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CONTRACEPTION 2004年第2期70卷 141-147页

作者： Iweala, OI Harvard Univ Sch Med Md PhD Program Boston MA 02115 USA

This article provides an overview of different HIV diagnostic tests, describing how they work and the advantages and limitations of the various tests. This article also briefly reviews the structure and genetic diversity of HIV, the mechanism the virus uses to infect host cells and the different phases of HIV infection. This information is included to facilitate understanding of how HIV diagnostic tests work and what molecular markers these tests use to pinpoint an HIV infection. (C) 2004 Elsevier Inc. All rights reserved.

关键词： HIV infection HIV diagnostic test serology nucleic acid assay detuned assay

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LIMITING DILUTION ASSAYS FOR THE DETERMINATION OF IMMUNOCOMPETENT CELL FREQUENCIES .3. VALIDITY TESTS FOR THE SINGLE-HIT POISSON MODEL

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JOURNAL OF IMMUNOLOGICAL METHODS 1984年第1期72卷 29-40页

作者： TASWELL, C NYU SCH MED MD PHD PROGRAM NEW YORK NY 10016 USA

A statistical method was developed to test the validity of the single-hit Poisson model in limiting dilution assays used to determine immunocompetent cell frequencies. Principles of bioassay, validity tests and the distinction between model-discrimination experiments and parameter-estimation assays are reviewed in the introduction. The new test derived and then demonstrated with previously published data is intended to be used for parameter-estimation assays based upon the single-hit Poisson model. It is a family of related .chi.2, t and F tests for deviations from O of the slopes of weighted least squares regression plots. These plots regress the logarithms of single-dose estimates fi of the frequency .vphi. on the total cell doses .lambda.i and fi on the total cell dose reciprocals 1/.lambda.i, that is, Yi = In fi on Xi = .lambda.i and Yi = fi on Xi = 1/.lambda.i. The test discriminates against alternative models with multiple-hit/target response-generation processes, a variable number (dose-dependent) of false negatives and a constant number (dose-independent) of false positives. Its purposes as a test for parameter-estimation assays is to detect deviations from the single-hit Poisson model and not to select one of these alternative models. Tests for model-discrimination experiments to select or prove an unknown alternative model are considered in light of relevant literature reviewed in the discussion.

关键词： limiting dilution assays immunocompetent cell frequencies single-hit Poisson model validity tests model discrimination parameter estimation LDA limiting dilution assay(s) IC immunocompetent cell(s) SHPM single-hit Poisson model CTL-P cytolytic T lymphocyte precursor(s) all other mathematical and statistical notation as explained in the text

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High frequency ultrasound speckle flow imaging - Comparision with Doppler Optical Coherence Tomography (DOCT)

High frequency ultrasound speckle flow imaging - Comparision...

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IEEE Ultrasonics Symposium

作者： Yang, VXD Needles, A Vray, D Lo, S Wilson, BC Vitkin, IA Foster, FS Univ Toronto MD PhD Program Toronto ON Canada

ISBN: (纸本)078038413X

Visualization of the microcirculation can provide important diagnostic and therapeutic monitoring information in vascular and neoplastic diseases. Previously we have described a Doppler Optical Coherence Tomography (DOCT) system with a minimum detectable velocity of similar to 0.5 mm/s at 32 fps with limited imaging depth (similar to 2 nim). High frequency ultrasound (similar to 40 MHZ) has deeper penetration, however, real-time visualization of slow blood flow is difficult to achieve. Our aim is to develop a non-invasive ultrasound technique for microvascular imaging of slow flowing blood. Methods: We describe a speckle-variance flow processing (SFP) algorithm based on detecting the changes in B-mode pixel intensity on a high frequency ultrasound (HFUS) system operating at 40 - 60 MHz. The velocity sensitivity of the algorithm was determined by a flow phantom using blood mimicking fluid. In vivo experiments involving tadpoles and tumor-bearing mice were performed to compare the HFUS SFP performance to DOCT. Results: The velocity sensitivity was determined to he 0.2 mm/s at 30 fps, and the SFP index exhibit a nonlinear relationship with the flow velocity. Microcirculation in the tadpole cardiovascular system and superficial tumor blood flow in mouse were observed using HFUS SFP and DOCT. In addition, microcirculation in deeper structures, such as mouse kidney, was demonstrated. Conclusions: To our knowledge, this is the first demonstration of real-time microcirculation imaging using a non-Doppler HFUS. The velocity sensitivity and spatial resolution of such a system approaches that of DOCT, with improved depth penetration, and can be utilized to visualize slow blood flow in the microcirculation of small animals and humans.

