Intermittent rivers comprise a significant proportion of river networks globally and their spatial extent is predicted to increase with rising water abstraction pressures. Despite this, the ...ecological implications of hydrological modifications within intermittent rivers have received limited research attention. This paper examines macroinvertebrate assemblages across intermittent and perennial sections of headwater streams within the Hampshire Avon catchment (United Kingdom) over a five-year period. The composition of faunal assemblages was quantified in relation to four hydrological metrics: the duration of flowing conditions, the geographical proximity to the nearest perennial source along each watercourse (two observed flow parameters) and two modelled groundwater abstraction influences. The results highlight that macroinvertebrate communities inhabiting sites which dry periodically and are positioned at greater distances (>c. 2.5km) above the perennial source (the most upstream point of permanent flow within a given year) possessed the highest conservation values. These sites supported species that are rare in many areas of Europe (e.g. Ephemeroptera: Paraletophlebia werneri) or with limited geographical distribution across the United Kingdom (e.g. Trichoptera: Limnephilus bipunctatus). A range of faunal community diversity indices were found to be more sensitive to the antecedent flow duration and distance from the perennial source, rather than any effects of groundwater abstraction. Taxonomic richness responded most strongly to these observed flow parameters and varied more markedly with the distance from the perennial source compared to the antecedent flow duration. Several taxa were significantly associated with the observed flow parameters, particularly those predominantly inhabiting perennially flowing systems. However, the distance that such fauna could migrate into intermittent reaches varied between taxa. This research demonstrates the overriding importance of antecedent flow durations and the geographical proximity to perennial sources on macroinvertebrate communities within intermittent and perennial headwater streams.
Taxa migrating upstream from perennial to nearby intermittent reaches compete with and predate temporary water fauna. Display omitted
•Macroinvertebrate communities differed between intermittent and perennial streams.•Intermittent streams supported species of high conservation value.•No negative ecological effects of groundwater abstraction were detected.•Taxa richness was influenced by the geographical proximity to the perennial source along each watercourse.
Invasive non‐native species (INNS) threaten biodiversity and ecosystem functioning globally. However, there remains a pressing need to understand the environmental factors controlling the dispersal, ...successful establishment and subsequent ecological impacts of INNS for receiving ecosystems. Here, we examine how region‐wide flow regime magnitudes facilitate the successful establishment of an invasive crayfish species (Pacifastacus leniusculus, signal crayfish) in England (UK). We also consider the interactive effects of invasive crayfish with flow regime variations on the structural and functional diversity of macroinvertebrate communities.
Low‐flow magnitudes increased the likelihood of P. leniusculus establishment, with 80% of recorded invasion dates falling in years with flow magnitudes below average (low‐ and low‐moderate flow classes), whilst only 1.6% occurred in high‐flow years.
Temporal trajectories of structural and functional macroinvertebrate responses in invaded rivers demonstrated reduced diversity compared to control rivers. Lower taxonomic and functional richness measures typically coincided with periods of low discharge in invaded rivers and were greatest during regionally high‐flows.
Macroinvertebrate communities displayed significant structural and functional responses to the interaction between invasive crayfish and flow regime variations. Specifically, a number of low‐ and high‐flow indices yielded significant associations, highlighting the role of extreme hydrological events in shaping INNS effects on receiving ecosystems. We also detected greater ecological effects of invasive crayfish under hydrologically stable conditions. Importantly, and for the first time, we observed that invasive crayfish reversed macroinvertebrate community responses to flow regime cues (e.g. discharge fall rate and minimum flows in the preceding 180 days).
Synthesis and applications. Results from this study indicate that low‐flow events facilitate the spread/establishment of invasive crayfish and correspond with greater ecological effects for receiving ecosystems. Given that low‐flow events are predicted to increase in intensity, duration and frequency over the 21st century, our results highlight the potential threat that invasive crayfish may pose under future hydroclimatic changes. Managing river flow regimes effectively (including maintaining higher flow events and flow variability) is likely to be vital in conserving ecological diversity following crayfish invasion.
