bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiology of Atrial Fibrillation in theAll of UsResearch Program
Authors: Alonso Alvaro , Alam Aniqa B. , Kamel Hooman , Subbian Vignesh , Qian Jun , Boerwinkle Eric , Cicek Mine , Clark Cheryl R. , Cohn Elizabeth G. , Gebo Kelly A. , Loperena-Cortes Roxana , Mayo Kelsey R. , Mockrin Stephen , Ohno-Machado Lucila , Schully Sheri D. , Ramirez Andrea H. , Greenland Philip
Published: July 2021

Background

The prevalence, incidence and risk factors of atrial fibrillation (AF) in a large, geographically and ethnically diverse cohort in the United States have not been fully described.

Methods

We analyzed data from 173,099 participants of theAll of UsResearch Program recruited in the period 2017-2019, with 92,318 of them having electronic health records (EHR) data available, and 35,483 having completed a medical history survey. Presence of AF at baseline was identified from self-report and EHR records. Incident AF was obtained from EHR. Demographic, anthropometric and clinical risk factors were obtained from questionnaires, baseline physical measurements and EHR.

Results

At enrollment, mean age was 52 years old (range 18-89). Females and males accounted for 61% and 39% respectively. Non-Hispanic Whites accounted for 67% of participants, with non-Hispanic Blacks, non-Hispanic Asians and Hispanics accounting for 26%, 4% and 3% of participants, respectively. Among 92,318 participants with available EHR data, 3,885 (4.2%) had AF at the time of study enrollment, while the corresponding figure among 35,483 with medical history data was 2,084 (5.9%). During a median follow-up of 16 months, 354 new cases of AF were identified among 88,433 eligible participants. Individuals who were older, male, non-Hispanic white, had higher body mass index, or a prior history of heart failure or coronary heart disease had higher prevalence and incidence of AF.

Conclusion

The epidemiology of AF in theAll of UsResearch Program is similar to that reported in smaller studies with careful phenotyping, highlighting the value of this new resource for the study of AF and, potentially, other cardiovascular diseases.
Digitizing ECG image: new fully automated method and open-source software code
Authors: Fortune Julian D. , Coppa Natalie E. , Haq Kazi T. , Patel Hetal , Tereshchenko Larisa G.
Published: July 2021

Background

We aimed to develop and validate an automated, open-source code ECG-digitizing tool and assess agreements of ECG measurements across three types of median beats, comprised of digitally recorded, simultaneous and asynchronous ECG leads and digitized asynchronous ECG leads.

Methods

We used the data of clinical studies participants (n=230; mean age 30±15 y; 25% female; 52% had the cardiovascular disease) with available both digitally recorded and printed on paper and then scanned ECGs, split into development (n=150) and validation (n=80) datasets. The agreement between ECG and VCG measurements on the digitally recorded time-coherent median beat, representative asynchronous digitized, and digitally recorded beats was assessed by Bland-Altman analysis.

Results

Agreement between digitally recorded and digitized representative beat was high [area spatial ventricular gradient (SVG) elevation bias 2.5(95% limits of agreement [LOA] -7.9-13.0)°; precision 96.8%; inter-class correlation [ICC] 0.988; Lin’s concordance coefficient ρc0.97(95% confidence interval [CI] 0.95-0.98)]. Agreement between digitally recorded asynchronous and time-coherent median beats was moderate for area-based VCG metrics (spatial QRS-T angle bias 1.4(95%LOA -33.2-30.3)°; precision 94.8%; ICC 0.95; Lin’s concordance coefficient ρc0.90(95%CI 0.82-0.95)], but poor for peak-based VCG metrics of global electrical heterogeneity.

Conclusions

We developed and validated an open-source software tool for paper-ECG digitization. Asynchronous ECG leads are the primary source of disagreement in measurements on digitally recorded and digitized ECGs.
The minor allele of the CREBRF rs373863828 p.R457Q coding variant is associated with reduced levels of myostatin in males: Implications for body composition
Authors: Lee Kate , Vakili Sanaz , Burden Hannah J. , Adams Shannon , Smith Greg C. , Kulatea Braydon , Wright-McNaughton Morag , Sword Danielle , Watene-O’Sullivan Conor , Atiola Robert D. , Paul Ryan G. , Plank Lindsay D. , Wilcox Phillip , Kallingappa Prasanna , Merriman Tony R. , Krebs Jeremy D. , Hall Rosemary M. , Murphy Rinki , Merry Troy L. , Shepherd Peter R.
Published: July 2021

The minor allele (A) of the rs373863828 variant (p.Arg457Gln) in CREBRF is restricted to indigenous peoples of the Pacific islands (including New Zealand Māori and peoples of Polynesia), with a frequency up to 25% in these populations. This allele associates with a large increase in body mass index (BMI) but with significantly lower risk of type-2 diabetes (T2D). It is unclear whether the increased BMI is driven by increased adiposity or by increased lean mass. Hence, we undertook body composition analysis using DXA in 189 young men of Māori and Pacific descent living in Aotearoa New Zealand. The rs373863828 A allele was associated with a trend toward increased relative lean mass although this was not statistically significant (p=0.06). Notably though this allele was associated with significantly lower circulating levels of the muscle inhibitory hormone myostatin (p<0.05). This was further investigated in two Arg458Gln knockin mouse models on FVB/Nj and C57Bl/6j backgrounds. Supporting the human data, significant increases in relative lean mass were observed in male knockin mice. This was more significant in older mice (p<0.01) where it was associated with increased grip strength (p<0.01) and lower levels of myostatin (p <0.05). Overall these results provide new evidence that the rs373863828 A-allele is associated with a reduction of myostatin levels which likely contributes to increased lean muscle mass component of BMI, at least in males.
Mutational landscape of high-grade B-cell lymphoma with MYC-, BCL2 and/or BCL6 rearrangements characterized by whole-exome sequencing
Authors: Künstner Axel , Witte Hanno M. , Riedl Jörg , Bernard Veronica , Stölting Stephanie , Merz Hartmut , Olschewski Vito , Peter Wolfgang , Ketzer Julius , Busch Yannik , Trojok Peter , Bubnoff Nikolas von , Busch Hauke , Feller Alfred C. , Gebauer Niklas
Published: July 2021

