The bacterial pathogen Yersinia pestis, the cause of plague in humans and animals, normally has a sylvatic lifestyle, cycling between fleas and mammals. In contrast, laboratory-grown Y. pestis ...experiences a more constant environment and conditions that it would not normally encounter. The transition from the natural environment to the laboratory results in a vastly different set of selective pressures, and represents what could be considered domestication. Understanding the kinds of adaptations Y. pestis undergoes as it becomes domesticated will contribute to understanding the basic biology of this important pathogen. In this study, we performed a parallel serial passage experiment (PSPE) to explore the mechanisms by which Y. pestis adapts to laboratory conditions, hypothesizing that cells would undergo significant changes in virulence and nutrient acquisition systems. Two wild strains were serially passaged in 12 independent populations each for ~750 generations, after which each population was analyzed using whole-genome sequencing, LC-MS/MS proteomic analysis, and GC/MS metabolomics. We observed considerable parallel evolution in the endpoint populations, detecting multiple independent mutations in ail, pepA, and zwf, suggesting that specific selective pressures are shaping evolutionary responses. Complementary LC-MS/MS proteomic data provide physiological context to the observed mutations, and reveal regulatory changes not necessarily associated with specific mutations, including changes in amino acid metabolism and cell envelope biogenesis. Proteomic data support hypotheses generated by genomic data in addition to suggesting future mechanistic studies, indicating that future whole-genome sequencing studies be designed to leverage proteomics as a critical complement.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Amyloidosis is a malignant pathology associated with the formation of proteinaceous amyloid fibrils that deposit in organs and tissues, leading to dysfunction and severe morbidity. More than 25 ...proteins have been identified as components of amyloid, but the most common form of systemic amyloidosis is associated with the deposition of amyloid composed of Ig light chains (AL). Clinical management of amyloidosis focuses on reducing synthesis of the amyloid precursor protein. However, recently, passive immunotherapy using amyloid fibril-reactive antibodies, such as 11-1F4, to remove amyloid from organs has been shown to be effective at restoring organ function in patients with AL amyloidosis. However, 11-1F4 does not bind amyloid in all AL patients, as evidenced by PET/CT imaging, nor does it efficiently bind the many other forms of amyloid. To enhance the reactivity and expand the utility of the 11-1F4 mAb as an amyloid immunotherapeutic, we have developed a pretargeting “peptope” comprising a multiamyloid-reactive peptide, p5+14, fused to a high-affinity peptide epitope recognized by 11-1F4. The peptope, known as p66, bound the 11-1F4 mAb in vitro with subnanomolar efficiency, exhibited multiamyloid reactivity in vitro and, using tissue biodistribution and SPECT imaging, colocalized with amyloid deposits in a mouse model of systemic serum amyloid A amyloidosis. Pretreatment with the peptope induced 11-1F4 mAb accumulation in serum amyloid A deposits in vivo and enhanced 11-1F4–mediated dissolution of a human AL amyloid extract implanted in mice.
X-Ray Imaging Spectrometer (XIS) on Board Suzaku Koyama, Katsuji; Tsunemi, Hiroshi; Dotani, Tadayasu ...
Publications of the Astronomical Society of Japan,
01/2007, Letnik:
59, Številka:
sp1
Journal Article
Recenzirano
Odprti dostop
The XIS is an X-ray Imaging Spectrometer system, consisting of state-of-the-art charge-coupled devices (CCDs) optimized for X-ray detection, camera bodies, and control electronics. Four sets of XIS ...sensors are placed at the focal planes of the grazing-incidence, nested thin-foil mirrors (XRT: X-Ray Telescope) onboard the Suzaku satellite. Three of the XIS sensors have front-illuminated CCDs, while the other has a back-illuminated CCD. Coupled with the XRT, the energy range of 0.2–12 keV with energy resolution of 130 eV at 5.9 keV, and a field of view of
$18^\prime \times 18^\prime$
are realized. Since the Suzaku launch on 2005 July 10, the XIS has been functioning well.
