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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a variable clinical presentation that ranges from asymptomatic, to severe disease with cytokine storm. The mortality rates also differ across the globe, ranging from 0.5-13%. This variation is likely due to both pathogen and host factors. Host factors may include genetic differences in the immune response genes as well as variation in HLA and KIR allotypes. To better understand what impact these genetic variants in immune response genes may have in the differences observed in the immune response to SARS-CoV-2, a quantitative analysis of a dynamical systems model that considers both, the magnitude of viral growth, and the subsequent innate and adaptive response required to achieve control of infection is considered. Based on this broad quantitative framework it may be posited that the spectrum of symptomatic to severely symptomatic presentations of COVID19 represents the balance between innate and adaptive immune responses. In asymptomatic patients, prompt and adequate adaptive immune response quells infection, whereas in those with severe symptoms a slower inadequate adaptive response leads to a runaway cytokine cascade fueled by ongoing viral replication. Polymorphisms in the various components of the innate and adaptive immune response may cause altered immune response kinetics that would result in variable severity of illness. Understanding how this genetic variation may alter the response to SARS-CoV-2 infection is critical to develop successful treatment strategies., Comment: 36 pages, 1 table, 5 figures

The association between human cytomegalovirus (hCMV) reactivation and the development of graft-versus-host-disease (GVHD) has been observed in stem cell transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA matched unrelated donor (MUD), n=50; matched related donor (MRD), n=27) underwent whole exome sequencing to identify single nucleotide polymorphisms (SNPs) generating alloreactive peptide libraries for each DRP (9-mer peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence) Database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA was calculated by NetMHCpan 2.8 and hCMV- derived 9-mers algorithmically compared to the alloreactive peptide-HLA complex libraries. Short consecutive (6 or greater) amino acid (AA) sequence homology matching hCMV to recipient peptides was considered for HLA-bound-peptide (IC50<500 nM) cross reactivity. Of the 70,686 hCMV 9-mers contained within the hCMV CROSS database, 29,658.8 +/- 9038.5 were found to match MRD DRP alloreactive peptides and 52,910.2 +/- 16121.8 matched MUD DRP peptides (Student's T-test, p<0.001). In silico analysis revealed multiple high affinity, immunogenic CMV-Human peptide matches (IC50<500 nM) expressed in GVHD-affected tissue-specific manner (proteins expressed at 10 RPKM or greater). hCMV+GVHD was found in 18 patients, 13 developing hCMV viremia before GVHD onset with a subset analysis of 7 instances of hCMV viremia prior to acute GVHD onset (n=3), chronic GVHD (n=2) and acute + chronic GVHD (n=2) indicating cross reactive peptide expression within affected organs. We propose that based on our analysis and preliminary clinical correlations that hCMV immune cross-reactivity may cause antigenic mimicry of human alloreactive peptides triggering GVHD., Comment: Pre-submission manuscript, 4 tables, 5 figures, 2 supplements & 2 Appendices-available upon request from first author

Recent advances in next-generation sequencing have revolutionized genomic research. 16S rRNA amplicon sequencing using paired-end sequencing on the MiSeq platform from Illumina, Inc., is being used to characterize the composition and dynamics of extremely complex/diverse microbial communities. For this analysis on the Illumina platform, merging and quality filtering of paired-end reads are essential first steps in data analysis to ensure the accuracy and reliability of downstream analysis. We have developed the Merging and Filtering Tool (MeFiT) to combine these pre-processing steps into one simple, intuitive pipeline. MeFiT provides an open-source solution that permits users to merge and filter paired end illumina reads based on user-selected quality parameters. The tool has been implemented in python and the source-code is freely available at https://github.com/nisheth/MeFiT.

