Prototype Sequence Research Articles

Genomic characteristics of human respiratory syncytial virus from children in China during 2017-2020.

Acute lower respiratory tract infections (ALRTIs) are a leading cause of mortality in young children worldwide due to human respiratory syncytial virus (RSV). The aim of this study was to monitor genetic variations in RSV and provide genomic data support for RSV prevention and control. A total of 105 complete RSV genome sequences were determined during 2017-2020. Phylogenetic analysis showed that all of the RSVA sequences were of genotype ON1, and all of the RSVB sequences were of genotype BA9. Notably, a phylogenetic tree based on the whole genome had more branches than a tree based on the G gene. In comparison to the RSV prototype sequences, 71.43% (50/70) of the ON1 sequences had five amino acid substitutions (T113I, V131N, N178G, H258Q, and H266L) that occurred simultaneously, and 68.57% (24/35) of the BA9 genotype sequences had 12 amino acid substitutions, four of which (A131T, T137I, T288I, and T310I) occurred simultaneously. In the F gene, there were 19 amino acid substitutions, which were mainly located in the antigenic sites Ø, II, V, and VII. Other amino acid substitutions were found in the NS1, NS2, P, SH, and L proteins. No significant evidence of recombination was found in any of the sequences. These findings provide important data that will be useful for prevention, control, and vaccine development against RSV.

The HIV-1 Nuclear Export Complex Reveals the Role of RNA in Crm1 Cargo Recognition.

Crm1 is a highly conserved nuclear exportin that transports >1000 human proteins including ribonucleoprotein (RNP) complexes. The interface between Crm1 and RNP cargos is unknown. The HIV regulatory protein, Rev, was one of the first identified cargos for Crm1 and contains a prototypic nuclear export sequence (NES). We present the cryo-electron microscopy structure of the HIV-1 nuclear export complex (Crm1/Ran-GTP and the Rev/RRE RNP). Rev binds at a previously unseen protein-protein binding site that stabilizes a unique Crm1 dimer and positions two NESs within the Crm1 dimer. The orientation of Rev binding positions the RRE within a charged pocket on the inside of the Crm1 toroid, mediating direct RNA-Ran-GTP contacts, highlighting the significant role of the RRE in the interaction. Structure based mutations, combined with cell-based assays, show that Crm1 has multiple distinct cargo recognition sites and explains how Crm1 can recognize a diverse range of protein and RNP cargos.

Phylo-geo haplotype network-based characterization of SARS-CoV-2 strains circulating in India (2020-2022).

Background & objectives Genetic analysis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) strains circulating in India during 2020-2022 was carried out to understand the evolution of potentially expanding and divergent clades. Methods SARS-CoV-2 sequences (n=612) randomly selected from among the sequences of samples collected through a nationwide network of Virus Research Diagnostic Laboratories during 2020 (n=1532) and Indian sequences available in Global Initiative on Sharing All Influenza Data during March 2020-March 2022 (n=53077), were analyzed using the phylo-geo haplotype network approach with reference to the Wuhan prototype sequence. Results On haplotype analysis, 420 haplotypes were revealed from 643 segregating sites among the sequences. Haplotype sharing was noted among the strains from different geographical regions. Nevertheless, the genetic distance among the viral haplotypes from different clades could differentiate the strains into distinct haplo groups regarding variant emergence. Interpretation & conclusions The haplotype analysis revealed that the G and GR clades were co-evolved and an epicentrefor the evolution of the GH, GK and GRA clades. GH was more frequently identified in northern parts of India than in other parts, whereas GK was detected less in north India than in other parts. Thus, the network analysis facilitated a detailed illustration of the pathways of evolution and circulation of SARS-CoV-2 variants.

Southern African Origin of HTLV-1 in Romania.

