The Role of FoxO Transcription Factors in Alcohol-Induced Deficient Fracture Repair

Proper and complete repair of a bone fracture is essential in quality of life maintenance, but poor healing and fracture malunion are still medically and socially relevant problems. Alcohol abuse impairs normal fracture healing, leading to delayed or incomplete union. This dissertation aims to clarify mechanisms behind this alcohol-induced impaired healing, thereby elucidating potential methods of intervention. Alcohol-induced oxidative stress has been linked to many morbidities associated with alcohol abuse. This dissertation elucidates a potential mechanism through which alcohol inhibits fracture healing by increasing oxidative stress. Using a rodent model, I found that alcohol exposure decreases fracture callus formation and endochondral ossification, and these changes are associated with markers of activation of FoxO transcription factors. FoxO transcription factors are known to be activated by oxidative stress and inhibit proper mesenchymal stem cell differentiation, which is crucial in callus formation. These deleterious effects of alcohol were prevented with the administration of an antioxidant. These results begin to illuminate how alcohol abuse can negatively affect fracture healing and bone health in general, while characterizing aspects of skeletal biology that are applicable beyond alcohol-associated pathologies

Multitasking by the OC lineage during bone infection: Bone resorption, immune modulation, and microbial niche

Bone infections, also known as infectious osteomyelitis, are accompanied by significant inflammation, osteolysis, and necrosis. Osteoclasts (OCs) are the bone-resorbing cells that work in concert with osteoblasts and osteocytes to properly maintain skeletal health and are well known to respond to inflammation by increasing their resorptive activity. OCs have typically been viewed merely as effectors of pathologic bone resorption, but recent evidence suggests they may play an active role in the progression of infections through direct effects on pathogens and via the immune system. This review discusses the host- and pathogen-derived factors involved in the in generation of OCs during infection, the crosstalk between OCs and immune cells, and the role of OC lineage cells in the growth and survival of pathogens, and highlights unanswered questions in the field

Computing exponentially faster: Implementing a nondeterministic universal Turing machine using DNA

The theory of computer science is based around Universal Turing Machines (UTMs): abstract machines able to execute all possible algorithms. Modern digital computers are physical embodiments of UTMs. The nondeterministic polynomial (NP) time complexity class of problems is the most significant in computer science, and an efficient (i.e. polynomial P) way to solve such problems would be of profound economic and social importance. By definition nondeterministic UTMs (NUTMs) solve NP complete problems in P time. However, NUTMs have previously been believed to be physically impossible to construct. Thue string rewriting systems are computationally equivalent to UTMs, and are naturally nondeterministic. Here we describe the physical design for a NUTM that implements a universal Thue system. The design exploits the ability of DNA to replicate to execute an exponential number of computational paths in P time. Each Thue rewriting step is embodied in a DNA edit implemented using a novel combination of polymerase chain reactions and site-directed mutagenesis. We demonstrate that this design works using both computational modelling and in vitro molecular biology experimentation. The current design has limitations, such as restricted error-correction. However, it opens up the prospect of engineering NUTM based computers able to outperform all standard computers on important practical problems

Estimating Increased Transient Water Storage With Increases in Beaver Dam Activity

Dam building by beaver (Castor spp.) slows water movement through montane valleys, increasing transient water storage and the diversity of residence times. In some cases, water storage created by beaver dam construction is correlated to changes in streamflow magnitude and timing. However, the total amount of additional surface and groundwater storage that beaver dams may create (and, thus, their maximum potential impact on streamflow) has not been contextualized in the water balance of larger river basins. We estimate the potential transient water storage increases that could be created at 5, 25, 50, and 100% of maximum modeled beaver dam capacity in the Bear River basin, USA, by adapting the height above nearest drainage (HAND) algorithm to spatially estimate surface water storage. Surface water storage estimates were combined with the MODFLOW groundwater model to estimate potential increases in groundwater storage throughout the basin. We tested four scenarios to estimate potential transient water storage increases resulting from the construction of 1179 to 34,897 beaver dams, and estimated surface water storage to range from 57.5 to 72.8 m3 per dam and groundwater storage to range from 182.2 to 313.3 m3 per dam. Overall, we estimate that beaver dam construction could increase transient water storage by up to 10.38 million m3 in the Bear River basin. We further contextualize beaver dam-related water storage increases with streamflow, reservoir, and snowpack volumes

Greatly reduced lymphoproliferation in lpr mice lacking major histocompatibility complex class I

