Nevin Manimala

Sci Rep. 2021 Jun 21;11(1):13001. doi: 10.1038/s41598-021-92263-3.

ABSTRACT

Although international airports served as main entry points for SARS-CoV-2, the factors driving the uneven geographic spread of COVID-19 cases and deaths in Brazil remain mostly unknown. Here we show that three major factors influenced the early macro-geographical dynamics of COVID-19 in Brazil. Mathematical modeling revealed that the “super-spreading city” of São Paulo initially accounted for more than 85% of the case spread in the entire country. By adding only 16 other spreading cities, we accounted for 98-99% of the cases reported during the first 3 months of the pandemic in Brazil. Moreover, 26 federal highways accounted for about 30% of SARS-CoV-2’s case spread. As cases increased in the Brazilian interior, the distribution of COVID-19 deaths began to correlate with the allocation of the country’s intensive care units (ICUs), which is heavily weighted towards state capitals. Thus, severely ill patients living in the countryside had to be transported to state capitals to access ICU beds, creating a “boomerang effect” that contributed to skew the distribution of COVID-19 deaths. Therefore, if (i) a lockdown had been imposed earlier on in spreader-capitals, (ii) mandatory road traffic restrictions had been enforced, and (iii) a more equitable geographic distribution of ICU beds existed, the impact of COVID-19 in Brazil would be significantly lower.

PMID:34155241 | DOI:10.1038/s41598-021-92263-3

Sci Rep. 2021 Jun 21;11(1):12921. doi: 10.1038/s41598-021-92196-x.

ABSTRACT

Chimeric antigen receptor (CAR) T cells are engineered cells used in cancer therapy and are studied to treat infectious diseases. Trafficking and persistence of CAR T cells is an important requirement for efficacy to target cancer. Here, we describe a CAR RNA FISH histo-cytometry platform combined with a random reaction seed image analysis algorithm to quantitate spatial distribution and in vivo functional activity of a CAR T cell population at a single cell resolution for preclinical models. In situ, CAR T cell exhibited a heterogenous effector gene expression and this was related to the distance from tumor cells, allowing a quantitative assessment of the potential in vivo effectiveness. The platform offers the potential to study immune functions of genetically engineered cells in situ with their target cells in tissues with high statistical power and thus, can serve as an important tool for preclinical assessment of CAR T cell effectiveness.

PMID:34155235 | DOI:10.1038/s41598-021-92196-x

Sci Rep. 2021 Jun 21;11(1):12948. doi: 10.1038/s41598-021-92068-4.

ABSTRACT

COVID 19 disease has become a global catastrophe over the past year that has claimed the lives of over two million people around the world. Despite the introduction of vaccines against the disease, there is still a long way to completely eradicate it. There are concerns about the complications following infection with SARS-CoV-2. This research aimed to evaluate the possible correlation between infection with SARS-CoV viruses and cancer in an in-silico study model. To do this, the relevent dataset was selected from GEO database. Identification of differentially expressed genes among defined groups including SARS-CoV, SARS-dORF6, SARS-BatSRBD, and H1N1 were screened where the |Log FC| ≥ 1and p < 0.05 were considered statistically significant. Later, the pathway enrichment analysis and gene ontology (GO) were used by Enrichr and Shiny GO databases. Evaluation with STRING online was applied to predict the functional interactions of proteins, followed by Cytoscape analysis to identify the master genes. Finally, analysis with GEPIA2 server was carried out to reveal the possible correlation between candidate genes and cancer development. The results showed that the main molecular function of up- and down-regulated genes was “double-stranded RNA binding” and actin-binding, respectively. STRING and Cytoscape analysis presented four genes, PTEN, CREB1, CASP3, and SMAD3 as the key genes involved in cancer development. According to TCGA database results, these four genes were up-regulated notably in pancreatic adenocarcinoma. Our findings suggest that pancreatic adenocarcinoma is the most probably malignancy happening after infection with SARS-CoV family.

