Systematic Assessment of the Contribution of Superantigens to Nasopharyngeal Colonization in a Mouse Model of Streptococcal Infection

Streptococcus pyogenes is adapted for persistence in humans. It typically colonizes the tonsils and skin, and humans are the only known reservoir. S. pyogenes can cause a wide range of mild to serious infections. Most streptococci-related deaths are due to complications of rheumatic fever and invasive infections. S. pyogenes produces virulence factors that contribute to the pathogen’s ability to colonize and cause disease, including streptococcal superantigens (SAgs), also known as streptococcal pyrogenic exotoxins (Spes). SAgs function by cross-linking T cells and antigen presenting cells (APC) which may cause a massive inflammatory response, and as such have been found to contribute to streptococcal toxic shock syndrome (STSS). The role of SAgs in adaptation of S. pyogenes to its target niche has not been investigated. S. pyogenes experimentally colonizes mouse complete nasal turbinates (cNT). Murine models of streptococcal infection are imperfect systems due to inherent host-specific tropism. In this thesis, the colonization potential of S. pyogenes MGAS8232, associated with rheumatic heart disease, and S. pyogenes MGAS5005, associated with invasive infections, were assessed to explore the contribution of SAgs to nasal colonization in a mouse model. Colonization was tested in multiple mouse strains expressing human or mouse major histocompatibility complex (MHC) class II. C57BL/6 (B6) mice expressing human leukocyte antigen (HLA) transgenes showed enhanced colonization, up to ~100,000-fold at 48 hours post-inoculation. Individual and combined SAg deletions were assessed for nasal colonization. S. pyogenes MGAS8232 deletion colonization in mice expressing HLA-DR4 and HLA-DQ8 (DR4/DQ8) determined that SpeA was the major contributing SAg to the establishment of colonization, with minor contributions from SpeL and streptococcal mitogenic exotoxin Z (SmeZ). Colonization of S. pyogenes MGAS5005 was assessed in FVB mice, which express murine MHC class II q (H-2q), and SpeJ and SmeZ were the main contributing SAgs to the establishment of nasal colonization. SAgs contribute to 48-hour streptococcal recovery, but do not change the kinetics of bacterial clearance from cNT. These findings support the hypothesis that SAgs play an important role in niche adaptation and the establishment of colonization in mild or asymptomatic streptococcal infections in a murine model of nasal infection

Early JWST imaging reveals strong optical and NIR color gradients in galaxies at z∼2z\sim2 driven mostly by dust

Recent studies have shown that galaxies at cosmic noon are redder in the center and bluer in the outskirts, mirroring results in the local universe. These color gradients could be caused by either gradients in the stellar age or dust opacity; however, distinguishing between these two causes is impossible with rest-frame optical photometry alone. Here we investigate the underlying causes of the gradients from spatially-resolved rest-frame $U-V$ vs. $V-J$ color-color diagrams, measured from early observations with the James Webb Space Telescope. We use $1\, \mu m - 4\, \mu m$ NIRCam photometry from the CEERS survey of a sample of 54 galaxies with $M_* / M_\odot>10$ at redshifts $1.7<z<2.3$ selected from the 3D-HST catalog. We model the light profiles in the F115W, F200W and F356W NIRCam bands using \texttt{imcascade}, a Bayesian implementation of the Multi-Gaussian expansion (MGE) technique which flexibly represents galaxy profiles using a series of Gaussians. We construct resolved rest-frame $U-V$ and $V-J$ color profiles. The majority of star-forming galaxies have negative gradients (i.e. redder in the center, bluer in the outskirts) in both $U-V$ and $V-J$ colors consistent with radially decreasing dust attenuation. A smaller population (roughly 15\%) of star-forming galaxies have positive $U-V$ but negative $V-J$ gradients implying centrally concentrated star-formation. For quiescent galaxies we find a diversity of UVJ color profiles, with roughly one-third showing star-formation in their center. This study showcases the potential of JWST to study the resolved stellar populations of galaxies at cosmic noon.Comment: Updated to match published version, new Figure 5 and some text change

FXYD3: A Promising Biomarker for Urothelial Carcinoma

Objective Urothelial carcinoma (UC) of the kidney is a relatively rare but aggressive form of kidney cancer. Differential diagnosis of renal UC from renal cell carcinoma (RCC) can be difficult, but is critical for correct patient management. We aimed to use global gene expression profiling to identify genes specifically expressed in urothelial carcinoma (UC) of the kidney, with purpose of finding new biomarkers for differential diagnosis of UC of both upper and lower tract from normal tissues. Materials and Methods Microarray gene expression profiling was performed on a variety of human kidney tumor samples, including clear cell, papillary, chromophobe, oncocytoma, renal UC and normal kidney controls. Differentially expressed mRNAs in various kidney tumor subtypes were thus identified. Protein expression in human UC tumor samples from both upper and lower urinary tract was evaluated by immunohistochemistry. Results FXYD3 (MAT-8) mRNA was specifically expressed in UC of the kidney and not in normal kidney tissue or in any RCC tumor subtypes. FXYD3 mRNA levels displayed equal or better prediction rate for the detection of renal UC than the mRNA levels of selected known UC markers as p63, vimentin, S100P, KRT20 and KRT7. Finally, immunohistochemical staining of clinical UC samples showed that FXYD3 protein is overexpressed in majority of UC of the upper genitourinary tract (encompassing the kidney, ~90%) and in majority of high grade bladder UC (~84%, it's < 40% in low grade tumors, P < 0.001) compared to normal kidney and bladder tissues. Conclusion FXYD3 may be a promising novel biomarker for the differential diagnosis of renal UC and a promising prognosis marker of UC from bladder. Because it was identified genome-widely, FXYD3 may have important biological ramifications for the genetic study of UC

