bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of different undergarment designs on the compliance and acceptance of the patients with adolescent idiopathic scoliosis under orthotic treatment
Authors: Wong Man Sang , Beygi Babak Hassan , Wong Kim Wai , Sin Sai Wing , Kwok Wing Kwan , Wu Hui Dong
Published: June 2022

Background:

Patient's acceptance and compliance to spinal orthosis could influence the outcome of orthotic treatment in adolescent idiopathic scoliosis. Two innovative undergarments (thin and thick designs) were designed to improve the patient's orthosis wearing experience and acceptance.

Objective:

This study aimed to evaluate the effects of patients' self-provided undergarment and 2 newly designed undergarments with respect to the orthosis wearing compliance and quality of life (QoL) measures.

Methods:

A prospective randomized-controlled study was conducted to compare the effect of three types of undergarments. Thirty-eight subjects with adolescent idiopathic scoliosis were randomly assigned to one of the three groups: self-provided, thin-design, or thick-design undergarment. Wearing compliance logbook, Scoliosis Research Society questionnaire, and Brace Questionnaire were used to document the orthosis wearing period and quantify the health-related and orthosis-related QoL measures. Kruskal-Wallis one-way analysis of variance (ANOVA) and Friedman two-way ANOVA by ranks tests were conducted for intergroup and intragroup comparisons, respectively.

Results:

The compliance and QoL domains of the subjects in the thin-design undergarment group were significantly higher than those of the other two undergarment groups (P < .05). The intragroup compliance and QoL scores varied significantly in the 4 visits throughout the study period (P < .05).

Conclusions:

It was observed that an adaptation period toward the prescribed spinal orthosis is required to help patients gradually achieve a more stable acceptance. The thin-design undergarment was ranked higher than the other two tested undergarments in compliance and QoL measures.
Evaluation of NG-Test CARBA 5 for the detection of carbapenemase-producing Gram-negative bacilli
Authors: Saito Kai , Mizuno Sayaka , Nakano Ryuichi , Tanouchi Ayako , Mizuno Tomoki , Nakano Akiyo , Suzuki Yuki , Kakuta Naoki , Yano Hisakazu
Published: June 2022

Carbapenemase-producing

Enterobacterales

(CPE) pose one of the most serious antimicrobial resistance threats to public health worldwide. The outcome of CPE infection differs depending on the resistance mechanism. Therefore, rapid detection of CPE infection is essential for optimizing patient management. The carbapenem inactivation method (CIM) and modified CIM (mCIM) are standard methods for detecting CPE, but they usually require 24 h to generate results.

Recently, an immunochromatographic assay, NG-Test CARBA 5, has become commercially available. It detects the five most common carbapenemase producers (KPC, IMP, NDM, VIM, and OXA-48) rapidly and accurately.

We aimed to evaluate the diagnostic accuracy of NG-Test CARBA 5 for detecting carbapenemase-producing Gram-negative bacilli (CPGNB).

We used 116 carbapenemase-producing strains and 48 non-carbapenemase-producing strains. Of the 116 carbapenemase-producing strains, 107 harboured genes for at least one of the five most common carbapenemases, KPC, IMP, NDM, VIM, and OXA-48-like. Forty-eight non-carbapenemase-producing strains, including carbapenem-resistant

Enterobacterales

, harboured genes for extended-spectrum β-lactamases (CTX-M groups [n=25] and SHV groups [n=2]) or plasmid-mediated AmpC β-lactamases (DHA [n=3], CMY-2 [n=2], and CFE-1 [n=1]). Antimicrobial susceptibility was tested using the agar dilution method, according to the Clinical and Laboratory Standards Institute guidelines.

Of the 116 carbapenemase-producing strains, 79 were resistant to at least meropenem or imipenem. The sensitivity and specificity of the NG-Test CARBA 5 for the strains were 99.1 % (106 strains positive for 107 strains of the five most common carbapenemase producers) and 100 % (60 strains negative for other types of CPGNB [n=10] and non-CPGNB strains [n=48]), respectively. The carbapenemase-producing strain with a false-negative result produced IMP-66.

The NG-Test CARBA 5 had high sensitivity and specificity for detecting carbapenemase-producing strains.
Emergent visual creativity in frontotemporal dementia is associated with dorsomedial visual cortex enhancement
Authors: Friedberg Adit , Pasquini Lorenzo , Diggs Ryan , Glaubitz Erika A. , Lopez Lucia , Illán-Gala Ignacio , Iaccarino Leonardo , La Joie Renaud , Mundada Nidhi , Brown Jesse , Allen Isabel Elaine , Rankin Katherine P. , Bonham Luke W. , Yokoyama Jennifer S. , Ramos Eliana M. , Geschwind Daniel H. , Spina Salvatore , Grinberg Lea T. , Miller Zachary A. , Kramer Joel H. , Rosen Howard , Gorno-Tempini Maria Luisa , Rabinovici Gil , Seeley William W. , Miller Bruce L.
Published: June 2022

IMPORTANCE

The neurological substrates of visual creativity are unknown. We demonstrate the role of dorsomedial visual cortex in emergence of visual artistic creativity (VAC) in the setting of dementia. Our findings illuminate neural substrates of human creativity and suggest that hyperactivation of specific brain areas may manifest as enhanced cognitive or behavioral capacities.

