ABSTRACT
In-situ marine cloud droplet number concentrations (CDNCs), cloud condensation nuclei (CCN), and CCN proxies, based on particle sizes and optical properties, are accumulated from seven field campaigns: ACTIVATE; NAAMES; CAMP2EX; ORACLES; SOCRATES; MARCUS; and CAPRICORN2. Each campaign involves aircraft measurements, ship-based measurements, or both. Measurements collected over the North and Central Atlantic, Indo-Pacific, and Southern Oceans, represent a range of clean to polluted conditions in various climate regimes. With the extensive range of environmental conditions sampled, this data collection is ideal for testing satellite remote detection methods of CDNC and CCN in marine environments. Remote measurement methods are vital to expanding the available data in these difficult-to-reach regions of the Earth and improving our understanding of aerosol-cloud interactions. The data collection includes particle composition and continental tracers to identify potential contributing CCN sources. Several of these campaigns include High Spectral Resolution Lidar (HSRL) and polarimetric imaging measurements and retrievals that will be the basis for the next generation of space-based remote sensors and, thus, can be utilized as satellite surrogates.
ABSTRACT
Surgical resection of cancer remains the frontline therapy for millions of patients annually, but post-operative recurrence is common, with a relapse rate of around 45% for non-small cell lung cancer. The tumour draining lymph nodes (dLN) are resected at the time of surgery for staging purposes, and this cannot be a null event for patient survival and future response to immune checkpoint blockade treatment. This project investigates cancer surgery, lymphadenectomy, onset of metastatic disease, and response to immunotherapy in a novel model that closely reflects the clinical setting. In a murine metastatic lung cancer model, primary subcutaneous tumours were resected with associated dLNs remaining intact, completely resected or partially resected. Median survival after surgery was significantly shorter with complete dLN resection at the time of surgery (49 days (95%CI)) compared to when lymph nodes remained intact (> 88 days; p < 0.05). Survival was partially restored with incomplete lymph node resection and CD8 T cell dependent. Treatment with aCTLA4 whilst effective against the primary tumour was ineffective for metastatic lung disease. Conversely, aPD-1/aCD40 treatment was effective in both the primary and metastatic disease settings and restored the detrimental effects of complete dLN resection on survival. In this pre-clinical lung metastatic disease model that closely reflects the clinical setting, we observe decreased frequency of survival after complete lymphadenectomy, which was ameliorated with partial lymph node removal or with early administration of aPD-1/aCD40 therapy. These findings have direct relevance to surgical lymph node resection and adjuvant immunotherapy in lung cancer, and perhaps other cancer, patients.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Lymph Node Excision , Neoplasm Metastasis/immunology , Animals , Chemotherapy, Adjuvant/methods , Immune Checkpoint Inhibitors/pharmacology , Lymph Nodes/drug effects , Lymph Nodes/immunology , Mice , Neoplasm Metastasis/pathology , Neoplasm Recurrence, Local/pathologyABSTRACT
A particle-into-liquid sampler (PILS) was coupled to a flow-through conductivity cell to provide a continuous, nondestructive, online measurement in support of offline ion chromatography analysis. The conductivity measurement provides a rapid assessment of the total ion concentration augmenting slower batch-sample data from offline analysis and is developed primarily to assist airborne measurements, where fast time-response is essential. A conductivity model was developed for measured ions and excellent closure was derived for laboratory-generated aerosols (97% conductivity explained, R2 > 0.99). The PILS-conductivity measurement was extensively tested throughout the NASA Cloud, Aerosol and Monsoon Processes: Philippines Experiment (CAMP2Ex) during nineteen research flights. A diverse range of ambient aerosol was sampled from biomass burning, fresh and aged urban pollution, and marine sources. Ambient aerosol did not exhibit the same degree of closure as the laboratory aerosol, with measured ions only accountable for 43% of the conductivity. The remaining fraction of the conductivity was examined in combination with ion charge balance and found to provide additional supporting information for diagnosing and modeling particle acidity. An urban plume case study was used to demonstrate the utility of the measurement for supplementing compositional data and augmenting the temporal capability of the PILS.
