The thickness of dental enamel is often discussed in paleoanthropological literature, particularly with regard to differences in growth, health, and diet between Neandertals and modern humans. ...Paleoanthropologists employ enamel thickness in paleodietary and taxonomic studies regarding earlier hominins, but variation in enamel thickness within the genus
Homo has not been thoroughly explored despite its potential to discriminate species and its relevance to studies of growth and development. Radiographic two-dimensional studies indicate that Neandertal molar enamel is thin relative to the thick enamel of modern humans, although such methods have limited accuracy. Here we show that, measured via accurate high-resolution microtomographic imaging, Neandertal molar enamel is absolutely and relatively thinner than modern human enamel at most molar positions. However, this difference relates to the ratio of coronal dentine volume to total crown volume, rather than the quantity of enamel per se. The absolute volume of Neandertal molar enamel is similar to that of modern humans, but Neandertal enamel is deposited over a larger volume of coronal dentine, resulting in lower average (and relative) enamel thickness values. Sample sizes do not permit rigorous intragroup comparisons, but Neandertal molar tissue proportions evince less variation than the modern human sample. Differences in three- and two-dimensional enamel thickness data describing Neandertal molars may be explained by dimensional reduction. Although molar tissue proportions distinguish Neanderthals from recent
Homo sapiens, additional study is necessary to assess trends in tissue proportions in the genus
Homo throughout the Pleistocene.
We investigated the safety and efficacy of a combination of the oral tyrosine kinase inhibitor, nintedanib (BIBF 1120) with oral cyclophosphamide in patients with relapsed ovarian cancer.
Patients ...with relapsed ovarian, fallopian tube or primary peritoneal cancer received oral cyclophosphamide (100 mg o.d.) and were randomised (1,1) to also have either oral nintedanib or placebo. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), response rate, toxicity, and quality of life.
117 patients were randomised, 3 did not start trial treatment, median age 64 years. Forty-five (39%) had received ≥5 lines chemotherapy. 30% had received prior bevacizumab. The median OS was 6.8 (nintedanib) versus 6.4 (placebo) months (hazard ratio 1.08; 95% confidence interval 0.72–1.62; P = 0.72). The 6-month PFS rate was 29.6% versus 22.8% (P = 0.57). Grade 3/4 adverse events occurred in 64% (nintedanib) versus 54% (placebo) of patients (P = 0.28); the most frequent G3/4 toxicities were lymphopenia (18.6% nintedanib versus 16.4% placebo), diarrhoea (13.6% versus 0%), neutropenia (11.9% versus 0%), fatigue (10.2% versus 9.1%), and vomiting (10.2% versus 7.3%). Patients who had received prior bevacizumab treatment had 52 days less time on treatment (P < 0.01). 26 patients (23%) took oral cyclophosphamide for ≥6 months. There were no differences in quality of life between treatment arms.
This is the largest reported cohort of patients with relapsed ovarian cancer treated with oral cyclophosphamide. Nintedanib did not improve outcomes when added to oral cyclophosphamide. Although not significant, more patients than expected remained on treatment for ≥6 months. This may reflect a higher proportion of patients with more indolent disease or the higher dose of cyclophosphamide used.
Clinical Trial Registration: Clinicaltrials.govNCT01610869
•Nintedanib added to oral cyclophosphamide did not improve outcome in heavily treated patients with relapsed ovarian cancer.•36% of patients derived clinical benefit from cyclophosphamide (10% PR/CR and 26% SD); 23% continued treatment at 6 months.•Oral cyclophosphamide 100 mg daily is tolerable; adverse events were mostly related to the companion antiangiogenic agent.•Prolonged disease stabilisation was seen in 11 patients.
We investigated whether the Src inhibitor saracatinib (AZD0530) improved efficacy of weekly paclitaxel in platinum-resistant ovarian cancer.
Patients with platinum-resistant ovarian, fallopian tube ...or primary peritoneal cancer were randomised 2 : 1 to receive 8-week cycles of weekly paclitaxel (wPxl; 80 mg/m2/week ×6 with 2-week break) plus saracatinib (S; 175 mg o.d.) or placebo (P) continuously, starting 1 week before wPxl, until disease progression. Patients were stratified by taxane-free interval (<6 versus ≥6 months/no prior taxane). The primary end point was progression-free survival (PFS) rate at 6 months. Secondary end points included overall survival (OS) and response rate (RR).