OBJECTIVE

To determine the anatomical and physiological underpinnings of VAC in dementia.

DESIGN, SETTING, AND PARTICIPANTS

As part of a prospective, longitudinal cohort study focused on frontotemporal dementia (FTD), 734 patients met research criteria for an FTD spectrum disorder between 2002 and 2019. Of these, seventeen showed emergence of visual artistic creativity (VAC-FTD). Two control groups (n = 51 each) were matched to VAC-FTD based on demographic and clinical parameters: (1) Not Visually Artistic FTD (NVA-FTD) and (2) Healthy Controls (HC).

MAIN OUTCOMES AND MEASURES

Clinical, neuropsychological, genetic and neuroimaging data were analyzed to characterize VAC-FTD and compare VAC-FTD to control groups.

RESULTS

Emergence of VAC occurred around the time of onset of symptoms, and was disproportionately seen in patients with temporal lobe predominant degeneration (n = 8/17). Atrophy network mapping identified a dorsomedial occipital region whose activity inversely correlated, in healthy brains, with activity in the patient-specific atrophy patterns in VAC-FTD (n = 17/17) and NVA-FTD (n = 45/51). Structural covariance analysis revealed that volume of this dorsal occipital region was strongly correlated, in VAC-FTD, but not in NVA-FTD or HC, with a volume in the primary motor cortex corresponding to the right hand representation. One patient, who underwent fluorodeoxyglucose positron emission tomography before and after VAC onset, showed increasing glucose metabolism in the dorsal occipital region over the interval when creativity emerged.

CONCLUSIONS AND RELEVANCE

FTD lesion-induced intensification of dorsal visual association cortex structure and function predisposes to emergence of VAC in certain environmental or genetic conditions. Paradoxical gains of function are early manifestations of neurodegenerative disease, and this study delineates a specific brain region associated with the emergence of VAC.
Zooanthroponotic transmission of SARS-CoV-2 and host-specific viral mutations revealed by genome-wide phylogenetic analysis
Authors: Naderi Sana , Chen Peter E. , Murall Carmen Lía , Poujol Raphael , Kraemer Susanne , Pickering Bradley S. , Sagan Selena M. , Jesse Shapiro B.
Published: June 2022

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a generalist virus, infecting and evolving in numerous mammals, including captive and companion animals, free-ranging wildlife, and humans. Transmission among non-human species poses a risk for the establishment of SARS-CoV-2 reservoirs, makes eradication difficult, and provides the virus with opportunities for new evolutionary trajectories, including selection of adaptive mutations and emergence of new variant lineages. Here we use publicly available viral genome sequences and phylogenetic analysis to systematically investigate transmission of SARS-CoV-2 between human and non-human species and to identify mutations associated with each species. We found the highest frequency of animal-to-human transmission from mink, compared with lower transmission from other sampled species (cat, dog, and deer). Although inferred transmission events could be limited by sampling biases, our results provide a useful baseline for further studies. Using genome-wide association studies, no single nucleotide variants (SNVs) were significantly associated with cats and dogs, potentially due to small sample sizes. However, we identified three SNVs statistically associated with mink and 26 with deer. Of these SNVs, ∼⅔ were plausibly introduced into these animal species from local human populations, while the remaining ∼⅓ were more likely derived in animal populations and are thus top candidates for experimental studies of species-specific adaptation. Together, our results highlight the importance of studying animal-associated SARS-CoV-2 mutations to assess their potential impact on human and animal health.

Importance

SARS-CoV-2, the causative agent of COVID-19, can infect many animal species, making eradication difficult because it can be reseeded from different reservoirs. When viruses replicate in different species, they may be faced with different evolutionary pressures and acquire new mutations, with unknown consequences for transmission and virulence in humans. Here we analyzed SARS-CoV-2 genome sequences from cats, dogs, deer, and mink to estimate transmission between each of these species and humans. We found several transmission events from humans to each animal, but relatively few detectable transmissions from animals back to humans, with the exception of mink. We also identified three mutations more likely to be found in mink than humans, and 26 in deer. These mutations could help the virus adapt to life in these different species. Ongoing surveillance of SARS-CoV-2 from animals will be important to understand their potential impacts on both human and animal health.
Predictive analytics that reflect disease burden – the cumulative COMET score
Authors: Monfredi Oliver , Andris Robert T , Lake Douglas E , Moorman J Randall
Published: June 2022

