with restriction modification (RM) systems, they also provide a defence against foreign DNA. Little is known regarding the methylome of the mycoplasma genus, which encompasses several pathogenic species with small genomes. Here, single molecule real-time (SMRT) and bisulphite sequencing combined with whole-genome analysis identified 19 methylated motifs associated with three orphan methyltransferases (MTases) and eight RM systems in Mycoplasma agalactiae, a ruminant pathogen and a model organism. All systems had a homolog in at least one phylogenetically distinct Mycoplasma spp. Our study also revealed that several superimposed genetic events may participate in the M. agalactiae dynamic epigenome landscape. These included (i) DNA shuffling and frameshift mutations that affect the MTase and restriction endonuclease content of a clonal population and (ii) gene duplication, erosion, and horizontal transfer that modulate MTase and RM repertoires of the species. Some of these systems were experimentally shown to play a major role in mycoplasma conjugative, horizontal DNA transfer. While the versatility of DNA methylation may contribute to regulating essential biological functions at cell and population levels, RM systems may be key in mycoplasma genome evolution and adaptation by controlling horizontal gene transfers.
Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses
Authors: Schulz Rouven , Korkut-Demirbaş Medina , Colombo Gloria , Siegert Sandra
Published: June 2021

G protein-coupled receptors (GPCRs) regulate multiple processes ranging from cell growth and immune responses to neuronal signal transmission. However, ligands for many GPCRs remain unknown, suffer from off-target effects or have poor bioavailability. Additional challenges exist to dissect cell type-specific responses when the same GPCR is expressed on different cells within the body. Here, we overcome these limitations by engineering DREADD-based GPCR chimeras that selectively bind their agonist clozapine-N-oxide (CNO) and mimic a GPCR-of-interest. We show that the chimeric DREADD-β2-adrenergic receptor (β2AR/ADRB2) triggers comparable responses to levalbuterol on second messenger and kinase activity, post-translational modifications, and protein-protein interactions. Moreover, we successfully recapitulate β2AR-mediated filopodia formation in microglia, a β2AR-expressing immune cell that can drive inflammation in the nervous system. To further dissect microglial inflammation, we compared DREADD-β2AR with two additionally designed DREADD-based chimeras mimicking GPR65 and GPR109A/HCAR2, both enriched in microglia. DREADD-β2AR and DREADD-GPR65 modulate the inflammatory response with a similar profile as endogenously expressed β2AR, while DREADD-GPR109A had no impact. Our DREADD-based approach allows investigation of cell type-dependent signaling pathways and function without known endogenous ligands.
Emotion increases the similarity between neural representations of pictures, but not their perceived similarity
Authors: Riberto Martina , Paz Rony , Pobric Gorana , Talmi Deborah
Published: June 2021

Stimuli that evoke the same feelings can nevertheless look different and have different semantic meanings. Although we know much about the neural representation of emotion, the neural underpinnings that govern judgements of emotional similarity are unknown. One possibility is that the same brain regions will represent similarity between emotional and neutral stimuli, perhaps with different strengths. Alternatively, emotional similarity could be coded in separate regions, possibly those known to express emotional valence and arousal preferentially. In behaviour, the extent to which people consider similarity along the emotional dimension when they evaluate the overall similarity between stimuli has never been investigated. While the emotional features of stimuli may dominate explicit ratings of similarity, it is also possible that people neglect the emotional dimension as irrelevant. We contrasted these hypotheses with two measures of similarity and two different databases of complex negative and neutral pictures, the second of which afforded exquisite control over semantic and visual attributes. Emotion increased neural similarity in a set of regions that represented both emotional and neutral stimuli, including the inferior temporal cortex, the fusiform face area, and the precuneus. Emotion also increased neural similarity in early visual cortex, anterior insula and dorsal anterior cingulate cortex, despite no increase in BOLD-signal amplitudes in these regions. Despite the stronger neural similarity between emotional stimuli, participants rated pictures taken from two distinct emotional categories as equally similar. These results contribute to our understanding of how emotion is represented within a general conceptual workspace.
VarGenius-HZD allows accurate detection of rare homozygous or hemizygous deletions in targeted sequencing leveraging breadth of coverage
Authors: Musacchia Francesco , Karali Marianthi , Torella Annalaura , Laurie Steve , Policastro Valeria , Pizzo Mariateresa , Beltran Sergi , Casari Giorgio , Nigro Vincenzo , Banfi Sandro
Published: June 2021

Motivation

Homozygous deletions (HDs) may be the cause of rare diseases and cancer and their discovery in targeted sequencing is a challenging task. Different tools have been developed to disentangle HD discovery but a sensitive caller is still lacking.

