Chimeric antigen receptor (CAR) T cell therapy has transformed the care of refractory B cell malignancies and holds tremendous promise for many aggressive tumors. Despite overwhelming scientific, ...clinical, and public interest in this rapidly expanding field, fundamental inquiries into CAR T cell mechanistic functioning are still in their infancy. Because CAR T cells are manufactured from donor T lymphocytes, and because CARs incorporate well-characterized T cell signaling components, it has largely been assumed that CARs signal analogously to canonical T cell receptors (TCRs). However, recent studies demonstrate that many aspects of CAR signaling are unique, distinct from endogenous TCR signaling, and potentially even distinct among various CAR constructs. Thus, rigorous and comprehensive proteomic investigations are required for rational engineering of improved CARs. Here, we review what is known about proximal CAR signaling in T cells, compare it to conventional TCR signaling, and outline unmet challenges to improving CAR T cell therapy.
Pulses of respiration from coarse woody debris (CWD) have been observed immediately following canopy disturbances, but it is unclear how long these pulses are sustained. Several factors are known to ...influence carbon flux rates from CWD, but few studies have evaluated more than temperature and moisture. We experimentally manipulated forest structure in a second-growth northern hardwood forest and measured CO₂ flux periodically for seven growing seasons following gap creation. We present an analysis of which factors, including the composition of the wood-decay fungal community influence CO₂ flux. CO₂ flux from CWD was strongly and positively related to wood temperature and varied significantly between substrate types (logs vs. stumps). For five growing seasons after treatment, the CO₂ flux of stumps reached rates up to seven times higher than that of logs. CO₂ flux of logs did not differ significantly between canopy-gap and closed-canopy conditions in the fourth through seventh post-treatment growing seasons. By the seventh season, the seasonal carbon flux of both logs and stumps had decreased significantly from prior years. Linear mixed models indicated the variation in the wood inhabiting fungal community composition explained a significant portion of variability in the CO₂ flux along with measures of substrate conditions. CO₂ flux rates were inversely related to fungal diversity, with logs hosting more species but emitting less CO₂ than stumps. Overall, our results suggest that the current treatment of CWD in dynamic forest carbon models may be oversimplified, thereby hampering our ability to predict realistic carbon fluxes associated with wood decomposition.
Much remains unknown regarding the linkages between forest structure and microclimate as they regulate detrital decomposition. In this study, we use a factorial field experiment that included canopy ...gap creation and downed woody material (DW) additions conducted in a mature northern hardwood forest. Our objectives were to (1) test the individual and combined effects of canopy gaps and DW additions on detrital mass loss; (2) determine whether the factors regulating mass loss are similar among leaf litter, experimental wood stakes, and coarse DW; and (3) assess the microclimatic variables that most strongly influence mass loss of these detrital types. After three years, leaf litter mass loss within gaps, without or with DW additions, was significantly greater than that of any non-gap treatments. Mass loss of stakes was significantly greater in gaps, intermediate in gaps with DW additions, and lowest in non-gap treatments. Mass loss of wood stakes after 8 years varied by species, with aspen (
Populus tremuloides
) losing up to 93% and sugar maple (
Acer saccharum
) up to 82% of its original mass. Fourteen years following treatment, the experimental logs lost 55–70% of their original mass, with ash (
Fraxinus
spp.) decaying faster than maple. Gap creation and DW additions individually, but not in combination, increased mass loss of coarse DW. For most substrates tested, gaps were consistently and positively related to mass loss, with approximately 10% greater mass loss in gaps compared to non-gaps. The presence of deadwood strongly moderated litter decomposition, had minimal effect on small woody substrates in the short-term after gap creation, but was influential on longer-term decay patterns of larger DW. Predictive models for each substrate varied, though shared some similar drivers. Litter mass loss was positively correlated to increasing gap size, canopy openness, and soil moisture. Stake mass loss was positively correlated to increasing gap size and canopy openness for maple, but soil temperature for aspen. Mass loss for logs was driven by increasing DW volume and gap size for ash, but soil temperature for maple. Smaller-sized materials may be more sensitive to environmental conditions as opposed to logs for which microclimatic influence may lag or remain a minor driver for at least the initial decade of decomposition. Regardless of substrate type, the findings of this work highlight the potential for greater rates of detrital mass loss from forest systems under predicted increases in canopy disturbance rates with climate change and invasive insects and diseases.