Predictive analytics tools variably take into account data from the electronic medical record, lab tests, nursing charted vital signs and continuous cardiorespiratory monitoring data to deliver an instantaneous score that indicates patient risk or instability. Few, if any, of these tools reflect the risk to a patient accumulated over the course of an entire hospital stay. This approach fails to best utilize all of the collated data regarding the risk or instability sustained by the patient, and hence fails to fully characterize this to optimize the ability of treating clinicians to maximize the chances of a favorable outcome. We have built on our instantaneous CoMET predictive analytics score to generate the cumulative CoMET score (cCOMET), which sums all of the instantaneous CoMET scores throughout a hospital admission relative to a baseline expected risk unique to that patient. We have shown that higher cCOMET scores predict mortality, but not length of stay, and that higher baseline CoMET scores predict higher cCoMET scores at discharge/death. cCoMET scores were higher in males in our cohort, and added information to the final CoMET when it came to the prediction of death. In summary, if one is going to go to the trouble and expense of performing repeated measures when performing predictive analytics calculations, we have shown that including all of these measures in a cumulative way adds data to instantaneous predictive analytics, and could improve the ability of clinicians to predict deterioration, and improve patient outcomes in so doing.
Leadless Pacemaker with Transcatheter Aortic Valve Implantation: A Single Center Experience
Authors: Gao Feng , Kherallah Riyad , Koetting Mackenzie , Simpson Leo , Seger John , Koneru Srikanth , Coselli Joseph , Preventza Ourania , Orozco-Sevilla Vicente , Manon Nastasya , Silva Guilherme V
Published: June 2022

Background

The safety and efficacy of leadless pacemakers (LP) in transcatheter aortic valve implant (TAVI) patients is not well known due to paucity of data. Herein, we compared outcomes between leadless pacemakers to traditional dual chamber pacemakers (DCP) following TAVI.

Methods

A single-center retrospective study was conducted, including a total of 27 patients with LP and 33 patients with DCP after TAVI between November 2013 to May 2021. We compared baseline demographics, pacemaker indications, percent pacing, ejection fractions, and pacemaker related complication rates.

Results

Leading indications for pacemaker implant were complete heart block (74% LP, 73% DCP) and high degree atrioventricular block (26% LP, 21% DCP). No significant differences were observed between LP and DCP in device usage and ejection fraction at 1, 6, and 12 months. Within each pacemaker group, we did not observe a significant reduction in percent ventricular pacing or ejection fraction at follow up. Three DCP patients required rehospitalization for pocket related complications.

Conclusion

From this single-center study, TAVI patients appear to have comparable pacemaker usage and ejection fraction between LP and DCP groups, suggesting that LP may be a reasonable alternative where single ventricular pacing is indicated. Larger studies are required to validate these findings.
An Automated Entrustment Professional Activities Tracking System (EPA-TRAC) That Holistically Capture Competence: A Paradigm Shift to Programmatic Assessment
Authors: Hamed Omayma
Published: June 2022

Competence is a complex phenomenon that requires comprehensive and holistic assessment. This could be only be achieved through a complete assessment program that navigates poles between assessment for learning, assessment of learning and assessment as learning. Assessment of competence is not an easy task; educationists resorted to unfolding competence into sub-sub-competences and assessing them as separate chunks which violated the purpose of competency-based education. This is attributed to the reduction of the rich information from an assessment to a numerical score. In addition, evaluations of chunks from different competency domains are collated together in a compensatory manner rather than in a conjunctive manner resulting in adding oranges to apples with resultant meaningless assessment information. A useful contribution to this whole issue is the introduction of entrustable professional activities (EPAs) which are considered portal for capturing and visualizing competences in a holistic manner. EPAs provide a better language to make education more task-based. This necessitated a different assessment paradigm “Programmatic Assessment”. This assessment paradigm ensures convergence of assessment data points that keep competence integrated into a whole meaningful picture. In this type of assessment model, the trainee has role in gathering, collating and reflecting on the various assessments in an informative way that triangulates evidence and translates them into learning goals. Hence longitudinal, information-rich feedback and reflection are crucial in such assessment system and could be collated in a developmental portfolio. In such model a variety of assessment tools could be used so long as they constitute a high utility index; assessment could be psychometric and workplace-based. Whether scores from psychometric assessments or enaction of feedback and learning goals are used for making judgment, remains the decision of the curriculum and assessment system designers according to context and purpose of assessment. Being complex to realize, an automated system (EPA-TRAC) is developed to capture that assessment system.
Computational and functional characterization of the PI(4,5)P2 binding site of the TRPM3 ion channel
Authors: Zhao Siyuan , Carnevale Vincenzo , Gianti Eleonora , Rohacs Tibor
Published: June 2022