关键词： high frequency ultrasound ultrasound biomicroscopy volumetric blood flow microcirculation decorrelation

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Using information security as a response to competitor analysis systems

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COMMUNICATIONS OF THE ACM 2001年第9期44卷 70-75页

作者： Gordon, LA Loeb, MP Univ Maryland Robert H Smith Sch Business PhD Program College Pk MD 20742 USA

Competitor Analysis Systems (CAS) seems to be entering an era of almost unlimited vistas due to the information age. In fact, nearly every organization is both a CAS predator and CAS prey in today's IT environment. In today's information environment, a logical competitive response to having the firm become a part of the CAS of a rival firm is information security. Of course, firms already expend much effort and funds to protect company information that would give rival firms a competitive advantage. Surprisingly, however, the literature concerned with CAS has not explicitly addressed the issue of information security. At the same time, the information security literature has not explicitly addressed the CAS issue. The purpose of this article is to rectify this situation. The primary focus of this framework is using information security to prevent rival firms from including sensitive information on the firm in their CAS. Recent developments related to information technology have moved CAS to center stage. In particular, the role of computers, publicly available databases, the Internet, and data analysis techniques, like data mining now permit a level of CAS unimaginable even a decade ago. As a result, firms have invested in a variety of CAS-related activities.

关键词： Data protection Database security Information technology Competitive advantage Internet Data analysis

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Overcoming CD226-related immune evasion in acute myeloid leukemia with CD38 CAR-engineered NK cells

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CELL REPORTS 2025年第1期44卷 115122页

作者： Garcia, Luciana Melo Gangadharan, Achintyan Banerjee, Pinaki Li, Ye Zeng, Andy G. X. Rafei, Hind Lin, Paul Kumar, Bijender Acharya, Sunil Daher, May Muniz-Feliciano, Luis Deyter, Gary M. Dominguez, Gabriel Park, Jeong Min Silva, Francia Reyes Cortes, Ana Karen Nunez Basar, Rafet Uprety, Nadima Shanley, Mayra Univ Texas MD Anderson Canc Ctr Dept Stem Cell Transplantat & Cellular Therapy Houston TX 77030 USA Univ Laval Dept Med Quebec City PQ G1V 0A6 Canada Univ Laval Hematol Oncol Serv CHU Quebec Quebec City PQ G1V 0A6 Canada H Lee Moffitt Canc Ctr & Res Inst Dept Immunol Tampa FL 33612 USA Univ S Florida Canc Biol PhD Program Tampa FL 33616 USA Univ Hlth Network Princess Margaret Canc Ctr Toronto ON M5G 1L7 Canada Univ Toronto Dept Mol Genet Toronto ON M5S 1A8 Canada

CD226 plays a vital role in natural killer (NK) cell cytotoxicity, interacting with its ligands CD112 and CD155 to initiate immune synapse formation, primarily through leukocyte function-associated-1 (LFA-1). Our study examined the role of CD226 in NK cell surveillance of acute myeloid leukemia (AML). NK cells in patients with AML had lower expression of CD226. CRISPR-Cas9 deletion of CD226 led to reduced LFA-1 recruitment, poor synapse formation, and decreased NK cell anti-leukemic activity. Engineering NK cells to express a chimeric antigen receptor targeting the AML antigen CD38 (CAR38) could overcome the need for CD226 to establish strong immune synapses. LFA-1 blockade reduced CAR38 NK cell activity, and this depended on the CD38 expression levels of AML cells. This suggests parallel but potentially cooperative roles for LFA-1 and CAR38 in synapse formation. Our findings suggest that CAR38 NK cells could be an effective therapeutic strategy to overcome CD226-mediated immune evasion in AML.