PMID:34155232 | DOI:10.1038/s41598-021-92068-4

Nat Commun. 2021 Jun 21;12(1):3804. doi: 10.1038/s41467-021-23510-4.

ABSTRACT

In mammalian genomes, differentially methylated regions (DMRs) and histone marks including trimethylation of histone 3 lysine 27 (H3K27me3) at imprinted genes are asymmetrically inherited to control parentally-biased gene expression. However, neither parent-of-origin-specific transcription nor imprints have been comprehensively mapped at the blastocyst stage of preimplantation development. Here, we address this by integrating transcriptomic and epigenomic approaches in mouse preimplantation embryos. We find that seventy-one genes exhibit previously unreported parent-of-origin-specific expression in blastocysts (nBiX: novel blastocyst-imprinted expressed). Uniparental expression of nBiX genes disappears soon after implantation. Micro-whole-genome bisulfite sequencing (µWGBS) of individual uniparental blastocysts detects 859 DMRs. We further find that 16% of nBiX genes are associated with a DMR, whereas most are associated with parentally-biased H3K27me3, suggesting a role for Polycomb-mediated imprinting in blastocysts. nBiX genes are clustered: five clusters contained at least one published imprinted gene, and five clusters exclusively contained nBiX genes. These data suggest that early development undergoes a complex program of stage-specific imprinting involving different tiers of regulation.

PMID:34155196 | DOI:10.1038/s41467-021-23510-4

J Pediatr Orthop. 2021 Jun 22. doi: 10.1097/BPO.0000000000001835. Online ahead of print.

ABSTRACT

BACKGROUND: We modified the original technique for percutaneous transphyseal screw which was described in 1998 by Metaizeau and colleagues for distal femoral coronal angular deformity correction; the modification is related to the screw direction, whereas the screw is administered in a retrograde pattern, starting from the epiphysis and directed toward the metaphysis. This technique opposes the original technique that was started with a metaphyseal entry point which aimed toward the epiphysis. This study evaluates the efficacy of the newly suggested surgical technique regarding the rate of correction and growth resumption after screw removal.

METHODS: This prospective study looked at 40 patients (65 distal femoral physes), who underwent a percutaneous retrograde transphyseal guided growth screw procedure, from October 2017 to September 2019. All the patients included had distal femoral coronal angular deformities; 52 in valgus and 13 in varus deformities. The study included 17 females with an average age of 11.75 (range: 8.4 to 14.5 y) for 29 femurs and 23 males with an average age of 13.75 (range: 11.75 to 15.6 y) for 36 femurs. The mechanical lateral distal femoral angle was measured initially, and then again was measured after reaching the desired corrected orientation. The patients were then followed up after the screw removal and followed up to maturity, if the physis had continued to grow postcorrection. The degree of correction per month was calculated, and the consequence of screw removal was detected. Follow-up average time was 12.6 months (range: 30 to 6 mo).

RESULTS: The average correction in the distal femur was 1.3 degrees per month (range: 0.5 to 1.857 degrees/mo). In all of the 65 segments (61 femurs had significant growth remaining and 4 femurs had reached skeletal maturity with suboptimal mechanical lateral distal femoral angle correction), the screws were removed at the time of angular correction. Rebound growth was observed in 15 physes with an average of 1.8 degrees (range: 2 to 3 degrees); they were stable in 42 physes and progressed in 4 physes with an average of 1.6 degrees (range: 1 to 2 degrees). Complications were minor and related to entrapment of soft tissue under the screw washer.

CONCLUSION: Percutaneous retrograde transphyseal guided growth screw for distal femur coronal angular deformity is a minimally invasive procedure, with a statistically significant correction rate when compared with the original transphyseal screw technique. The new technique has proven to have growth resumption after screw removal with minimal complication risk.

LEVEL OF EVIDENCE: Level III-prospective observational study.

PMID:34155176 | DOI:10.1097/BPO.0000000000001835

Nurs Educ Perspect. 2021 Jun 22. doi: 10.1097/01.NEP.0000000000000840. Online ahead of print.