Transient Receptor Potential Melastatin 3 (TRPM3) is a heat-activated ion channel expressed in peripheral sensory neurons and the central nervous system. TRPM3 activity depends on the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], but the molecular mechanism of activation by PI(4,5)P2 is not known. As no experimental structure of TRPM3 is available, we built a homology model of the channel in complex with PI(4,5)P2via molecular modeling. We identified putative contact residues for PI(4,5)P2 in the pre-S1 segment, the S4-S5 linker, and the proximal C-terminal TRP-domain. Mutating these residues increased sensitivity to inhibition of TRPM3 by decreasing PI(4,5)P2 levels by phosphatidylinositol 4-kinase inhibition. Changes in ligand-binding affinities via MM/GBSA showed reduced PI(4,5)P2 affinity for the mutants. Mutating PI(4,5)P2 interacting residues also reduced sensitivity for activation by the endogenous ligand pregnenolone sulfate (PregS), pointing to an allosteric interaction between PI(4,5)P2 and PregS. Mutating residues in the PI(4,5)P2 binding site in TRPM8 had similar effects, increased sensitivity to PI(4,5)P2 depletion, and reduced sensitivity to menthol. Mutation of most PI(4,5)P2 interacting residues in TRPM3 also increased sensitivity to inhibition by Gβγ, indicating allosteric interaction between Gβγ and PI(4,5)P2. Disease-associated gain of function TRPM3 mutations on the other hand, resulted in no change of PI(4,5)P2 sensitivity, indicating that mutations did not increase channel activity via increasing PI(4,5)P2 interactions. Our data provide insight into the mechanism of regulation of TRPM3 by PI(4,5)P2, its relationship to endogenous activators and inhibitors of TRPM3, as well as identify similarities and differences between PI(4,5)P2 regulation of TRPM3 and TRPM8.
Evaluation of variant calling algorithms for wastewater-based epidemiology using mixed populations of SARS-CoV-2 variants in synthetic and wastewater samples
Authors: Bassano Irene , Ramachandran Vinoy K. , Khalifa Mohammad S. , Lilley Chris J. , Brown Mathew R. , van Aerle Ronny , Denise Hubert , Rowe William , George Airey , Cairns Edward , Wierzbicki Claudia , Pickwell Natalie D. , Wilson Myles , Carlile Matthew , Holmes Nadine , Payne Alexander , Loose Matthew , Burke Terry A. , Paterson Steve , Wade Matthew J. , Grimsley Jasmine M.S.
Published: June 2022

Wastewater-based epidemiology (WBE) has been used extensively throughout the COVID-19 pandemic to detect and monitor the spread and prevalence of SARS-CoV-2 and its variants. It has proven an excellent, complementary tool to clinical sequencing, supporting the insights gained and helping to make informed public health decisions. Consequently, many groups globally have developed bioinformatics pipelines to analyse sequencing data from wastewater. Accurate calling of mutations is critical in this process and in the assignment of circulating variants, yet, to date, the performance of variant-calling algorithms in wastewater samples has not been investigated. To address this, we compared the performance of six variant callers (VarScan, iVar, GATK, FreeBayes, LoFreq and BCFtools), used widely in bioinformatics pipelines, on 19 synthetic samples with known ratios of three different SARS-CoV-2 variants (Alpha, Beta and Delta), as well as 13 wastewater samples collected in London between the 15–18 December 2021. We used the fundamental parameters of recall (sensitivity) and precision (specificity) to confirm the presence of mutational profiles defining specific variants across the six variant callers.

Our results show that BCFtools, FreeBayes and VarScan found the expected variants with higher precision and recall than GATK or iVar, although the latter identified more expected defining mutations than other callers. LoFreq gave the least reliable results due to the high number of false-positive mutations detected, resulting in lower precision. Similar results were obtained for both the synthetic and wastewater samples.
Travel-related Twenty-eight Days Cyclical Thrombosis and Subgroups of COVID-19 Cardiac Biomarker Data: Novel Review Strategy and Meta-analysis Method
Authors: Kimoto Keiichiro , Yamakuchi Munekazu , Takenouchi Kazunori , Hashiguchi Teruto
Published: June 2022

Backgrounds

Strange controversies have remained in thrombosis-related fields (traveler’s and COVID-19-related thrombosis), although traveler’s thrombosis is well-known even among non-professionals as “economy class syndrome.” We hypothesized there might be something overlooked behind those strange situations.

Methods

Since ordinary review methods (e.g., systematic review or meta-analysis) had already been conducted, we focused on reviewing a “previously published” “chart.” Also, we developed a novel “review method” for the meta-regression analysis result. We applied those to some previously published and well-known data.

Results

We newly found an approximately 28 days cycle of thrombosis onset over several weeks after travel in a figure. Also, we found an eighteen-day cycle of thrombosis onset in another chart. In COVID-19 cardiovascular biomarker studies, we newly extracted subgroup patterns in a scatterplot (Troponin T and NT-proBNP) that applied simple linear regression analysis. Also, these subgroups had already appeared in the cardiomyopathy study.

Conclusions

Traveler’s thrombosis sometimes occurs over two months after leaving the risky in-flight environment. This phenomenon has been explained that the thrombus is formed in a cabin but dislodged after. However, from the cyclic patterns, explaining that the “high-risk period of thrombosis with Oral Contraceptive (OC) use initiation” coincided with “travel” is more reasonable (e.g., honeymoon and OC initiation). Regarding risk-benefit balance, it is conceivable that “spreading the risk” by starting the dosing away from the travel period is essential to ensure safer use because the in-flight environment may have a non-zero effect, and optimal care by a primary care physician (prescriber) is not available during the travel. In COVID-19, there seems to be a complex scatterplot structure that is unsuitable for usually used simple linear fitting. In a literature review, a pattern on a chart should be given more paying attention.
Matrix fibroblast function during alveolarization is dependent on GATA6
Authors: Ushakumary Mereena George , Green Jenna , Riccetti Matthew Richard , Na Cheng-Lun , Mohanraj Divya , Guo Minzhe , Perl Anne-Karina Theresia
Published: June 2022