In Europe, most HTLV-1-infected individuals originate from highly endemic regions such as West Indies, sub-Saharan Africa, and South America. The only genuine endemic region for HTLV-1 in Europe is Romania where ATL series have been reported among Romanian patients. Our objective is to better understand the origin of this endemic focus based on a study of the genetic diversity of HTLV-1 in Romanians. DNA was obtained from PBMCs/buffy coats of 11 unrelated HTLV-1-infected individuals of Romanian origin. They include 9 ATL cases and 2 asymptomatic carriers. LTR sequences were obtained for all specimens. Complete genomic HTLV-1 sequences were obtained using four PCR series on 10 specimens. Phylogenetic trees were generated from multiple alignments using HTLV-1 prototypic sequences and the new generated sequences. Most of the complete LTR sequences (756-bp) showed low nucleotide diversity, ranging from 0% to 0.8% difference, and were closely related (less than 0.8% divergence) to the only previously characterized Romanian strain, RKI2. One strain, ROU7, diverged slightly (1.5% on average) from the others. Phylogenetic analyses both on partial LTR and the complete genome demonstrate that the 11 sequences belong to the HTLV-1a cosmopolitan genotype and 10 of them belong to the previously denominated a-TC Mozambique-Southern Africa A subgroup. In this study, we demonstrated that the HTLV-1 present in Romania most probably originated in Southern Africa. As most Romanian HTLV-1 strains are very closely related, we can assume that HTLV-1 has been introduced into the Romanian population recently. Further studies are ongoing to decipher the routes of arrival and dissemination of these HTLV-1 strains, and to date the emergence of this endemic focus in Central Europe.

Innate and Adaptive Immune Parameters following mRNA Vaccination in Mice.

The COVID-19 pandemic has raised the standard regarding the current vaccine development pace, as several messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines have proved their ability to induce strong immunogenicity and protective efficacy. We developed 1-methylpseudouridine-containing mRNA-LNP vaccines, expressing either the more conserved SARS-CoV-2 nucleoprotein (mRNA-N) or spike protein (mRNA-S), both based on the prototypic viral sequences. When combining both mRNA-S and mRNA-N together (mRNA-S+N), the vaccine showed high immunogenicity and broad protection against different SARS-CoV-2 variants, including wildtype, Delta, BA.1, BA.5, and BQ.1. To better understand the mechanisms behind this broad protection obtained by mRNA-S+N, we analyzed innate and adaptive immune parameters following vaccination in mice. Compared to either mRNA-S or mRNA-N alone, mice vaccinated with mRNA-S+N exhibited an increase in the innate immune response, as depicted by the higher cytokine (IL-6 and chemokine (MCP-1) levels. In addition, lymph node immunophenotyping showed the maturation and activation of dendritic cells and natural killer cells, respectively. To understand the adaptive immune response, RNA-Seq analyses of the lung and spleen samples of the vaccinated mice were performed in parallel and revealed a stronger immune gene-expression profile in the lung than that in the spleen. Compared to mRNA-S alone, mRNA-S+N vaccination elicited higher levels of expression for genes involved in multiple immune pathways, including T cells, cytokine signaling, antigen presentation, B cells, and innate immunity. Together, our studies provide immunological insights into the mechanisms of broad protection conferred by dual mRNA vaccination against SARS-CoV-2 variants.

Criticality-based planning of prototype sequences

AbstractThe understanding of prototyping has changed in recent years to an approach that accompanies the product development process. This paper examines whether classic approaches from product development are also suitable for planning prototyping sequences. The stepwise process-oriented and the problem-oriented approach are discussed. A criticality assessment is proposed as a metric for the prioritization of the functional areas and a procedure is derived from this. The procedure is illustrated using an example. The result is discussed and future steps are suggested.

Normative volumes and relaxation times at 3T during brain development

While research has unveiled and quantified brain markers of abnormal neurodevelopment, clinicians still work with qualitative metrics for MRI brain investigation. The purpose of the current article is to bridge the knowledge gap between case-control cohort studies and individual patient care. Here, we provide a unique dataset of seventy-three 3-to-17 years-old healthy subjects acquired with a 6-minute MRI protocol encompassing T1 and T2 relaxation quantitative sequence that can be readily implemented in the clinical setting; MP2RAGE for T1 mapping and the prototype sequence GRAPPATINI for T2 mapping. White matter and grey matter volumes were automatically quantified. We further provide normative developmental curves based on these two imaging sequences; T1, T2 and volume normative ranges with respect to age were computed, for each ROI of a pediatric brain atlas. This open-source dataset provides normative values allowing to position individual patients acquired with the same protocol on the brain maturation curve and as such provides potentially useful quantitative biomarkers facilitating precise and personalized care.