A direct antidepressant effect has been reported for certain dopaminergic medications used in the treatment of Parkinson's disease (PD).
To examine whether dopaminergic medications may exert ...differential effects on mood in early PD.
We analyzed prospectively-collected 5-year data on 405 early, drug-naïve (at baseline) PD patients enrolled in the Parkinson's Progression Markers Initiative (PPMI) cohort study, initiated on levodopa, dopamine agonists (DAs), or monoamine-oxidase type B inhibitors (iMAO-B) under naturalistic conditions. The outcome for depressive symptoms was the 15-item Geriatric Depression Scale (GDS-15) score. Potential motor and cognitive confounders were measured using the Unified Parkinson's disease Rating Scale (MDS-UPDRS-III) and the Montreal Cognitive Assessment (MoCA). Three statistical models were used to determine medication effects on GDS-15 scores: unadjusted, adjusted, and a marginal structural model.
One-third of patients in this cohort met GDS-15 threshold for clinically-significant depressive symptoms (GDS-15 ≥ 5). There was a marginal positive effect on GDS-15 scores after iMAO-B treatment initiation (−0.35 95%; CI: −0.73, 0.04; p = 0.08). There were no significant interactions between any of the three medication groups, but robust interactions between MoCA scores and both DAs (p = 0.005) and iMAO-B (p = 0.03) use on GDS-15 scores. Specifically, as MoCA scores worsened, DAs yielded a steeper worsening of GDS-15 scores while iMAO-B a moderating effect on GDS-15.
Dopaminergic medications have no direct effect on mood in early, unselected PD patients.
•Mood effects by dopaminergic effects are confounded by cognitive and motor function.•There was no adjusted mood stabilizing or enhancing effect by any dopaminergic drug.•As cognition worsens, dopamine agonists are associated with worse depression scores.•MAO-B inhibitors may have a modest attenuating effect in the cognition-depression link.
BACKGROUND:The poorly healing perineal wound is a significant complication of abdominoperineal resection. The authors examined criteria for immediate flap coverage of the perineum and long-term ...cross-sectional surgical outcomes.
METHODS:Patients who underwent abdominoperineal resection or pelvic exenteration for anorectal cancer were retrospectively analyzed. Demographic characteristics, premorbid and oncologic data, surgical treatment, reconstruction method, and recovery were recorded. Outcomes of successful wound healing, surgical complications necessitating intervention (admission or return to the operating room), and progression to chronic wounds were assessed.
RESULTS:The authors identified 214 patients who underwent this procedure from 1995 to 2013. Forty-seven patients received pedicled flaps and had higher rates of recurrence and reoperation, active smoking, Crohn disease, human immunodeficiency virus, and anal cancers, and had higher American Joint Committee on Cancer tumor stages. Thirty-day complication rates were equivalent in the two groups. There were no complete flap losses or reconstructive failures. Perineal wound complication rates were marginally but not significantly higher in the flap group (55 percent versus 41 percent; p = 0.088). Infectious complications, readmissions for antibiotics, and operative revision were more frequent in the flap cohort. A larger proportion of the primary closure cohort developed chronic draining perineal wounds (23.3 versus 8.5 percent; p = 0.025).
CONCLUSIONS:Immediate flap coverage of the perineum was less likely to progress to a chronic draining wound, but had higher local infectious complication rates. The authors attribute this to increased comorbidity in the selected patient population, reflecting the surgical decision making in approaching these high-risk closures and ascertainment bias in diagnosis of infectious complications with multidisciplinary examination.
CLINICAL QUESTION/LEVEL OF EVIDENCE:Risk, III.
Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms.
Primary specimens, cell lines, patient-derived xenograft models, commercially available, and ...proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation.
Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1- naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy.
Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms. See related commentary by Varma and Diefenbach, p. 2300.