Donor T cell mediated graft vs. host effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the HLA in each donor-recipient pair (DRP) undergoing stem cell transplantation (SCT). Whole exome sequencing has demonstrated extensive nucleotide sequence variation in HLA-matched DRP. Non-synonymous single nucleotide polymorphisms (nsSNPs) in the GVH direction (polymorphisms present in recipient and absent in donor) were identified in 4 HLA-matched related and 5 unrelated DRP. The nucleotide sequence flanking each SNP was obtained utilizing the ANNOVAR software package. All possible nonameric-peptides encoded by the non-synonymous SNP were then interrogated in-silico for their likelihood to be presented by the HLA class I molecules in individual DRP, using the Immune-Epitope Database (IEDB) SMM algorithm. The IEDB-SMM algorithm predicted a median 18,396 peptides/DRP which bound HLA with an IC50 of <500nM, and 2254 peptides/DRP with an IC50 of <50nM. Unrelated donors generally had higher numbers of peptides presented by the HLA. A similarly large library of presented peptides was identified when the data was interrogated using the Net MHCPan algorithm. These peptides were uniformly distributed in the various organ systems. The bioinformatic algorithm presented here demonstrates that there may be a high level of minor histocompatibility antigen variation in HLA-matched individuals, constituting an HLA-specific alloreactivity potential. These data provide a possible explanation for how relatively minor adjustments in GVHD prophylaxis yield relatively similar outcomes in HLA matched and mismatched SCT recipients., Comment: Abstract: 235, Words: 6422, Figures: 7, Tables: 3, Supplementary figures: 2, Supplementary tables: 2

Outcomes in stem cell transplantation (SCT) are modeled using probability theory. However the clinical course following SCT appears to demonstrate many characteristics of dynamical systems, especially when outcomes are considered in the context of immune reconstitution. Dynamical systems tend to evolve over time according to mathematically determined rules. Characteristically, the future states of the system are predicated on the states preceding them, and there is sensitivity to initial conditions. In SCT, the interaction between donor T cells and the recipient may be considered as such a system in which, graft source, conditioning and early immunosuppression profoundly influence immune reconstitution over time. This eventually determines clinical outcomes, either the emergence of tolerance or the development of graft versus host disease. In this paper parallels between SCT and dynamical systems are explored and a conceptual framework for developing mathematical models to understand disparate transplant outcomes is proposed., Comment: 23 pages, 4 figures. Updated version with additional data, 2 new figures and editorial revisions. New authors added

Whole exome sequencing was performed on HLA-matched stem cell donors and transplant recipients to measure sequence variation contributing to minor histocompatibility antigen differences between the two. A large number of nonsynonymous single nucleotide polymorphisms were identified in each of the nine unique donor-recipient pairs tested. This variation was greater in magnitude in unrelated donors as compared with matched related donors. Knowledge of the magnitude of exome variation between stem cell transplant recipients and donors may allow more accurate titration of immunosuppressive therapy following stem cell transplantation., Comment: 12 pages- main article, 29 pages total, 5 figures, 1 supplementary figure

Using an equation of motion for a self-gravitating filament, we show how galactic spiral arms might be created and sustained. We find that the combination of differential rotation of the galactic disk and the self-gravity of the arm (as given by the equation) leads to a rotating spiral structure. Moreover, using this analysis, we then find a second differential equation that explicitly relates this spiral structure to the rotation curve of the galaxy -- it connects several factors, including spiral shape and pattern speed. We also describe a simple many-body numerical experiment that supports our approach. The findings are with consistent with observational evidence concerning arm structure and rotation curves, including leading arm structures.

We establish a new fundamental relationship between total curvature of knots and crossing number. If K is a smooth knot in 3-space, R the cross-section radius of a uniform tube neighborhood of K, L the arclength of K, and k the total curvature of K, then (up to a coefficient independent of K), crossing number of K < (k)(L/R). There are families of knots whose crossing numbers grow faster than either k or L/R separately. For example, the knots whose crossing numbers grow with the (4/3)-power of ropelength must have total curvature growing arbitrarily large as well., Comment: 19 pages, no figures. This update of the Oct. 03 version has improved Lemma 1.1 and resulting improved coefficients