A new study shows that plasma levels of branched-chain amino acids are elevated in subjects several years before they are diagnosed with pancreatic cancer. This may reflect breakdown of peripheral ...protein stores in the early stages of the disease.
Shigella flexneri contact with enterocytes induces a burst of protein secretion via its type III secretion apparatus (TTSA) as an initial step in cellular invasion. We have previously reported that ...IpaD is positioned at the TTSA needle tip (M. Espina et al., Infect. Immuno. 74:4391-4400, 2006). From this position, IpaD senses small molecules in the environment to control the presentation of IpaB to the needle tip. This step occurs without type III secretion induction or IpaC recruitment to the S. flexneri surface. IpaC is then transported to the S. flexneri surface when target cell lipids are added, and this event presumably mimics host cell contact. Unlike IpaB mobilization, IpaC surface presentation is closely linked to secretion induction. This study demonstrates that sphingomyelin and cholesterol are key players in type III secretion induction and that they appear to interact with IpaB to elicit IpaC presentation at the TTSA needle tip. Furthermore, IpaB localization at the needle tip prior to membrane contact provides the optimal set of conditions for host cell invasion. Thus, the S. flexneri type III secretion system can be induced in a stepwise manner, with the first step being the stable association of IpaD with the needle tip, the second step being the sensing of small molecules by IpaD to mobilize IpaB to the tip, and the third step being the interaction of lipids with IpaB to induce IpaC localization at the needle tip concomitant with translocon insertion into the host membrane and type III secretion induction.
Context.The detection of gamma rays in the very-high-energy (VHE) energy range (100 GeV–100 TeV) provides a direct view of the parent population of ultra-relativistic particles found in astrophysical ...sources. For this reason, VHE gamma rays are useful for understanding the underlying astrophysical processes in non-thermal sources. Aims.We investigate unidentified VHE gamma-ray sources that have been discovered with HESS in the most sensitive blind survey of the Galactic plane at VHE energies conducted so far. Methods.The HESS array of imaging atmospheric Cherenkov telescopes (IACTs) has a high sensitivity compared with previous instruments (~$0.01\:\mathrm{Crab}$ in 25 h observation time for a $5\sigma$ point-source detection), and with its large field of view, is well suited for scan-based observations. The on-going HESS survey of the inner Galaxy has revealed a large number of new VHE sources, and for each we attempt to associate the VHE emission with multi-wavelength data in the radio through X-ray wavebands. Results. For each of the eight unidentified VHE sources considered here, we present the energy spectra and sky maps of the sources and their environment. The VHE morphology is compared with available multi-wavelength data (mainly radio and X-rays). No plausible counterparts are found.
Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 1,086 ...cancer cell lines to identify selective coessentiality modules and found that a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1, and UBR4 is required for the survival of a subset of epithelial tumors that exhibit a high degree of aneuploidy. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) by stabilization of the heme-regulated inhibitor, a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new therapeutic strategy.
We describe the identification of a heretofore unrecognized ubiquitin ligase complex that prevents the aberrant activation of the ISR in a subset of cancer cells. This provides a novel insight on the regulation of ISR and exposes a therapeutic opportunity to selectively eliminate these cancer cells. See related commentary Leli and Koumenis, p. 535. This article is highlighted in the In This Issue feature, p. 517.
The role of brain HIV load in the pathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. To try and determine if the amount of HIV drives the severity of pathology, a severe ...combined immunodeficient (SCID) mouse model of HIV encephalitis (HIVE) was utilized to determine the effectiveness of a systemically administered combined antiretroviral (cART) regimen. SCID mice were inoculated intracerebrally with HIV-infected or uninfected (control) human macrophages and treated subcutaneously with cART or saline for 10 days. Immunohistochemistry was then used to examine gliosis and neuronal damage. Drug levels were measured in brain and plasma using high-performance liquid chromatography. Peak plasma and brain levels of atazanavir, tenofovir, and emtricitabine were determined to be 1 h post-injection of cART therapy. cART significantly reduced neuropathological features of HIVE, including astrogliosis and the presence of mononuclear phagocytes, and ameliorated reduced MAP2 (neuronal integrity) staining. However, cART did not eradicate HIV from the brain. Using this animal model of HIVE, these data indicate effective penetration of cART reduces brain viral loads and HIV pathology, possibly by eliminating the production of HIV proteins, virus infected cells, or both. Importantly, these data suggest that viral load directly affects the extent of pathology seen in the brain, particularly neuronal damage, which implies that more effective suppression of HIV in the CNS could reduce currently highly prevalent forms of HAND. However, these data also strongly suggest that cART will not eliminate HIV from the brain and that adjunctive therapies must be developed.
