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We have discovered that the peak phase time of predawn thermosphere‐ionosphere Na (TINa) layers (∼110–150 km altitude) undergoes clear annual variations with the earliest occurrence in summer and latest in winter over Boulder (40.13°N, 105.24°W), which are closely correlated to annual phase variations of sunrise and tidal winds. Such discoveries were enabled by the first characterization of 12 monthly composites of TINa layers from January through December using 7 years of lidar observations (2011–2017). Despite their tenuous densities, the predawn TINa layers have nearly 100% occurrence rate (160 out of 164 nights of observations). Monthly composites show downward‐phase‐progression TINa descending at similar phase speeds as Climatological Tidal Model of the Thermosphere tidal winds. These TINa layers occur in ion convergence but neutral divergence regions, modeled using tidal winds. These results support the formation mechanism (neutralization of converged TINa+ forming TINa) proposed previously and suggest that migrating tidal winds experience annual phase variations. Plain Language Summary With tons of cosmic dust falling on Earth every day, metallic atoms and ions (e.g., Fe, Na, K, and Ca+) are released via meteor ablation and sputtering into the upper atmosphere, forming permanent metal layers (∼75–105 km) that have been known for nearly a century. What was unknown until 2011 was the existence of thermosphere‐ionosphere metal (TIMt) layers that were discovered with high‐sensitivity lidar observations first from Antarctica and then were observed globally. These neutral TIMt layers locate above the permanent layers with an upper reach to ∼200 km and exhibit intermittent occurrence. In 2021 surprising regular occurrence of TIMt layers in Na species (TINa) was reported for the first time from lidar observations over Boulder, Colorado, where TINa layers occur before dawn and after dusk nearly every night. By analyzing 7 years of lidar data, we have further discovered that the Boulder predawn TINa layers occur in earlier hours in summer than in winter. Such annual phase variations are correlated with sunrise and solar‐heating‐driven tidal winds. These TIMt layers are of great scientific interest as they provide unique tracers for making direct measurements in the least understood but crucially important “thermospheric gap” region of 100–200 km. Key Points First characterization of 12 monthly composites of Na mixing ratios reveals annual phase variations of predawn thermosphere‐ionosphere Na (TINa) layers (110–150 km) Predawn TINa occur ∼2.5 hr earlier in summer than in winter, closely correlating to annual phase variations of sunrise and Climatological Tidal Model of the Thermosphere semidiurnal westward‐propagating tidal winds TINa layers descend at similar rates as and in tidal‐wind‐modeled ion convergence regions, supporting neutralization of TINa+ forming TINa

Background The crAss-like phages are ubiquitous and highly abundant members of the human gut virome that infect commensal bacteria of the order Bacteroidales. Although incapable of lysogeny, these viruses demonstrate long-term persistence in the human gut microbiome, dominating the virome in some individuals. Results Here we show that rapid phase variation of alternate capsular polysaccharides in Bacteroides intestinalis cultures plays an important role in a dynamic equilibrium between phage sensitivity and resistance, allowing phage and bacteria to multiply in parallel. The data also suggests the role of a concomitant phage persistence mechanism associated with delayed lysis of infected cells, similar to carrier state infection. From an ecological and evolutionary standpoint, this type of phage-host interaction is consistent with the Piggyback-the-Winner model, which suggests a preference towards lysogenic or other “benign” forms of phage infection when the host is stably present at high abundance. Conclusion Long-term persistence of bacteriophage and host could result from mutually beneficial mechanisms driving bacterial strain-level diversity and phage survival in complex environments.