Abstract
Bat-borne zoonotic pathogens belonging to the family Paramxyoviridae, including Nipah and Hendra viruses, and the family Filoviridae, including Ebola and Marburg viruses, can cause severe ...disease and high mortality rates on spillover into human populations. Surveillance efforts for henipaviruses and filoviruses have been largely restricted to the Old World; however, recent studies suggest a potentially broader distribution for henipaviruses and filoviruses than previously recognized. In the current study, we screened for henipaviruses and filoviruses in New World bats collected across 4 locations in Trinidad near the coast of Venezuela. Bat tissue samples were screened using previously established reverse-transcription polymerase chain reaction assays. Serum were screened using a multiplex immunoassay to detect antibodies reactive with the envelope glycoprotein of viruses in the genus Henipavirus and the family Filoviridae. Serum samples were also screened by means of enzyme-linked immunosorbent assay for antibodies reactive with Nipah G and F glycoproteins. Of 84 serum samples, 28 were reactive with ≥1 henipavirus glycoprotein by ≥1 serological method, and 6 serum samples were reactive against ≥1 filovirus glycoproteins. These data provide evidence of potential circulation of viruses related to the henipaviruses and filoviruses in New World bats.
Uncertainties in atomic models will introduce noticeable additional systematics in calculating the flux of weak dielectronic recombination (DR) satellite lines, affecting the detection and flux ...measurements of other weak spectral lines. One important example is the Ar xvii Heβ DR, which is expected to be present in emission from the hot intracluster medium of galaxy clusters and could impact measurements of the flux of the 3.5 keV line that has been suggested as a secondary emission from a dark matter interaction. We perform a set of experiments using the Lawrence Livermore National Laboratory's electron beam ion trap (EBIT-I) and the X-ray Spectrometer quantum calorimeter (XRS/EBIT) to test the Ar xvii Heβ DR origin of the 3.5 keV line. We measured the X-ray emission following resonant DR onto helium-like and lithium-like Argon using EBIT-I's Maxwellian simulator mode at a simulated electron temperature of Te = 1.74 keV. The measured flux of the Ar xvii Heβ DR lined is too weak to account for the flux in the 3.5 keV line, assuming reasonable plasma parameters. We, therefore, rule out Ar xvii Heβ DR as a significant contributor to the 3.5 keV line. A comprehensive comparison between the atomic theory and the EBIT experiment results is also provided.
To evaluate the dosimetric impact of rotational setup errors in stereotactic body radiotherapy (SBRT) treatment of liver tumors and to investigate whether translational shifts can compensate for ...rotation.
The positioning accuracy in 20 patients with liver malignancies treated with SBRT was reevaluated offline by matching the patients' cone-beam computed tomography (CT) scans (n=75) to the planning CT scans and adjusting the 3 rotational angles (pitch, roll, and yaw). Systematic and random setup errors were calculated. The dosimetric changes caused by rotational setup errors were quantified for both simulated and observed patient rotations. Dose distributions recalculated on the rotated CT scans were compared with the original planned doses. Translational corrections were simulated based on manual translational registration of the rotated images to the original CT scans. The correction efficacy was evaluated by comparing the recalculated plans with the original plans.
The systematic rotational setup errors were -0.06° ± 0.68°, -0.29° ± 0.62°, and -0.24° ± 0.61°; the random setup errors were 0.80°, 1.05°, and 0.61° for pitch, roll, and yaw, respectively. Analysis of CBCT images showed that 56.0%, 14.7%, and 1.3% of treated fractions had rotational errors of >1°, >2°, and >3°, respectively, in any one of the rotational axes. Rotational simulations demonstrated that the reduction of gross tumor volume (GTV) coverage was <2% when rotation was <3°. Recalculated plans using actual patient roll motions showed similar reduction (<2%) in GTV coverage. Translational corrections improved the GTV coverage to within 3% of the original values. For organs at risk (OAR), the dosimetric impact varied case by case.
Actual rotational setup errors in SBRT for liver tumors are relatively small in magnitude and are unlikely to affect GTV coverage significantly. Translational corrections can be optimized to compensate for rotational setup errors. However, caution regarding possible dose increases to OAR needs to be exercised.
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