ABSTRACT
Aquatic bladderworts (Utricularia gibba and U. australis) capture zooplankton in mechanically triggered underwater traps. With characteristic dimensions less than 1 mm, the trapping structures are among the smallest known to capture prey by suction, a mechanism that is not effective in the creeping-flow regime where viscous forces prevent the generation of fast and energy-efficient suction flows. To understand what makes suction feeding possible on the small scale of bladderwort traps, we characterised their suction flows experimentally (using particle image velocimetry) and mathematically (using computational fluid dynamics and analytical mathematical models). We show that bladderwort traps avoid the adverse effects of creeping flow by generating strong, fast-onset suction pressures. Our findings suggest that traps use three morphological adaptations: the trap walls' fast release of elastic energy ensures strong and constant suction pressure; the trap door's fast opening ensures effectively instantaneous onset of suction; the short channel leading into the trap ensures undeveloped flow, which maintains a wide effective channel diameter. Bladderwort traps generate much stronger suction flows than larval fish with similar gape sizes because of the traps' considerably stronger suction pressures. However, bladderworts' ability to generate strong suction flows comes at considerable energetic expense.
Subject(s)
Adaptation, Physiological , Hydrodynamics , Animals , Biomechanical Phenomena , Rheology , SuctionABSTRACT
BACKGROUND: Middle school students are recommended as the primary target population for human papillomavirus (HPV) vaccination. This study aimed to assess HPV and HPV vaccine knowledge, and to evaluate the effect of a school-based educational intervention, immediately and one year later, on HPV knowledge and vaccine acceptability among adolescents in mainland China. METHODS: A school-based interventional follow-up study was conducted in seven representative cities in mainland China from May 2015 to May 2017. "Train-the-trainer" strategy was employed to educate school teachers in this study. Students aged 13 to 14 years old were assigned to intervention classes and control classes. All students were required to complete the baseline questionnaire. Students in the intervention classes were given a 45-minute lecture regarding HPV and HPV vaccine knowledge and were then asked to complete a post-education questionnaire. One year later, all students were asked to complete the post-education questionnaire again. RESULTS: Baseline HPV knowledge was low among Chinese adolescents, with only 12.6% and 15.7% of students having heard of HPV and HPV vaccines, respectively. After the intervention, the level of HPV-related knowledge increased immediately, and students with higher knowledge levels of HPV and HPV vaccines were more willing to get vaccinated. One year after the intervention, the knowledge of HPV and HPV vaccines was dramatically diminished. However, knowledge was significantly higher in intervention classes compared to control classes. CONCLUSIONS: Knowledge and awareness of HPV and vaccination are generally deficient among Chinese adolescents. School-based health education was very effective in improving awareness and positive attitudes about HPV and HPV vaccines within a short time. Integrating health education on HPV into the existing school-based sexual health curriculum could be an effective way to increase HPV vaccination coverage and help to eliminate preventable HPV-associated cancers in China.
Subject(s)
Health Knowledge, Attitudes, Practice , Papillomavirus Infections , Papillomavirus Vaccines , Patient Acceptance of Health Care , Uterine Cervical Neoplasms , Adolescent , China , Female , Follow-Up Studies , Humans , Papillomavirus Infections/prevention & control , Schools , Surveys and Questionnaires , VaccinationABSTRACT
The aquatic bladderwort Utricularia gibba captures zooplankton in mechanically triggered underwater traps. With characteristic dimensions <1 mm, the trapping structures are among the smallest known that work by suction-a mechanism that would not be effective in the creeping-flow regime. To understand the adaptations that make suction feeding possible on this small scale, we have measured internal flow speeds during artificially triggered feeding strikes in the absence of prey. These data are compared with complementary analytical models of the suction event: an inviscid model of the jet development in time and a steady-state model incorporating friction. The initial dynamics are well described by a time-dependent Bernoulli equation in which the action of the trap door is represented by a step increase in driving pressure. According to this model, the observed maximum flow speed (5.2 m/s) depends only on the pressure difference, whereas the initial acceleration (3 × 104 m/s2 ) is determined by pressure difference and channel length. Because the terminal speed is achieved quickly (~0.2 ms) and the channel is short, the remainder of the suction event (~2.0 ms) is effectively an undeveloped viscous steady state. The steady-state model predicts that only 17% of power is lost to friction. The energy efficiency and steady-state fluid speed decrease rapidly with decreasing channel diameter, setting a lower limit on practical bladderwort size.