High-grade B-cell lymphoma accompanied with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) poses a cytogenetically-defined provisional entity among aggressive B-cell lymphomas that is traditionally associated with unfavorable prognosis.

To better understand the mutational and molecular landscape of HGBL-DH/TH we here performed whole-exome sequencing and deep panel next-generation-sequencing (NGS) of 47 clinically annotated cases. Oncogenic drivers, mutational signatures and perturbed pathways were compared with data from follicular lymphoma (FL), diffuse large-B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).

We find an accumulation of oncogenic mutations in NOTCH, IL6/JAK/STAT and NFκB signaling pathways and delineate the mutational relationship within the continuum between FL/DLBCL, HGBL-DH/TH and BL. Further, we provide evidence of a molecular divergence between BCL2 and BCL6 rearranged HGBL-DH. Beyond a significant congruency with the C3/EZB DLBCL cluster in BCL2 rearranged cases on an exome-wide level, we observe an enrichment of the SBS6 mutation signature in BCL6 rearranged cases. Differential gene set enrichment and subsequent network propagation analysis according to cytogenetically defined subgroups revealed an impairment of TP53 and MYC pathway signaling in BCL2 rearranged cases, whereas BCL6 rearranged cases lacked this enrichment, but instead exhibited showed impairment of E2F targets. Intriguingly, HGBL-TH displayed intermediate mutational features in all three aspects.

This study elucidates a recurrent pattern of mutational events driving FL into MYC-driven BCL2 rearranged HGBL, unveiling the mutational pathogenesis of this provisional entity. Through this refinement of the molecular taxonomy for aggressive, germinal-center derived B-cell lymphomas, this calls into question the current WHO classification system, especially regarding the status of MYC/BCL6 rearranged HGBL.
Fifty Ways to Tag your Pubtypes: Multi-Tagger, a Set of Probabilistic Publication Type and Study Design Taggers to Support Biomedical Indexing and Evidence-Based Medicine
Authors: Cohen Aaron M. , Schneider Jodi , Fu Yuanxi , McDonagh Marian S. , Das Prerna , Holt Arthur W. , Smalheiser Neil R.
Published: July 2021

Objective

Indexing articles according to publication types (PTs) and study designs can be a great aid to filtering literature for information retrieval, especially for evidence syntheses. In this study, 50 automated machine learning based probabilistic PT and study design taggers were built and applied to all articles in PubMed.

Materials and Methods

PubMed article metadata from 1987-2014 were used as training data, with 2015 used for recalibration. The set of articles indexed with a particular study design MeSH term or PT tag was used as positive training sets. For each PT, the rest of the literature from the same time period was used as its negative training set. Multiple features based on each article title, abstract and metadata were used in training the models. Taggers were evaluated on PubMed articles from 2016 and 2019. A manual analysis was also performed.

Results

Of the 50 predictive models that we created, 44 of these achieved an AUC of ∼0.90 or greater, with many having performance above 0.95. Of the clinically related study designs, the best performing was SYSTEMATIC_REVIEW with an AUC of 0.998; the lowest performing was RANDOM_ALLOCATION, with an AUC of 0.823.

Discussion

This work demonstrates that is feasible to build a large set of probabilistic publication type and study design taggers with high accuracy and ranking performance. Automated tagging permits users to identify qualifying articles as soon as they are published, and allows consistent criteria to be applied across different bibliographic databases. Probabilistic predictive scores are more flexible than binary yes/no predictions, since thresholds can be tailored for specific uses such as high recall literature search, user-adjustable retrieval size, and quality improvement of manually annotated databases.

Conclusion

The PT predictive probability scores for all PubMed articles are freely downloadable at http://arrowsmith.psych.uic.edu/evidence_based_medicine/mt_download.html for incorporation into user tools and workflows. Users can also perform PubMed queries at our Anne O’Tate value-added PubMed search engine http://arrowsmith.psych.uic.edu/cgi-bin/arrowsmith_uic/AnneOTate.cgi and filter retrieved articles according to both NLM-annotated and model-predicted publication types and study designs.
ANALYSIS OF FOUR DIFFERENT TRANSPORT AND PRESERVATION MEDIUM KITS FOR SARS-COV-2 DIAGNOSIS FROM NASOPHARYNGEAL SWAB BY REAL-TIME PCR: ADAPTING TO THE CONSTANTLY INCREASING DEMAND OF SAMPLING PROCESSING AND STOCK-OUTS DURING THE PANDEMIC
Authors: Barrera-Avalos Carlos , Luraschi Roberto , Vallejos-Vidal Eva , Figueroa Maximiliano , Arenillas Esteban , Barría Daniela , Hernández Felipe , Mateluna Carlos , Mena Javier , Rioseco Claudia , Torrent Claudia , Vergara Claudio , Gutiérrez Gaby , Quiroz Javiera , Alarcón Javiera , Cartagena Julio , Cayunao Javiera , Mella Andrea , Santibañez Álvaro , Tapia Sebastián , Undurraga Alejandro , Vargas Deborah , Wong Valentina , Inostroza Ailen , Valdés Daniel , Imarai Mónica , Acuña-Castillo Claudio , Reyes-López Felipe E. , María Sandino Ana
Published: July 2021