Alveolarization is dependent on myo-, matrix- and lipo- fibroblast functions by interstitial PDGFRa+ fibroblasts. While these fibroblasts are derived from GLI and PDGFRa expressing fibroblasts, the transcriptional control of their functional specification remains unknown. Perinatally, the transcription factor GATA6 is upregulated in PDGFRa+ fibroblasts. To study the role of GATA6 during fibroblast differentiation, we generated PDGFRaCreER/GATA6flx/flx mice and deleted GATA6 in the perinatal period and in adult mice prior to left lobe pneumonectomy. Loss of GATA6 in the PDGFRa+-fibroblasts impaired alveolarization, and extracellular matrix deposition, in association with increased TCF21 expression and lipofibroblast differentiation. Loss of GATA6 in PDGFRa+ fibroblasts resulted in loss of alveolar type 1 (AT1) cells and gain of transitional alveolar type 2 (AT2) cells. Loss of GATA6 was associated with reduced WNT signaling. Restoration of WNT signaling in GATA6 deficient alveolar lung organoids restored AT2 and AT1 cell differentiation. GATA6 induces matrix fibroblast functions and represses lipofibroblast functions, serving as key regulator of fibroblast differentiation during alveolarization and regeneration. Present findings link matrix fibroblast functions with the ability of transitional AT2 cells to differentiate into AT1 cells.

Graphical abstract

Graphical abstract:
A scalable approach for continuous time Markov models with covariates
Authors: Hatami Farhad , Ocampo Alex , Graham Gordon , Nichols Thomas E. , Ganjgahi Habib
Published: June 2022

Existing methods for fitting continuous time Markov models (CTMM) in the presence of covariates suffer from scalability issues due to high computational cost of matrix exponentials calculated for each observation. In this paper we propose an optimization technique for CTMM which uses a stochastic gradient descent algorithm combined with differentiation of the matrix exponential using a Padé approximation which we show then makes fitting large scale data feasible. We compare two methods for computing standard errors, one using Padé expansion, and the other using power series expansion of the matrix exponential. Through simulations we find improved performance relative to existing CTMM methods, and we demonstrate the method on the large-scale multiple sclerosis NO.MS dataset.
A fibrin enhanced thrombosis model for medical devices operating at low shear regimes or large surface areas
Authors: Méndez Rojano Rodrigo , Lai Angela , Zhussupbekov Mansur , Burgreen Greg W. , Cook Keith , Antaki James F.
Published: June 2022

Over the past decade, much of the development of computational models of device-related thrombosis has focused on platelet activity. While those models have been successful in predicting thrombus formation in medical devices operating at high shear rates (> 5000 s−1), they cannot be directly applied to low-shear devices, such as blood oxygenators and catheters, where emerging information suggest that fibrin formation is the predominant mechanism of clotting and platelet activity plays a secondary role. In the current work, we augment an existing platelet-based model of thrombosis with a partial model of the coagulation cascade that includes contact activation of factor XII and fibrin production. To calibrate the model, we simulate a backward-facing-step flow channel that has been extensively characterized in-vitro. Next, we perform blood perfusion experiments through a microfluidic chamber mimicking a hollow fiber membrane oxygenator and validate the model against these observations. The simulation results closely match the time evolution of the thrombus height and length in the backward-facing-step experiment. Application of the model to the microfluidic hollow fiber bundle chamber capture both gross features such as the increasing clotting trend towards the outlet of the chamber, as well as finer local features such as the structure of fibrin around individual hollow fibers. Our results are in line with recent findings that suggest fibrin production, through contact activation of factor XII, drives the thrombus formation in medical devices operating at low shear rates with large surface area to volume ratios.

Author summary

Patients treated with blood-contacting medical devices suffer from clotting complications. Over the past decades, a great effort has been made to develop computational tools to predict and prevent clot formation in these devices. However, most models have focused on platelet activity and neglected other important parts of the problem such as the coagulation cascade reactions that lead to fibrin formation. In the current work, we incorporate this missing element into a well-established and validated model for platelet activity. We then use this novel approach to predict thrombus formation in two experimental configurations. Our results confirm that to accurately predict the clotting process in devices where surface area to volume ratios are large and flow velocity and shear stresses remain low, coagulation reactions and subsequent fibrin formation must be considered. This new model could have great implications for the design and optimization of medical devices such as blood oxygenators. In the long term, the model could evolve into a functional tool to inform anticoagulation therapies for these patients.
Genomic Surveillance of SARS CoV2 in COVID-19 vaccinated healthcare workers in Lebanon
Authors: Al Kalamouni Habib , Abou Hassan Farouk F. , Bou Hamdan Mirna , Page Andrew J. , Lott Martin , Ghosn Nada , Rady Alissar , Mahfouz Rami , Araj George F. , Dbaibo Ghassan , Zaraket Hassan , Melhem Nada M. , Matar Ghassan M.
Published: June 2022