Quantitative T2 Mapping of Acute Pancreatitis.

Quantification of the T2 signal by means of T2 mapping in acute pancreatitis (AP) has the potential to quantify the parenchymal edema. Quantitative T2 mapping may overcome the limitations of previously reported scoring systems for reliable assessment of AP. To evaluate MR-derived pancreatic T2 mapping values in AP and correlate them with markers of disease severity. Prospective single-center study. 76 adults with AP (20-91 years, females/males: 39/37). Fat suppressed multiecho spin-echo prototype sequence to quantify T2 signal at 3T MRI. The severity of AP was assessed clinically, biologically, and by contrast-enhanced CT (CECT) performed 48-72 hours after symptom onset. MRI was then performed ≤24 hours after CT. Two readers blinded to any clinical information independently evaluated the T2 values by placing three regions of interest inside the pancreatic head, body, and tail on the T2 mapping MR sequence. Results were compared with corresponding CECT images as the standard and clinical severity parameters, using the length of hospital stay as our primary endpoint. Continuous variables were compared using the Spearman's rank correlation coefficient, analysis of variance (ANOVA) or Student's t-test. T2 values significantly correlated with the length of hospital stay (rs (74) = 0.29), CT severity index (CTSI) (rs (73) = 0.61; CTSI 0-3: 72 ± 14 msec, CTSI 4-10: 88 ± 15), intensive care unit (ICU) admission (t(2.77) = -3.41) and presence of organ failure (t(6.72) = -3.42), whereas the CTSI and Ranson score were not significantly related with ICU admission (CTSI: P = 0.24; Ranson score: P = 0.24) and organ failure (CTSI: P = 0.11; Ranson score P = 0.11). T2 mapping correlates with AP severity parameters and is useful for assessing the severity of AP with higher sensitivity than the usual clinical and radiological scoring systems. 1 TECHNICAL EFFICACY: Stage 2.

Improved gray-white matter contrast using magnetization prepared fast imaging with steady-state free precession (MP-FISP) brain imaging at 0.55 T.

To improve the gray/white matter contrast of magnetization prepared rapid gradient echo (MP-RAGE) MRI at 0.55 T by optimizing the acquisition and sequence kernel parameters. A segmented magnetization prepared rapid gradient echo prototype sequence was implemented with (MP-RAGE*) and without (MP-FISP*) radiofrequency spoiling. Optimized parameters were derived with the assistance of an extended phase graph signal simulation as a function of the relaxation times, the flip angle, the delay times, and the effective inversion time using segmentation. The resulting protocols were compared to the MP-RAGE product sequence offered by the vendor in terms of signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). A tissue segmentation reproducibility study was performed on three volunteers for the product MP-RAGE and the MP-FISP*. The MP-RAGE simulation reproduced the parameters already used in the product MP-RAGE on the scanner. An average CNR improvement of 15% for the custom MP-RAGE* over the product MP-RAGE and additional 22% for the MP-FISP* over the MP-RAGE* were observed, which is in accordance with the simulation results. The total improvement, averaged over all volunteers and regions, was 41%. The reproducibility study did not yield a significant difference between MP-RAGE and MP-FISP*. We presented some easy-to-implement adjustments to the MP-RAGE sequence at 0.55 T, which can lead to an overall average improvement of 41% in CNR.

Intracavitary blood flow dynamics in the systemic right ventricle: a 4D-Flow MRI study