Fire corals are the only branching corals in the South Atlantic and provide an important ecological role as habitat-builders in the region. With three endemic species (
Millepora brazilensis
,
M. ...nitida
and
M. laboreli
) and one amphi-Atlantic species (
M. alcicornis
), fire coral diversity in the Brazilian Province rivals that of the Caribbean Province. Phylogenetic relationships and patterns of population genetic structure and diversity were investigated in all four fire coral species occurring in the Brazilian Province to understand patterns of speciation and biogeography in the genus. A total of 273 colonies from the four species were collected from 17 locations spanning their geographic ranges. Sequences from the 16S ribosomal DNA (rDNA) were used to evaluate phylogenetic relationships. Patterns in genetic diversity and connectivity were inferred by measures of molecular diversity, analyses of molecular variance, pairwise differentiation, and by spatial analyses of molecular variance. Morphometrics of the endemic species
M. braziliensis
and
M. nitida
were evaluated by discriminant function analysis; macro-morphological characters were not sufficient to distinguish the two species. Genetic analyses showed that, although they are closely related, each species forms a well-supported clade. Furthermore, the endemic species characterized a distinct biogeographic barrier:
M. braziliensis
is restricted to the north of the São Francisco River, whereas
M. nitida
occurs only to the south.
Millepora laboreli
is restricted to a single location and has low genetic diversity. In contrast, the amphi-Atlantic species
M. alcicornis
shows high genetic connectivity within the Brazilian Province, and within the Caribbean Province (including Bermuda), despite low levels of gene flow between these populations and across the tropical Atlantic. These patterns reflect the importance of the Amazon–Orinoco Plume and the Mid-Atlantic Barrier as biogeographic barriers, and suggest that, while
M. alcicornis
is capable of long-distance dispersal, the three endemics have restricted ranges and more limited dispersal capabilities.
One of the key challenges for nuclear physics today is to understand from first principles the effective interaction between hadrons with different quark content. First successes have been achieved ...using techniques that solve the dynamics of quarks and gluons on discrete space-time lattices
. Experimentally, the dynamics of the strong interaction have been studied by scattering hadrons off each other. Such scattering experiments are difficult or impossible for unstable hadrons
and so high-quality measurements exist only for hadrons containing up and down quarks
. Here we demonstrate that measuring correlations in the momentum space between hadron pairs
produced in ultrarelativistic proton-proton collisions at the CERN Large Hadron Collider (LHC) provides a precise method with which to obtain the missing information on the interaction dynamics between any pair of unstable hadrons. Specifically, we discuss the case of the interaction of baryons containing strange quarks (hyperons). We demonstrate how, using precision measurements of proton-omega baryon correlations, the effect of the strong interaction for this hadron-hadron pair can be studied with precision similar to, and compared with, predictions from lattice calculations
. The large number of hyperons identified in proton-proton collisions at the LHC, together with accurate modelling
of the small (approximately one femtometre) inter-particle distance and exact predictions for the correlation functions, enables a detailed determination of the short-range part of the nucleon-hyperon interaction.
Summary
Collections of micro‐organisms are a crucial element of life science research infrastructure but are vulnerable to loss and damage caused by natural or man‐made disasters, the untimely death ...or retirement of personnel, or the loss of research funding. Preservation of biological collections has risen in priority due to a new appreciation for discoveries linked to preserved specimens, emerging hurdles to international collecting and decreased funding for new collecting. While many historic collections have been lost, several have been preserved, some with dramatic rescue stories. Rescued microbes have been used for discoveries in areas of health, biotechnology and basic life science. Suggestions for long‐term planning for microbial stocks are listed, as well as inducements for long‐term preservation.
Darvadstrocel is an expanded allogeneic adipose-derived mesenchymal stem cell therapy for the treatment of complex perianal fistulas in patients with Crohn's disease. Safety and efficacy outcomes ...from the clinical trial known as "Adipose derived mesenchymal stem cells for induction of remission in perianal fistulizing Crohn's disease," or ADMIRE-CD (NCT01541579), from up to 52 weeks posttreatment were previously reported. Here, the outcomes from an extended 104-week follow-up are reported.