Subject(s)
Adaptation, Physiological , Hydrodynamics , Magnoliopsida/physiology , Models, Biological , Biomechanical PhenomenaABSTRACT
BACKGROUND: Understanding disparities in the burden of cancer attributable to different risk factors is crucial to inform and improve cancer prevention and control. In this report, we estimate the site-specific population-attributable fractions (PAFs) for 23 potentially modifiable risk factors across all provinces in China. METHODS: In this comparative risk assessment study, we used 2014 cancer mortality data for adults from 978 county-level surveillance points in 31 provinces of mainland China. Risk-factor prevalence estimates were obtained from representative surveys. We used summary relative risks obtained from several recent large-scale pooled analyses or high-quality meta-analyses of studies in China. We calculated PAFs using multiple formulae incorporating exposure prevalence and relative risk data stratified by age, sex and province and then combined to create summary PAFs by sex, cancer site, and risk factors. FINDINGS: About 1â036â004 cancer deaths (45·2% of all cancer deaths [95% CI 44·0-46·4]) in China in 2014 in adults aged 20 years or older were attributable to 23 evaluated risk factors. The PAF was higher in men (51·2% [95% CI 50·0-52·4]) than in women (34·9% [33·6-36·2]), with the leading risk factors being active smoking in men and low fruit intake in women. By province, the PAF in both sexes combined ranged from 35·2% in Shanghai to 52·9% in Heilongjiang, while the PAF varied from 40·9% in Shanghai to 56·4% in Guangdong among men and from 26·9% in Shanghai to 48·0% in Heilongjiang among women. The highest PAF among men was smoking in all 31 provinces, whereas among women it varied among low fruit intake (14 provinces), hepatitis B virus infection (seven provinces), smoking (six provinces), excess bodyweight (three provinces), and human papilloma virus infection (one province). INTERPRETATION: The PAFs of cancers attributable to potentially modifiable risk factors vary substantially across provinces in China. Regional adoption of effective primary cancer prevention strategies has a vast potential to reduce the burden of cancer and disparities in China. Smoking, poor diet, and infection warrant particular policy attention as they contributed a large proportion to the total cancer burden. FUNDING: National Science and Technology Basic Research Special Foundation of China.
Subject(s)
Diet/statistics & numerical data , Hepatitis B/epidemiology , Neoplasms/epidemiology , Overweight/epidemiology , Papillomavirus Infections/epidemiology , Smoking/epidemiology , Adult , Aged , Alcohol Drinking/epidemiology , China/epidemiology , Diabetes Mellitus/epidemiology , Dietary Fiber , Environmental Exposure/statistics & numerical data , Epstein-Barr Virus Infections/epidemiology , Female , Fruit , Geography , HIV Infections/epidemiology , Health Policy , Health Status Disparities , Helicobacter Infections/epidemiology , Hepatitis C/epidemiology , Humans , Male , Middle Aged , Prevalence , Risk Assessment , Risk Factors , Sedentary Behavior , Sex Factors , Young AdultABSTRACT
This mixed methods exploratory study illustrates the influence of pervasive misconceptions about Islam on the experiences of 314 adult Muslims across the United States. Quantitative results suggest that Muslim stress levels are comparable to the stress levels of other marginalized groups in the United States. Qualitative analysis revealed four themes that highlight the challenges faced by Muslims as well as their resiliency in the face of microaggressions and marginalization. Family therapists may utilize these personal accounts to expand their understanding of Muslim experiences, and to reflect on their own implicit biases toward Muslims in order to reduce chances of premature termination. Clinical implications include using resiliency-based models and creating collaborative partnerships with community leaders when working with this religious minority group.