Abstract Funding Acknowledgements Type of funding sources: None. Background Failure of the systemic right ventricle (SRV) is based on morphological differences between right and left ventricles (RVs and LVs). RV adaptation to systemic afterload includes increased circumferential (GCS) over longitudinal global myocardial strain (GLS) with an unknown impact on intracavitary blood flow distribution. This study aimed to explore the SRV pattern of hemodynamic forces (HFs). Methods 4D-Flow cardiovascular magnetic resonance data were acquired using a prototype sequence on a 1.5-T MAGNETOM Aera. The ratio between transverse (inferior-anterior, HFIA and septal-lateral, HFSL) and longitudinal (basal-apical, HFBA) HFs (RRMS) was calculated as in Figure 1, for systole and diastole. Results We enrolled 12 adults with SRV (6 D-transposition of great arteries after atrial switch operation and 6 L-transpositions) and 12 age-matched healthy subjects (41±12 vs 42±13,p = 0.89). SRVs reported comparable end-diastolic volumes (83±18 ml/m2), ejection fraction (60±8%) and GLS (−20.2±3.8%) to control RVs (75±13 ml/m2,p = 0.18; 64±5%,p = 0.25; −23±5.6%,p = 0.21). Differently, SRV mass (55±24 g/m2) and GCS (−18.9±7.8%) were greater than RVs (20±3 g/m2,p<0.001 and −12.4±4,p = 0.016) and comparable to control LVs (57±11 g/m2,p = 0.7 and −20.2±3.8%,p = 0.3). The 4D-Flow analysis showed that SRV systolic RRMS (0.98±0.31) was similar to LVs (0.94±0.27,p = 0.78) but lower than RVs (1.32±0.45,p = 0.04). This reflected a significantly increased HFBA with respect to RVs (0.338±0.150 vs. 0.162±0.097, p = 0.0025) and similar to LVs (0.462 ± 0.186, p = 0.087). Concomitantly, a moderate correlation was demonstrated between SRV systolic HFBA magnitude and GCS (r2=0.47,p = 0.013). During diastole, SRVs showed lower HFBA (0.173±0.086) than LVs (0.304±0.104,p = 0.0028), revealing a diastolic RRMS (0.74 ± 0.14) comparable to RVs (0.73 ± 0.17,p = 0.95) and significantly different from LVs (0.50 ± 0.19,p = 0.003). Conclusions In SRVs, RRMS is similar to LVs during systole, possibly as a result of increased GCS. Inversely, the SRV filling appears to be closely related to ventricular morphology as suggested by RRMS comparable to RVs during diastole.

Four-Dimensional Flow MRI for the Evaluation of Aortic Endovascular Graft: A Pilot Study.

We aimed to explore the feasibility of 4D flow magnetic resonance imaging (MRI) for patients undergoing thoracic aorta endovascular repair (TEVAR). We retrospectively evaluated ten patients (two female), with a mean (±standard deviation) age of 61 ± 20 years, undergoing MRI for a follow-up after TEVAR. All 4D flow examinations were performed using a 1.5-T system (MAGNETOM Aera, Siemens Healthcare, Erlangen, Germany). In addition to the standard examination protocol, a 4D flow-sensitive 3D spatial-encoding, time-resolved, phase-contrast prototype sequence was acquired. Among our cases, flow evaluation was feasible in all patients, although we observed some artifacts in 3 out of 10 patients. Three individuals displayed a reduced signal within the vessel lumen where the endograft was placed, while others presented with turbulent or increased flow. An aortic endograft did not necessarily hinder the visualization of blood flow through 4D flow sequences, although the graft could generate flow artifacts in some cases. A 4D Flow MRI may represent the ideal tool to follow up on both healthy subjects deemed to be at an increased risk based on their anatomical characteristics or patients submitted to TEVAR for whom a surveillance protocol with computed tomography angiography would be cumbersome and unjustified.

Genomic and Evolutionary Features of Nine AHPND Positive Vibrio parahaemolyticus Strains Isolated from South American Shrimp Farms.