The high demand for supplies during the COVID19-pandemic has generated several stock-out of material and essential reagents needed to meet the current high demand for diagnosis in the worldwide population. In this way, there is limited information regarding the performance of different virus transport medium (VTM) for nasopharyngeal swab sampling (NPS) aimed for SARS-CoV-2 detection. We compared the RT-qPCR amplification profile of four different commercial transport medium kits, including DNA/RNA Shield™, NAT™, VTM, and Phosphate-buffered saline (PBS) transport medium, for NPSs samples from Central Metropolitan Health Service, Santiago, Chile. The RT-qPCR showed a slight lower RNase P Cq value of the samples preserved and transported in DNA/RNA Shield™ compared to NAT medium. By contrast, a marked increase in the RNase P Cq value was registered in the samples transported with VTM compared to DNA/RNA Shield™ medium. For PBS-preserved NPS, the performance of two strategies were assessed due to the potential presence of any remaining active virus in the sample: (1) thermal inactivation; and (2) thermal inactivation treatment followed by RNA extraction. The heat inactivation showed a significantly lower Cq value for RNase P and viral ORF1ab Cq compared to the followed by RNA extraction. This study indicates that new medium alternatives could be used if supplies run out to diagnose COVID19.
The Association of Stay-at-Home Orders and the Spread of COVID-19 in Rural and Urban United States
Authors: Jiang David H. , Roy Darius J. , Pollock Benjamin D. , Shah Nilay D. , McCoy Rozalina G.
Published: July 2021

Background

Throughout the spring of 2020, stay-at-home orders were imposed to curb the spread of COVID-19. There is limited data on the effectiveness of stay-at-home orders, particularly in rural as compared to urban areas.

Objective

To examine the association between stay-at-home order implementation and the incidence of COVID-19 in rural vs. urban counties.

Design

Interrupted time series analysis using a mixed effects zero-inflated Poisson model.

Participants

3,142 U.S. counties.

Interventions

Stay-at-home orders.

Main Measures

COVID-19 daily incidence (primary) and mobility (secondary and intermediate measure of stay-at-home effectiveness)

Key Results

Stay-at-home orders were implemented later (median March 30 vs. March 28) and were shorter (median 35 vs. 54 days) in rural than urban counties. Indoor mobility was, on average, 2.6-6.9% higher in rural than urban counties both during and after stay-at-home orders. Compared to the baseline (pre-stay-at-home) period, the number of new COVID-19 cases increased under stay-at-home by IRR 1.60 (95% CI, 1.57-1.64) in rural and 1.36 (95% CI, 1.30-1.42) in urban counties. For each day under stay-at-home orders, the number of new cases changed by a factor of 0.982 (95% CI 0.981-0.982) in rural and 0.952 (95% CI, 0.951-0.953) in urban counties compared to prior to stay-at-home. Each day after stay-at-home orders expired, the number of new cases changed by a factor of 0.995 (95% CI, 0.994-0.995) in rural and 0.997 (95% CI, 0.995-0.999) in urban counties compared to prior to stay-at-home.

Conclusion

Stay-at-home orders decreased mobility and slowed the spread of COVID-19, but less effectively in rural than in urban counties. This necessitates a critical reevaluation of how stay-at-home orders are designed, communicated, and implemented in rural areas.
Optimising Early Management of Acute Severe Ulcerative Colitis in the Biologics Era: Admission Model for Intensification of Therapy in Acute Severe Colitis (ADMIT–ASC)
Authors: Adams Alex , Gupta Vipin , Mohsen Waled , Chapman Thomas P , Subhaharan Deloshaan , Ramaswamy Pradeep Kakkadasam , Vuyyuru Sudheer Kumar , Kedia Saurabh , McGregor Colleen GC , Ambrose Tim , George Bruce D , Palmer Rebecca , Brain Oliver , Walsh Alissa , Ahuja Vineet , Travis Simon , Satsangi Jack
Published: July 2021

Background & aims

We aimed to determine whether changes in ulcerative colitis management have translated to improved outcomes, in order to develop a simple model to predict steroid non-response on admission.

Methods

Outcomes of 131 adult ASC admissions (117 patients) in Oxford, UK between 2015-19 were compared with prospectively collected data from 1992-3. All patients received standard treatment with intravenous corticosteroids and endoscopic disease activity scoring (UCEIS). Steroid non-response was defined as receiving rescue medical therapy or surgery. A predictive model created in the Oxford cohort was validated in Australia and India (110 hospitalised patients Gold Coast University Hospital 2015-20; 62 hospitalised patients AIIMS, New Delhi 2018-20).