ABSTRACT

AIM: The purpose of the study was to examine the influence of academic nurse educator doctoral degree preparation on National League for Nursing (NLN) core competency skill acquisition.

BACKGROUND: Doctor of nursing practice (DNP) and doctor of philosophy (PhD) graduates frequently seek faculty positions, yet neither degree exclusively prepares graduates for careers in academia.

METHOD: A descriptive, correlational design was utilized to examine the influence of doctoral degree preparation on NLN core competency skill acquisition. A randomized, nationwide sample (N = 160) of full-time nurse educators teaching in American Association of Colleges of Nursing member schools across the United States completed the Nurse Educator Skill Acquisition Assessment.

RESULTS: PhD-prepared educators reported higher NLN core competency skill acquisition scores than DNP-prepared nurse educators. There were statistically significant differences in overall skill acquisition scores between DNP- and PhD-prepared nurse educators and for the “use assessment and evaluation” and “engage in scholarship” domains.

CONCLUSION: These findings provide opportunities for NLN core competency skill acquisition among DNP- and PhD-prepared faculty.

PMID:34155173 | DOI:10.1097/01.NEP.0000000000000840

Proc Natl Acad Sci U S A. 2021 Jun 22;118(25):e2015005118. doi: 10.1073/pnas.2015005118.

ABSTRACT

Genetic variation segregates as linked sets of variants or haplotypes. Haplotypes and linkage are central to genetics and underpin virtually all genetic and selection analysis. Yet, genomic data often omit haplotype information due to constraints in sequencing technologies. Here, we present “haplotagging,” a simple, low-cost linked-read sequencing technique that allows sequencing of hundreds of individuals while retaining linkage information. We apply haplotagging to construct megabase-size haplotypes for over 600 individual butterflies (Heliconius erato and H. melpomene), which form overlapping hybrid zones across an elevational gradient in Ecuador. Haplotagging identifies loci controlling distinctive high- and lowland wing color patterns. Divergent haplotypes are found at the same major loci in both species, while chromosome rearrangements show no parallelism. Remarkably, in both species, the geographic clines for the major wing-pattern loci are displaced by 18 km, leading to the rise of a novel hybrid morph in the center of the hybrid zone. We propose that shared warning signaling (Müllerian mimicry) may couple the cline shifts seen in both species and facilitate the parallel coemergence of a novel hybrid morph in both comimetic species. Our results show the power of efficient haplotyping methods when combined with large-scale sequencing data from natural populations.

PMID:34155138 | DOI:10.1073/pnas.2015005118

Proc Natl Acad Sci U S A. 2021 Jun 29;118(26):e2026808118. doi: 10.1073/pnas.2026808118.

ABSTRACT

Most stars in the Universe are red dwarfs. They outnumber stars like our Sun by a factor of 5 and outlive them by another factor of 20 (population-weighted mean). When combined with recent observations uncovering an abundance of temperate, rocky planets around these diminutive stars, we are faced with an apparent logical contradiction-Why do we not see a red dwarf in our sky? To address this “red sky paradox,” we formulate a Bayesian probability function concerning the odds of finding oneself around an F/G/K-spectral type (Sun-like) star. If the development of intelligent life from prebiotic chemistry is a universally rapid and ensured process, the temporal advantage of red dwarfs dissolves, softening the red sky paradox, but exacerbating the classic Fermi paradox. Otherwise, we find that humanity appears to be a 1-in-100 outlier. While this could be random chance (resolution I), we outline three other nonmutually exclusive resolutions (II to IV) that broadly act as filters to attenuate the suitability of red dwarfs for complex life. Future observations may be able to provide support for some of these. Notably, if surveys reveal a paucity of temperate rocky planets around the smallest (and most numerous) red dwarfs, then this would support resolution II. As another example, if future characterization efforts were to find that red dwarf worlds have limited windows for complex life due to stellar evolution, this would support resolution III. Solving this paradox would reveal guidance for the targeting of future remote life sensing experiments and the limits of life in the cosmos.

