There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

CA : A Cancer Journal for Clinicians

Adequate initial configurations for molecular dynamics simulations consist of arrangements of molecules distributed in space in such a way to approximately represent the system's overall structure. In order that the simulations are not disrupted by large van der Waals repulsive interactions, atoms from different molecules must keep safe pairwise distances. Obtaining such a molecular arrangement can be considered a packing problem: Each type molecule must satisfy spatial constraints related to the geometry of the system, and the distance between atoms of different molecules must be greater than some specified tolerance. We have developed a code able to pack millions of atoms, grouped in arbitrarily complex molecules, inside a variety of three-dimensional regions. The regions may be intersections of spheres, ellipses, cylinders, planes, or boxes. The user must provide only the structure of one molecule of each type and the geometrical constraints that each type of molecule must satisfy. Building complex mixtures, interfaces, solvating biomolecules in water, other solvents, or mixtures of solvents, is straightforward. In addition, different atoms belonging to the same molecule may also be restricted to different spatial regions, in such a way that more ordered molecular arrangements can be built, as micelles, lipid double-layers, etc. The packing time for state-of-the-art molecular dynamics systems varies from a few seconds to a few minutes in a personal computer. The input files are simple and currently compatible with PDB, Tinker, Molden, or Moldy coordinate files. The package is distributed as free software and can be downloaded from http://www.ime.unicamp.br/~martinez/packmol/.

/pdf/packmol-a-package-for-building-initial-configurations-for-qsy9r74wrw.pdf

PACKMOL: a package for building initial configurations for molecular dynamics simulations.


 Small interfering RNA are suitable for gene silencing through a sequence-specific RNA interference process. The redundancy and complexity of molecular pathways in cancer create a need for multiplexed targeting that can be achieved with multiplexed siRNA delivery. Here we delivered multiplexed siRNA with a PSMA-targeted biocompatible dextran nanoparticle (NP) to downregulate CD46 and PD-L1 siRNA in PSMA expressing prostate cancer cells. The multiplexed gene targets selected, PD-L1 and CD46, play important roles in the escape of cancer cells from immune surveillance. PSMA is abundantly expressed by prostate cancer cells allowing prostate cancer specific delivery of the NPs. The NP was decorated with acid cleavable amine functional groups through acetal bonds that undergo degradation under acidic conditions providing rapid release of siRNA. Cell imaging and flow cytometry studies confirmed PSMA-specific delivery of CD46 and PD-L1 siRNA to high PSMA expressing PC-3 PIP cells. Immunoblot, qRT-PCR and flow cytometry confirmed downregulation of CD46 and PD-L1 following treatment with multiplexed siRNA at a concentration of 50 nM. These studies pave the way for delivering multiplexed siRNA to tumors in vivo to unmask tumors to the immune system using PSMA targeted biocompatible NPs.
 Citation Format: Zhihang Chen, Balaji Krishnamachary, Yelena Mironchik, Sangeeta R. Banerjee, Martin G. Pomper, Zaver M. Bhujwalla. Prostate-specific membrane antigen (PSMA) targeted multiplexed siRNA-mediated gene silencing of CD46 and PD-L1 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5070.

Abstract 5070: Prostate-specific membrane antigen (PSMA) targeted multiplexed siRNA-mediated gene silencing of CD46 and PD-L1 in prostate cancer

Death receptor 5 (DR5) agonist compositions and methods for treating pancreatitis have been developed. The compositions include Tumor Necrosis Factor-related apoptosis-inducing ligand (TRAIL), its analogues, and anti-DR5 agonistic antibodies. In certain embodiments, TRAIL analogs and anti-death receptor 5 agonistic antibodies have analgesic and disease modifying effects on the pancreas.

Compositions and methods for treating pancreatitis and pain with death receptor agonists

