885 research outputs found
Stability and the Evolvability of Function in a Model Protein
Functional proteins must fold with some minimal stability to a structure that
can perform a biochemical task. Here we use a simple model to investigate the
relationship between the stability requirement and the capacity of a protein to
evolve the function of binding to a ligand. Although our model contains no
built-in tradeoff between stability and function, proteins evolved function
more efficiently when the stability requirement was relaxed. Proteins with both
high stability and high function evolved more efficiently when the stability
requirement was gradually increased than when there was constant selection for
high stability. These results show that in our model, the evolution of function
is enhanced by allowing proteins to explore sequences corresponding to
marginally stable structures, and that it is easier to improve stability while
maintaining high function than to improve function while maintaining high
stability. Our model also demonstrates that even in the absence of a
fundamental biophysical tradeoff between stability and function, the speed with
which function can evolve is limited by the stability requirement imposed on
the protein.Comment: Biophysical Journal in pres
Increased primary tumor growth in mice null for beta3- or beta3/beta5-integrins or selectins.
Compact groups from semi-analytical models of galaxy formation -- V: their assembly channels as a function of the environment
We delved into the assembly pathways and environments of compact groups (CGs)
of galaxies using mock catalogues generated from semi-analytical models (SAMs)
on the Millennium simulation. We investigate the ability of SAMs to replicate
the observed CG environments and whether CGs with different assembly histories
tend to inhabit specific cosmic environments. We also analyse whether the
environment or the assembly history is more important in tailoring CG
properties. We find that about half of the CGs in SAMs are non-embedded
systems, 40% are inhabiting loose groups or nodes of filaments, while the rest
distribute evenly in filaments and voids, in agreement with observations. We
observe that early-assembled CGs preferentially inhabit large galaxy systems (~
60%), while around 30% remain non-embedded. Conversely, lately-formed CGs
exhibit the opposite trend. We also obtain that lately-formed CGs have lower
velocity dispersions and larger crossing times than early-formed CGs, but
mainly because they are preferentially non-embedded. Those lately-formed CGs
that inhabit large systems do not show the same features. Therefore, the
environment plays a strong role in these properties for lately-formed CGs.
Early-formed CGs are more evolved, displaying larger velocity dispersions,
shorter crossing times, and more dominant first-ranked galaxies, regardless of
the environment. Finally, the difference in brightness between the two
brightest members of CGs is dependent only on the assembly history and not on
the environment. CGs residing in diverse environments have undergone varied
assembly processes, making them suitable for studying their evolution and the
interplay of nature and nurture on their traits.Comment: 13 pages, 8 figures. Accepted for publication in MNRA
Finite size effects on thermal denaturation of globular proteins
Finite size effects on the cooperative thermal denaturation of proteins are
considered. A dimensionless measure of cooperativity, Omega, scales as N^zeta,
where N is the number of amino acids. Surprisingly, we find that zeta is
universal with zeta = 1 + gamma, where the exponent gamma characterizes the
divergence of the susceptibility for a self-avoiding walk. Our lattice model
simulations and experimental data are consistent with the theory. Our finding
rationalizes the marginal stability of proteins and substantiates the earlier
predictions that the efficient folding of two-state proteins requires the
folding transition temperature to be close to the collapse temperature.Comment: 3 figures. Physical Review Letters (in press
Hickson-like compact groups inhabiting different environments
Although Compact Groups of galaxies (CGs) have been envisioned as isolated
extremely dense structures in the Universe, it is accepted today that many of
them could be not as isolated as thought. In this work, we study Hickson-like
CGs identified in the Sloan Digital Sky Survey Data Release 16 to analyse these
systems and their galaxies when embedded in different cosmological structures.