Subject(s)
Aggression/psychology , Islam/psychology , Minority Groups/psychology , Resilience, Psychological , Stress, Psychological/ethnology , Xenophobia/ethnology , Adult , Family Therapy , Female , Humans , Male , Qualitative Research , Social Marginalization , Stress, Psychological/therapy , United States/ethnology , Young AdultABSTRACT
BACKGROUND: Global health diplomacy (GHD) is a burgeoning field bridging the priorities of global health and foreign affairs. Given the increasing need to mobilize disparate global health stakeholders coupled with the need to design complex public health partnerships to tackle issues of international concern, effective and timely cooperation among state actors is critical. Health Attachés represent this coordination focal point and are key diplomatic professionals at the forefront of GHD. Despite their unique mandate, little is published about this profession and the perspectives of those who work in the field. METHODS: Through purposive sampling, we performed in-depth qualitative interviews with seven Health Attachés: three foreign Health Attachés accredited to the United States and four U.S. Health Attachés accredited to foreign governments. Our interviews explored four key topics: the role and mission of Health Attachés, skills needed to perform GHD, examples of successes and challenges in accomplishing their respective missions, and suggestions for the future development of the diplomatic profession. RESULTS: We identified several lessons to apply to the growing field of GHD. First, GHD actors need to receive appropriate training to successfully negotiate the intersection of global health and foreign affairs. Participants suggested several areas of training that would benefit GHD actors: diplomacy and negotiation, applied science, and cross-cultural competency. Second, participants articulated the need for a career path for GHD practitioners, increased opportunities for on-the-job training and mentored experiences, and GHD competencies with defined levels of mastery that can be used in occupational evaluation and career development. CONCLUSIONS: Our findings indicate that skills in diplomacy and negotiation, applied science, and cross cultural competency are essential for the statecraft of Health Attachés. Additionally, establishing a clear career pathway for Health Attachés is critical for future maturation of the profession and for fostering effective global health action that aligns public health and foreign diplomacy outcomes. Achieving these goals would ensure that this special cadre of diplomats could effectively practice GHD and would also better position Health Attachés to take the lead in advancing shared global health goals among nation states in a new era of twenty-first century diplomacy.
Subject(s)
Diplomacy , Global Health , International Cooperation , Government , Humans , United StatesABSTRACT
A new aircraft-mounted probe for collecting samples of cloud water has been designed, fabricated, and extensively tested. Following previous designs, the probe uses inertial separation to remove cloud droplets from the airstream, which are subsequently collected and stored for offline analysis. We report details of the design, operation, and modelled and measured probe performance. Computational fluid dynamics (CFD) was used to understand the flow patterns around the complex interior geometrical features that were optimized to ensure efficient droplet capture. CFD simulations coupled with particle tracking and multiphase surface transport modelling provide detailed estimates of the probe performance across the entire range of flight operating conditions and sampling scenarios. Physical operation of the probe was tested on a Lockheed C-130 Hercules (fuselage mounted) and de Havilland Twin Otter (wing pylon mounted) during three airborne field campaigns. During C-130 flights on the final field campaign, the probe reflected the most developed version of the design and a median cloud water collection rate of 4.5 mL min-1 was achieved. This allowed samples to be collected over 1-2 min under optimal cloud conditions. Flights on the Twin Otter featured an inter-comparison of the new probe with a slotted-rod collector, which has an extensive airborne campaign legacy. Comparison of trace species concentrations showed good agreement between collection techniques, with absolute concentrations of most major ions agreeing within 30 %, over a range of several orders of magnitude.
ABSTRACT
OBJECTIVE: To use an alumni-centered, practice-based research network to evaluate white spot lesions (WSLs) among treated orthodontic patients. MATERIALS AND METHODS: An initial survey was conducted to ascertain whether orthodontic alumni from Texas A&M University Baylor College of Dentistry were willing to participate. Twenty randomly selected alumni participated, providing 158 treated cases. Each alumnus (1) obtained internal review board consent; (2) submitted pre- and posttreatment photographs of 10 consecutively finished cases; (3) completed a treatment survey; and (4) had the patient/parent complete the American Dental Association (ADA) Caries Risk Assessment. RESULTS: Almost 90% of the alumni surveyed were willing to participate in the practice-based research, primarily because a fellow alumnus asked them to. Approximately 28% of the patients developed WSLs. The average patient developed 2.4 white spots, affecting 12.7% of the teeth examined. WSLs were significantly (P < .001) more (2.3-3.2 times) likely for patients who were identified on the ADA Caries Risk Assessment. The risk of developing WSLs during treatment was also increased for those with fair (2.7 times) or poor (3.5 times) oral hygiene, poor gingival health (2.3 times), and extended treatment times (2.1 times). CONCLUSIONS: There is a substantial risk of developing WSLs among private practice patients, depending partially on the length of treatment. Patients at greatest risk can be identified prior to treatment based on the ADA Caries Risk Assessment, oral hygiene, and gingival health.