Results

In the 2015-19 Oxford cohort, 71 (54%) patients received medical rescue therapy (27% ciclosporin, 27% anti-TNF), compared to 27% ciclosporin in 1992-3, p=0.0015. Only 15% required colectomy during admission vs 29% in 1992-3 (p=0.033). Admission CRP, albumin, and UCEIS scores predicted steroid non-response (FDR p=0.00066, 0.0066 and 0.015). A four-point model was developed involving CRP ≥100mg/L (1 point), albumin ≤25g/L (1 point), UCEIS ≥4 (1 point) or ≥7 (2 points). Scoring 0 or 4 was 100% predictive of steroid response and non-response, respectively, in all three cohorts. Patients scoring 3-4 had 83% risk of steroid non-response in Oxford and 84% (0.70-0.98) in the validation cohorts – OR 11.9 (10.8-13).

Conclusion

Colectomy rates for ASC have halved in 25 years, while use of rescue medical therapy has doubled. Patients who are highly unlikely to respond to parenteral steroid treatment alone may be readily identified on admission, to be prioritised for early intensification of therapy.

WHAT YOU NEED TO KNOW

Background and context

Acute severe colitis (ASC) requires hospitalisation and, frequently, colectomy. The accepted management of ASC is three-five days of intravenous steroids followed by protocolised response assessment.

New findings

Medical rescue therapy has doubled and the colectomy rate halved in 25 years. A predictive index identifying steroid non-response was derived and validated in three independent centres in three countries.

Limitations

A need remains to demonstrate that earlier rescue medical therapy for patients predicted to be steroid non-responders will further improve outcomes.

Impact

The outcome of ASC has substantially improved in the past 25 years, with the potential for further improvement by identifying patients on admission for early escalation of therapy.
Effects of a 33-ion sequential beam galactic cosmic ray analog on male mouse behavior and evaluation of CDDO-EA as a radiation countermeasure
Authors: Kiffer Frederico C , Luitel Krishna , Tran Fionya H , Patel Riya A , Guzman Catalina S , Soler Ivan , Xiao Rui , Shay Jerry W , Yun Sanghee , Eisch Amelia J
Published: July 2021

In long-term spaceflight, astronauts will face unique cognitive loads and social challenges which will be complicated by communication delays with Earth. It is important to understand the central nervous system (CNS) effects of deep spaceflight and the associated unavoidable exposure to galactic cosmic radiation (GCR). Rodent studies show single- or simple-particle combination exposure alters CNS endpoints, including hippocampal-dependent behavior. An even better Earth-based simulation of GCR is now available, consisting of a 33-beam (33-GCR) exposure. However, the effect of whole-body 33-GCR exposure on rodent behavior is unknown, and no 33-GCR CNS countermeasures have been tested. Here astronaut-age-equivalent (6mo-old) C57BL/6J male mice were exposed to 33-GCR (75cGy, a Mars mission dose). Pre-/during/post-Sham or 33-GCR exposure, mice received a diet containing a ‘vehicle’ formulation alone or with the antioxidant/anti-inflammatory compound CDDO‐EA as a potential countermeasure. Behavioral testing beginning 4mo post-irradiation suggested radiation and diet did not affect measures of exploration/anxiety-like behaviors (open field, elevated plus maze) or recognition of a novel object. However, in 3-Chamber Social Interaction (3-CSI), CDDO-EA/33-GCR mice failed to spend more time exploring a holder containing a novel mouse vs. a novel object (empty holder), suggesting sociability deficits. Also, Vehicle/33-GCR and CDDO-EA/Sham mice failed to discriminate between a novel stranger vs. familiarized stranger mouse, suggesting blunted preference for social novelty. CDDO-EA given pre-/during/post-irradiation did not attenuate the 33-GCR-induced blunting of preference for social novelty. Future elucidation of the mechanisms underlying 33-GCR-induced blunting of preference for social novelty will improve risk analysis for astronauts which may in-turn improve countermeasures.
c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease
Authors: Smith Abigail O. , Jonassen Julie A. , Preval Kenley M. , Davis Roger J. , Pazour Gregory J.
Published: July 2021

Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people. It primarily is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2). The most proximal effects of Pkd mutations leading to cyst formation are not known, but pro-proliferative signaling must be involved for the tubule epithelial cells to increase in number over time. The c-Jun N-terminal kinase (JNK) pathway promotes proliferation and is activated in acute and chronic kidney diseases. Using a mouse model of cystic kidney disease caused by Pkd2 loss, we observe JNK activation in cystic kidneys and observe increased nuclear phospho c-Jun in cystic epithelium. Genetic removal of Jnk1 and Jnk2 suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, we find that Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2. Jnk pathway inhibitors are in development for neurodegeneration, cancer, and fibrotic diseases. Our work suggests that the JNK pathway should be explored as a therapeutic target for ADPKD.