The emergence of SARS-CoV-2 variants including the Delta and Omicron along with waning of vaccine-induced immunity over time contributed to increased rates of breakthrough infection specifically among healthcare workers (HCWs). SARS-CoV-2 genomic surveillance is an important tool for timely detection and characterization of circulating variants as well as monitoring the emergence of new strains. Our study is the first national SARS-CoV-2 genomic surveillance among HCWs in Lebanon. We collected 250 samples from five hospitals across Lebanon between December 2021 and January 2022. We extracted viral RNA and performed whole genome sequencing using the Illumina NextSeq 500 platform. A total of 133 (57.1%) samples belonging to the Omicron (BA.1.1) sub-lineage were identified, as well as 44 (18.9%) samples belonging to the BA.1 sub-lineage, 28 (12%) belonging to the BA.2 sub-lineage, and only 15 (6.6%) samples belonging to the Delta variant sub-lineage B.1.617.2. These results show that Lebanon followed the global trend in terms of circulating SARS-CoV-2 variants with Delta rapidly replaced by the Omicron variant. This study underscores the importance of continuous genomic surveillance programs in Lebanon for the timely detection and characterization of circulating variants. The latter is critical to guide public health policy making and to timely implement public health interventions.
TE invasion fuels molecular adaptation in laboratory populations of Drosophila melanogaster
Authors: Wang Luyang , Zhang Shuo , Hadjipanteli Savana , Saiz Lorissa , Nguyen Lisa , Silva Efren , Kelleher Erin S.
Published: June 2022

Transposable elements are mobile genetic parasites that frequently invade new host genomes through horizontal transfer. Invading TEs often exhibit a burst of transposition, followed by reduced transposition rates as repression evolves in the host. We recreated the horizontal transfer of P-element DNA transposons into a D. melanogaster host, and followed the expansion of TE copies and evolution of host repression in replicate laboratory populations reared at different temperatures. We observed that while populations maintained at high temperatures rapidly go extinct after TE invasion, those maintained at lower temperatures persist, allowing for TE spread and the evolution of host repression. We also surprisingly discovered that invaded populations experienced recurrent insertion of P-elements into a specific long non-coding RNA, lncRNA:CR43651, and that these insertion alleles are segregating at unusually high frequency in experimental populations, indicative of positive selection. We propose that, in addition to driving the evolution of repression, transpositional bursts of invading TEs can drive molecular adaptation.
Speciation genomics and the role of depth in the divergence of rockfishes (Sebastes) revealed through Pool-seq analysis of enriched sequences
Authors: Olivares-Zambrano Daniel , Daane Jacob , Hyde John , Sandel Michael W. , Aguilar Andres
Published: June 2022

Speciation in the marine environment is challenged by the wide geographic distribution of many taxa and potential for high rates of gene flow through larval dispersal mechanisms. Depth has recently been proposed as a potential driver of ecological divergence in fishes and yet it is unclear how adaptation along these gradients’ shapes genomic divergence. The genus Sebastes contains numerous species pairs that are depth segregated and can provide a better understanding of the mode and tempo of genomic diversification. Here we present exome data on two species pairs of rockfishes that are depth segregated and have different degrees of divergence: S. chlorostictus-S. rosenblatti and S. crocotulus-S. miniatus. We were able to reliably identify ‘islands of divergence’ in the species pair with more recent divergence (S. chlorostictus-S. rosenblatti) and discovered a number of genes associated with neurosensory function, suggesting a role for this pathway in the early speciation process. We also reconstructed demographic histories of divergence and found the best supported model was isolation followed by asymmetric secondary contact for both species pairs. These results suggest past ecological/geographic isolation followed by asymmetric secondary contact of deep to shallow species. Our results provide another example of using rockfish as a model for studying speciation and support the role of depth as an important mechanism for diversification in the marine environment.
Transposable elements drive intron gain in diverse eukaryotes
Authors: Gozashti Landen , Roy Scott W. , Thornlow Bryan , Kramer Alexander , Ares Manuel , Corbett-Detig Russell
Published: June 2022

There is massive variation in intron numbers across eukaryotic genomes, yet the major drivers of intron content during evolution remain elusive. Rapid intron loss and gain in some lineages contrasts with long term evolutionary stasis in others. Episodic intron gain could be explained by recently discovered specialized transposons called Introners, but so far introners are only known from a handful of species. Here, we performed a systematic search across 3,325 eukaryotic genomes and identified 27,563 Introner-derived introns in 175 genomes (5.2%). Species with introners span remarkable phylogenetic diversity, from animals to basal protists, representing lineages whose last common ancestor dates to over 1.7 billion years ago. Marine organisms were 6.5 times more likely to contain Introners than their terrestrial counterparts. Introners exhibit mechanistic diversity but most are consistent with DNA transposition, indicating that Introners have evolved convergently hundreds of times from autonomous transposable elements. Transposable elements and marine taxa are associated with high rates of horizontal gene transfer, suggesting that this combination of factors may explain the punctuated and biased diversity of species containing Introners. More generally our data suggest that Introners may explain the episodic nature of intron gain across the eukaryotic tree of life. These results illuminate the major source of ongoing intron creation in eukaryotic genomes.
Dishevelled controls bulk cadherin dynamics and the stability of individual cadherin clusters during convergent extension
Authors: Huebner Robert J. , Wallingford John B.
Published: June 2022