关键词： CD226 LFA-1 CAR-NK cell immune synapse acute myeloid leukemia

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Role of non-government organizations in engaging medical students in research

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JOURNAL OF INVESTIGATIVE MEDICINE 2017年第3期65卷 709-716页

作者： Manoranjan, Branavan Dey, Ayan K. Wang, Xin Kuzyk, Alexandra Petticrew, Karen Carruthers, Chris Arnold, Ian Clinician Investigator Trainee Assoc Canada Toronto ON Canada McMaster Univ Michael G DeGroote Sch Med MD PhD Program Hamilton ON Canada Univ Toronto Sch Med MD PhD Program Toronto ON Canada Univ Manitoba Sch Med MD PhD Program Winnipeg MB Canada Mach Gaensslen Fdn Canada Ottawa ON Canada

The continued decline in medical trainees entering the workforce as clinician-scientists has elevated the need to engage medical students in research. While past studies have shown early exposure to generate interest among medical students for research and academic careers, financial constraints have limited the number of such formal research training programs. In light of recent government budget cuts to support research training for medical students, non-government organizations (NGOs) may play a progressively larger role in supporting the development of clinician-scientists. Since 2005, the Mach-Gaensslen Foundation has sponsored 621 Canadian medical student research projects, which represents the largest longitudinal data set of Canadian medical students engaged in research. We present the results of the pre- and post-research studentship questionnaires, program evaluation survey and the 5-year and 10-year follow-up questionnaires of past recipients. This paper provides insight into the role of NGOs as stakeholders in the training of clinician-scientists and evaluates the impact of such programs on the attitudes and career trajectory of medical students. While the problem of too few physicians entering academic and research-oriented careers continues to grow, alternative-funding strategies from NGOs may prove to be an effective approach in developing and maintaining medical student interest in research.

关键词： Medical Research Education Medical Students Translational Medical Research Academic Medical Centers

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Pharmacological inhibition of spinal cord injury-stimulated ribosomal biogenesis does not affect locomotor outcome

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NEUROSCIENCE LETTERS 2017年第0期642卷 153-157页

作者： Kilanczyk, Ewa Andres, Kariena R. Hallgren, Justin Ohri, Sujata Saraswat Laiho, Marikki Whittemore, Scott R. Hetman, Michal Univ Louisville Kentucky Spinal Cord Injury Res Ctr MD PhD Program Louisville KY 40292 USA Univ Louisville Dept Neurol Surg MD PhD Program Louisville KY 40292 USA Univ Louisville Dept Pharmacol & Toxicol MD PhD Program Louisville KY 40292 USA Univ Louisville Dept Anat Sci & Neurobiol MD PhD Program Louisville KY 40292 USA Johns Hopkins Univ Sch Med Baltimore MD 21218 USA

After unresolved endoplasmic reticulum stress, recovery of protein synthesis including increased expression of ribosomal components and translation factors may induce cell death. Using a mouse model of moderate contusive spinal cord injury (SCI) at the T9 level, upregulation of ribosomal biogenesis was observed in the injury epicenter at 24 h after trauma. Such upregulation coincided with endoplasmic reticulum stress response as previously reported in this model. It was also accompanied by changes in expression of many other genes associated with translational regulation. Systemic treatment with a pharmacological inhibitor of RNA-Polymerase-1, BMH-21 reduced rRNA transcription in the spinal cord. Moreover, in the injury epicenter, treatment with BMH-21 increased expression of oligodendrocytespecific transcripts including Mbp and Cldn11 at 3 days post injury. Although such findings may suggest at least transient reduction of oligodendrocyte death, locomotor outcome was mostly unaffected except slightly accelerated recovery of hindlimb function at week 2 post-injury. Therefore, at least in mice, RNA-Polymerase-1 does not appear to be a robust target for therapies to protect spinal cord tissue after contusion. However, these findings raise an interesting possibility that altered rate of ribosomal biogenesis contributes to the apparent translational reprogramming after contusive SCI. Such a reprogramming could be a major regulator of SCI-induced gene expression. (C) 2017 Elsevier B.V. All rights reserved.