•A deep learning-based phase reconstruction scheme is proposed for high-resolution multi-shot (MSH) DWI reconstruction.•Higher SNR (especially with high acceleration rates), fewer aliasing artifacts, lower ghost-to-signal-ratio (GSR), higher tracked fiber counts, and finer fiber delineation can be obtained with MSH-DWI reconstruction compared to conventional MUSE.•Single-shot (SSH) DWIs were used for training, making the proposed method readily applicable for routine clinical exams. A phase correction method for high-resolution multi-shot (MSH) diffusion weighted imaging (DWI) is proposed. The efficacy and generalization capability of the method were validated on both healthy volunteers and patients. Conventionally, inter-shot phase variations for MSH echo-planar imaging (EPI) DWI are corrected by model-based algorithms. However, many acquisition imperfections are hard to measure accurately for conventional model-based methods, making the phase estimation and artifacts suppression unreliable. We propose a deep learning multiplexed sensitivity-encoding (DL-MUSE) framework to improve the phase estimations based on convolutional neural network (CNN) reconstruction. Aliasing-free single-shot (SSH) DW images, which have been used routinely in clinical settings, were used for training before the aliasing correction of MSH-DWI images. A dual-channel U-net comprising multiple convolutional layers was used for the phase estimation of MSH-EPI. The network was trained on a dataset containing 30 healthy volunteers and tested on another dataset of 52 healthy subjects and 15 patients with lesions or tumors with different shot numbers (4, 6 and 8). To further validate the generalization capability of our network, we acquired a dataset with different numbers of shots, TEs, partial Fourier factors, resolutions, ETLs, FOVs, coil numbers, and image orientations from two sites. We also compared the reconstruction performance of our proposed method with that of the conventional MUSE and SSH-EPI qualitatively and quantitatively. Our results show that DL-MUSE is capable of correcting inter-shot phase errors with high and robust performance. Compared to conventional model-based MUSE, our method, by applying deep learning-based phase corrections, showed reduced distortion, noise level, and signal loss in high b-value DWIs. The improvements of image quality become more evident as the shot number increases from 4 to 8, especially in those central regions of the images, where g-factor artifacts are severe. Furthermore, the proposed method could provide the information about the orientation of the white matter with better consistency and achieve finer fibers delineation compared to the SSH-EPI method. Besides, the experiments on volunteers and patients from two different sites demonstrated the generalizability of our proposed method preliminarily. A deep learning-based reconstruction algorithm for MSH-EPI images, which helps improve image quality greatly, was proposed. Results from healthy volunteers and tumor patients demonstrated the feasibility and generalization performances of our method for high-resolution MSH-EPI DWI, which can be used for routine clinical applications as well as neuroimaging research.

Having powerful antibacterial and antioxidant effects, zinc oxide and manganese oxide nanomaterials are of great interest. Here we have synthesized manganese oxide decorated zinc oxide (MZO) nanocomposites by co-precipitation method, calcined at different temperatures (300–750 °C) and studied various properties. Here the crystalline structure of the nanocomposite and phase change of the manganese oxide are observed with calcination temperature. The average crystalline size increases and the dislocation density and microstrain decrease with the increase in calcined temperature for the same structural features. The formation of composites was confirmed by XRD pattern and SEM images. EDAX spectra proved the high purity of the composites. Here, different biological properties change with the calcination temperature for different shapes, sizes and structures of the nanocomposite. Nanomaterial calcined at 750 °C provides the best anti-microbial activity against Escherichia coli, Salmonella typhimurium, Shigella flexneri (gram-negative), Bacillus subtilis and Bacillus megaterium (gram-positive) bacterial strain at 300 µg/mL concentration. The nanomaterial with calcination temperatures of 300 °C and 450 °C provided better antioxidant properties.

The opportunistic nosocomial pathogen Clostridioides difficile exhibits phenotypic heterogeneity through phase variation, a stochastic, reversible process that modulates expression. In C . difficile , multiple sequences in the genome undergo inversion through site-specific recombination. Two such loci lie upstream of pdcB and pdcC , which encode phosphodiesterases (PDEs) that degrade the signaling molecule c-di-GMP. Numerous phenotypes are influenced by c-di-GMP in C . difficile including cell and colony morphology, motility, colonization, and virulence. In this study, we aimed to assess whether PdcB phase varies, identify the mechanism of regulation, and determine the effects on intracellular c-di-GMP levels and regulated phenotypes. We found that expression of pdcB is heterogeneous and the orientation of the invertible sequence, or ‘ pdcB switch’, determines expression. The pdcB switch contains a promoter that when properly oriented promotes pdcB expression. Expression is augmented by an additional promoter upstream of the pdcB switch. Mutation of nucleotides at the site of recombination resulted in phase-locked strains with significant differences in pdcB expression. Characterization of these mutants showed that the pdcB locked-ON mutant has reduced intracellular c-di-GMP compared to the locked-OFF mutant, consistent with increased and decreased PdcB activity, respectively. These alterations in c-di-GMP had concomitant effects on multiple known c-di-GMP regulated processes, indicating that phase variation of PdcB allows C . difficile to coordinately diversify multiple phenotypes in the population to enhance survival.