Animals are shaped through the movement of large cellular collectives. Such morphogenetic processes require cadherin-based cell adhesion to maintain tissue cohesion and planar cell polarity to coordinate movement. Despite a vast literature surrounding cadherin-based adhesion and planar cell polarity it is unclear how these molecular networks interface. Here we investigate the relationship between cadherins and planar cell polarity during gastrulation cell movements inXenopus laevis. We first assessed the bulk cadherin localization and found that cadherins were enriched at a specific subset of morphogenetically active cell-cell junctions. We then found that disruption of planar cell polarity desynchronized temporal cadherin and actin dynamics. Next, using super-resolution time-lapse miscopy and quantitative image analysis we were able to measure the lifespan and size of individual cadherin clusters. Finally, we show that planar cell polarity not only controls the size of cadherin clusters but, more interestingly, regulates cluster stability. These results reveal an intriguing link between two essential cellular properties, adhesion and planar polarity, and provide insight into the molecular control of morphogenetic cell movements.

Highlights

Planar cell polarity is required for cadherin spatiotemporal dynamics.

Super-resolution imaging reveals the spatiotemporal patterns of cadherin clustering.

Cadherin cluster lifespan and size are highly heterogenous.

Planar cell polarity controls cadherin cluster stability and size.
Sound Frequency Predicts the Bodily Location of Auditory-Induced Tactile Sensations in Synesthetic and Ordinary Perception
Authors: Koenig Lua , Ro Tony
Published: June 2022

For individuals who experience sound-touch synesthesia, sounds consistently evoke strong, localized sensations on the body. Interestingly, visual and auditory information can also evoke bodily sensations in ordinary perception, such as the sight or sound of a mosquito producing phantom sensations of touch. We systematically investigated the functional relationship between sound frequency and several characteristics of induced tactile experiences in synesthetes and controls. Sound frequency strongly predicted the location of tactile sensations on the body in both synesthetes and controls. Synesthetes felt sound-induced touch more frequently and in significantly more concentrated locations on their bodies compared to sound-induced touch perceptions in controls. This spatial distribution of touch reflects a behavioral mapping between tonotopy and somatotopy that suggests the involvement of early, tonotopically- and somatotopically-organized brain areas. Sound frequency also predicted the hardness, roughness, and sharpness of tactile sensations in both groups. Together, these findings highlight a strong similarity between auditory-tactile mappings in synesthetic and ordinary perception, suggesting that synesthesia only differs in the strength of the mappings and therefore is on a spectrum with ordinary perception. Furthermore, these findings offer insights into the possible underlying neural mechanisms of sound-touch mappings, suggesting that they rely on cross-modal neural pathways already in use in ordinary perception.
A Statistical Detector for Ribosomal Frameshifts and Dual Encodings based on Ribosome Profiling
Authors: Yurovsky Alisa , Gardin Justin , Futcher Bruce , Skiena Steven
Published: June 2022

During protein synthesis, the ribosome shifts along the messenger RNA (mRNA) by exactly three nucleotides for each amino acid added to the protein being translated. However, in special cases, the sequence of the mRNA somehow induces the ribosome to shift forward by either two or four nucleotides. This shifts the “reading frame” in which the mRNA is translated, and gives rise to an otherwise unexpected protein. Such “programmed frameshifts” are well-known in viruses, including coronavirus, and a few cases of programmed frameshifting are also known in cellular genes. However, there is no good way, either experimental or informatic, to identify novel cases of programmed frameshifting. Thus it is possible that substantial numbers of cellular proteins generated by programmed frameshifting in human and other organisms remain unknown. Here, we build on prior work observing that data from ribosome profiling can be analyzed for anomalies in mRNA reading frame periodicity to identify putative programmed frameshifts. We develop a statistical framework to identify all likely (even for very low frameshifting rates) frameshift positions in a genome. We also develop a frameshift simulator for ribosome profiling data to verify our algorithm. We show high sensitivity of prediction on the simulated data, retrieving 97.4% of the simulated frameshifts. Furthermore, our method found all three of the known yeast genes with programmed frameshifts. We list several hundred yeast genes that may contain +1 or −1 frameshifts. Our results suggest there could be a large number of un-annotated alternative proteins in the yeast genome generated by programmed frameshifting. This motivates further study and parallel investigations in the human genome. Frameshift Detector algorithms and instructions can be accessed in Github: https://github.com/ayurovsky/Frame-Shift-Detector.
Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent integrated stress response in C9orf72 FTD/ALS
Authors: Parameswaran Janani , Zhang Nancy , Tilahun Kedamawit , Pant Devesh C. , Chilukuri Ganesh , Asress Seneshaw , Banerjee Anwesha , Davis Emma , Schwartz Samantha L. , Conn Graeme L. , Bassell Gary J. , Jiang Jie
Published: June 2022