Results from this study indicate that low‐flow events facilitate the spread/establishment of invasive crayfish and correspond with greater ecological effects for receiving ecosystems. Given that low‐flow events are predicted to increase in intensity, duration and frequency over the 21st century, our results highlight the potential threat that invasive crayfish may pose under future hydroclimatic changes. Managing river flow regimes effectively (including maintaining higher flow events and flow variability) is likely to be vital in conserving ecological diversity following crayfish invasion.
Purpose: A phase I study was conducted to assess the safety of adoptive immunotherapy using gene-modified autologous T cells for the
treatment of metastatic ovarian cancer.
Experimental Design: T ...cells with reactivity against the ovarian cancer–associated antigen α-folate receptor (FR) were generated by genetic modification
of autologous T cells with a chimeric gene incorporating an anti-FR single-chain antibody linked to the signaling domain of
the Fc receptor γ chain. Patients were assigned to one of two cohorts in the study. Eight patients in cohort 1 received a
dose escalation of T cells in combination with high-dose interleukin-2, and six patients in cohort 2 received dual-specific
T cells (reactive with both FR and allogeneic cells) followed by immunization with allogeneic peripheral blood mononuclear
cells.
Results: Five patients in cohort 1 experienced some grade 3 to 4 treatment-related toxicity that was probably due to interleukin-2
administration, which could be managed using standard measures. Patients in cohort 2 experienced relatively mild side effects
with grade 1 to 2 symptoms. No reduction in tumor burden was seen in any patient. Tracking 111 In-labeled adoptively transferred T cells in cohort 1 revealed a lack of specific localization of T cells to tumor except
in one patient where some signal was detected in a peritoneal deposit. PCR analysis showed that gene-modified T cells were
present in the circulation in large numbers for the first 2 days after transfer, but these quickly declined to be barely detectable
1 month later in most patients. An inhibitory factor developed in the serum of three of six patients tested over the period
of treatment, which significantly reduced the ability of gene-modified T cells to respond against FR + tumor cells.
Conclusions: Large numbers of gene-modified tumor-reactive T cells can be safely given to patients, but these cells do not persist in
large numbers long term. Future studies need to employ strategies to extend T cell persistence. This report is the first to
document the use of genetically redirected T cells for the treatment of ovarian cancer.
Human papillomaviruses (HPVs) contribute to approximately 5% of all human cancers. Species-specific barriers limit the ability to study HPV pathogenesis in animal models. Murine papillomavirus ...(MmuPV1) provides a powerful tool to study the roles of papillomavirus genes in pathogenesis arising from a natural infection. We previously identified Protein Tyrosine Phosphatase Non-Receptor Type 14 (PTPN14), a tumor suppressor targeted by HPV E7 proteins, as a putative cellular target of MmuPV1 E7. Here, we confirmed the MmuPV1 E7-PTPN14 interaction. Based on the published structure of the HPV18 E7/PTPN14 complex, we generated a MmuPV1 E7 mutant, E7K81S, that was defective for binding PTPN14. Wild-type (WT) and E7K81S mutant viral genomes replicated as extrachromosomal circular DNAs to comparable levels in mouse keratinocytes. E7K81S mutant virus (E7K81S MmuPV1) was generated and used to infect FoxN/Nude mice. E7K81S MmuPV1 caused neoplastic lesions at a frequency similar to that of WT MmuPV1, but the lesions arose later and were smaller than WT-induced lesions. The E7K81S MmuPV1-induced lesions also had a trend towards a less severe grade of neoplastic disease. In the lesions, E7K81S MmuPV1 supported the late (productive) stage of the viral life cycle and promoted E2F activity and cellular DNA synthesis in suprabasal epithelial cells to similar degrees as WT MmuPV1. There was a similar frequency of lateral spread of infections among mice infected with E7K81S or WT MmuPV1. Compared to WT MmuPV1-induced lesions, E7K81S MmuPV1-induced lesions had a significant expansion of cells expressing differentiation markers, Keratin 10 and Involucrin. We conclude that an intact PTPN14 binding site is necessary for MmuPV1 E7's ability to contribute to papillomavirus-induced pathogenesis and this correlates with MmuPV1 E7 causing a delay in epithelial differentiation, which is a hallmark of papillomavirus-induced neoplasia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The teeth of all vertebrates predominantly comprise the same materials, but their lifespans vary widely: in stark contrast to mammals, shark teeth are functional only for weeks, rather than decades, ...making lifelong durability largely irrelevant. However, their diets are diverse and often mechanically demanding, and as such, their teeth should maintain a functional morphology, even in the face of extremely high and potentially damaging contact stresses. Here, we reconcile the dilemma between the need for an operative tooth geometry and the unavoidable damage inherent to feeding on hard foods, demonstrating that the tooth cusps of Port Jackson sharks, hard-shelled prey specialists, possess unusual microarchitecture that controls tooth erosion in a way that maintains functional cusp shape. The graded architecture in the enameloid provokes a location-specific damage response, combining chipping of outer enameloid and smooth wear of inner enameloid to preserve an efficient shape for grasping hard prey. Our discovery provides experimental support for the dominant theory that multi-layered tooth enameloid facilitated evolutionary diversification of shark ecologies.