The goal of this study was to assess the long-term safety and efficacy of darvadstrocel at 2 years post-treatment in patients with Crohn's disease and complex perianal fistulas.
This was a phase 3 double-blind randomized controlled study (ADMIRE-CD) in patients with perianal fistulizing Crohn's disease.
This study extension was conducted in multiple hospitals across 7 European countries and Israel.
Forty patients entered the extended follow-up period: 25 patients in the darvadstrocel treatment group and 15 in the control group.
Darvadstrocel or saline solution (control group) was administered once, locally, after fistula tract curettage and internal opening closure (with previous seton placement). All patients were permitted to continue ongoing medical treatments for fistulas.
Treatment-emergent serious adverse events were recorded through week 104. Clinical remission, defined as closure of all treated external openings that were draining at baseline despite gentle finger compression, was assessed at week 104.
Of 40 patients, 37 completed the extended follow-up. Through week 104, 7 treatment-emergent serious adverse events were reported, of which 4 occurred between weeks 52 and 104. At week 104, clinical remission was reported in 14/25 (56%) patients in the darvadstrocel group and 6/15 (40%) patients in the control group.
Limitations include the small number of patients who entered the extended follow-up period, and no imaging examinations were performed at the 104-week time point.
Darvadstrocel was well tolerated and clinical remission after treatment with darvadstrocel may be sustained for up to 104 weeks in patients with perianal fistulizing Crohn's disease. See Video Abstract at http://links.lww.com/DCR/B812.ClinicalTrials.gov No: NCT01541579.
ANTECEDENTES:Darvadstrocel es una terapia con células madre mesenquimales alogénicas expandidas derivadas de tejido adiposo para el tratamiento de fístulas perianales complejas en pacientes con enfermedad de Crohn. Los resultados del ensayo clínico conocido como "Células madre mesenquimales derivadas de tejido adiposo para la inducción de la remisión en la enfermedad de Crohn fistulizante perianal" o ADMIRE-CD (NCT01541579), en cuanto a la seguridad y eficacia hasta 52 semanas después del tratamiento, fueron previamente informados. Seguidamente, se presentan los resultados de un seguimiento extendido de 104 semanas.OBJETIVO:Evaluar la seguridad y eficacia a largo plazo de darvadstrocel a dos años del tratamiento en pacientes con enfermedad de Crohn y fístulas perianales complejas.DISEÑO:Este fue un estudio de fase 3, aleatorizado, a doble ciego, controlado (ADMIRE-CD) en pacientes con enfermedad de Crohn perianal fistulizante.DESARROLLO:Esta extensión del estudio se realizó en varios hospitales de siete países europeos e Israel.PACIENTES:Cuarenta pacientes participaron en la extensión de seguimiento: tratamiento con darvadstrocel (n = 25); grupo control (n = 15).INTERVENCIONES:Se administró Darvadstrocel o solución salina (grupo control) una vez, localmente, tras el legrado del trayecto fístuloso y cierre del orificio interno (con la colocación previa de setón). A todos los pacientes se les permitió continuar con los tratamientos médicos en curso para las fístulas.PRINCIPALES MEDIDAS DE RESULTADO:Los eventos de efectos adversos graves derivados del tratamiento se registraron hasta la semana 104. La remisión clínica, definida como el cierre de todas las aberturas externas tratadas que drenaban al inicio espontáneamente o por compresión suave de los dedos, fue evaluado en la semana 104.RESULTADOS:Del total de 40 pacientes, 37 completaron la extensión de seguimiento. Hasta la semana 104, se reportaron 7 eventos de efectos adversos graves resultantes del tratamiento, de los cuales 4 ocurrieron entre las semanas 52 y 104. En la semana 104, se reportó remisión clínica en 14/25 (56%) pacientes en el grupo de darvadstrocel y 6/15 (40%) pacientes en el grupo de control.LIMITACIONES:Solo una pequeña cantidad de pacientes participaron en el período de seguimiento extendido y no se realizaron exámenes por técnicas de imagen en la visita a 104 semanas.CONCLUSIONES:Darvadstrocel fue bien tolerado y la remisión clínica después del tratamiento con darvadstrocel puede mantenerse hasta 104 semanas en pacientes con enfermedad de Crohn perianal fistulizante. Consulte Video Resumen en http://links.lww.com/DCR/B812. (Traducción-Dr Osvaldo Gauto and Dr Julian Panés.)ClinicalTrials.gov No. NCT01541579.
