The slow growth rate and genetic intractability of tubercle bacilli has hindered progress toward understanding tuberculosis, one of the most frequent causes of death worldwide. We overcame this ...roadblock through development of near-infrared (NIR) fluorogenic substrates for β-lactamase, an enzyme expressed by tubercle bacilli, but not by their eukaryotic hosts, to allow real-time imaging of pulmonary infections and rapid quantification of bacteria in living animals by a strategy called reporter enzyme fluorescence (REF). This strategy has a detection limit of 6 ± 2 x 10² colony-forming units (CFU) of bacteria with the NIR substrate CNIR5 in only 24 h of incubation in vitro, and as few as 10⁴ CFU in the lungs of live mice. REF can also be used to differentiate infected from uninfected macrophages by using confocal microscopy and fluorescence activated cell sorting. Mycobacterium tuberculosis and the bacillus Calmette-Guérin can be tracked directly in the lungs of living mice without sacrificing the animals. Therapeutic efficacy can also be evaluated through loss of REF signal within 24 h posttreatment by using in vitro whole-bacteria assays directly in living mice. We expect that rapid quantification of bacteria within tissues of a living host and in the laboratory is potentially transformative for tuberculosis virulence studies, evaluation of therapeutics, and efficacy of vaccine candidates. This is a unique use of an endogenous bacterial enzyme probe to detect and image tubercle bacilli that demonstrates REF is likely to be useful for the study of many bacterial infections.
Purpose Adoptive transfer of genetically modified T cells is being explored as a treatment for patients with metastatic cancer. Most current strategies use genes that encode major histocompatibility ...complex (MHC) class I-restricted T-cell receptors (TCRs) or chimeric antigen receptors to genetically modify CD8
T cells or bulk T cells for treatment. Here, we evaluated the safety and efficacy of an adoptive CD4
T-cell therapy using an MHC class II-restricted, HLA-DPB1*0401-restricted TCR that recognized the cancer germline antigen, MAGE-A3 (melanoma-associated antigen-A3). Patients and Methods Patients received a lymphodepleting preparative regimen, followed by adoptive transfer of purified CD4
T cells, retrovirally transduced with MAGE-A3 TCR plus systemic high-dose IL-2. A cell dose escalation was conducted, starting at 10
total cells and escalating at half-log increments to approximately 10
cells. Nine patients were treated at the highest dose level (0.78 to 1.23 × 10
cells). Results Seventeen patients were treated. During the cell dose-escalation phase, an objective complete response was observed in a patient with metastatic cervical cancer who received 2.7 × 10
cells (ongoing at ≥ 29 months). Among nine patients who were treated at the highest dose level, objective partial responses were observed in a patient with esophageal cancer (duration, 4 months), a patient with urothelial cancer (ongoing at ≥ 19 months), and a patient with osteosarcoma (duration, 4 months). Most patients experienced transient fevers and the expected hematologic toxicities from lymphodepletion pretreatment. Two patients experienced transient grade 3 and 4 transaminase elevations. There were no treatment-related deaths. Conclusion These results demonstrate the safety and efficacy of administering autologous CD4
T cells that are genetically engineered to express an MHC class II-restricted antitumor TCR that targets MAGE-A3. This clinical trial extends the reach of TCR gene therapy for patients with metastatic cancer.
Dysfunction of cerebral endothelial cells (CECs) has been implicated in the pathology of Alzheimer's disease (AD). Despite evidence showing cytotoxic effects of oligomeric amyloid-β (oAβ) and Tau ...(oTau) in the central nervous system, their direct effects on CECs have not been fully investigated. In this study, we examined the direct effects of oAβ, oTau, and their combination on cell adhesion properties and inflammatory responses in CECs. We found that both oAβ and oTau increased cell stiffness, as well as the p-selectin/Sialyl-Lewis
(sLe
) bonding-mediated membrane tether force and probability of adhesion in CECs. Consistent with these biomechanical alterations, treatments with oAβ or oTau also increased actin polymerization and the expression of p-selectin at the cell surface. These toxic oligomeric peptides also triggered inflammatory responses, including upregulations of p-NF-kB p65, IL-1β, and TNF-α. In addition, they rapidly activated the RhoA/ROCK pathway. These biochemical and biomechanical changes were further enhanced by the treatment with the combination of oAβ and oTau, which were significantly suppressed by Fasudil, a specific inhibitor for the RhoA/ROCK pathway. In conclusion, our data suggest that oAβ, oTau, and their combination triggered subcellular mechanical alterations and inflammatory responses in CECs through the RhoA/ROCK pathway.