Author Summary

Autosomal dominant polycystic kidney disease is a leading cause of end stage renal disease requiring dialysis or kidney transplant. During disease development, the cells lining the kidney tubules proliferate. This proliferation transforms normally small diameter tubules into fluid-filled cysts that enlarge with time, eventually destroying all kidney function. Despite decades of research, polycystic kidney disease remains incurable. Furthermore, the precise signaling events involved in cyst initiation and growth remain unclear. The c-Jun N-terminal kinase (JNK), is a major pathway regulating cellular proliferation and differentiation but its importance to polycystic kidney disease was not known. We show that JNK activity is elevated in cystic kidneys and that reducing JNK activity decreases cyst growth pointing to JNK inhibition as a therapeutic strategy for treating polycystic kidney disease.
BAZ2A-RNA mediated association with TOP2A and KDM1A represses genes implicated in prostate cancer
Authors: Roganowicz Marcin , Bär Dominik , Bersaglieri Cristiana , Aprigliano Rossana , Santoro Raffaella
Published: July 2021

BAZ2A is the repressor of rRNA genes that are transcribed by RNA Polymerase I. In prostate cancer (PCa), however, BAZ2A function goes beyond this role since it can also repress other genes that are frequently silenced in metastatic disease. However, the mechanisms of BAZ2A-mediated repression in PCa remain elusive. Here we show that BAZ2A represses genes implicated in PCa through its RNA-binding TAM domain using mechanisms differing from rRNA gene silencing. While TAM domain mediates BAZ2A recruitment to rRNA genes, in PCa cells this is not required for BAZ2A association with target genes. Instead, BAZ2A-TAM domain in association with RNA mediates the interaction with topoisomerase 2A (TOP2A) and histone demethylase KDM1A, whose expression positively correlates with BAZ2A levels in both localized and aggressive PCa. Pharmacological inhibition of TOP2A and KDM1A activities upregulates the expression of BAZ2A-repressed genes that are regulated by a class of inactive enhancers bound by BAZ2A whereas rRNA genes are not affected. Our findings showed a novel RNA-based mechanism of gene regulation in PCa. Further, the data indicate that RNA-mediated interactions between BAZ2A and TOP2A and KDM1A repress genes critical to PCa and may prove to be useful to stratify prostate cancer risk and treatment in patients.
Monitoring the spread of SARS-CoV-2 variants in Moscow and the Moscow region using targeted high-throughput sequencing
Authors: Borisova N.I. , Kotov I.A. , Kolesnikov A.A. , Kaptelova V.V. , Speranskaya A.S. , Kondrasheva L.Yu. , Tivanova E.V. , Khafizov K.F. , Akimkin V. G.
Published: July 2021

Since the outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 coronavirus, the international community has been concerned about the emergence of mutations that alter the biological properties of the pathogen, for example, increasing its infectivity or virulence. In particular, since the end of 2020, several variants of concern have been identified around the world, including variants “alpha” (B.1.1.7, “British”), “beta” (B.1.351, “South African”), “gamma” (P.1, “Brazilian”) and “delta” (B.1.617.2, “Indian”). However, the existing mechanism for searching for important mutations and identifying strains may not be effective enough, since only a relatively small fraction of all identified pathogen samples can be examined for genetic changes by whole genome sequencing due to its high cost. In this study, we used the method of targeted high-throughput sequencing of the most significant regions of the gene encoding the S-glycoprotein of the SARS-CoV-2 virus, for which a primer panel was developed. Using this technique, we examined 579 random samples obtained from patients in Moscow and the Moscow region with coronavirus infection from February to June 2021. The study demonstrated the dynamics of the representation in the Moscow region of a number of SARS-CoV-2 strains and its most significant individual mutations in the period from February to June 2021. It was found that the strain B.1.617.2 began to spread rapidly in Moscow and the Moscow region in May, and in June it became dominant, partially displacing other varieties of the virus. The results obtained make it possible to accurately determine the belonging of the samples to the abovementioned and some other strains. The approach can be used to standardize the procedure for searching for new and existing epidemiologically significant mutations in certain regions of the SARS-CoV-2 genome, which allows studying a large number of samples in a short time and to get a more detailed picture of the epidemiological situation in the region.
Latent neural dynamics encode temporal context in speech
Authors: Stephen Emily P , Li Yuanning , Metzger Sean , Oganian Yulia , Chang Edward F
Published: July 2021

Direct neural recordings from human auditory cortex have demonstrated encoding for acoustic-phonetic features of consonants and vowels. Neural responses also encode distinct acoustic amplitude cues related to timing, such as those that occur at the onset of a sentence after a silent period or the onset of the vowel in each syllable. Here, we used a group reduced rank regression model to show that distributed cortical responses support a low-dimensional latent state representation of temporal context in speech. The timing cues each capture more unique variance than all other phonetic features and exhibit rotational or cyclical dynamics in latent space from activity that is widespread over the superior temporal gyrus. We propose that these spatially distributed timing signals could serve to provide temporal context for, and possibly bind across time, the concurrent processing of individual phonetic features, to compose higher-order phonological (e.g. word-level) representations.
Engineering functional human gastrointestinal organoid tissues using the three primary germ layers separately derived from pluripotent stem cells
Authors: Eicher Alexandra K. , Kechele Daniel O. , Sundaram Nambirajan , Berns H. Matthew , Poling Holly M. , Haines Lauren E. , Sanchez J. Guillermo , Kishimoto Keishi , Krishnamurthy Mansa , Han Lu , Zorn Aaron M. , Helmrath Michael A. , Wells James M.
Published: July 2021

The development of human organoid model systems has provided new avenues for patient-specific clinical care and disease modeling. However, all organoid systems are missing important cell types that, in the embryo, get incorporated into organ tissues during development. Based on the concept of how embryonic organs are assembled, we developed an organoid assembly approach starting with cells from the three primary germ layers; enteric neuroglial, mesenchymal, and epithelial precursors, all separately derived from human pluripotent stem cells. From these we generated human gastric tissue containing differentiated glands, surrounded by layers of smooth muscle containing functional enteric neurons that controlled contractions of the engineered tissue. We used this highly tractable system to identify essential roles for the enteric nervous system in the growth and regional identity of the gastric epithelium and mesenchyme and for glandular morphogenesis of the antral stomach. This approach of starting with separately-derived germ layer components was applied to building more complex fundic and esophageal tissue, suggesting this as a new paradigm for tissue engineering.
Integrated transcriptomics identifies β-cell subpopulations and genetic networks associated with obesity and glycemic control in SM/J mice
Authors: Miranda Mario A , Macias-Velasco Juan F , Schmidt Heather , Lawson Heather A
Published: July 2021