Biodiversity on coral reefs depends not only on primary reef-builders, but also on associated taxa that create microhabitats for other species. Hydrocorals of the genus
Stylaster
, commonly known as ...lace corals, form small branching colonies that enhance three-dimensional complexity on reefs and are known to support a variety of commensal species. Furthermore, the genus is highly speciose, further increasing biodiversity. Despite their important ecological roles, little is known about the evolutionary history and the intraspecific diversity and structure in these broadly distributed hydrocorals. Here, we assessed the phylogenetic relationships among Atlantic species in the genus
Stylaster
and examined the genetic structure of
S. roseus
in the Tropical Western Atlantic (Caribbean and Brazil) and of
S. blatteus
in the Tropical Eastern Atlantic (Africa), using DNA sequences from the 16S ribosomal gene. Time-calibrated phylogenetic analyses showed that
S. roseus
and
S. blatteus
diverged at ~ 24.6 Ma. A well-supported Brazilian clade within
S. roseus
indicates a possible cryptic species that diverged at ~ 11.6 Ma, consistent with the formation of the Amazon River at 9 Ma (Hoorn et al. in Glob Planet Change 153:51–65, 2017). Strong genetic structure was observed even over moderate distances, with Φ
ST
values over all populations being 0.98 for
S. roseus
and 0.90 for
S. blatteus
. Nearly, all haplotypes were private (found in a single location) and diverged by many mutational steps from one another. In contrast, genetic diversity was low at the local scale for both species, with most sites showing no variation (a single haplotype). These results are coherent with the reproductive strategy of Stylasteridae, where larvae are brooded and are highly developed at the time of release, often settling near the parental colony. Limited dispersal coupled with possible clonal reproduction have likely contributed to the high levels of genetic differentiation observed here. Lace corals show unusual reproductive and population dynamics compared to other reef inhabiting cnidarians. Future work may reveal additional cryptic diversity in this poorly studied family.
Pelger-Huët anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes. Affected individuals show ...hypolobulated neutrophil nuclei with coarse chromatin. Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities. Homozygous offspring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies and increased pre- and postnatal mortality. Here we show, by carrying out a genome-wide linkage scan, that PHA is linked to chromosome 1q41-43. We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor. The lamin B receptor (LBR), a member of the sterol reductase family, is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane. Lymphoblastoid cells from heterozygous individuals affected with PHA show reduced expression of the lamin B receptor, and cells homozygous with respect to PHA contain only trace amounts of it. We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner. Our findings have implications for understanding nuclear envelope-heterochromatin interactions, the pathogenesis of Pelger-like conditions in leukemia, infection and toxic drug reactions, and the evolution of neutrophil nuclear shape.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A
bstract
Systematic studies of charge-dependent two- and three-particle correlations in Pb-Pb collisions at
s
NN
= 2.76 and 5.02 TeV used to probe the Chiral Magnetic Effect (CME) are presented. ...These measurements are performed for charged particles in the pseudorapidity (
η
) and transverse momentum (
p
T
) ranges |
η
|
<
0
.
8 and 0
.
2
< p
T
<
5 GeV/
c
. A significant charge-dependent signal that becomes more pronounced for peripheral collisions is reported for the CME-sensitive correlators
γ
1, 1
= 〈cos(
φ
α
+
φ
β
− 2Ψ
2
)〉 and
γ
1, − 3
= 〈cos(
φ
α
− 3
φ
β
+ 2Ψ
2
)〉. The results are used to estimate the contribution of background effects, associated with local charge conservation coupled to anisotropic flow modulations, to measurements of the CME. A blast-wave parametrisation that incorporates local charge conservation tuned to reproduce the centrality dependent background effects is not able to fully describe the measured
γ
1
,
1
. Finally, the charge and centrality dependence of mixed-harmonics three-particle correlations, of the form
γ
1, 2
= 〈cos(
φ
α
+ 2
φ
β
− 3Ψ
3
)〉, which are insensitive to the CME signal, verify again that background contributions dominate the measurement of
γ
1
,
1
.
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