Experimental observations and numerical modeling of lipid-shell microbubbles with calcium-adhering moieties for minimally-invasive treatment of urinary stones

A novel treatment modality incorporating calcium-adhering microbubbles has recently entered human clinical trials as a new minimally-invasive approach to treat urinary stones. In this treatment method, lipid-shell gas-core microbubbles can be introduced into the urinary tract through a catheter. Lipid moities with calcium-adherance properties incorporated into the lipid shell facilitate binding to stones. The microbubbles can be excited by an extracorporeal source of quasi-collimated ultrasound. Alternatively, the microbubbles can be excited by an intraluminal source, such as a fiber-optic laser. With either excitation technique, calcium-adhering microbubbles can significantly increase rates of erosion, pitting, and fragmentation of stones. We report here on new experiments using high-speed photography to characterize microbubble expansion and collapse. The bubble geometry observed in the experiments was used as one of the initial shapes for the numerical modeling. The modeling showed that the bubble dynamics strongly depends on bubble shape and stand-off distance. For the experimentally observed shape of microbubbles, the numerical modeling showed that the collapse of the microbubbles was associated with pressure increases of some two-to-three orders of magnitude compared to the excitation source pressures. This in-vitro study provides key insights into the use of microbubbles with calcium-adhering moieties in treatment of urinary stones

IL-2(high) tissue-resident T cells in the human liver: Sentinels for hepatotropic infection

The liver provides a tolerogenic immune niche exploited by several highly prevalent pathogens as well as by primary and metastatic tumors. We have sampled healthy and hepatitis B virus (HBV)-infected human livers to probe for a subset of T cells specialized to overcome local constraints and mediate immunity. We characterize a population of T-bet(lo)Eomes(lo)Blimp-1(hi)Hobit(lo) T cells found within the intrahepatic but not the circulating memory CD8 T cell pool expressing liver-homing/retention markers (CD69(+)CD103(+) CXCR6(+)CXCR3(+)). These tissue-resident memory T cells (TRM) are preferentially expanded in patients with partial immune control of HBV infection and can remain in the liver after the resolution of infection, including compartmentalized responses against epitopes within all major HBV proteins. Sequential IL-15 or antigen exposure followed by TGFβ induces liver-adapted TRM, including their signature high expression of exhaustion markers PD-1 and CD39. We suggest that these inhibitory molecules, together with paradoxically robust, rapid, cell-autonomous IL-2 and IFNγ production, equip liver CD8 TRM to survive while exerting local noncytolytic hepatic immunosurveillance

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Global development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017. METHODS: The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries-Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODEm), to generate cause fractions and cause-specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised

Development of acid-sensitive N-ethoxybenzylimidazoles for use as linkers in drug delivery systems

This thesis describes the development of acid-sensitive N- ethoxybenzylimidazoles (NEBIs) for use as linkers in drug delivery systems (DDSs). A common characteristic of many DDSs is the rapid internalization and intracellular localization of the DDS into the acidic endosomes and lysosomes of cells upon arrival to the targeted tissue. NEBIs, like other acid-sensitive moieties, can serve as crosslinkers for DDSs to conjugate small molecule drugs to macromolecules. While these conjugates are stable at physiological conditions, they hydrolyze in mildly acidic environments for the triggered release of small molecule drugs. Chapter 2 describes the initial studies performed to characterize the NEBI platform. We found that hydrolysis of the NEBI at pH 5.5 exhibited a > 10-fold acceleration in rate of hydrolysis compared to in solutions at normal, physiological pH. Chapter 3 describes the incorporation of an amine containing chemotherapeutic, doxorubicin, to the NEBI, and its hydrolytic properties and cytotoxicity. Chapter 4 describes the design of an acid-sensitive bifunctional NEBI cross-linker with a carboxylic acid functionality on one side and an azide functionality on the other side. This bifunctional crosslinker was used to construct a model DDS, by conjugating the anticancer drug doxorubicin to a human serum album model carrier. This model DDS was used to evaluate the utility of a NEBI as an acid-sensitive linker by analyzing the uptake and activity of the DDS on human ovarian cancer cells. Our most difficult challenge in Chapter 4, the inability to release native drug, was addressed in Chapter 5. An ortho-NEBI was designed to undergo two sequential hydrolysis steps, hydrolysis of the NEBI followed by the hydrolysis of an ester, to release native alcohol containing drugs. Studies with 5-fluoro-2'- deoxyuridine (5-FU) conjugated to the ortho-NEBI via an ester bond found that native 5-FU was released from this ortho-NEBI system. The cytotoxicity of the ortho-NEBI-5-FU exhibited IC50 values equal in the same order of magnitude of native 5-FU. Chapters 6 and 7 describe attempts in releasing amine containing drugs from the ortho-NEBI platform and studies towards the development of methods for site selective conjugation of a drug to a breast cancer targeting antibody, trastuzuma

Fast estimation of the Integrated Completed Likelihood criterion for change-point detection problems with applications to Next-Generation Sequencing data

In this paper, we consider the Integrated Completed Likelihood (ICL) as a useful criterion for estimating the number of changes in the underlying distribution of data, specifically in problems where detecting the precise location of these changes is the main goal. The exact computation of the ICL requires O(Kn(2)) operations (with K the number of segments and n the number of data-points) which is prohibitive in many practical situations with large sequences of data. We describe a framework to estimate the ICL with O(K(2)n) complexity. Our approach is general in the sense that it can accommodate any given model distribution. We checked the run-time and validity of our approach on simulated data and demonstrate its good performance when analyzing real Next-Generation Sequencing (NGS) data using a negative binomial model. Our method is implemented in the R package postCP and available on the CRAN repository