The Spatial Extent and Distribution of Star Formation in 3D-HST Mergers at z~1.5

We present an analysis of the spatial distribution of star formation in a sample of 60 visually identified galaxy merger candidates at z>1. Our sample, drawn from the 3D-HST survey, is flux-limited and was selected to have high star formation rates based on fits of their broad-band, low spatial resolution spectral energy distributions. It includes plausible pre-merger (close pairs) and post-merger (single objects with tidal features) systems, with total stellar masses and star formation rates derived from multi-wavelength photometry. Here we use near-infrared slitless spectra from 3D-HST which produce Halpha or [OIII] emission line maps as proxies for star-formation maps. This provides a first comprehensive high-resolution, empirical picture of where star formation occurred in galaxy mergers at the epoch of peak cosmic star formation rate. We find that detectable star formation can occur in one or both galaxy centres, or in tidal tails. The most common case (58%) is that star formation is largely concentrated in a single, compact region, coincident with the centre of (one of) the merger components. No correlations between star formation morphology and redshift, total stellar mass, or star formation rate are found. A restricted set of hydrodynamical merger simulations between similarly massive and gas-rich objects implies that star formation should be detectable in both merger components, when the gas fractions of the individual components are the same. This suggests that z~1.5 mergers typically occur between galaxies whose gas fractions, masses, and/or star formation rates are distinctly different from one another.Comment: Accepted for publication in MNRAS, 16 pages, 10 figure

Machine learning in Huntington’s disease:exploring the Enroll-HD dataset for prognosis and driving capability prediction

Background: In biomedicine, machine learning (ML) has proven beneficial for the prognosis and diagnosis of different diseases, including cancer and neurodegenerative disorders. For rare diseases, however, the requirement for large datasets often prevents this approach. Huntington’s disease (HD) is a rare neurodegenerative disorder caused by a CAG repeat expansion in the coding region of the huntingtin gene. The world’s largest observational study for HD, Enroll-HD, describes over 21,000 participants. As such, Enroll-HD is amenable to ML methods. In this study, we pre-processed and imputed Enroll-HD with ML methods to maximise the inclusion of participants and variables. With this dataset we developed models to improve the prediction of the age at onset (AAO) and compared it to the well-established Langbehn formula. In addition, we used recurrent neural networks (RNNs) to demonstrate the utility of ML methods for longitudinal datasets, assessing driving capabilities by learning from previous participant assessments. Results: Simple pre-processing imputed around 42% of missing values in Enroll-HD. Also, 167 variables were retained as a result of imputing with ML. We found that multiple ML models were able to outperform the Langbehn formula. The best ML model (light gradient boosting machine) improved the prognosis of AAO compared to the Langbehn formula by 9.2%, based on root mean squared error in the test set. In addition, our ML model provides more accurate prognosis for a wider CAG repeat range compared to the Langbehn formula. Driving capability was predicted with an accuracy of 85.2%. The resulting pre-processing workflow and code to train the ML models are available to be used for related HD predictions at: https://github.com/JasperO98/hdml/tree/main . Conclusions: Our pre-processing workflow made it possible to resolve the missing values and include most participants and variables in Enroll-HD. We show the added value of a ML approach, which improved AAO predictions and allowed for the development of an advisory model that can assist clinicians and participants in estimating future driving capability.</p

Structural Integrity of the -Carboxyglutamic Acid Domain of Human Blood Coagulation Factor IXa Is Required for Its Binding to Cofactor VIIIa

This report describes the analysis of a novel mutant human factor IX protein from a patient with hemophilia B (factor IX activity adenine transition) in exon 2 at nucleotide 6409 which results in a glycine --> arginine substitution at amino acid 12 in the gamma-carboxyglutamic acid rich (Gla) domain of the mature protein. Factor IX was isolated by immunoaffinity chromatography from plasma obtained from the proband. The purified protein is indistinguishable from normal factor IX by polyacrylamide gel electrophoresis. Characterization of the variant in purified component assays reveals that it is activated normally by its physiologic activator factor XIa, but its phospholipid-dependent activation by the factor VIIa-tissue factor complex is diminished. In the presence of phospholipid and 5 mM Ca2+, the activities of variant and normal plasma-derived factor IX are similar; however, in the presence of activated factor VIIIa (intrinsic tenase complex), the normal augmentation of the cleavage of the specific substrate of factor IX, factor X, is not observed. The determination of the association constants for normal and variant factor IXa with factor VIIIa shows that the affinity of the activated variant factor IX for the cofactor factor VIIIa is 172-fold lower than normal. Competition studies using active site-inactivated factor IXas in the intrinsic tenase complex confirm that the defect in the variant protein is in its binding to factor VIIIa. We conclude that the structural integrity of the Gla domain of human factor IX is critical for the normal binding of factor IXa to factor VIIIa in the intrinsic tenase complex. In addition, a glycine at amino acid 12 is necessary for normal activation of factor IX by the factor VIIa-tissue factor complex