GGGGCC (G4C2) hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat is bidirectionally transcribed and confers gain of toxicity. However, the underlying toxic species is debated, and it is not clear whether antisense CCCCGG (C4G2) repeat expanded RNAs contribute to disease pathogenesis. Our study shows that C9orf72 (C4G2) antisense repeat expanded RNAs trigger the activation of the PKR/eIF2α-dependent integrated stress response independent of dipeptide repeat proteins that are produced through repeat-associated non-AUG initiated translation, leading to global translation inhibition and stress granule formation. Increased phosphorylation of PKR/eIF2α is also observed in the frontal cortex of C9orf72 FTD/ALS patients. Finally, only antisense (C4G2), but not sense (G4C2), repeat expanded RNAs can activate the PKR/eIF2α pathway. These results provide a mechanism by which antisense repeat expanded RNAs elicit neuronal toxicity in FTD/ALS caused by C9orf72 repeat expansions.
Optogenetic stimulation of anterior insular cortex neurons reveals causal mechanisms underlying suppression of the default mode network by the salience network
Authors: Menon Vinod , Cerri Domenic , Lee Byeongwook , Yuan Rui , Lee Sung-Ho , Shih Yen-Yu Ian
Published: June 2022

The salience network (SN) and default mode network (DMN) play a crucial role in cognitive function. The SN, anchored in the anterior insular cortex (AI), has been hypothesized to modulate DMN activity during stimulus-driven cognition. However, the causal neural mechanisms underlying changes in DMN activity and its functional connectivity with the SN are poorly understood. Here we combine feedforward optogenetic stimulation with fMRI and computational modeling to dissect the causal role of AI neurons in dynamic functional interactions between SN and DMN nodes in the rat brain. Optogenetic stimulation of Chronos-expressing AI neurons in rats suppressed DMN activity, and decreased AI-DMN and intra-DMN functional connectivity. Our findings demonstrate that feedforward optogenetic stimulation of AI neurons induces dynamic suppression and decoupling of the DMN and elucidates previously unknown features of rodent brain network organization. Our study advances foundational knowledge of causal mechanisms underlying dynamic cross-network interactions and brain network switching.

Teaser

Insular cortex stimulation reveals causal mechanisms underlying default mode network suppression by the salience network
Activation mechanism of the human Smoothened receptor
Authors: Bansal Prateek D. , Dutta Soumajit , Shukla Diwakar
Published: June 2022

Smoothened (SMO) is a membrane protein of the Class F subfamily of G-Protein Coupled Receptors (GPCRs) and maintains homeostasis of cellular differentiation. SMO undergoes conformational change during activation, transmitting the signal across the membrane, making it amenable to bind to its intracellular signaling partner. Receptor activation has been studied at length for Class A receptors, but the mechanism of Class F receptor activation remain unknown. Agonists and antagonists bound to SMO at sites in the Transmembrane Domain (TMD) and the Cysteine Rich Domain have been characterized, giving a static view of the various conformations SMO adopts. While the structures of the inactive and active SMO outline the residue-level transitions, a kinetic view of the overall activation process remains unexplored for Class F receptors. We describe SMO’s activation process in atomistic detail by performing 300μs of molecular dynamics simulations and combining it with Markov state model theory. A molecular switch, conserved across Class F and analogous to the activation-mediating D-R-Y motif in Class A receptors, is observed to break during activation. We also show that this transition occurs in a stage-wise movement of the transmembrane helices - TM6 first, followed by TM5. To see how modulators affect SMO activity, we simulated agonist and antagonist-bound SMO. We observed that agonist-bound SMO has an expanded hydrophobic tunnel in SMO’s core TMD, while antagonist-bound SMO shrinks this tunnel, further supporting the hypothesis that cholesterol travels through a tunnel inside Smoothened to activate it. In summary, this study elucidates the distinct activation mechanism of Class F GPCRs and shows that SMO’s activation process rearranges the core transmembrane domain to open a hydrophobic conduit for cholesterol transport.
Force-biased nuclear import sets nuclear-cytoplasmic volumetric coupling by osmosis
Authors: Pennacchio Fabrizio A. , Poli Alessandro , Pramotton Francesca Michela , Lavore Stefania , Rancati Ilaria , Cinquanta Mario , Vorselen Daan , Prina Elisabetta , Romano Orso Maria , Ferrari Aldo , Piel Matthieu , Lagomarsino Marco Cosentino , Maiuri Paolo
Published: June 2022

In eukaryotes, cytoplasmic and nuclear volumes are tightly regulated to ensure proper cell homeostasis. However, the detailed mechanisms underlying nucleus-cytoplasm volumetric coupling remain unknown. Recent evidence supports a primary role of osmotic mechanisms in determining a tight link between nuclear and cytoplasmic volume, but this hypothesis remains largely untested in mammalian cells. We approach the question in single cultured adhering human cells, by jointly measuring cytoplasmic and nuclear volumes, in real time and across cell cycles. Surprisingly, we find that cytoplasmic and nuclear volumes follow different average growth laws: while the cytoplasm grows exponentially, the nucleus grows linearly. Moreover, by combining several experimental perturbations and analyzing a mathematical model including osmotic effects and tension, we conclude that the mechanical forces exerted by the cytoskeleton on the nuclear envelope can strongly affect nucleus-cytoplasm volumetric coupling by biasing nuclear import. Our results unveil how osmo-mechanical equilibrium regulates nuclear size in mammalian cells.

One-Sentence Summary

Cytoskeletal forces exerted on the nuclear envelope impact on nuclear volume through modulation of force-coupled nucleo-cytoplasmic transport, affecting osmosis.