Constructions of generalized complex structures in dimension four

Four-manifold theory is employed to study the existence of (twisted) generalized complex structures. It is shown that there exist (twisted) generalized complex structures that have more than one type change loci. In an example-driven fashion, (twisted) generalized complex structures are constructed on a myriad of four-manifolds, both simply and non-simply connected, which are neither complex nor symplectic

Exotic smooth structures on 4-manifolds with zero signature

For every integer $k\geq 2$, we construct infinite families of mutually nondiffeomorphic irreducible smooth structures on the topological $4$-manifolds $(2k-1)(S^2\times S^2)$ and (2k-1)(\CP#\CPb), the connected sums of $2k-1$ copies of $S^2\times S^2$ and \CP#\CPb.Comment: 6 page

How to Stop the Bleed: First Care Provider model for developing public trauma response beyond basic hemorrhage control

INTRODUCTION: Since 2013, the First Care Provider (FCP) model has successfully educated the non-medical population on how to recognize life-threatening injuries and perform interventions recommended by the Committee for Tactical Emergency Casualty Care (C-TECC) and the Hartford Consensus in the disaster setting. Recent programs, such as the federal Stop The Bleed campaign, have placed the emphasis of public training on hemorrhage control. However, recent attacks demonstrate that access to wounded, recognition of injury, and rapid evacuation are equally as important as hemorrhage control in minimizing mortality. To date, no training programs have produced a validated study with regard to training a community population in these necessary principles of disaster response. METHODS: In our study, we created a reproducible community training model for implementation into prehospital systems. Two matched demographic groups were chosen and divided into trained and untrained groups. The trained group was taught the FCP curriculum, which the Department of Homeland Security recognizes as a Stop the Bleed program, while the untrained group received no instruction. Both groups then participated in a simulated mass casualty event, which required evaluation of multiple victims with varying degree of injury, particularly a patient with an arterial bleed and a patient with an airway obstruction. RESULTS: The objective measures in comparing the two groups were the time elapse until their first action was taken (T1A) and time to their solution of the simulation (TtS). We compared their times using one-sided t-test to demonstrate their responses were not due to chance alone. At the arterial bleed simulation, the T1A for the trained and untrained groups, respectively, were 34.75 seconds and 111 seconds (p-value = .1064), while the TtS were 3 minutes and 33 seconds in the trained group and eight minutes in the untrained groups (physiologic cutoff) (p-value = .0014). At the airway obstruction simulation, the T1A for the trained and untrained groups, respectively, were 20.5 seconds and 43 seconds (p-value = .1064), while the TtS were 32.6 seconds in the trained group and 7 minutes and 3 seconds in the untrained group (p-value = .0087). Simulation values for recently graduated nursing students and a local fire department engine company (emergency medical services [EMS]) were also given for reference. The trained group\u27s results mirrored times of EMS. CONCLUSION: This study demonstrates an effective training model to civilian trauma response, while adhering to established recommendations. We offer our model as a potential solution for accomplishing the Stop The Bleed mission while advancing the potential of public disaster response

Evaluating the Accuracy of the 3-Sieve Particle Size Analysis Method Compared to the 12-Sieve Method

The 3-sieve particle size analysis method was developed to estimate the particle size of ground grain within feed mills without the time and expense required for a 12-sieve analysis. The 3-sieve method is more simplistic because it is hand-shaken and uses fewer sieves but has drawbacks because it is not as precise as the 12-sieve method. Because shaking is not automated, technician variation may impact results. Furthermore, the accuracy of the original 3-sieve method has been questioned because the method was developed for corn between 400 to 1,200 μm, and the industry now grinds various grains more finely. Some variations, such as changing the top sieve to a smaller diameter hole or using flow agent, may help improve its accuracy. In this instance, 420 grain samples were used to determine the impact of top sieve size, grain type, technician, and flow agent on the ability of a 3-sieve analytical method to accurately predict the mean particle size determined by a standardized 12-sieve method. The experiment was a 3 × 2 × 2 × 3 factorial with three technicians, two sieve sizes (U.S. No. 12 vs. 16 sieve as the top sieve), flow agent (0 vs. 0.5 g), and three grain types (corn, sorghum, or wheat). Prior to the experiment, all samples were analyzed according to the standard ASAE S319.4 method using a 12-sieve stack with a 15-min tap time and 1 g of flow agent. Linear regression was used to develop individual equations to predict the mean particle size for each of the 3-sieve methods compared to the standard 12-sieve method, and the GLIMMIX procedure of SAS was used to evaluate the impact main effects and interactions on prediction accuracy. All interactions were removed from the model due to insignificance (P \u3e 0.10). Technician, screen size, and flow agent did not affect the accuracy of the prediction equations. Grain was the only main effect of significance (P \u3c 0.05), where the prediction equation overestimated the particle size of wheat by approximately 15 μm and underestimated the particle size of corn by approximately 12 μm. While statistically significant, these variations were deemed to be sufficiently accurate for the 3-sieve method, and separate equations for each grain type were not warranted to retain the simplicity of the method. In summary, technician, sieve size, grain type, and the use of flow agent did not greatly affect the accuracy of the 3-sieve particle size analytical method, so the original method was concluded to be accurate and the preferred method