To achieve this goal, we identify several cosmological structures where CGs can
reside: Nodes of filaments, Loose Groups, Filaments and cosmic Voids. Our
results indicate that 45 per cent of CGs do not reside in any of these
structures, i.e., they can be considered non-embedded or isolated systems. Most
of the embedded CGs are found inhabiting Loose Groups and Nodes, while there
are almost no CGs residing well inside cosmic Voids. Some physical properties
of CGs vary depending on the environment they inhabit. CGs in Nodes show the
largest velocity dispersions, the brightest absolute magnitude of the
first-ranked galaxy, and the smallest crossing times, while the opposite occurs
in Non-Embedded CGs. When comparing galaxies in all the environments and
galaxies in CGs, CGs show the highest fractions of red/early-type galaxy
members in most of the absolute magnitudes ranges. The variation between
galaxies in CGs inhabiting one or another environment is not as significant as
the differences caused by belonging or not to a CG. Our results suggest a
plausible scenario for galaxy evolution in CGs in which both, large-scale and
local environments play essential roles.Comment: 16 pages, 9 figures, 1 table, accepted for publication in MNRA
Second-line high-dose chemotherapy in patients with mediastinal and retroperitoneal primary non-seminomatous germ cell tumors: the EBMT experience
Background: Results of second-line chemotherapy in patients with extragonadal non-seminomatous germ cell tumor (NSGCT) appear inferior to results in testicular NSGCT. Patients with retroperitoneal NSGCT achieve a comparable long-term survival rate of 30%, but the salvage rates of patients with mediastinal primary are less than 10%. We conducted a retrospective analysis on patients with mediastinal and retroperitoneal NSGCT treated with second-line high-dose chemotherapy (HDCT) registered with the European Group for Blood and Marrow Transplantation (EBMT). Patients and methods: Between 1987 and 1999, 59 registered patients with retroperitoneal (n=37) and mediastinal (n=22) primary NSGCT, median age 28 years (range 18-60), were treated with second-line HDCT. All had received cisplatin-containing chemotherapy as first-line treatment. Results: Toxic death occurred in three cases (5%). With a median follow-up of 58 months (range 14-114), 18/59 patients (30%) continue to be disease-free. Of three patients who had a disease recurrence after HDCT, one patient achieved a disease-free status with further chemotherapy and surgery. In total, 19 patients (32%) are currently disease-free. Sixteen of 37 patients (43%) with retroperitoneal NSGCT, and three of 22 patients (14%) with mediastinal NSGCT are currently alive and disease-free. Conclusions: Second-line HDCT might represent a possible option for patients with retroperitoneal primary NSGCT. New salvage strategies are needed for patients with mediastinal NSGC
Rituximab-EPOCH, an effective salvage therapy for relapsed, refractory or transformed B-cell lymphomas: results of a phase II study
Background: Relapsed or refractory diffuse large B-cell and mantle-cell lymphoma have a poor prognosis. The EPOCH regimen and rituximab monotherapy have demonstrated activity as salvage therapies. Because of their non-overlapping toxicity, we evaluated their combination as salvage therapy in a phase II study. Patients and methods: Patients with relapsed or refractory CD20-positive large B-cell and mantle-cell lymphoma were offered treatment with rituximab 375 mg/m2 intravenously (i.v.) on day 1, doxorubicin 15 mg/m2 as a continuous i.v. infusion on days 2-4, etoposide 65 mg/m2 as a continuous i.v. infusion on days 2-4, vincristine 0.5 mg as a continuous i.v. infusion on days 2-4, cyclophosphamide 750 mg/m2 i.v. on day 5 and prednisone 60 mg/m2 orally on days 1-14. Results: Fifty patients, with a median age of 56 years (range 23-72), entered the study. Twenty-five had primary diffuse large B-cell lymphoma, 18 transformed large B-cell lymphoma and seven mantle-cell lymphoma. The median number of prior chemotherapy regimens was 1.7 (range one to four). The median number of treatment cycles was four (range one to six). Possible treatment-related death occurred in two patients. Objective responses were obtained in 68% of patients (28% complete responses, 40% partial responses). Nineteen patients received consolidating high-dose chemotherapy with autologous stem-cell transplantation. The median follow-up was 33 months. Three patients developed a secondary myelodysplastic syndrome. The median overall survival was 17.9 months; the projected overall survival at 1, 2 and 3 years was 66, 42 and 35%, respectively. The median event-free survival was 11.8 months; the projected event-free survival at 1, 2 and 3 years was 50, 30 and 26%, respectively. Conclusion: The rituximab-EPOCH regimen is effective and well tolerated, even in extensively pretreated patients with relapsed or refractory large B-cell lymphoma and mantle-cell lymphom