Deterministic evolution and stringent selection during preneoplasia

The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention1. Here we model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over 2 years. TP53 loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single-cell sequencing of TP53-deficient gastric organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programmes repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a marked degree of phenotypic convergence in premalignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and show evolutionary constraints and barriers to malignant transformation, with implications for earlier detection and interception of aggressive, genome-instable tumours

Electron Energy Partition across Interplanetary Shocks. III. Analysis

An analysis of model fit results of 15,210 electron velocity distribution functions (VDFs), observed within 2 hr of 52 interplanetary (IP) shocks by the Wind spacecraft near 1 au, is presented as the third and final part on electron VDFs near IP shocks. The core electrons and protons dominate in the magnitude and change in the partial-to-total thermal pressure ratio, with the core electrons often gaining as much or more than the protons. Only a moderate positive correlation is observed between the electron temperature and the kinetic energy change across the shock, while weaker, if any, correlations were found with any other macroscopic shock parameter. No VDF parameter correlated with the shock normal angle. The electron VDF evolves from a narrowly peaked core with flaring suprathermal tails in the upstream to either a slightly hotter core with steeper tails or much hotter flattop core with even steeper tails downstream of the weaker and strongest shocks, respectively. Both quasi-static and fluctuating fields are examined as possible mechanisms modifying the VDF, but neither is sufficient alone. For instance, flattop VDFs can be generated by nonlinear ion acoustic wave stochastic acceleration (i.e., inelastic collisions), while other work suggested they result from the combination of quasi-static and fluctuating fields. This three-part study shows that not only are these systems not thermodynamic in nature; even kinetic models may require modification to include things like inelastic collision operators to properly model electron VDF evolution across shocks or in the solar wind.Peer reviewe

Electron Energy Partition across Interplanetary Shocks. II. Statistics

A statistical analysis of 15,210 electron velocity distribution function (VDF) fits, observed within +/- 2 hr of 52 interplanetary (IP) shocks by the Wind spacecraft near 1 au, is presented. This is the second in a three-part series on electron VDFs near IP shocks. The electron velocity moment statistics for the dense, low-energy core, tenuous, hot halo, and field-aligned beam/strahl are a statistically significant list of values illustrated with both histograms and tabular lists for reference and baselines in future work. Given the large statistics in this investigation, the beam/strahl fit results in the upstream are now the most comprehensive attempt to parameterize the beam/strahl electron velocity moments in the ambient solar wind. The median density, temperature, beta, and temperature anisotropy values for the core(halo)[beam/strahl] components, with subscripts ec(eh)[eb], of all fit results, respectively, are n(ec(h)[b]) similar to 11.3(0.36)[0.17] cm(-3), T-ec(h)[b],T-tot similar to 14.6(48.4)[40.2] eV, beta(ec(h)[b],tot) similar to 0.93(0.11)[0.05], and Alpha(ec(h)[b]) similar to 0.98(1.03)[0.93]. This work will also serve as a 1 au baseline and reference for missions like Parker Solar Probe and Solar Orbiter.Peer reviewe

JWST reveals a population of ultra-red, flattened disk galaxies at 2<z<6 previously missed by HST

With just a month of data, JWST is already transforming our view of the Universe, revealing and resolving starlight in unprecedented populations of galaxies. Although ``HST-dark" galaxies have previously been detected at long wavelengths, these observations generally suffer from a lack of spatial resolution which limits our ability to characterize their sizes and morphologies. Here we report on a first view of starlight from a subset of the HST-dark population that are bright with JWST/NIRCam (4.4$\mu$m<24.5mag) and very faint or even invisible with HST ($<$1.6$\mu$m). In this Letter we focus on a dramatic and unanticipated population of physically extended galaxies ($\gtrsim$0.17''). These 12 galaxies have photometric redshifts $2<z<6$, high stellar masses $M_{\star}\gtrsim 10^{10}~M_{\odot}$, and significant dust-attenuated star formation. Surprisingly, the galaxies have elongated projected axis ratios at 4.4$\mu$m, suggesting that the population is disk-dominated or prolate. Most of the galaxies appear red at all radii, suggesting significant dust attenuation throughout. We refer to these red, disky, HST-dark galaxies as Ultra-red Flattened Objects (UFOs). With $r_e$(F444W)$\sim1-2$~kpc, the galaxies are similar in size to compact massive galaxies at $z\sim2$ and the cores of massive galaxies and S0s at $z\sim0$. The stellar masses, sizes, and morphologies of the sample suggest that some could be progenitors of lenticular or fast-rotating galaxies in the local Universe. The existence of this population suggests that our previous censuses of the universe may have missed massive, dusty edge-on disks, in addition to dust-obscured starbursts