Mice homozygous for the lpr gene have a defect in fas (CD95), a cell surface receptor that belongs to the tumor necrosis factor receptor family and that mediates apoptosis. This genetic abnormality results in lymphoproliferation characterized by the accumulation of CD4-CD8- (double negative [DN]) T cells, autoantibody production, and background strain-dependent, end-organ disease. Our previous results suggested that major histocompatibility complex (MHC) class I may be involved in the development of DN cells. To test this hypothesis, we derived C57BL/6-lpr/lpr (B6/lpr) mice that were deficient for the beta 2- microglobulin gene (beta 2m lpr) and had no detectable class I expression. At 6 mo of age, compared with B6/lpr littermates with normal class I genes, these mice showed greatly reduced lymphadenopathy, mostly due to a dramatic decrease in the number of DN cells. Significant changes in the percentage of other T cell subsets were noted, but only gamma/delta+ T cells showed a marked increase in both percentage and absolute numbers. Analysis of T cell receptor V beta expression of the remaining DN T cells in beta 2m -lpr mice showed a shift to a CD4-like repertoire from a CD8-like repertoire in control B6/lpr mice, indicating that a small MHC class II selected DN population was unmasked in lpr mice lacking class I. We also found that the production of immunoglobulin G (IgG) autoantibodies (antichromatin and anti-single stranded DNA), total IgG and IgG2a, but not total IgM or IgM rheumatoid factor, was significantly reduced in the beta 2m -lpr mice. This work suggests that >90% of DN T cells in lpr mice are derived from the CD8 lineage and are selected on class I. However, a T cell subset selected on class II and T cells expressing gamma/delta are also affected by the lpr defect and become minor components of the aberrant DN population

Staphylococcus aureus infects osteoclasts and replicates intracellularly

Osteomyelitis (OM), or inflammation of bone tissue, occurs most frequently as a result of bacterial infection and severely perturbs bone structure. OM is predominantly caused b

Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer

PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer. Keywords: PI3K; MEK; KRAS; Colorectal cancer; Mouse model of cance

World Antimalarial Resistance Network (WARN) III: Molecular Markers for Drug Resistant Malaria

Molecular markers for drug resistant malaria represent public health tools of great but mostly unrealized potential value. A key reason for the failure of molecular resistance markers to live up to their potential is that data on the their prevalence is scattered in disparate databases with no linkage to the clinical, in vitro and pharmacokinetic data that are needed to relate the genetic data to relevant phenotypes. The ongoing replacement of older monotherapies for malaria by new, more effective combination therapies presents an opportunity to create an open access database that brings together standardized data on molecular markers of drug resistant malaria from around the world. This paper presents a rationale for creating a global database of molecular markers for drug resistant malaria and for linking it to similar databases containing results from clinical trials of drug efficacy, in vitro studies of drug susceptibility, and pharmacokinetic studies of antimalarial drugs, in a World Antimalarial Resistance Network (WARN). This database will be a global resource, guiding the selection of first line drugs for treating uncomplicated malaria, for preventing malaria in travelers and for intermittent preventive treatment of malaria in pregnant women, infants and other vulnerable groups. Perhaps most important, a global database for molecular markers of drug resistant malaria will accelerate the identification and validation of markers for resistance to artemisinin-based combination therapies and, thereby, potentially prolong the useful therapeutic lives of these important new drugs

World Antimalarial Resistance Network (WARN) III: Molecular markers for drug resistant malaria

Molecular markers for drug resistant malaria represent public health tools of great but mostly unrealized potential value. A key reason for the failure of molecular resistance markers to live up to their potential is that data on the their prevalence is scattered in disparate databases with no linkage to the clinical, in vitro and pharmacokinetic data that are needed to relate the genetic data to relevant phenotypes. The ongoing replacement of older monotherapies for malaria by new, more effective combination therapies presents an opportunity to create an open access database that brings together standardized data on molecular markers of drug resistant malaria from around the world. This paper presents a rationale for creating a global database of molecular markers for drug resistant malaria and for linking it to similar databases containing results from clinical trials of drug efficacy, in vitro studies of drug susceptibility, and pharmacokinetic studies of antimalarial drugs, in a World Antimalarial Resistance Network (WARN). This database will be a global resource, guiding the selection of first line drugs for treating uncomplicated malaria, for preventing malaria in travelers and for intermittent preventive treatment of malaria in pregnant women, infants and other vulnerable groups. Perhaps most important, a global database for molecular markers of drug resistant malaria will accelerate the identification and validation of markers for resistance to artemisinin-based combination therapies and, thereby, potentially prolong the useful therapeutic lives of these important new drugs

Books in Arabic Script

The chapter approaches the book in Arabic script as the indispensable means for the transmission of knowledge across Eurasia and Africa, within cultures and across cultural boundaries, since the seventh century ad. The state of research can be divided into manuscript and print studies, but there is not yet a history of the book in Arabic script that captures its plurilinear development for over fourteen hundred years. The chapter explores the conceptual and practical challenges that impede the integration of the book in Arabic script into book history at large and includes an extensive reference list that reflects its diversity. The final published version was slightly updated, and includes seven illustrations of six Qurans from the holdings of Columbia University Libraries, four manuscripts and two printed versions. Moreover, the illustrations are images of historical artifacts which are in the public domain - despite Wiley's copyright claim