The roles of Ca/Fe phases on selenium (Se) enrichment behavior in fly ash during coal combustion were investigated by examining the Ca/Fe mineralogy of various ash samples, exploring the binding ...forms of Se in fly ashes, and performing bench-scale adsorption experiments (150-1000 ℃). The results indicated that Se capture by fly ash is a function of flue gas temperature, particle size, and more importantly, the contents and form of Ca/Fe in combustion ash. Physical condensation/adsorption was mainly determined by temperature and particle size, contributing to less than 25% of total Se in fly ash. The remaining Se in fly ash was captured by chemical reactions of Se with ash components. Calcium in ash mostly was present as Ca-aluminosilicates, Ca-silicates, gypsum, or complex Ca-Al-Si-Fe-O mixed phases. Iron mainly occurred as Fe-silicates and some crystalline minerals including hematite, magnetite, and maghemite. Although adsorption experiments found that only CaO was able to capture SeO2 (g) at high temperature (> 900 ℃), the roles of lime as well as Fe2+-/Fe3+-silicates (conclusion from previous literature) can be excluded, as inferred from the small amount of CaO in ash and the lack of correlation between Fe-silicate and Se. Sequential extraction experiments and electron microscopy analysis revealed that Fe-bound Se was dominant and iron oxides might be the critical phase for Se retention. Simulated adsorption experiments demonstrated that magnetite had the best Se capture ability among the iron minerals. The extraction of Fe-bound Se from coal fly ash required more stringent conditions than that of physiosorbed-Se and Ca-bound Se. Therefore, pretreatment methods including magnetic separation, flotation, size segregation, etc. were suggested to be used prior to acid leaching. This study can provide scientific basis for developing high-efficiency Se recovery methods or Se emission control techniques for high-Se coal utilization in thermal power stations.
We examine the epidemiology, natural history, and prognostic factors that affect the duration of survival for islet cell carcinoma by using population-based registries.
The Surveillance, ...Epidemiology, and End Results (SEER) Program database (1973-2003 release, April 2006) was used to identify cases of islet cell carcinoma by histology codes and tumor site.
A total of 1310 (619 women and 691 men) cases with a median age of 59 years were identified. The annual age-adjusted incidence in the periods covered by SEER 9 (1973-1991), SEER 13 (1992-1999), and SEER 17 (2000-2003) were .16, .14, and .12 per 100,000, respectively. The estimated 28-year limited duration prevalence on January 1, 2003, in the United States was 2705 cases. Classified by SEER stage, localized, regional, and distant stages corresponded to 14%, 23%, and 54% of cases. The median survival was 38 months. By stage, median survival for patients with localized, regional, and distant disease were 124 (95% CI, 80-168) months, 70 (95% CI, 54-86) months, and 23 (95% CI, 20-26) months, respectively. By multivariate Cox proportional modeling, stage (P < .001), primary tumor location (P = .04), and age at diagnosis (P < .001) were found to be significant predictors of survival.
Islet cell carcinomas account for approximately 1.3% of cancers arising in the pancreas. Most patients have advanced disease at the time of diagnosis. Despite the disease's reputation of being indolent, survival of patients with advanced disease remains only 2 years. Development of novel therapeutic approaches is needed.