Understanding how heterogeneous β-cell function and stress response impact diabetic etiology is imperative for therapy development. Standard single-cell RNA sequencing analysis illuminates some genetic underpinnings driving heterogeneity, but new strategies are required to capture information lost due to technical limitations. Here, we integrate pancreatic islet single-cell and bulk RNA sequencing data to identify β-cell subpopulations based on gene expression and characterize genetic networks associated with β-cell function in high- and low-fat fed male and female SM/J mice at 20 and 30wks of age. Previous studies have shown that high-fat fed SM/J mice resolve glycemic dysfunction between 20 and 30wks. We identify 4 β-cell subpopulations associated with insulin secretion, hypoxia response, cell polarity, and stress response. Relative proportions of these cells are influenced by age, sex, and diet. Network analysis identifies fatty acid metabolism and β-cell physiology gene expression modules associated with the hyperglycemic-obese state. We identify subtype-specific expression of Pdyn and Fam151a as candidate regulators of genetic pathways associated with β-cell function in obesity. In sum, this study uses a novel data integration method to explore how β-cells respond to obesity and glycemic stress, helping to define the relationship between β-cell heterogeneity and diabetes, and shedding light on novel genetic pathways with therapeutic potential.
LincRNA-Cox2 functions to regulate inflammation in alveolar macrophages during acute lung injury
Authors: Robinson Elektra Kantzari , Worthington Atesh K. , Poscablo Donna M. , Shapleigh Barbara , Salih Mays Mohammed , Halasz Haley , Seninge Lucas , Mosqueira Benny , Smaliy Valeriya , Forsberg E. Camilla , Carpenter Susan
Published: July 2021

The respiratory system exists at the interface between our body and the surrounding non-sterile environment; therefore, it is critical for a state of homeostasis to be maintained through a balance of pro- and anti- inflammatory cues. An appropriate inflammatory response is vital for combating pathogens, while an excessive or uncontrolled inflammatory response can lead to the development of chronic diseases. Recent studies show that actively transcribed noncoding regions of the genome are emerging as key regulators of biological processes, including inflammation. LincRNA-Cox2 is one such example of an inflammatory inducible long noncoding RNA functioning to control immune response genes. Here using bulk and single cell RNA-seq, in addition to florescence activated cell sorting, we show that lincRNA-Cox2 is most highly expressed in the lung, particularly in alveolar macrophages where it functions to control immune gene expression following acute lung injury. Utilizing a newly generated lincRNA-Cox2 transgenic overexpressing mouse, we show that it can function in trans to control genes including Ccl3, 4 and 5. This work greatly expands our understanding of the role for lincRNA-Cox2 in host defense and sets in place a new layer of regulation in RNA-immune-regulation of genes within the lung.
Genome-wide analysis of long terminal repeat retrotransposons from the cranberry Vaccinium macrocarpon
Authors: Sultana Nusrat , Menzel Gerhard , Seibt Kathrin M. , Garcia Sònia , Weber Beatrice , Serçe Sedat , Heitkam Tony
Published: July 2021

BACKGROUND

Long terminal repeat (LTR) retrotransposons are widespread in plant genomes and play a large role in the generation of genomic variation. Despite this, their identification and characterization remains challenging, especially for non-model genomes. Hence, LTR retrotransposons remain undercharacterized in Vaccinium genomes, although they may be beneficial for current berry breeding efforts.

OBJECTIVE

Exemplarily focusing on the genome of American cranberry (Vaccinium macrocarpon Aiton), we aim to generate an overview of the LTR retrotransposon landscape, highlighting the abundance, transcriptional activity, sequence, and structure of the major retrotransposon lineages.

METHODS

Graph-based clustering of whole genome shotgun Illumina reads was performed to identify the most abundant LTR retrotransposons and to reconstruct representative in silico full-length elements. To generate insights into the LTR retrotransposon diversity in V. macrocarpon, we also queried the genome assembly for presence of reverse transcriptases (RTs), the key domain of LTR retrotransposons. Using transcriptomic data, transcriptional activity of retrotransposons corresponding to the consensuses was analyzed.

RESULTS

We provide an in-depth characterization of the LTR retrotransposon landscape in the V. macrocarpon genome. Based on 475 RTs harvested from the genome assembly, we detect a high retrotransposon variety, with all major lineages present. To better understand their structural hallmarks, we reconstructed 26 Ty1-copia and 28 Ty3-gypsy in silico consensuses that capture the detected diversity. Accordingly, we frequently identify association with tandemly repeated motifs, extra open reading frames, and specialized, lineage-typical domains. Based on the overall high genomic abundance and transcriptional activity, we suggest that retrotransposons of the Ale and Athila lineages are most promising to monitor retrotransposon-derived polymorphisms across accessions.