Results

We present VarGenius-HZD, a sensitive and scalable algorithm that leverages breadth-of-coverage for the detection of rare homozygous and hemizygous single-exon deletions (HDs). To assess its effectiveness we detected both real and synthetic rare HDs in fifty exomes from the 1000 Genomes Project obtaining higher sensitivity in comparison with state-of-the-art algorithms which missed at least one event each. We then applied our tool on targeted sequencing data from patients with Inherited Retinal Dystrophies and solved five cases that still lacked a genetic diagnosis.

Availability and implementation

We provide VarGenius-HZD either stand-alone or integrated within our recently developed software enabling the automated selection of samples using the internal database. Hence, it could be extremely useful for both diagnostic and research purposes. Our tool is available under GNU General Public License, version 3 at: https://github.com/frankMusacchia/VarGenius-HZD

Contact: francesco.musacchia@iit.it

Supplementary information is available online.
Identification of the stress granule transcriptome via RNA-editing in single cells andin vivo
Authors: van Leeuwen Wessel , VanInsberghe Michael , Battich Nico , Salmén Fredrik , van Oudenaarden Alexander , Rabouille Catherine
Published: June 2021

Stress granules are phase separated assemblies formed around mRNAs whose identities remain elusive. The techniques available to identify the RNA content of stress granules rely on their physical purification, and are therefore not suitable for single cells and tissues displaying cell heterogeneity. Here, we adapted TRIBE (Target of RNA-binding proteins Identified by Editing) to detect stress granule RNAs by fusing a stress granule RNA-binding protein (FMR1) to the catalytic domain of an RNA-editing enzyme (ADAR). RNAs colocalized with this fusion are edited, producing mutations that are detectable by sequencing. We first optimized the expression of this fusion protein so that RNA editing preferentially occurs in stress granules. We then show that this purification-free method can reliably identify stress granule RNAs in bulk and single S2 cells, and in Drosophila tissues, such as 398 neuronal stress granule mRNAs encoding ATP binding, cell cycle and transcription factors. This new method opens the possibility to identify the RNA content of stress granules as well other RNA based assemblies in single cells derived from tissues.
Diversity and evolution of pigment types and the phycobilisome rod gene region of marine Synechococcus cyanobacteria
Authors: Grébert Théophile , Garczarek Laurence , Daubin Vincent , Humily Florian , Marie Dominique , Ratin Morgane , Devailly Alban , Farrant Gregory K. , Mary Isabelle , Mella-Flores Daniella , Tanguy Gwen , Labadie Karine , Wincker Patrick , Kehoe David M. , Partensky Frédéric
Published: June 2021

Synechococcus picocyanobacteria are ubiquitous and abundant photosynthetic organisms in the marine environment and contribute for an estimated 16% of the ocean net primary productivity. Their light-harvesting complexes, called phycobilisomes (PBS), are composed of a conserved allophycocyanin core from which radiates six to eight rods with variable phycobiliprotein and chromophore content. This variability allows Synechococcus to optimally exploit the wide variety of spectral niches existing in marine ecosystems. Seven distinct pigment types or subtypes have been identified so far in this taxon, based on the phycobiliprotein composition and/or the proportion of the different chromophores in PBS rods. Most genes involved in their biosynthesis and regulation are located in a dedicated genomic region called the PBS rod region. Here, we examined the variability of gene sequences and organization of this genomic region in a large set of sequenced isolates and natural populations of Synechococcus representative of all known pigment types. All regions start with a tRNA-PheGAA and some possess mobile elements including tyrosine recombinases, suggesting that their genomic plasticity relies on a tycheposon-like mechanism. Comparison of the phylogenies obtained for PBS and core genes revealed that the evolutionary history of PBS rod genes differs from the rest of the genome and is characterized by the co-existence of different alleles and frequent allelic exchange. We propose a scenario for the evolution of the different pigment types and highlight the importance of population-scale mechanisms in maintaining a wide diversity of pigment types in different Synechococcus lineages despite multiple speciation events.
Conformational decoupling in acid-sensing ion channels uncovers mechanism and stoichiometry of PcTx1-mediated inhibition
Authors: Heusser Stephanie A. , Borg Christian B. , Colding Janne M. , Pless Stephan A.
Published: June 2021