The objective of this study was to identify the aggregation pheromone of the melon thrips Thrips palmi, a major pest of vegetable and ornamental plants around the world. The species causes damage ...both through feeding activities and as a vector of tospoviruses, and is a threat to world trade and European horticulture. Improved methods of detecting and controlling this species are needed and the identification of an aggregation pheromone will contribute to this requirement. Bioassays with a Y-tube olfactometer showed that virgin female T. palmi were attracted to the odour of live males, but not to that of live females, and that mixed-age adults of both sexes were attracted to the odour of live males, indicating the presence of a male-produced aggregation pheromone. Examination of the headspace volatiles of adult male T. palmi revealed only one compound that was not found in adult females. It was identified by comparison of its mass spectrum and chromatographic details with those of similar compounds. This compound had a structure like that of the previously identified male-produced aggregation pheromone of the western flower thrips Frankliniella occidentalis. The compound was synthesised and tested in eggplant crops infested with T. palmi in Japan. Significantly greater numbers of both males and females were attracted to traps baited with the putative aggregation pheromone compared to unbaited traps. The aggregation pheromone of T. palmi is thus identified as (R)-lavandulyl 3-methyl-3-butenoate by spectroscopic, chromatographic and behavioural analysis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Neuroendocrine tumors are a heterogeneous group of tumors originating in various anatomic locations. The management of this disease poses a significant challenge because of the heterogeneous clinical ...presentations and varying degrees of aggressiveness. The recent completion of several phase 3 trials, including those evaluating octreotide, sunitinib, and everolimus, demonstrate that rigorous evaluation of novel agents in this disease is possible and can lead to practice-changing outcomes. Nevertheless, there are many aspects to the treatment of neuroendocrine tumors that remain unclear and controversial. The North American Neuroendocrine Tumor Society published a set of consensus guidelines in 2010, which provided an overview for the treatment of patients with these malignancies. Here, we present a set of consensus tables intended to complement these guidelines and serve as a quick, accessible reference for the practicing physician.
Accurate and reliable damage characterization (i.e., damage detection, localization, and evaluation of extent) in civil structures and infrastructure is an important objective of structural health ...monitoring (SHM). Highly accurate and reliable characterization of damage at early stages requires continuous or quasi-continuous direct sensing of the critical parameters. Direct sensing requires deploying dense arrays of sensors, to enhance the probability that damage will result in signals that can be directly acquired by the sensors. However, coverage by dense arrays of sensors over the large areas that are of relevance represents an enormous challenge for current technologies. Large area electronics (LAE) is an emerging technology that can enable the formation of dense sensor arrays spanning large areas (several square meters) on flexible substrates. This paper explores the requirements and technology for a sensing sheet for SHM based on LAE and crystalline silicon CMOS integrated circuits (ICs). The sensing sheet contains a dense array of thin-film full-bridge resistive strain sensors, along with the electronics for strain readout, full-system self-powering, and communication. Research on several stages is presented for translating the sensing sheet to practical SHM applications. This includes experimental characterization of an individual sensor's response when exposed to cracks in concrete and steel; theoretical and experimental performance evaluation of various geometrical parameters of the sensing sheet; and development of the electronics necessary for sensor readout, power management, and sensor-data communication. The concept of direct sensing has been experimentally validated, and the potential of a sensing sheet to provide direct sensing and successful damage characterization has been evaluated in the laboratory setting. A prototype of the sensing sheet has also been successfully developed and independently characterized in the laboratory, meeting the required specifications. Thus, a sensing sheet for SHM applications shows promise both in terms of practicality and effectiveness.
Abstract
We present X-ray, UV, optical, and radio observations of the nearby (≈78 Mpc) tidal disruption event AT2021ehb/ZTF21aanxhjv during its first 430 days of evolution. AT2021ehb occurs in the ...nucleus of a galaxy hosting a≈10
7
M
⊙
black hole (
M
BH
inferred from host galaxy scaling relations). High-cadence Swift and Neutron Star Interior Composition Explorer (NICER) monitoring reveals a delayed X-ray brightening. The spectrum first undergoes a gradual soft → hard transition and then suddenly turns soft again within 3 days at
δ
t
≈272 days during which the X-ray flux drops by a factor of 10. In the joint NICER+NuSTAR observation (
δ
t
= 264 days, harder state), we observe a prominent nonthermal component up to 30 keV and an extremely broad emission line in the iron
K
band. The bolometric luminosity of AT2021ehb reaches a maximum of
6.0
−
3.8
+
10.4
%
L
Edd
when the X-ray spectrum is the hardest. During the dramatic X-ray evolution, no radio emission is detected, the UV/optical luminosity stays relatively constant, and the optical spectra are featureless. We propose the following interpretations: (i) the soft → hard transition may be caused by the gradual formation of a magnetically dominated corona; (ii) hard X-ray photons escape from the system along solid angles with low scattering optical depth (∼a few) whereas the UV/optical emission is likely generated by reprocessing materials with much larger column density—the system is highly aspherical; and (iii) the abrupt X-ray flux drop may be triggered by the thermal–viscous instability in the inner accretion flow, leading to a much thinner disk.
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