关键词： Ribosomal biogenesis Spinal cord injury White matter loss Cell death Neuroprotection Pharmacotherapy

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Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2025年第5期122卷 e2412029122页

作者： Bagnoli, Enrico Lin, Yu- En Burel, Sophie Jaimon, Ebsy Antico, Odetta Themistokleous, Christos Nikoloff, Jonas M. Squires, Samuel Morella, Ilaria Watzlawik, Jens O. Fiesel, Fabienne C. Springer, Wolfdieter Tonelli, Francesca Lis, Pawel Brooks, Simon P. Dunnett, Stephen B. Brambilla, Riccardo Alessi, Dario R. Pfeffer, Suzanne R. Muqit, Miratul M. K. Univ Dundee Sch Life Sci MRC Prot Phosphorylat & Ubiquitylat Unit Dundee DD1 5EH Scotland Aligning Sci Parkinsons Collaborat Res Network Chevy Chase MD 20815 USA Stanford Univ Sch Med Dept Biochem Stanford CA 94305 USA Univ Pavia Dept Biol & Biotechnol Lazzaro Spallanzani I-27100 Pavia Italy Cardiff Univ Neurosci & Mental Hlth Innovat Inst Sch Biosci Cardiff CF10 3AX Wales Mayo Clin Dept Neurosci Jacksonville FL 32224 USA Mayo Clin Grad Sch Biomed Sci Neurosci PhD Program Jacksonville FL 32224 USA Cardiff Univ Sch Biosci Div Neurosci Brain Repair Grp Cardiff CF10 3AX Wales

Mutations in Leucine- rich repeat kinase 2 (LRRK2) and PTEN- induced kinase 1 (PINK1) are associated with familial Parkinson's disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock- in mice with PINK1 knock- out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2- mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1- mediated Rab and Ub phosphorylation. In addition, we observe that a pool of up- regulated and recruited to damaged mitochondria, independent of PINK1 or LRRK2 activity. Parallel signaling of LRRK2 and PINK1 pathways is supported by assessment of motor behavioral studies that show no evidence of genetic interaction in crossed mouse lines. Previously we showed loss of cilia in LRRK2 R1441C mice and herein we show that PINK1 KO mice exhibit a ciliogenesis defect in striatal cholinergic interneurons and astrocytes that interferes with Hedgehog induction of glial derived- neurotrophic factor transcription. This is not exacerbated in double- mutant LRRK2 and PINK1 mice. Overall, our analysis indicates that LRRK2 activation and/or loss of PINK1 function along parallel pathways to impair ciliogenesis, suggesting a convergent mechanism toward PD. Our data suggest that reversal of defects downstream of ciliogenesis offers a common therapeutic strategy for LRRK2 or PINK1 PD patients, whereas LRRK2 inhibitors that are currently in clinical trials are unlikely to benefit PINK1 PD patients.

关键词： LRRK2 PINK1 ciliogenesis phosphorylation brain

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Inhibiting IP6K1 confers atheroprotection by elevating circulating apolipoprotein A-I

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METABOLISM-CLINICAL AND EXPERIMENTAL 2025年 163卷 156098-156098页

作者： Liu, Xiaoqi Zhang, Zixuan Aguirre, Tim Shipton, Megan L. Fu, Lin Du, Jimin Furkert, David Qi, Ji Chin, Alfred C. Riley, Andrew M. Liu, Tong Zhang, Xu Potter, Barry V. L. Fiedler, Dorothea Zhu, Yi Fu, Chenglai Tianjin Med Univ Prov & Minist Cosponsored Collaborat Innovat Ctr M Dept Physiol & Pathophysiol Tianjin Key Lab Metab Dis 22 Qixiangtai Rd Tianjin 300070 Peoples R China Leibniz Forschungsinstitut Mol Pharmakol FMP D-13125 Berlin Germany Univ Oxford Dept Pharmacol Med Chem & Drug Discovery Mansfield Rd Oxford OX1 3QT England Tianjin Med Univ Tianjin Inst CardiolHosp 2 Tianjin Key Lab Ion Mol Funct Cardiovasc Dis Dept Cardiol Tianjin 300211 Peoples R China Shanghai Jiao Tong Univ Xinhua Hosp Inst Dev & Regenerat Cardiovasc Med Sch Med Shanghai 200092 Peoples R China Weill Cornell Rockefeller Sloan Kettering Triinst MD PhD Program New York NY 10065 USA