PMID:34155109 | DOI:10.1073/pnas.2026808118

Thorax. 2021 Jun 21:thoraxjnl-2020-215600. doi: 10.1136/thoraxjnl-2020-215600. Online ahead of print.

ABSTRACT

INTRODUCTION: Observational studies suggested lung function is inversely associated with cardiovascular disease (CVD) although these studies could be confounded. We conducted a two sample Mendelian randomisation study using summary statistics from genome-wide association studies (GWAS) to clarify the role of lung function in CVD and its risk factors, and conversely the role of CVD in lung function.

METHODS: We obtained genetic instruments for forced expiratory volume in 1 s (FEV₁: 260) and forced vital capacity (FVC: 320) from publicly available UK Biobank summary statistics (n=421 986) and applied to GWAS summary statistics for coronary artery disease (CAD) (n=184 305), stroke (n=446 696), atrial fibrillation (n=1 030 836) and heart failure (n=977 320) and cardiovascular risk factors. Inverse variance weighting was used to assess the impact of lung function on these outcomes, with various sensitivity analyses. Bidirectional Mendelian randomisation was used to assess reverse causation.

RESULTS: FEV₁ and FVC were inversely associated with CAD (OR per SD increase, 0.72 (95% CI 0.63 to 0.82) and 0.70 (95%CI 0.62 to 0.78)), overall stroke (0.87 (95%CI 0.77 to 0.97), 0.90 (95% CI 0.82 to 1.00)) and some stroke subtypes. FEV₁ and FVC were inversely associated with type 2 diabetes and systolic blood pressure. Sensitivity analyses produced similar findings although the association with CAD was attenuated after adjusting for height (eg, OR for 1SD FEV₁0.95 (0.75 to 1.19), but not for stroke or type 2 diabetes. There was no strong evidence for reverse causation.

CONCLUSION: Higher lung function likely protect against CAD and stroke.

PMID:34155093 | DOI:10.1136/thoraxjnl-2020-215600

J Clin Pathol. 2021 Jun 21:jclinpath-2021-207595. doi: 10.1136/jclinpath-2021-207595. Online ahead of print.

ABSTRACT

AIMS: Novel prognostic markers are warranted for gastrointestinal stromal tumours. Caveolin-1 is a multifunctional protein that proved to be associated with outcome in multiple tumour types. Aim of this study was to investigate Caveolin-1 expression and prognostic efficacy in a series of gastrointestinal stromal tumours.

METHODS: Caveolin-1 expression was assessed by immunohistochemistry in a retrospective series of 66 gastrointestinal stromal tumours representative of the different molecular subtypes. Correlations with clinical, histopathological and molecular features were investigated. Statistical analyses were performed as appropriate.

RESULTS: Thirty-five cases out of 66 (53.0%) expressed Caveolin-1. Presence of Caveolin-1 expression correlated with favourable histopathologic and clinical traits, including a lower mitotic count (p=0.003) and lower relapse rate (p=0.005). Caveolin-1 expression also resulted associated with the presence of PDGFRA mutations (p=0.010). Outcome analyses showed a favourable prognostic significance of Caveolin-1 expression in terms of relapse-free survival (HR=0.14; 95% CI=0.03 to 0.63) and overall survival (HR=0.29; 95% CI=0.11 to 0.74), even after adjusting for the mutational subgroup (relapse-free survival: HR=0.14, 95% CI=0.04 to 0.44; overall survival: HR=0.29, 95% CI=0.11 to 0.51) and imatinib treatment (relapse-free survival: HR=0.14, 95% CI=0.02 to 0.81; overall survival: HR=0.29, 95% CI=0.17 to 0.48).

CONCLUSION: Caveolin-1 represents a novel prognostic marker in gastrointestinal stromal tumours. Further studies are warranted to validate these results and to explore the mechanisms linking Caveolin-1 expression with the PDGFRA oncogenic pathway.

PMID:34155091 | DOI:10.1136/jclinpath-2021-207595