When functional data come as multiple curves per subject, characterizing the source of variations is not a trivial problem. The complexity of the problem goes deeper when there is phase variation in addition to amplitude variation. We consider clustering problem with multivariate functional data that have phase variations among the functional variables. We propose a conditional subject-specific warping framework in order to extract relevant features for clustering. Using multivariate growth curves of various parts of the body as a motivating example, we demonstrate the effectiveness of the proposed approach. The found clusters have individuals who show different relative growth patterns among different parts of the body.

Campylobacter jejuni is the leading bacterial cause of foodborne gastroenteritis in developed countries and occasionally progresses to the autoimmune disease Guillain-Barré syndrome. A relatively large number of hypermutable simple sequence repeat (SSR) tracts in the C. jejuni genome markedly decreases its phenotypic stability through reversible changes in the ON or OFF expression states of the genes in which they reside, a phenomenon called phase variation. Hypermutable simple sequence repeats (SSRs) are major drivers of phase variation in Campylobacter jejuni . The presence of multiple SSR-mediated phase-variable genes encoding enzymes that modify surface structures, including capsular polysaccharide (CPS) and lipooligosaccharide (LOS), generates extreme cell surface diversity within bacterial populations, thereby promoting adaptation to selective pressures in host environments. Therefore, genetically controlling SSR-mediated phase variation can be important for achieving stable and reproducible research on C. jejuni . Here, we show that natural “cotransformation” is an effective method for C. jejuni genome editing. Cotransformation is a trait of naturally competent bacteria that causes uptake/integration of multiple different DNA molecules, which has been recently adapted to multiplex genome editing by natural transformation (MuGENT), a method for introducing multiple mutations into the genomes of these bacteria. We found that cotransformation efficiently occurred in C. jejuni . To examine the feasibility of MuGENT in C. jejuni , we “locked” different polyG SSR tracts in strain NCTC11168 (which are located in the biosynthetic CPS/LOS gene clusters) into either the ON or OFF configurations. This approach, termed “MuGENT-SSR,” enabled the generation of all eight edits within 2 weeks and the identification of a phase-locked strain with a highly stable type of Penner serotyping, a CPS-based serotyping scheme. Furthermore, extensive genome editing of this strain by MuGENT-SSR identified a phase-variable gene that determines the Penner serotype of NCTC11168. Thus, MuGENT-SSR provides a platform for genetic and phenotypic engineering of genetically unstable C. jejuni , making it a reliable approach for elucidating the mechanisms underlying phase-variable expression of specific phenotypes. IMPORTANCE Campylobacter jejuni is the leading bacterial cause of foodborne gastroenteritis in developed countries and occasionally progresses to the autoimmune disease Guillain-Barré syndrome. A relatively large number of hypermutable simple sequence repeat (SSR) tracts in the C. jejuni genome markedly decreases its phenotypic stability through reversible changes in the ON or OFF expression states of the genes in which they reside, a phenomenon called phase variation. Thus, controlling SSR-mediated phase variation can be important for achieving stable and reproducible research on C. jejuni . In this study, we developed a feasible and effective approach for genetically manipulate multiple SSR tracts in the C. jejuni genome using natural cotransformation, a trait of naturally transformable bacterial species that causes the uptake and integration of multiple different DNA molecules. This approach will greatly help to improve the genetic and phenotypic stability of C. jejuni to enable diverse applications in research and development.

Mycobacterium tuberculosis (Mtb) is responsible for more deaths worldwide than any other single infectious agent. Understanding how this pathogen adapts to the varied environmental pressures imposed by host immunity and antibiotics has important implications for the design of more effective therapies. In this work, we show that the genome of Mtb contains multiple contingency loci that control the activity of the ESX-1 secretion system, which is critical for interactions with the host. These loci consist of homopolymeric DNA tracts in gene regulatory regions that are subject to high-frequency reversible variation and act to tune the activity of ESX-1. We find that variation at these sites increases the fitness of Mtb in the presence of antibiotic and/or during infection. These findings indicate that Mtb has the ability to diversify its genome in specific sites to create subpopulations of cells that are preadapted to new conditions.