In the light of directed evolution: Pathways of adaptive protein evolution
Directed evolution is a widely-used engineering strategy for improving the stabilities or biochemical functions of proteins by repeated rounds of mutation and selection. These experiments offer empirical lessons about how proteins evolve in the face of clearly-defined laboratory selection pressures. Directed evolution has revealed that single amino acid mutations can enhance properties such as catalytic activity or stability and that adaptation can often occur through pathways consisting of sequential beneficial mutations. When there are no single mutations that improve a particular protein property experiments always find a wealth of mutations that are neutral with respect to the laboratory-defined measure of fitness. These neutral mutations can open new adaptive pathways by at least 2 different mechanisms. Functionally-neutral mutations can enhance a protein's stability, thereby increasing its tolerance for subsequent functionally beneficial but destabilizing mutations. They can also lead to changes in “promiscuous” functions that are not currently under selective pressure, but can subsequently become the starting points for the adaptive evolution of new functions. These lessons about the coupling between adaptive and neutral protein evolution in the laboratory offer insight into the evolution of proteins in nature
Prostatic stromal tumor with fatal outcome in a young man: histopathological and immunohistochemical case presentation
Stromal tumors of the prostate are rare and only a few cases have been described in the literature, including exceptional cases of stromal tumors with unknown malignant potential (STUMP) and a fatal outcome in young patients. Morphologically distinguishing a STUMP from a stromal sarcoma of the prostate (PSS) is still a challenge. We describe the histopathological and immunohistochemical findings in a 34-year-old man with a malignant specialized cell stromal tumor of the prostate that was diagnosed initially as STUMP, and he developed lung metastases within a few months. The patient attended our hospital because of lower urinary tract symptoms, after having excreted tissue through the urethra a few months before. Ultrasonography and urethrocystoscopy examinations showed a mass arising from the verumontanum, and a transurethral resection (TUR) revealed a highgrade spindle cell sarcoma reminiscent of a phyllode tumor of the breast. The tumor cells were immunoreactive for vimentin, progesterone receptor and, focally, CD34. The preliminary histological findings were subsequently confirmed after radical prostatectomy. The patient developed bilateral lung metastases and died 25 months after the initial diagnosis. Although rare in young patients, the challenging differential diagnosis of STUMP and PSS means that a prostate STUMP diagnosis made on the basis of biopsy or TUR specimens also requires urethrocystoscopic monitoring for the early detection of any progression to PSS. Radical prostatectomy should also be carefully considered
Novel role of microRNA146b in promoting mammary alveolar progenitor cell maintenance
In this report, we have shown that miR146b promotes the maintenance of pregnancy-derived mammary luminal alveolar progenitors. MiR146b expression was significantly higher in the mammary glands of pregnant and lactating mice than in virgin mice. Furthermore, miR146b levels were significantly higher in mouse mammary glands exposed to the sex hormones, estrogen and progesterone, compared with those of untreated control animals. Pregnancy-derived primary mouse mammary epithelial cells in which miR146b was knocked down showed a significant reduction in the number of hollow acinar organoid structures formed on three-dimensional Matrigel and in β-casein expression. This demonstrates that miR146b promotes the maintenance of pregnancy-derived mammary luminal alveolar progenitors. It has been shown that mouse mammary luminal progenitors give rise to hollow organoid structures, whereas solid organoid structures are derived from stem cells. Among several miR146b targets, miR146b knockdown resulted in preferential STAT3β overexpression. In the primary mouse mammary epithelial cells, overexpression of STAT3β isoform caused mammary epithelial cell death and a significant reduction in β-casein mRNA expression. Therefore, we conclude that during pregnancy miR146b is involved in luminal alveolar progenitor cell maintenance, at least partially, by regulating STAT3β
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