CONCLUSIONS

We conclude that LTR retrotransposons are major components of the V. macrocarpon genome. The representative consensuses provide an entry point for further Vaccinium genome analyses and may be applied to derive molecular markers for enhancing cranberry selection and breeding.
Revealing Protein-Level Functional Redundancy in the Human Gut Microbiome using Ultra-deep Metaproteomics
Authors: Li Leyuan , Ning Zhibin , Zhang Xu , Butcher James , Simopoulos Caitlin , Mayne Janice , Stintzi Alain , Mack David R. , Liu Yang-Yu , Figeys Daniel
Published: July 2021

Functional redundancy is a key property of ecosystems and represents the fact that phylogenetically unrelated taxa can play similar functional roles within an ecosystem. The redundancy of potential functions of human microbiome has been recently quantified using metagenomics data. Yet, the redundancy of functions which are actually expressed within the human microbiome remains largely unexplored. Here, we quantify the protein-level functional redundancy in the human gut microbiome using metaproteomics and network approaches. In particular, our ultra-deep metaproteomics approach revealed high protein-level functional redundancy and high nestedness in proteomic content networks - bipartite graphs that connect taxa with their expressed functions. We further examined multiple metaproteomics datasets and showed that various environmental factors, including individuality, biogeography, xenobiotics, and disease, significantly altered the protein-level functional redundancy. Finally, by projecting the bipartite proteomic content networks into unipartite weighted genus networks, functional hub genera across individual microbiomes were discovered, suggesting that there may be a universal principle of functional organization in microbiome assembly.

Highlights

Ultra-deep metaproteomics reveals high protein-level functional redundancy in the human gut microbiome

Within-sample proteomic content networks display universal topology

Various environmental factors influence the redundancy of expressed functions

Functional hub genera are present across different datasets
Accurate prediction of functional states of cis-regulatory modules reveals the common epigenetic rules in humans and mice
Authors: Ni Pengyu , Moe Joshua , Su Zhengchang
Published: July 2021

We proposed a two-step approach for predicting active cis-regulatory modules (CRMs) in a cell/tissue type. We first predict a map of CRM loci in the genome using all available transcription factor binding data in the organism, and then predict functional states of all the putative CRMs in any cell/tissue type using few epigenetic marks. We have recently developed a pipeline dePCRM2 for the first step, and now presented machine-learning methods for the second step. Our approach substantially outperforms existing methods. Our results suggest common epigenetic rules for defining functional states of CRMs in various cell/tissue types in humans and mice.
Low dose AKT inhibitor miransertib cures PI3K-related vascular malformations in preclinical models of human disease
Authors: Kobialka Piotr , Sabata Helena , Vilalta Odena , Angulo-Urarte Ana , Muixí Laia , Zanoncello Jasmina , Muñoz-Aznar Oscar , Olaciregui Nagore G. , Lavarino Cinzia , Celis Veronica , Rovira Carlota , López Susana , Baselga Eulàlia , Mora Jaume , Castillo Sandra D. , Graupera Mariona
Published: July 2021

Low-flow vascular malformations are congenital overgrowths composed by abnormal blood vessels potentially causing pain, bleeding, and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium which result in overactivation of the PI3K/AKT pathway. Lack of robustin vivopreclinical data has prevented the development and translation into clinical trials of specific molecular therapies for these diseases. Here, we describe a new reproducible preclinicalin vivomodel of PI3K-driven vascular malformations using the postnatal mouse retina. This model reproduces human disease withPik3caactivating mutations expressed in a mosaic pattern and vascular malformations formed in veins and capillaries. We show that active angiogenesis is required for the pathogenesis of vascular malformations caused by activatingPik3camutations. Using this model, we demonstrate that low doses of the AKT inhibitor miransertib both prevents and induces the regression of PI3K-driven vascular malformations. We confirmed miransertib efficacy in isolated human endothelial cells with genotypes spanning most of human low-flow vascular malformations.

Graphical abstract

Low-flow vascular malformations are caused by PI3K signalling overactivation in endothelial cells. We have generated an optimised and robust preclinical system of PI3K-driven vascular malformations by inducing the mosaic expression ofPik3caH1047Rin the retinal angiogenic endothelium. This preclinical model displays traits constituting the main hallmarks of the pathogenesis of low-flow blood vascular malformations: overactivation of PI3K signalling (high phospho-S6), vascular compartment specificity, loss of pericyte coverage, and endothelial cell hyperproliferation. Using this preclinical model we report that low dose AKT inhibitor miransertib prevents and regress PI3K-driven vascular malformations.
Temperature and guanidine hydrochloride effects on the folding thermodynamics of WW domain and variants
Authors: Qin Meng , Denesyuk Natalia , Liu Zhenxing , Wang Wei , Thirumalai D.
Published: July 2021

We used simulations based on an all atom Go model to calculate the folding temperatures (Tfs) and free energies (ΔGs) of two variants of the WW domain, which is a small allβ-sheet protein. The results,without adjusting any parameter, are in good agreement with experiments, thus validating the simulations. We then used the Molecular Transfer Model to predict the changes in the ΔGandTfs as guanidine hydrochloride concentration is varied. The predictions can be readily tested in experiments.
Crystal structure and Hirshfeld surface analysis of 1,3-bis{2,2-dichloro-1-[(E)-phenyldiazenyl]ethenyl}benzene
Authors: Shikhaliyev Namiq Q. , Atioğlu Zeliha , Akkurt Mehmet , Ahmadova Nigar E. , Askerov Rizvan K. , Bhattarai Ajaya
Published: July 2021