Subject(s)
Dental Caries/epidemiology , Dental Caries/etiology , Gingiva/pathology , Humans , Oral Hygiene , Orthodontics, Interceptive , Prevalence , Risk Assessment , TexasABSTRACT
Echocardiography is an important first-line investigation for detection of anomalous origin of a coronary artery from the pulmonary artery (ALCAPA). We report two cases of ALCAPA that illustrate the importance of systematic performance of the echocardiogram, mindful of technical artifacts that may mislead the echocardiographer color Doppler imaging in diagnosis of this condition.
ABSTRACT
Postresection recurrences of cancer arising from occult tumor deposits, either local or metastatic, represent major causes of death in patients with operable solid tumors. Thus, new therapies are required that complement existing treatments to eradicate these occult deposits. Agonistic anti-CD40 antibody is one of the most powerful new cancer immunotherapies, enhancing immune priming of effector CD8 T cells by dendritic cells, leading to increased antitumor activity. We investigated the use of anti-CD40 antibody for the treatment of postoperative recurrence and metastasis, with regional lymphadenectomy, in a murine model of cancer. Subcutaneous AB1-HA mesothelioma tumors were induced in BALB/c mice. Established tumors were surgically excised on day 16, with or without sentinel lymph node removal. On the day of surgery, animals were rechallenged with AB1-HA tumor cells at the surgical site (local recurrence) or the opposite flank (metastasis). Postoperative tumors were treated with anti-CD40 (FGK45) on emergence, delivered either intratumorally, peritumorally, or systemically. Local or systemic anti-CD40 treatment slowed postsurgical metastatic growth relative to untreated controls (P = 0.020) and improved survival from metastasis. Anti-CD40 also retarded the growth of local recurrences (P = 0.004) and improved survival from recurrence. Sentinel lymph node dissection did not impair efficacy (P > 0.05). This study demonstrates that anti-CD40 therapy, given either locally or systemically, may be a powerful and readily translatable adjuvant to cancer surgery, including in cases where regional lymphadenectomy is indicated.
Subject(s)
Adjuvants, Immunologic/therapeutic use , Antibodies, Monoclonal/therapeutic use , CD40 Antigens/immunology , Immunotherapy , Mesothelioma/therapy , Animals , Cell Line, Tumor , Disease Models, Animal , Female , Lymph Nodes/surgery , Mesothelioma/pathology , Mice , Mice, Inbred BALB C , Neoplasm Metastasis , Neoplasm Recurrence, Local , Postoperative Complications/pathology , Postoperative Complications/therapy , Tumor Burden/drug effectsABSTRACT
The endothelin-A receptor (Ednra) is involved in several physiological, pathological, and developmental pathways. Known for its function in vasoconstriction after being activated by endothelin-1, Ednra also controls cephalic neural crest cell development and appears to play a role in several pathologies, including cancer and periodontitis. However, the mechanisms regulating Ednra expression have not been identified despite its important functions. In this study, we investigated the role progesterone plays in Ednra gene expression in vivo and in vitro. In mice, pregnancy promotes Ednra expression in the heart, kidney, lung, uterus, and placenta, and the up-regulation is mediated by progesterone. We determined that the conserved region between -5.7 and -4.2 kb upstream of the mouse Ednra gene is necessary for the progesterone response. We also found that progesterone mediates Ednra activation through progesterone receptor B activation by its recruitment to PRE6, one of the 6 progesterone response elements found in that locus. However, gene activation by means of a GATA2 site was also necessary for the progesterone response. The Gata2 transcription factor enhances the progesterone response mediated by the progesterone receptor B. Together these results indicate that progesterone regulates Ednra expression by synergizing with Gata2 activity, a previously unknown mechanism. This mechanism may have an impact on pathologies involving the endothelin signaling.