Development of Shuttle Vectors for Transformation of Diverse Rickettsia Species

Plasmids have been identified in most species of Rickettsia examined, with some species maintaining multiple different plasmids. Three distinct plasmids were demonstrated in Rickettsia amblyommii AaR/SC by Southern analysis using plasmid specific probes. Copy numbers of pRAM18, pRAM23 and pRAM32 per chromosome in AaR/SC were estimated by real-time PCR to be 2.0, 1.9 and 1.3 respectively. Cloning and sequencing of R. amblyommii AaR/SC plasmids provided an opportunity to develop shuttle vectors for transformation of rickettsiae. A selection cassette encoding rifampin resistance and a fluorescent marker was inserted into pRAM18 yielding a 27.6 kbp recombinant plasmid, pRAM18/Rif/GFPuv. Electroporation of Rickettsia parkeri and Rickettsia bellii with pRAM18/Rif/GFPuv yielded GFPuv-expressing rickettsiae within 2 weeks. Smaller vectors, pRAM18dRG, pRAM18dRGA and pRAM32dRGA each bearing the same selection cassette, were made by moving the parA and dnaA-like genes from pRAM18 or pRAM32 into a vector backbone. R. bellii maintained the highest numbers of pRAM18dRGA (13.3 – 28.1 copies), and R. parkeri, Rickettsia monacensis and Rickettsia montanensis contained 9.9, 5.5 and 7.5 copies respectively. The same species transformed with pRAM32dRGA maintained 2.6, 2.5, 3.2 and 3.6 copies. pRM, the plasmid native to R. monacensis, was still present in shuttle vector transformed R. monacensis at a level similar to that found in wild type R. monacensis after 15 subcultures. Stable transformation of diverse rickettsiae was achieved with a shuttle vector system based on R. amblyommii plasmids pRAM18 and pRAM32, providing a new research tool that will greatly facilitate genetic and biological studies of rickettsiae

Establishment of a Replicating Plasmid in Rickettsia prowazekii

Rickettsia prowazekii, the causative agent of epidemic typhus, grows only within the cytosol of eukaryotic host cells. This obligate intracellular lifestyle has restricted the genetic analysis of this pathogen and critical tools, such as replicating plasmid vectors, have not been developed for this species. Although replicating plasmids have not been reported in R. prowazekii, the existence of well-characterized plasmids in several less pathogenic rickettsial species provides an opportunity to expand the genetic systems available for the study of this human pathogen. Competent R. prowazekii were transformed with pRAM18dRGA, a 10.3 kb vector derived from pRAM18 of R. amblyommii. A plasmid-containing population of R. prowazekii was obtained following growth under antibiotic selection, and the rickettsial plasmid was maintained extrachromosomally throughout multiple passages. The transformant population exhibited a generation time comparable to that of the wild type strain with a copy number of approximately 1 plasmid per rickettsia. These results demonstrate for the first time that a plasmid can be maintained in R. prowazekii, providing an important genetic tool for the study of this obligate intracellular pathogen

Tumor targeting strategies of smart fluorescent nanoparticles and their applications in cancer diagnosis and treatment