Vibrio vulnificus , a significant marine pathogen, undergoes opaque (Op)-translucent (Tr) colony switching based on whether capsular polysaccharide (CPS) is produced. CPS phase variation is sometime accompanied by genetic variation or down-regulation of particular genes, such as wzb . In addition, CPS prevents biofilm formation and is important to the virulence of V. vulnificus . However, the extent to which there is a difference in gene expression between Tr and Op colonies and the impact of CPS phase variation on other behaviors of V. vulnificus remain unknown. In this work, the data have shown that CPS phase variation of V. vulnificus is affected by incubation time. Tr and Op strains exhibited similar growth rates. However, Tr strains had enhanced biofilm formation capacities but reduced swimming motility compared to Op strains. The RNA-seq assay revealed 488 differentially expressed genes, with 214 downregulated and 274 upregulated genes, between Tr and Op colonies. Genes associated with Tad pili and CPS were downregulated, whereas those involved in flagellum were upregulated, in Tr colonies compared with Op colonies. In addition, 9 putative c-di-GMP metabolism-associated genes and 28 genes encoding putative regulators were significantly differentially expressed, suggesting that CPS phase variation is probably strictly regulated in V. vulnificus . Moreover, 8 genes encoding putative porins were also differentially expressed between the two phenotypic colonies, indicating that bacterial outer membrane was remodeled during CPS phase variation. In brief, this work highlighted the gene expression profiles associated with CPS phase variation, but more studies should be performed to disclose the intrinsic mechanisms in the future.

Streptococcus pneumoniae is a major human pathogen, and its virulence factors and especially the capsular polysaccharide have been extensively studied. In addition to virulence components that are present on its cell surface that directly interact with the host, S. pneumoniae undergoes a spontaneous and reversible phase variation that allows survival in different host environments. Streptococcus pneumoniae is an opportunistic pathogen that can alter its cell surface phenotype in response to the host environment. We demonstrated that the transcriptional regulator FabT is an indirect regulator of capsular polysaccharide, an important virulence factor of Streptococcus pneumoniae . Transcriptome analysis between the wild-type D39s and D39Δ fabT mutant strains unexpectedly identified a differentially expressed gene encoding a site-specific recombinase, PsrA. PsrA catalyzes the inversion of 3 homologous hsdS genes in a type I restriction-modification (RM) system SpnD39III locus and is responsible for the reversible switch of phase variation. Our study demonstrated that upregulation of PsrA in a D39Δ fabT mutant correlated with an increased ratio of transparent (T) phase variants. Inactivation of the invertase PsrA led to uniform opaque (O) variants. Direct quantification of allelic variants of hsdS derivatives and inversions of inverted repeats indicated that the recombinase PsrA fully catalyzes the inversion mediated by IR1 and IR3, and FabT mediated the recombination of the hsdS alleles in PsrA-dependent and PsrA-independent manners. In addition, compared to D39s, the Δ fabT mutant exhibited reduced nasopharyngeal colonization and was more resistant to phagocytosis and less adhesive to epithelial cells. These results indicated that phase variation in the Δ fabT mutant also affects other cell surface components involved in host interactions. IMPORTANCE Streptococcus pneumoniae is a major human pathogen, and its virulence factors and especially the capsular polysaccharide have been extensively studied. In addition to virulence components that are present on its cell surface that directly interact with the host, S. pneumoniae undergoes a spontaneous and reversible phase variation that allows survival in different host environments. This phase variation is manipulated by the recombination of allelic hsdS genes that encode the sequence recognition proteins of the type I RM system SpnD39III locus. The recombination of hsdS alleles is catalyzed by the DNA invertase PsrA. Interestingly, we found the opaque colony morphology can be reversed by inactivation of the transcriptional regulator FabT, which regulates fatty acid biosynthesis. Inactivation of FabT leads to a significant decrease in capsule production and systematic virulence, but these phase variations do not correlate with the capsule production. This phase variation is mediated via the upregulated invertase PsrA in the Δ fabT mutant. These results identify an unexpected link between the specific phase variations and FabT that strongly suggests an underlying mechanism regulating the DNA invertase PsrA.