Subject(s)
GATA2 Transcription Factor/physiology , Progesterone/physiology , Receptor, Endothelin A/genetics , Animals , Base Sequence , Female , Gene Expression Regulation , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Organ Specificity , Pregnancy , Primary Cell Culture , Promoter Regions, Genetic , Receptor, Endothelin A/metabolism , Response Elements , Sequence Analysis, DNA , Up-RegulationABSTRACT
An incomplete understanding on the effect of surgery on tumor-specific immunity continues to hamper efforts to combine surgery with immunotherapy in the clinic. Herein, we describe the impact of tumor resection on the tumor-specific T-cell response, showing that complete tumor resection is associated with (1) a decline in the amount of cross-presented tumor antigens, (2) a decline of cytolytic tumor-specific CD8(+) T cell activity, and (3) the development of systemic CD8(+) T cell-mediated protective immunity. Our findings are consistent with a model whereby tumor resection releases antitumor CD8(+) T cells from chronic antigen exposure, allowing a gradual differentiation toward functional antitumor memory T cells. This process depends on sentinel lymph nodes, as their removal at the time of surgery was associated with a strong negative effect on survival. We conclude that complete tumor resection provides a unique environment that boosts protective immunological memory and might provide a powerful platform for immunotherapy. Our findings also carry important implications for the design and timing of post-surgery immunotherapeutic regimens.
ABSTRACT
It has long been suggested that the essential and ubiquitous enzyme fructose 1,6-bisphosphate (FBP) aldolase could be a good drug target against bacteria and fungi, since lower organisms possess a metal-dependant (Class II) FBP aldolase, as opposed to higher organisms which possess a Schiff-base forming (Class I) FBP aldolase. We have tested the capacity of derivatives of the metal-chelating compound dipicolinic acid (DPA), as well a thiol-containing compound, to inhibit purified recombinant Class II FBP aldolases from Mycobacterium tuberculosis, Pseudomonas aeruginosa, Bacillus cereus, Bacillus anthracis, and from the Rice Blast causative agent Magnaporthe grisea. The aldolase from M. tuberculosis was the most sensitive to the metal-chelating inhibitors, with an IC(50) of 5.2 µM with 2,3-dimercaptopropanesulfonate (DMPS) and 28 µM with DPA. DMPS and the synthesized inhibitor 6-(phosphonomethyl)picolinic acid inhibited the enzyme in a time-dependent, competitive fashion, with second order rate constants of 273 and 270 M(-1) s(-1) respectively for the binding of these compounds to the M. tuberculosis aldolase's active site in the presence of the substrate FBP (K(M) 27.9 µM). The most potent first generation inhibitors were modeled into the active site of the M. tuberculosis aldolase structure, with results indicating that the metal chelators tested cannot bind the catalytic zinc in a bidentate fashion while it remains in its catalytic location, and that most enzyme-ligand interactions involve the phosphate binding pocket residues.
Subject(s)
Chelating Agents/chemistry , Enzyme Inhibitors/chemistry , Fructose-Bisphosphate Aldolase/antagonists & inhibitors , Fructose-Bisphosphate Aldolase/chemistry , Binding Sites , Binding, Competitive , Chelating Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Metals/chemistry , Models, Molecular , Mycobacterium tuberculosis/enzymology , Picolinic Acids/chemistry , Picolinic Acids/pharmacology , Protein Conformation , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacology , Unithiol/chemistry , Zinc/chemistryABSTRACT
STUDY DESIGN: Mechanical testing of cadaveric spines. OBJECTIVE: To test the hypothesis that, in the ageing spine, vertebrae deform more than discs, and contribute to time-dependent creep. SUMMARY OF BACKGROUND DATA: Intervertebral discs and vertebrae deform under load, narrowing the intervertebral foramen and increasing the risk of nerve root entrapment. Little is known about compressive deformations when elderly spines are subjected to sustained physiologic loading. METHODS: A total of 117 thoracolumbar motion segments, aged 19 to 96 yrs (mean, 69), were subjected to 1kN compressive loading for 0.5, 1, or 2 hours. Deformations during the first 7 seconds were designated "elastic" and subsequent deformations as "creep". A 3-parameter model was fitted to experimental data in order to characterize their viscous modulus E1, elastic modulus E2 (initial stiffness), and viscosity eta (resistance to fluid flow). Intradiscal pressure (IDP) was measured using a miniature needle-mounted transducer. In 17 specimens loaded for 0.5 hours, an optical MacReflex system measured compressive deformations separately in the disc and each vertebral body. RESULTS: On average, the disc contributed 28% of the spine's elastic deformation, 51% of the creep deformation, and 38% of total deformation. Elastic, creep, and total deformations of 84 motion segments in 2-hour tests averaged 0.87, 1.37, and 2.24 mm respectively. Measured deformations were predicted accurately by the model (average r2 = 0.97), but E1, E2, and eta depended on the duration of loading. E1 and eta decreased with advancing age and disc degeneration, in proportion to falling IDP (P < 0.001). Total compressive deformation increased with age, but rarely exceeded 3 mm. CONCLUSION: When the ageing spine is compressed, vertebral bodies show greater elastic deformations than intervertebral discs, and creep by a similar amount. Responses to axial compression depend largely on IDP, but deformations appear to be limited by impaction of adjacent neural arches. Total compressive deformations are sufficient to cause foraminal stenosis in some individuals.