Advantages such as strong signal strength, resistance to photobleaching, tunable fluorescence emissions, high sensitivity, and biocompatibility are the driving forces for the application of fluorescent nanoparticles (FNPs) in cancer diagnosis and therapy. In addition, the large surface area and easy modification of FNPs provide a platform for the design of multifunctional nanoparticles (MFNPs) for tumor targeting, diagnosis, and treatment. In order to obtain better targeting and therapeutic effects, it is necessary to understand the properties and targeting mechanisms of FNPs, which are the foundation and play a key role in the targeting design of nanoparticles (NPs). Widely accepted and applied targeting mechanisms such as enhanced permeability and retention (EPR) effect, active targeting, and tumor microenvironment (TME) targeting are summarized here. Additionally, a freshly discovered targeting mechanism is introduced, termed cell membrane permeability targeting (CMPT), which improves the tumorâ targeting rate from less than 5% of the EPR effect to more than 50%. A new design strategy is also summarized, which is promising for future clinical targeting NPs/nanomedicines design. The targeting mechanism and design strategy will inspire new insights and thoughts on targeting design and will speed up precision medicine and contribute to cancer therapy and early diagnosis.J.H., C.L., L.D., and Y.H. contributed equally to this work. This work was been supported by the National Natural Science Foundation of China (Nos. 21371115, 11025526, 21671131, 11875185), the Shanghai University-Universal Medical Imaging Diagnostic Research Foundation (19H00100), the Program for Changjiang Scholars and Innovative Research Team in University (No. IRT13078) and the Portuguese Foundation for Science and Technology (IF/00347/2015)

Cellular Responses and Tissue Depots for Nanoformulated Antiretroviral Therapy.

Long-acting nanoformulated antiretroviral therapy (nanoART) induces a range of innate immune migratory, phagocytic and secretory cell functions that perpetuate drug depots. While recycling endosomes serve as the macrophage subcellular depots, little is known of the dynamics of nanoART-cell interactions. To this end, we assessed temporal leukocyte responses, drug uptake and distribution following both intraperitoneal and intramuscular injection of nanoformulated atazanavir (nanoATV). Local inflammatory responses heralded drug distribution to peritoneal cell populations, regional lymph nodes, spleen and liver. This proceeded for three days in male Balb/c mice. NanoATV-induced changes in myeloid populations were assessed by fluorescence-activated cell sorting (FACS) with CD45, CD3, CD11b, F4/80, and GR-1 antibodies. The localization of nanoATV within leukocyte cell subsets was determined by confocal microscopy. Combined FACS and ultra-performance liquid chromatography tandem mass-spectrometry assays determined nanoATV carriages by cell-based vehicles. A robust granulocyte, but not peritoneal macrophage nanoATV response paralleled zymosan A treatment. ATV levels were highest at sites of injection in peritoneal or muscle macrophages, dependent on the injection site. The spleen and liver served as nanoATV tissue depots while drug levels in lymph nodes were higher than those recorded in plasma. Dual polymer and cell labeling demonstrated a nearly exclusive drug reservoir in macrophages within the liver and spleen. Overall, nanoART induces innate immune responses coincident with rapid tissue macrophage distribution. Taken together, these works provide avenues for therapeutic development designed towards chemical eradication of human immunodeficiency viral infection

Cellular Responses and Tissue Depots for Nanoformulated Antiretroviral Therapy.

Long-acting nanoformulated antiretroviral therapy (nanoART) induces a range of innate immune migratory, phagocytic and secretory cell functions that perpetuate drug depots. While recycling endosomes serve as the macrophage subcellular depots, little is known of the dynamics of nanoART-cell interactions. To this end, we assessed temporal leukocyte responses, drug uptake and distribution following both intraperitoneal and intramuscular injection of nanoformulated atazanavir (nanoATV). Local inflammatory responses heralded drug distribution to peritoneal cell populations, regional lymph nodes, spleen and liver. This proceeded for three days in male Balb/c mice. NanoATV-induced changes in myeloid populations were assessed by fluorescence-activated cell sorting (FACS) with CD45, CD3, CD11b, F4/80, and GR-1 antibodies. The localization of nanoATV within leukocyte cell subsets was determined by confocal microscopy. Combined FACS and ultra-performance liquid chromatography tandem mass-spectrometry assays determined nanoATV carriages by cell-based vehicles. A robust granulocyte, but not peritoneal macrophage nanoATV response paralleled zymosan A treatment. ATV levels were highest at sites of injection in peritoneal or muscle macrophages, dependent on the injection site. The spleen and liver served as nanoATV tissue depots while drug levels in lymph nodes were higher than those recorded in plasma. Dual polymer and cell labeling demonstrated a nearly exclusive drug reservoir in macrophages within the liver and spleen. Overall, nanoART induces innate immune responses coincident with rapid tissue macrophage distribution. Taken together, these works provide avenues for therapeutic development designed towards chemical eradication of human immunodeficiency viral infection