Aims. The X-ray–TeV connection and the evolution of the emitting particle population is studied in high-energy peaked BL Lac objects, by obtaining spectral information in both bands on sub-hour ...timescales. Methods. Simultaneous observations with HESS, Chandra and the Bronberg optical observatory were performed on the BL Lac object PKS 2155–304 in the night of July 29–30 2006, when the source underwent a major γ-ray outburst during its high-activity state of Summer 2006. This event took place about 44 h after the other major outburst of the night of July 27–28, which is known for its ultrafast variability. An unprecedented 6 to 8 h of simultaneous, uninterrupted coverage was achieved, with spectra and light curves measured down to 7 and 2 min timescales, respectively. Results. The source exhibited one major flare along the night, at high energies. The γ-ray flux reached a maximum of ~11 times the Crab flux (>400 GeV), with rise/decay timescales of ~1 h, plus a few smaller-amplitude flares superimposed on the decaying phase. The emission in the X-ray and VHE γ-ray bands is strongly correlated, with no evidence of lags. The spectra also evolve with similar patterns, and are always soft (photon index Γ > 2), indicating no strong shift of the peaks in the spectral energy distribution towards higher energies. Only at the flare maximum is there evidence that the γ-ray peak is inside the observed passband, at ~400–600 GeV. The VHE spectrum shows a curvature that is variable with time and stronger at higher fluxes. The huge VHE variations (~22$\times$) are only accompanied by small-amplitude X-ray and optical variations (factor 2 and 15% respectively). The source has shown for the first time in a high-energy peaked BL Lac object a large Compton dominance $(L_{\rm C}/L_{\rm S}\sim 10)$ – rapidly evolving – and a cubic relation between VHE and X-ray flux variations, during a decaying phase. These results challenge the common scenarios for the TeV-blazar emission.
This biennial
Review summarizes much of particle physics. Using data from previous editions, plus 2778 new measurements from 645 papers, we list, evaluate, and average measured properties of gauge ...bosons, leptons, quarks, mesons, and baryons. We also summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors, probability, and statistics. Among the 108 reviews are many that are new or heavily revised including those on CKM quark-mixing matrix,
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A booklet is available containing the Summary Tables and abbreviated versions of some of the other sections of this full
Review. All tables, listings, and reviews (and errata) are also available on the Particle Data Group website:
http://pdg.lbl.gov.
The sparse vascularity of pancreatic ductal adenocarcinoma (PDAC) presents a mystery: What prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support ...growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote HH signaling in fibroblasts, leading to inhibition of noncanonical WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues.
We present a key mechanism of tumor angiosuppression, a process that sculpts the physiologic, cellular, and metabolic environment of PDAC. We further present a computational and experimental framework for the dissection of complex signaling cascades that propagate among multiple cell types in the tissue environment. This article is featured in Selected Articles from This Issue, p. 201.
To examine the additive effect of age on disability for adults with spinal cord injury (SCI).
Prospective cohort study.
SCI Model Systems.
Individuals with SCI (median age at injury, 32 y; range, ...6-88 y) with a discharge motor FIM score and at least 1 follow-up motor FIM score who also provided measures of other covariates (N=1660). Of the total sample, 79% were men, 72% were white, 16% had incomplete paraplegia, 33% had complete paraplegia, 30% had incomplete tetraplegia, and 21% had complete tetraplegia.
Not applicable.
The primary study outcome was the motor subscale of the FIM. A mixed-models approach was used to examine the additive effect of age on disability for individuals with SCI.
When controlling for motor FIM at discharge from rehabilitation, level and severity of injury, age at injury, sex, race, and the age × time interaction were not significant (P=.07). Age at the time of SCI was significantly associated with motor FIM (F1,238=22.49, P<.001). Two sensitivity analyses found significant interactions for both age × time (P=.03, P=.02) and age × time-square (P=.01, P=.006) models. Trajectory of motor FIM scores is moderated slightly by age at the time of injury. The older participants were at the time of injury, the greater the curvature and the more rapid decline were found in later years.
These findings indicate that age moderately influences disability for some individuals with SCI: the older the age at the time of injury, the greater the influence age has on disability. The findings serve as an important empirical foundation for the evaluation and development of interventions designed to augment accelerated aging experienced by individuals with SCI.
Resumen Introducción Los niños afectados de inmunodeficiencias primarias presentan infecciones graves y mayor prevalencia de manifestaciones autoinmunitarias, alergias y enfermedad ...linfoproliferativa. El trasplante alogénico de precursores hematopoyéticos ha sido el único tratamiento curativo durante décadas. Pacientes y métodos Pacientes con inmunodeficiencias primarias que recibieron trasplante alogénico de precursores hematopoyéticos desde 1985 hasta 2011, recogidos en el Registro Nacional del Grupo Español para Trasplante de Médula Ósea en Niños. Resultados Ciento cincuenta y nueve niños recibieron un total de 173 trasplantes, 97 por inmunodeficiencia combinada grave, 30 por enfermedades de disregulación inmunitaria, 25 por síndrome de Wiskott-Aldrich y 21 por defectos de número y/o función de los fagocitos. La mediana de edad al diagnóstico fue de 6 meses (17 días-168 meses) y de 12 meses (1 mes-189 meses) al trasplante. Los donantes fueron hermano HLA idéntico en 30 (19%), donante familiar alternativo en 40 (25%) y donante no emparentado en 89 (56%). La fuente de progenitores fue médula ósea en 68 (43%), sangre de cordón umbilical en 52 (33%) y sangre periférica en 39 (24%). Permanecen vivos 98 niños (61,6%), 57 (35,9%) fallecieron. La supervivencia libre de enfermedad a los 10 años fue del 63, el 90% para los pacientes trasplantados de hermano HLA idéntico, el 36% para los trasplantados de un donante familiar alternativo y el 66 para los trasplantados de donante no emparentado. Conclusiones Los mejores resultados se obtienen con un hermano HLA idéntico, cuando no se dispone de este, otros donantes deben ser considerados.
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