In the molecule of the title compound, C22H14Cl4N4, the central benzene ring makes dihedral angles of 77.03 (9) and 81.42 (9)° with the two approximately planar 2,2-dichloro-1-[(E)-phenyldiazenyl]vinyl groups. In the crystal, molecules are linked by C—H...π, C—Cl...π, Cl...Cl and Cl...H interactions, forming a three-dimensional network. The Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H...H (30.4%), C...H/H...C (20.4%), Cl...H/H...Cl (19.4%), Cl...Cl (7.8%) and Cl...C/C...Cl (7.3%) interactions.
The Multichannel Challenge at Natura in Beauty and Personal Care
Authors: Guissoni Leandro A. , Farris Paul W. , Kusum Ailawadi , Boccia Murillo
Published: July 2021

Faced with declining market share and sales, Natura, Brazil’s second-largest brand in the cosmetics, fragrances, and toiletries market, expanded its customer reach by moving from a direct-sales company to a multichannel company. In 2014, Natura added online catalogs, physical stores, and drugstores to its well-established direct-selling model, but the results were disappointing. Between 2014 and 2016, three different Natura CEOs attempted to lead the company in the strategic transition to focus less on the direct sales consultants and more on reaching the end consumers directly with multiple channels and touchpoints. In October 2016, the company’s board appointed its former commercial vice president, João Paulo Ferreira, as the most recent CEO. Ferreira’s challenge was to find the right balance between the direct-selling and other channel formats to market Natura, thus enabling it to thrive in the face of intense competition in the beauty and personal care market in Brazil.
Heinz Ketchup: Pricing the Product Line
Authors: Goldberg Rebecca , Wilcox Ron
Published: July 2021

An iconic American brand must determine how to maximize net profit by increasing the sales of its highest-margin items in the face of constant retailer pushback including reduced shelf space and promotional support of those same products. This case is suitable for required MBA marketing courses as well as pricing and brand management electives at both the undergraduate and MBA levels. The analytics of the case assume that students can calculate both dollar and percentage margins.
Marketing and Ethics
Authors: Jacki Fritz , Mead Jenny , Mead Jenny , Freeman R. Edward
Published: July 2021

Marketing tactics such as pricing, promotion, placement, and product decisions all help business owners create a need for their products or services. What managers seldom realize, however, is that the marketing decisions they make primarily to increase sales and market share have a great impact on society at large and thus have significant ethical implications. These seven caselets, which cover a variety of topics (including “the article of the half-truth,” “creative interview tactics,” and “truthfully representing your company”), explore the ethical implications of decision making in the marketing arena.
An early-stage project complexity assessment tool for the AEC industry
Authors: Vaz-Serra Paulo , Edwards Peter , Aranda-Mena Guillermo
Published: July 2021

Purpose

Complex projects require careful management. They may expose stakeholders to greater risks and place additional demands upon resources. In the initial stages of project development, however, little may be known about the nature and magnitude of such complexity. This paper aims to ensure that this gap is at least subjectively assessed and addressed.

Design/methodology/approach

Research, using focus group workshops with a convenience sample of construction professionals, was carried out to test the validity of a Project Early Stage Complexity Assessment Tool (PESCAT). The PESCAT concept brings together selected complexity theories and uses subjectively based measures for assessment.

Findings

The findings confirm that an early-stage project complexity assessment tool is practicable and can contribute to project management practice in the construction industry. It should be applied by individual project stakeholders using small teams of experienced staff. PESCAT explores project complexity through “filter” sets of perspective factors which should be customised to reflect the stakeholder’s role and processes in a project.

Originality/value

In the initial complexity assessment model, resolution space and uncertainty were tested as project complexity parameters. However, in subsequent versions of the tool, four measures (differentiation and differentiation uncertainty; interdependency and interdependency uncertainty) are used in an innovative way that focuses users’ attention more clearly and points to a more targeted approach for addressing project complexity. The value of our model lies in its practical application and the project management benefits it can deliver.
A new conceptual framework for memorable Airbnb experiences: guests’ perspectives
Authors: Sthapit Erose , Björk Peter , Coudounaris Dafnis N. , Stone Matthew J.
Published: July 2021

Purpose

This qualitative study aims to explore the activities that guests perform while staying in Airbnbs, emotions associated with these experiences and the components of memorable Airbnb experiences.

Design/methodology/approach

An empirical study of a qualitative nature was conducted using a self-administered open-ended questionnaire among tourists who had stayed in an Airbnb in the past three years. Data were collected using two different sources for triangulation purposes, referred to as Studies 1 and 2.

Findings

Many respondents reported conducting similar activities while at home and while staying in an Airbnb, supporting Burch’s (1969) spill-over theory. Travellers mostly recalled mundane activities, such as cooking. The results suggest that the spill-over effect is more prevalent in the Airbnb context than in other accommodation types, as one often travels from one’s own home to another’s home. Respondents associated their Airbnb experience with the positive emotion of joy. Respondents mentioned numerous reasons for having felt joy during their Airbnb experiences, such as sharing the trip with travel companions and spending time with friends.

Practical implications

Airbnb should clearly define host’s tasks and responsibilities, hosts should treat guests in a friendly manner, which includes resolving any problems they face in relation to the rental property.

Originality/value

This paper proposes a new conceptual framework for a memorable Airbnb experience, which comprises several components: socialising and bonding with friends and family members, location, the host’s hospitality, a homely feeling, home amenities and negative experiences (the poor condition of the room and a dishonest host).