Aortic stenosis (AS) leads to diffuse fibrosis in the myocardium, which is linked to adverse outcome. Myocardial T1 values change with tissue composition.
To test the hypothesis that our recently ...developed non-contrast cardiac magnetic resonance (CMR) T1 mapping sequence could identify myocardial fibrosis without contrast agent.
A prospective CMR non-contrast T1 mapping study of 109 patients with moderate and severe AS and 33 age- and gender-matched controls.
CMR at 1.5 T, including non-contrast T1 mapping using a shortened modified Look-Locker inversion recovery sequence, was carried out. Biopsy samples for histological assessment of collagen volume fraction (CVF%) were obtained in 19 patients undergoing aortic valve replacement.
There was a significant correlation between T1 values and CVF% (r=0.65, p=0.002). Mean T1 values were significantly longer in all groups with severe AS (972 ± 33 ms in severe asymptomatic, 1014 ± 38 ms in severe symptomatic) than in normal controls (944 ± 16 ms) (p<0.05). The strongest associations with T1 values were for aortic valve area (r=-0.40, p=0.001) and left ventricular mass index (LVMI) (r=0.36, p=0.008), and these were the only independent predictors on multivariate analysis.
Non-contrast T1 values are increased in patients with severe AS and further increase in symptomatic compared with asymptomatic patients. T1 values lengthened with greater LVMI and correlated with the degree of biopsy-quantified fibrosis. This may provide a useful clinical assessment of diffuse myocardial fibrosis in the future.
Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor ...regressions. The optimal TIL product for ACT is unknown.
Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8(+)-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points.
Thirty-four patients received unselected young TILs with a median of 8.0% CD4(+) lymphocytes, and 35 patients received CD8(+)-enriched TILs with a median of 0.3% CD4(+) lymphocytes. One month after TIL infusion, patients who received CD8(+)-enriched TILs had significantly fewer CD4(+) peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors RECIST), and seven patients responded to CD8(+)-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8(+)-enriched TILs responded.
A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8(+)-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.
ABSTRACT
The Bacillus cereus group encompasses beneficial and harmful species in diverse niches and has a much debated taxonomy. Investigating whether selection has led to ecological divergence ...between phylogenetic clades can help understand the basis of speciation, and has implications for predicting biological safety across this group. Using three most terrestrial species in this group (B. cereus, Bacillus thuringiensis and Bacillus mycoides) we charactererized ecological specialization in terms of resource use, thermal adaptation and fitness in different environmental conditions and tested whether taxonomic species or phylogenetic clade best explained phenotypic variation. All isolates grew vigorously in protein rich media and insect cadavers, but exploitation of soil or plant derived nutrients was similarly weak for all. For B. thuringiensis and B. mycoides, clade and taxonomic species were important predictors of relative fitness in insect infections. Fully psychrotolerant isolates could outcompete B. thuringiensis in insects at low temperature, although psychrotolerance predicted growth in artificial media better than clade. In contrast to predictions, isolates in the Bacillus anthracis clade had sub-optimal growth at 37°C. The common ecological niche in these terrestrial B. cereus species is the ability to exploit protein rich resources such as cadavers. However, selection has led to different phylogenetic groups developing different strategies for accessing this resource. Thus, clades, as well as traditional taxonomic phenotypes, predict biologically important traits.