Acid-sensing ion channels (ASICs) are trimeric proton-gated cation channels involved in fast synaptic transmission. Pharmacological inhibition of ASIC1a reduces neurotoxicity and stroke infarct volumes, with the cysteine knot toxin Psalmotoxin-1 (PcTx1) being one of the most potent and selective inhibitors. PcTx1 binds at the subunit interface in the extracellular domain (ECD), but the mechanism and conformational consequences of the interaction, as well as the number of toxin molecules required for inhibition remain unknown. Here we use voltage-clamp fluorometry and subunit concatenation to decipher the mechanism and stoichiometry of PcTx1 inhibition of ASIC1a. Besides the known inhibitory binding mode, we propose PcTx1 to have at least two additional binding modes that are decoupled from the pore. One of these modes induces a long-lived ECD conformation that reduces the activity of an endogenous neuropeptide. This long-lived conformational state is proton-dependent and can be destabilized by a mutation that decreases PcTx1 sensitivity. Lastly, the use of concatemeric channel constructs reveal that disruption of a single PcTx1 binding site is sufficient to destabilize the toxin-induced conformation, while functional inhibition is not impaired until two or more binding sites are mutated. Together, our work provides insight into the mechanism of PcTx1 inhibition of ASICs and uncovers a prolonged conformational change with possible pharmacological implications.
Assessing neuromodulation effects of theta burst stimulation to the prefrontal cortex using TMS-evoked potentials
Authors: Moffa Adriano H. , Nikolin Stevan , Martin Donel , Loo Colleen , Boonstra Tjeerd W.
Published: June 2021

Theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (TMS), is capable of non-invasively modulating cortical excitability. TBS is gaining popularity as a therapeutic tool for psychiatric disorders such as depression, in which the dorsolateral prefrontal cortex (DLPFC) is the main therapeutic target. However, the neuromodulatory effects of TBS on prefrontal regions remain unclear. An emerging tool to assess neuromodulation in non-motor regions is concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) to measure TMS-evoked potentials (TEPs). We assessed twenty-four healthy participants (13 males, mean age 25.2±9.9 years) following intermittent TBS, continuous TBS, and sham applied to the left DLPFC using a double-blinded crossover design. TEPs were obtained at baseline and 2-, 15-, and 30-min post-stimulation. Four TEP components (N40, P60, N100 and P200) were analysed using mixed effects repeated measures models (MRMM). Results indicate no significant effects for any assessed components (all p>.05). The largest effect size (Cohen’s d = −0.5) comparing iTBS and sham was obtained for the N100 component at 15 minutes post-stimulation. This result was in the same direction but smaller than found in previous studies, suggesting that the true effect size may be lower than previously reported. Accurate estimates of the effects sizes and inter-individual heterogeneity will critically inform clinical applications using TEPs to assess the neuromodulatory effects of TBS.
Identification of the key role of white matter alteration in the pathogenesis of Huntington’s Disease
Authors: Pérot Jean-Baptiste , Célestine Marina , Palombo Marco , Dhenain Marc , Humbert Sandrine , Brouillet Emmanuel , Flament Julien
Published: June 2021

Pathogenesis of the inherited neurodegenerative disorder Huntington’s Disease (HD) is complex and progressive, with a long presymptomatic phase in which subtle changes occur in the brain of gene carriers up to 15 years before the onset of symptoms. Thus, there is a need of early, functional biomarker to better understand disease progression and to evaluate treatment efficacy far from onset. In particular, recent studies have shown that white matter may be affected early in HD. In this study, we scanned longitudinally Ki140CAG mice with structural MRI, Diffusion Tensor Imaging (DTI), Chemical Exchange Saturation Transfer of glutamate (gluCEST) and Magnetization Transfer (MT) imaging, in order to assess white matter integrity over the life of this very progressive mouse model. Our results show early defects of diffusion properties in the anterior part of the corpus callosum, preceding gluCEST defects in the same region (−10.8% at 8 months, −19% at 12 months) that spread to adjacent regions. At 12 months, frontal (−7.3%) and piriform (−16.7%) cortices showed reduced gluCEST, as well as the pallidum (−21.0%). MT imaging showed reduced signal in the septum (−21.7%) at 12 months. Cortical and striatal atrophy then appear at 18 months. Vulnerability of the striatum and motor cortex, combined with alterations of anterior corpus callosum, seems to point out the pivotal role of white matter, in the pathogenesis of HD and the pertinence of gluCEST and DTI as biomarkers in HD.

Highlights

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A knock-in mouse model of Huntington’s disease is longitudinally characterized

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A multimodal MRI protocol is performed to identify biomarkers of the disease

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The white matter plays a pivotal role in the pathogenesis of the disease

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The cortico-striatal pathway seems particularly vulnerable in Huntington’s disease
A novel binary k-mer approach for classification of coding and non-coding RNAs across diverse species
Authors: Periwal Neha , Sharma Priya , Arora Pooja , Pandey Saurabh , Kaur Baljeet , Sood Vikas
Published: June 2021