Subject(s)
Aging , Intervertebral Disc Degeneration/etiology , Intervertebral Disc/pathology , Lumbar Vertebrae/pathology , Spinal Stenosis/etiology , Thoracic Vertebrae/pathology , Adult , Age Factors , Aged , Aged, 80 and over , Biomechanical Phenomena , Cadaver , Elasticity , Humans , Intervertebral Disc/diagnostic imaging , Intervertebral Disc/physiopathology , Intervertebral Disc Degeneration/pathology , Intervertebral Disc Degeneration/physiopathology , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/physiopathology , Middle Aged , Models, Biological , Pressure , Radiography , Spinal Stenosis/pathology , Spinal Stenosis/physiopathology , Stress, Mechanical , Thoracic Vertebrae/diagnostic imaging , Thoracic Vertebrae/physiopathology , Viscosity , Weight-BearingABSTRACT
Host-adapted strains of Salmonella enterica cause systemic infections and have the ability to persist systemically for long periods of time despite the presence of a robust immune response. Chronically infected hosts are asymptomatic and transmit disease to naïve hosts via fecal shedding of bacteria, thereby serving as a critical reservoir for disease. We show that the bacterial effector protein SseI (also called SrfH), which is translocated into host cells by the Salmonella Pathogenicity Island 2 (SPI2) type III secretion system (T3SS), is required for Salmonella typhimurium to maintain a long-term chronic systemic infection in mice. SseI inhibits normal cell migration of primary macrophages and dendritic cells (DC) in vitro, and such inhibition requires the host factor IQ motif containing GTPase activating protein 1 (IQGAP1), an important regulator of cell migration. SseI binds directly to IQGAP1 and co-localizes with this factor at the cell periphery. The C-terminal domain of SseI is similar to PMT/ToxA, a bacterial toxin that contains a cysteine residue (C1165) that is critical for activity. Mutation of the corresponding residue in SseI (C178A) eliminates SseI function in vitro and in vivo, but not binding to IQGAP1. In addition, infection with wild-type (WT) S. typhimurium suppressed DC migration to the spleen in vivo in an SseI-dependent manner. Correspondingly, examination of spleens from mice infected with WT S. typhimurium revealed fewer DC and CD4(+) T lymphocytes compared to mice infected with Delta sseI S. typhimurium. Taken together, our results demonstrate that SseI inhibits normal host cell migration, which ultimately counteracts the ability of the host to clear systemic bacteria.
Subject(s)
Bacterial Proteins/physiology , Cell Movement , Host-Pathogen Interactions , Membrane Proteins/physiology , Salmonella Infections/etiology , Salmonella enterica/pathogenicity , Animals , Dendritic Cells/microbiology , Dendritic Cells/physiology , Macrophages/microbiology , Macrophages/physiology , Mice , Spleen/immunology , Time FactorsABSTRACT
The IQGAP family comprises three proteins in humans. The best characterized is IQGAP1, which participates in protein-protein interactions and integrates diverse signaling pathways. IQGAP2 and IQGAP3 harbor all the domains identified in IQGAP1, but their biological roles are poorly defined. Proteins that bind IQGAP1 include Cdc42 and Rac1, E-cadherin, beta-catenin, calmodulin and components of the mitogen-activated protein kinase pathway, all of which are involved in cancer. Here, we summarize the biological functions of IQGAPs that may contribute to neoplasia. Additionally, we review published data which implicate IQGAPs in cancer and tumorigenesis. The cumulative evidence suggests IQGAP1 is an oncogene while IQGAP2 may be a tumor suppressor.