Background and Purpose: Human immunodeficiency virus (HIV)-associated dementia (HAD) has been extensively studied using magnetic resonance spectroscopy (MRS) at field strengths of 1.5 T. Higher magnetic field strengths (such as 3 T) allow for more reliable determination of certain compounds, such as glutamate (Glu) and glutamine (Gln). The current study was undertaken to investigate the utility of 3-T MRS for evaluatingHIV+patientswithdifferentlevelsofcognitiveimpairmentwithemphasisonthemeasurementofGluandGlx(thesumofGluandGln). Methods: Eighty-six HIV+ subjects were evaluated at 3 T using quantitative short echo time single-voxel MRS of frontal white matter (FWM) and basal ganglia (BG). Subjects were divided into three groups according to the Memorial Sloan Kettering (MSK) HIV dementia stage: 21 had normal cognition (NC) (MSK 0), 31 had mild cognitive impairment (MCI) without dementia (clinical MSK stage=0.5), and 34 had dementia (HAD) (MSK≥1). HIV+ subjects had also undergone standardized cognitive testing covering the domains of executive function, verbal memory, attention, information processing speed and motor and psychomotor speed. Between-group differences in metabolite levels in FWM and BG were evaluated using ANOVA. Pearson correlation coefficients were used to explore the associations between the Glu and Glx metabolites and neurocognitive results. Results: FWM Glx was lower in HAD (8.1±2.1 mM) compared to both the MCI (9.17±2.1 mM) and NC groups (10.0±1.6 mM) (P=.006). FWM myo-inositol (mI) was higher in HAD (4.15±0.75 mM) compared to both MCI (3.86±0.85 mM) and NC status (3.4±0.67 mM) (P=.006). FWM Glx/creatine (Cr) was lower and FWM mI/Cr was significantly higher in the HAD compared to the MCI and NC groups (P=.01 and P=.004, respectively). BG N-acetyl aspartate (NAA) was lower in the HAD group (6.79±1.53 mM), compared to the MCI (7.5 ±1.06 mM) and NC (7.6±1.01 mM) groups (P=.036). Significant negative correlations were observed between Glu, Glx and NAA concentrations with Trail-Making Test B (P=.006, P=.0001 and P=.007, respectively), and significant positive correlation was found with the Digit symbol test (P=.02, P=.002 and P=.008, respectively). FWM Glx and NAA concentrations showed negative correlation with Grooved Pegboard nondominant hand (P=.02 and P=.04, respectively). Conclusion: Patients with HAD have lower levels of Glx concentrations and Glx/Cr ratio in FWM, which was associated with impaired performance in specific cognitive domains, including executive functioning, fine motor, attention and working memory performance. ThreeTesla MRS measurements of Glx may be a useful indicator of neuronal loss/dysfunction in patients with HIV infection.

Original contributions Brain metabolism and cognitive impairment in HIV infection: a 3-T magnetic resonance spectroscopy study ☆

New diagnostic probes are needed for detection of tumor cells and tumor-supporting immune cells (macrophages), which are increasingly of interest in tumor biology and the development of cancer therapies. Many tumor types express an abundance of the translocator protein (TSPO), for which several types of chemical probes exist for non-invasive imaging. These probes simultaneously detect the supporting macrophages and tumor but without the ability to resolve the two. We have discovered that analogs of one particular probe, DPA-713, detect tumors and macrophages soon after administration. Later, the probe exhibits selective trapping by macrophages (the process of internalizing and retaining the tracer in a cell), allowing time-resolved delineation of tumor from macrophage. We developed two optical analogs of DPA-713 that efficiently illuminate tumors and later activate macrophages. They are useful in observing inflammatory diseases including tuberculosis, rheumatoid arthritis, osteoporosis, and pancreatitis. Several groups have successfully imaged TSPO, mostly in the context of neuroinflammation1–4 or brain tumors5–8 due to a very low background of TSPO expression in healthy brains. TSPO expression in peripheral tissues such as heart, lungs, liver, kidneys, adrenal glands, gut, and gonads is very high, making imaging of tumors and macrophage cells difficult. Imaging of inflammation from peripheral limb arthritis9 or from infections in limbs is possible using probes for TSPO, but the tracer can be taken up by normal bone marrow adjacent to the cortical bone. The discovery of time-resolved separation of TSPO-specific uptake from pure macrophage uptake now allows for clear delineation of sites of inflammatory macrophage accumulation in any part of the body. Using our optical DPA-713 analogs, we injected animal models intravenously with 6nmol of imaging probe and imaged Figure 1. Near-IR fluorescence imaging of tumor xenografts, bacterial-induced inflammation with correlative fluorescence microscopy. (A) In vivo imaging of a human breast tumor xenograft (yellow arrows) after one hour, 24 hours, and an ex vivo image of DPA-713-IRDye680LT uptake (rainbow display) in mice. (B) In vivo imaging of inflammation due to extensive opportunistic cutaneous cornybacterium bovis infection as compared with a healthy mouse after 24 hours of DPA-713-IRDye680LT uptake (rainbow display). (C, D, E, and F) Epifluorescence micrographs of ex vivo DPA-713IRDye680LT accumulation (red, E) in breast cancer MDA-MB-231 xenografts from the mouse in (A) subsequently co-stained with antiCD68 antibody (macrophages, green, C), Hoechst33342 nuclear stain (blue, C-F), anti-TSPO antibody (white, F, merged with DPA-713IRDye680LT), and overlay of CD68 with DPA-713-IRDye680LT (E) showing macrophage-specific co-localization, not TSPO-specific after 24 hours of in vivo probe uptake.

Time-resolved near-IR imaging of tumors and macrophages

Imaging of the serotonin transporter in depressed HIV-positive patients using [11C]DASB-PET

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