Background and aims: Atherosclerotic cardiovascular diseases are the leading cause of death. Apolipoprotein A-I (apoA-I) mediates cholesterol efflux to lower the risks of atherosclerosis. Elevating circulating apoA-I is an effective strategy for atheroprotection. However, the regulatory mechanisms of apoA-I have been elusive. Methods: Protein-protein interactions were examined by co-immunoprecipitations. Chemical biology tools were used to determine the binding of 5PP-InsP5 to its target proteins and its roles in mediating protein-protein interactions. The mouse atherosclerotic model was generated by injecting AAV-PCSK9 and feeding a Western diet. Atherosclerotic plaques were determined by Oil Red O and H&E staining. Results: We show that blocking IP6K1 activity increases apoA-I production in hepatocytes. IP6K1 binds to apoA-I and via its product 5PP-InsP5 to induce apoA-I degradation, which requires ubiquitination factor E4A (UBE4A). Depleting 5PP-InsP5 by deleting IP6K1 or blocking IP6K1 activity disrupts the interaction between UBE4A and apoA-I, preventing apoA-I degradation, leading to increased production of apoA-I. Hepatocyte-specific deletion of IP6K1 elevates circulating apoA-I levels, which augments cholesterol efflux and lowers the burden of atherosclerosis. Mice with both apoA-I KO and hepatocyte-specific IP6K1 KO were generated to validate that IP6K1 deletion-induced atheroprotection requires apoA-I. Conclusions: Our findings reveal a mechanism by which blocking IP6K1 boosts apoA-I production. Blocking IP6K1 represents a potential treatment strategy to elevate circulating apoA-I for atheroprotection.

关键词： IP6K HDL Cholesterol efflux UBE4A Atherosclerosis Hepatocyte Inositol pyrophosphate

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Decoding heterogeneous single-cell perturbation responses

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NATURE CELL BIOLOGY 2025年第3期27卷 1-12页

作者： Song, Bicna Liu, Dingyu Dai, Weiwei Mcmyn, Natalie F. Wang, Qingyang Yang, Dapeng Krejci, Adam Vasilyev, Anatoly Untermoser, Nicole Loregger, Anke Song, Dongyuan Williams, Breanna Rosen, Bess Cheng, Xiaolong Chao, Lumen Kale, Hanuman T. Zhang, Hao Diao, Yarui Buerckstuemmer, Tilmann Siliciano, Janet D. Li, Jingyi Jessica Siliciano, Robert F. Huangfu, Danwei Li, Wei Childrens Natl Hosp Ctr Genet Med Res Washington DC 20010 USA George Washington Univ Dept Genom & Precis Med Washington DC 20010 USA Sloan Kettering Inst Dev Biol Program New York NY USA Mem Sloan Kettering Canc Ctr Louis V Gerstner Jr Grad Sch Biomed Sci New York NY 10021 USA Johns Hopkins Univ Sch Med Sch Med Baltimore MD USA Johns Hopkins Univ Sch Med Howard Hughes Med Inst Baltimore MD 21205 USA Univ Calif Los Angeles Dept Stat & Data Sci Los Angeles CA USA Exscientia GmbH Siemensstr 89-OG3 A-1210 Vienna Austria Univ Calif Los Angeles Bioinformat Interdept PhD Program Los Angeles CA USA Weill Cornell Med Weill Cornell Grad Sch Med Sci New York NY 10065 USA Duke Univ Med Ctr Durham NC 27710 USA Univ Calif Los Angeles Dept Human Genet Los Angeles CA USA Univ Calif Los Angeles Dept Biostat Los Angeles CA USA Univ Calif Los Angeles Dept Computat Med Los Angeles CA USA Univ Connecticut Hlth Ctr Dept Genet & Genome Sci Farmington CT USA

Understanding how cells respond differently to perturbation is crucial in cell biology, but existing methods often fail to accurately quantify and interpret heterogeneous single-cell responses. Here we introduce the perturbation-response score (PS), a method to quantify diverse perturbation responses at a single-cell level. Applied to single-cell perturbation datasets such as Perturb-seq, PS outperforms existing methods in quantifying partial gene perturbations. PS further enables single-cell dosage analysis without needing to titrate perturbations, and identifies 'buffered' and 'sensitive' response patterns of essential genes, depending on whether their moderate perturbations lead to strong downstream effects. PS reveals differential cellular responses on perturbing key genes in contexts such as T cell stimulation, latent HIV-1 expression and pancreatic differentiation. Notably, we identified a previously unknown role for the coiled-coil domain containing 6 (CCDC6) in regulating liver and pancreatic cell fate decisions. PS provides a powerful method for dose-to-function analysis, offering deeper insights from single-cell perturbation data.

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