Vibrio parahaemolyticus is a bacterial pathogen that becomes lethal to Penaeus shrimps when acquiring the pVA1-type plasmid carrying the PirABvp genes, causing acute hepatopancreatic necrosis disease (AHPND). This disease causes significant losses across the world, with outbreaks reported in Southeast Asia, Mexico, and South America. Virulence level and mortality differences have been reported in isolates from different locations, and whether this phenomenon is caused by plasmid-related elements or genomic-related elements from the bacteria remains unclear. Here, nine genomes of South American AHPND-causing V. parahaemolyticus (VPAHPND) isolates were assembled and analyzed using a comparative genomics approach at (i) whole-genome, (ii) secretion system, and (iii) plasmid level, and then included for a phylogenomic analysis with another 86 strains. Two main results were obtained from our analyses. First, all isolates contained pVA1-type plasmids harboring the toxin coding genes, and with high similarity with the prototypical sequence of Mexican-like origin, while phylogenomic analysis showed some level of heterogeneity with discrete clusters and wide diversity compared to other available genomes. Second, although a high genomic similarity was observed, variation in virulence genes and clusters was observed, which might be relevant in the expression of the disease. Overall, our results suggest that South American pathogenic isolates are derived from various genetic lineages which appear to have acquired the plasmid through horizontal gene transfer. Furthermore, pathogenicity seems to be a multifactorial trait where the degree of virulence could be altered by the presence or variations of several virulence factors. IMPORTANCE AHPND have caused losses of over $2.6 billion to the aquaculture industry around the world due to its high mortality rate in shrimp farming. The most common etiological agent is V. parahaemolyticus strains possessing the pVA1-type plasmid carrying the PirABvp toxin. Nevertheless, complete understanding of the role of genetic elements and their impact in the virulence of this pathogen remains unclear. In this work, we analyzed nine South American AHPND-causing V. parahaemolyticus isolates at a genomic level, and assessed their evolutionary relationship with other 86 strains. We found that all our isolates were highly similar and possessed the Mexican-type plasmid, but their genomic content did not cluster with other Mexican strains, but instead were spread across all isolates. These results suggest that South American VPAHPND have different genetic backgrounds, and probably proceed from diverse geographical locations, and acquire the pVA1-type plasmid via horizontal gene transfer at different times.

Front Cover: Protein Backbone Alteration in Non‐Hairpin β‐Turns: Impacts on Tertiary Folded Structure and Folded Stability (ChemBioChem 11/2023)

Backbone modification in β-turns is vital in the development of protein mimetics. Prior work has focused on the subset of turns that join strands of a β-sheet. The cover image, rendered in a style inspired by Pittsburgh native Andy Warhol, depicts four modification schemes among a series examined in a helix-loop-helix domain. Optimal artificial residue placement yields variants of the prototype sequence with native-like tertiary structure and improved thermal stability. More information can be found in the Research Article by T. W. Harmon and W. S. Horne.

A Novel Ultrafast Turn-Off Failure Detection Method of Integrated Gate Commutated Thyristor for VSC Application

Integrated gate commutated thyristor (IGCT) has prospects in voltage source converter application. However, it has no desaturation characteristic in conducting state like insulated gate bipolar transistor, for which fast turn- <sc xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">off</small> failure detection for blocking converter in deadtime is of great significance. In this letter, an ultrafast IGCT turn- <sc xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">off</small> failure detection method is proposed. First, turn- <sc xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">off</small> process and failure mechanism of IGCT is analyzed. It is clarified that turn-off capacitors of gate driver will continue to discharge in turn- <sc xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">off</small> failure, thus generating a voltage drop on turn- <sc xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">off mosfet</small> , which can be the criterion of failure. Then prototype, threshold and timing sequence are designed. Analog circuit including amplifier, hysteretic comparator and reference circuit is used for fast and accurate measurement of voltage on <sc xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">mosfet</small> . The failure gate current and fall time of turn- <sc xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">off</small> trail current is measured in pulse test. Finally, experiments are carried out to verify the feasibility of the proposed scheme. The results show that the proposed scheme can achieve reliable turn- <sc xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">off</small> failure detection within 19 microseconds. Neither false detection nor missed detection occurred. Proposed method has great accuracy and rapidity, and is convenient in implementation. It will greatly decrease the extreme failure rate of IGCT-based converters.

A data driven approach to mineral chemistry unveils magmatic processes associated with long-lasting, low-intensity volcanic activity

The most frequent volcanic eruptions are of low-intensity and small magnitude. They produce abundant ash-sized (< 2 mm) clasts, which are too small to establish quantitative links between magmatic processes and eruptive dynamics using classic approaches. This inhibits our ability to study the past behaviour of frequently erupting volcanoes, essential to predict their future activity and mitigate their impact. The Palizzi unit (10–13th century, Vulcano, Italy) includes a prototype sequence of ash deposits resulting from prolonged Vulcanian eruptions punctuated by those of two larger sub-Plinian events. We apply Hierarchical Clustering to chemical analyses of clinopyroxene collected along the stratigraphy to decipher magma dynamics during this eruptive period. We identify periods of magma input and we link deep magmatic processes to eruptive dynamics, also showing that our approach can be used to connect magma and eruptive dynamics in any volcanic sequence. This is essential to track the processes occurring during frequent eruptions and to identify the build-up to larger explosive events.