Selection drives ecological divergence in this important group of organisms—groups with shared evolutionary history have similar fitness in different environments irrespective of the names we ascribe to them.
Treatment with ipilimumab can cause objective tumor responses in patients with metastatic melanoma. We have treated 177 evaluable patients in three clinical trials and have long-term follow-up to ...evaluate the durability of responses.
Patients with metastatic melanoma were treated in three trials from 2002 to 2005. In protocol 1, 56 patients received ipilimumab with gp100 peptides. In protocol 2, 36 patients received ipilimumab with interleukin-2. In protocol 3, 85 patients received ipilimumab with intrapatient dose-escalation and were randomized to receive gp100 peptides. We have analyzed their long-term follow-up and survival data.
With median follow-up for protocols 1, 2, and 3 being 92, 84, and 71 months, median survival was 14, 16, and 13 months with 5-year survival rates being 13%, 25%, and 23%, respectively. Patients in protocol 2 had a 17% complete response (CR) rate, compared with 7% in protocol 1 and 6% in protocol 3. These CR rates are higher than previously reported for the same trials because some patients who eventually became complete responders had continual tumor regression months to years after therapy. All but one of the 15 complete responders are ongoing at 54+ to 99+ months.
This report provides the longest follow-up of patients with melanoma treated with ipilimumab and shows that ipilimumab can induce durable, potentially curative tumor regression in a small percentage of patients with metastatic melanoma. The combination of ipilimumab and interleukin-2 seems to have an increased CR rate, but this needs to be tested in a randomized trial.
The presence of intramyocardial hemorrhage (IMH) in ST-segment-elevation myocardial infarction patients reperfused by primary percutaneous coronary intervention has been associated with residual ...myocardial iron at follow-up, and its impact on adverse left ventricular (LV) remodeling is incompletely understood and is investigated here.
Forty-eight ST-segment-elevation myocardial infarction patients underwent cardiovascular magnetic resonance at 4±2 days post primary percutaneous coronary intervention, of whom 40 had a follow-up scan at 5±2 months. Native T1, T2, and T2* maps were acquired. Eight out of 40 (20%) patients developed adverse LV remodeling. A subset of 28 patients had matching T2* maps, of which 15/28 patients (54%) had IMH. Eighteen of 28 (64%) patients had microvascular obstruction on the acute scan, of whom 15/18 (83%) patients had microvascular obstruction with IMH. On the follow-up scan, 13/15 patients (87%) had evidence of residual iron within the infarct zone. Patients with residual iron had higher T2 in the infarct zone surrounding the residual iron when compared with those without. In patients with adverse LV remodeling, T2 in the infarct zone surrounding the residual iron was also higher than in those without (60 54-64 ms versus 53 51-56 ms; P=0.025). Acute myocardial infarct size, extent of microvascular obstruction, and IMH correlated with the change in LV end-diastolic volume (Pearson's rho of 0.64, 0.59, and 0.66, respectively; P=0.18 and 0.62, respectively, for correlation coefficient comparison) and performed equally well on receiver operating characteristic curve for predicting adverse LV remodeling (area under the curve: 0.99, 0.94, and 0.95, respectively; P=0.19 for receiver operating characteristic curve comparison).
The majority of ST-segment-elevation myocardial infarction patients with IMH had residual myocardial iron at follow-up. This was associated with persistently elevated T2 values in the surrounding infarct tissue and adverse LV remodeling. IMH and residual myocardial iron may be potential therapeutic targets for preventing adverse LV remodeling in reperfused ST-segment-elevation myocardial infarction patients.
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