Classification among coding (CDS) and non-coding RNA (ncRNA) sequences is a challenge and several machine learning models have been developed for the same. Since the frequency of curated coding sequences is many-folds as compared to that of the ncRNAs, we devised a novel approach to work with the complete datasets from fifteen diverse species. In our proposed novel binary approach, we replaced all the ‘A’s and ‘T’s with ‘0’s and ‘G’s and ‘C’s with ‘1’s to obtain a binary form of coding and ncRNAs. The k-mer analysis of these binary sequences revealed that the frequency of binary patterns among the coding and ncRNAs can be used as features to distinguish among them. Using insights from these distinguishing frequencies, we used k-nearest neighbour classifier to classify among them. Our strategy is not only time-efficient but leads to significantly increased performance metrics including Matthews correlation coefficient (MCC) for some species like P. paniscus, M. mulatta, M. lucifugus, G. gallus, C. japonica, C. abingdonii, A. carolinensis, D. melanogaster and C. elegans when compared with the conventional ATGC approach. Additionally, we also show that the values of MCC obtained for diverse species tested on the model based on H. sapiens correlated with the geological evolutionary timeline thereby further strengthening our approach. Therefore, we propose that CDS and ncRNAs can be efficiently classified using “2-character” frequency as compared to “4-character” frequency of ATGC approach. Thus, our highly efficient binary approach can replace the more complex ATGC approach successfully.
A streamlined CRISPR workflow to introduce mutations and generate isogenic iPSCs for modeling amyotrophic lateral sclerosis
Authors: Deneault Eric , Chaineau Mathilde , Montiel Maria José Castellanos , Flores Anna Kristyna Franco , Haghi Ghazal , Chen Carol X-Q , Abdian Narges , Nicouleau Michael , Shlaifer Irina , Beitel Lenore K. , Durcan Thomas M.
Published: June 2021

Amyotrophic lateral sclerosis (ALS) represents a complex neurodegenerative disorder with significant genetic heterogeneity. To date, both the genetic etiology and the underlying molecular mechanisms driving this disease remain poorly understood, although in recent years a number of studies have highlighted a number of genetic mutations causative for ALS. With these mutations pointing to potential pathways that may be affected within individuals with ALS, having the ability to generate human neurons and other disease relevant cells containing these mutations becomes even more critical if new therapies are to emerge. Recent developments with the advent of induced pluripotent stem cells (iPSCs) and clustered regularly interspaced short palindromic repeats (CRISPR) gene editing fields gave us the tools to introduce or correct a specific mutation at any site within the genome of an iPSC, and thus model the specific contribution of risk mutations. In this study we describe a rapid and efficient way to either introduce a mutation into a control line, or to correct a mutation, generating an isogenic control line from patient-derived iPSCs with a given mutation. The mutations introduced were the G93A mutation into SOD1 or H517Q into FUS, and the mutation corrected was a patient iPSC line with I114T in SOD1. A combination of small molecules and growth factors were used to guide a stepwise differentiation of the edited cells into motor neurons in order to demonstrate that disease-relevant cells could be generated for downstream applications. Through a combination of iPSCs and CRISPR editing, the cells generated here will provide fundamental insights into the molecular mechanisms underlying neuron degeneration in ALS.
A Physiometric Investigation of Inflammatory Composites: Comparison of “A Priori” Aggregates, Empirically-identified Factors, and Individual Proteins
Authors: Moriarity Daniel P. , Ellman Lauren M. , Coe Christopher L. , Olino Thomas M. , Alloy Lauren B.
Published: June 2021

Most research testing the association between inflammation and health outcomes (e.g., heart disease, diabetes, depression) has focused on individual proteins; however, some studies have used summed composites of inflammatory markers without first investigating dimensionality. Using two different samples (MIDUS-2: N = 1,255 adults, MIDUS-R: N = 863 adults), this study investigates the dimensionality of eight inflammatory proteins (C-reactive protein (CRP), interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), fibrinogen, E-selectin, and intercellular adhesion molecule (ICAM)-1) and compared the resulting factor structure to a) an “a priori”/tau-equivalent factor structure in which all inflammatory proteins equally load onto a single dimension (comparable to the summed composites) and b) proteins modeled individually (i.e., no latent variable) in terms of model fit, replicability, reliability, and their associations with health outcomes. An exploratory factor analysis indicated a two-factor structure (Factor 1: CRP and fibrinogen; Factor 2: IL-8 and IL-10) in MIDUS-2 and was replicated in MIDUS-R. Results did not clearly indicate whether the empirically-identified factor structure or the individual proteins modeled without a latent variable had superior model fit, but both strongly outperformed the “a priori”/tau-equivalent structure (which did not achieve acceptable model fit in any models). Modeling the empirically-identified factors and individual proteins (without a latent factor) as outcomes of medical diagnoses resulted in comparable conclusions. However, modeling individual proteins resulted in findings more robust to correction for multiple comparisons despite more conservative adjustments. Further, reliability for all latent variables was poor. These results indicate that modeling inflammation as a unidimensional construct equally associated with all available proteins does not fit the data well. Instead, individual inflammatory proteins or, potentially (if empirically supported and biologically-plausible) empirically-identified inflammatory factors should be used in accordance with theory.