Evolution and Introductions of Influenza A Virus H1N1 in a Farrow-to-Finish Farm in Guatemala.

Commercial swine farms provide unique systems for interspecies transmission of influenza A viruses (FLUAVs) at the animal-human interface. Bidirectional transmission of FLUAVs between pigs and humans plays a significant role in the generation of novel strains that become established in the new host population. Active FLUAV surveillance was conducted for 2 years on a commercial pig farm in Southern Guatemala with no history of FLUAV vaccination. Nasal swabs (n = 2,094) from fattening pigs (6 to 24 weeks old) with respiratory signs were collected weekly from May 2016 to February 2018. Swabs were screened for FLUAV by real-time reverse transcriptase PCR (RRT-PCR), and full virus genomes of FLUAV-positive swabs were sequenced by next-generation sequencing (NGS). FLUAV prevalence was 12.0% (95% confidence interval [CI], 10.6% to 13.4%) with two distinct periods of high infection. All samples were identified as FLUAVs of the H1N1 subtype within the H1 swine clade 1A.3.3.2 and whose ancestors are the human origin 2009 H1N1 influenza pandemic virus (H1N1 pdm09). Compared to the prototypic reference segment sequence, 10 amino acid signatures were observed on relevant antigenic sites on the hemagglutinin. The Guatemalan swine-origin FLUAVs show independent evolution from other H1N1 pdm09 FLUAVs circulating in Central America. The zoonotic risk of these viruses remains unknown but strongly calls for continued FLUAV surveillance in pigs in Guatemala. IMPORTANCE Despite increased surveillance efforts, the epidemiology of FLUAVs circulating in swine in Latin America remains understudied. For instance, the 2009 H1N1 influenza pandemic strain (H1N1 pdm09) emerged in Mexico, but its circulation remained undetected in pigs. In Central America, Guatemala is the country with the largest swine industry. We found a unique group of H1N1 pdm09 sequences that suggests independent evolution from similar viruses circulating in Central America. These viruses may represent the establishment of a novel genetic lineage with the potential to reassort with other cocirculating viruses and whose zoonotic risk remains to be determined.

Time to enhancement of breast lesions and normal breast parenchyma in light of menopausal status and menstrual cycle for ultrafast dynamic contrast-enhanced MRI using compressed sensing

PurposeTo assess the dependency of the Time to enhancement (TTE) of breast lesions and normal breast parenchyma from menopausal status and menstrual cycle using ultrafast compressed sensing (CS) -accelerated dynamic contrast-enhanced (DCE) MRI. MethodsThis institutional review board approved retrospective study included 89 breast cancers, 22 benign lesions and 131 normal breast parenchymal foci. A prototypical ultrafast DCE sequence obtained 30 phases with 2.9 s temporal resolution. Mean and median TTE of all breast cancers, benign lesions and normal breast parenchymal foci were assessed. we also assessed whether there were any differences in TTE regarding the menopausal status and menstrual cycle. ResultsThe TTE of breast cancer was significantly shorter than that of benign lesions and normal breast parenchymal foci in both the premenopausal status (5.8 vs. 8.7 and 8.7 s, respectively) (p = 0.0028 and < 0.0001, respectively) and postmenopausal status (5.8 vs. 11.6 and 11.6 s, respectively) (p < 0.0001 in both). The TTE of parenchymal foci in the premenopausal status was significantly shorter than that in the postmenopausal status (p = 0.0025). Although the TTE interval between cancer and parenchymal foci in premenopausal status is shorter than that in postmenopausal status, the AUCs in the pre- and postmenopausal status for differentiating breast cancer and parenchymal foci were comparable with using different cutoff TTE values. There were no differences in TTE regarding the menstrual cycle. ConclusionsThe TTE derived from ultrafast CS-accelerated DCE MRI was useful to differentiate breast cancer from benign lesions and normal breast parenchymal foci in both pre- and postmenopausal status.

Updated vaccine protects against SARS-CoV-2 variants including Omicron (B.1.1.529) and prevents transmission in hamsters

Current COVID-19 vaccines are based on prototypic spike sequences from ancestral 2019 SARS-CoV-2 strains. However, the ongoing pandemic is fueled by variants of concern (VOC) escaping vaccine-mediated protection. Here we demonstrate how immunization in hamsters using prototypic spike expressed from yellow fever 17D (YF17D) as vector blocks ancestral virus (B lineage) and VOC Alpha (B.1.1.7) yet fails to fully protect from Beta (B.1.351). However, the same YF17D vectored vaccine candidate with an evolved antigen induced considerably improved neutralizing antibody responses against VOCs Beta, Gamma (P.1) and the recently predominant Omicron (B.1.1.529), while maintaining immunogenicity against ancestral virus and VOC Delta (B.1.617.2). Thus vaccinated animals resisted challenge by all VOCs, including vigorous high titre exposure to the most difficult to cover Beta, Delta and Omicron variants, eliminating detectable virus and markedly improving lung pathology. Finally, vaccinated hamsters did not transmit Delta variant to non-vaccinated cage mates. Overall, our data illustrate how current first-generation COVID-19 vaccines may need to be updated to maintain efficacy against emerging VOCs and their spread at community level.

Evasion of neutralizing antibody responses by the SARS-CoV-2 BA.2.75 variant

The newly emerged BA.2.75 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant contains 9 additional mutations in its spike (S) protein compared to the ancestral BA.2 variant. Here we examine the neutralizing antibody escape of BA.2.75 in mRNA-vaccinated and BA.1-infected individuals, as well as the molecular basis underlying functional changes in S. Notably, BA.2.75 exhibits enhanced neutralization resistance over BA.2, but less than the BA.4/5 variant. The G446S and N460K mutations of BA.2.75 are primarily responsible for its enhanced resistance to neutralizing antibodies. The R493Q mutation, a reversion to the prototype sequence, also reduces BA.2.75 neutralization resistance. The impact of these mutations is consistent with their locations in common neutralizing antibody epitopes. Further, BA.2.75 shows enhanced cell-cell fusion over BA.2, driven largely by the N460K mutation, which enhances S processing. Structural modeling reveals enhanced receptor contacts introduced by N460K, suggesting a mechanism of potentiated receptor utilization and syncytia formation.

A diagnostic index based on pseudo-continuous arterial spin labeling and T1-mapping improves efficacy in discriminating Alzheimer's disease from normal cognition.

BackgroundPseudo-continuous arterial spin labeling (pCASL) is widely used to quantify cerebral blood flow (CBF) abnormalities in patients with Alzheimer’s disease (AD). T1-mapping techniques assess microstructural characteristics in various pathologic changes, but their application in AD remains in the exploratory stage. We hypothesized that combining quantitative CBF and T1 values would generate diagnostic results with higher accuracy than using either method alone in discriminating AD patients from cognitively normal control (NC) subjects.Materials and methodsA total of 45 patients diagnosed with AD and 33 NC subjects were enrolled, and cognitive assessment was performed for each participant according to the Chinese version of the Mini-Mental State Examination (MMSE). T1-weighted magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) and pCASL sequence were scanned on a 3T MR scanner. A brain morphometric analysis was integrated into prototype sequence, providing tissue classification and morphometric segmentation results. Quantitative CBF and T1 values of each brain region were automatically generated inline after data acquisition. Independent samples t-test was used to compare regional CBF and T1 values controlled by false discovery rate correction (corrected p < 0.01). The model with combined CBF and T1 values was compared with the individual index by performing receiver operating characteristic curves analysis. The associations between the MMSE score and CBF and T1 values of the brain were investigated using partial correlations.ResultsCerebral blood flow of the right caudate nucleus (RCc) and left hippocampus (LHc) was significantly lower in the AD group compared with the NC group, while the T1 values of the right caudate nucleus (RCt) and left hippocampus (LHt) increased in the AD group. Prediction accuracies of 73.1, 77.2, 75.9, and 81.3% were achieved for each of the above parameters, respectively. In distinguishing patients from controls using the corresponding optimized cut-off values, most combinations of parameters were elevated (area under curve = 0.775–0.894). The highest area under curve value was 0.944, by combining RCc, LHc, RCt, and LHt.ConclusionIn this preliminary study, the combined model based on pCASL and T1-mapping improved the diagnostic performance of discriminating AD and NC groups. T1-mapping may become a competitive technique for quantitatively measuring pathologic changes in the brain.