A total of 107 patients, median age 63 years, were randomised. Forty-three (40%) had received >2 lines of prior chemotherapy. The 6-month PFS rate was 29% (wPxl + S) versus 34% (wPxl + P) (P = 0.582). Median PFS was 4.7 versus 5.3 months (hazard ratio 1.00, 95% confidence interval 0.65–1.54; P = 0.99). RR (complete + partial) was 29% (wPxl + S) versus 43% (wPxl + P), P value = 0.158. Grade 3/4 adverse events were 36% versus 31% (P = 0.624); the most frequent G3/4 toxicities were vomiting (5.8% saracatinib versus 8.6% placebo), abdominal pain (5.8% versus 0%) and diarrhoea (4.3% versus 5.7%). Febrile neutropenia was more common in the saracatinib arm (4.3%) than placebo (0%). Response, PFS and OS were all significantly (P < 0.05) better in patients with taxane interval ≥6 months/no prior taxane (n = 85) than those <6 months (n = 22), regardless of randomisation.
Saracatinib does not improve activity of weekly paclitaxel in platinum-resistant ovarian cancer. Taxane-free interval of ≥6 months/no prior taxane was associated with better outcome in both groups.
Clinicaltrials.gov NCT01196741; ISRCTN 32163062.
Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations ...translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We have developed a method to introduce novel paratopes into the human antibody repertoire by modifying the immunoglobulin (Ig) genes of mature B cells directly using genome editing technologies. We ...used CRISPR-Cas9 in a homology directed repair strategy, to replace the heavy chain (HC) variable region in B cell lines with that from an HIV broadly neutralizing antibody (bnAb), PG9. Our strategy is designed to function in cells that have undergone VDJ recombination using any combination of variable (V), diversity (D) and joining (J) genes. The modified locus expresses PG9 HC which pairs with native light chains (LCs) resulting in the cell surface expression of HIV specific B cell receptors (BCRs). Endogenous activation-induced cytidine deaminase (AID) in engineered cells allowed for Ig class switching and generated BCR variants with improved HIV neutralizing activity. Thus, BCRs engineered in this way retain the genetic flexibility normally required for affinity maturation during adaptive immune responses. Peripheral blood derived primary B cells from three different donors were edited using this strategy. Engineered cells could bind the PG9 epitope and sequenced mRNA showed PG9 HC transcribed as several different isotypes after culture with CD40 ligand and IL-4.
Exploring cosmic origins with CORE: Cluster science Bonaldi, A.; Remazeilles, M.; Hernández-Monteagudo, C. ...
Journal of cosmology and astroparticle physics,
04/2018, Letnik:
2018, Številka:
4
Journal Article
Recenzirano
Odprti dostop
We examine the cosmological constraints that can be achieved with a galaxy cluster survey with the future CORE space mission. Using realistic simulations of the millimeter sky, produced with the ...latest version of the Planck Sky Model, we characterize the CORE cluster catalogues as a function of the main mission performance parameters. We pay particular attention to telescope size, key to improved angular resolution, and discuss the comparison and the complementarity of CORE with ambitious future ground-based CMB experiments that could be deployed in the next decade. A possible CORE mission concept with a 150 cm diameter primary mirror can detect of the order of 50,000 clusters through the thermal Sunyaev-Zeldovich effect (SZE). The total yield increases (decreases) by 25% when increasing (decreasing) the mirror diameter by 30 cm. The 150 cm telescope configuration will detect the most massive clusters (>1014 M⊙) at redshift z>1.5 over the whole sky, although the exact number above this redshift is tied to the uncertain evolution of the cluster SZE flux-mass relation; assuming self-similar evolution, CORE will detect 0~ 50 clusters at redshift z>1.5. This changes to 800 (200) when increasing (decreasing) the mirror size by 30 cm. CORE will be able to measure individual cluster halo masses through lensing of the cosmic microwave background anisotropies with a 1-σ sensitivity of 4×1014 M⊙, for a 120 cm aperture telescope, and 1014 M⊙ for a 180 cm one. From the ground, we estimate that, for example, a survey with about 150,000 detectors at the focus of 350 cm telescopes observing 65% of the sky would be shallower than CORE and detect about 11,000 clusters, while a survey with the same number of detectors observing 25% of sky with a 10 m telescope is expected to be deeper and to detect about 70,000 clusters. When combined with the latter, CORE would reach a limiting mass of M500 ~ 2−3 × 1013 M⊙ and detect 220,000 clusters (5 sigma detection limit). Cosmological constraints from CORE cluster counts alone are competitive with other scheduled large scale structure surveys in the 2020's for measuring the dark energy equation-of-state parameters w0 and wa (σw0=0.28, σwa=0.31). In combination with primary CMB constraints, CORE cluster counts can further reduce these error bars on w0 and wa to 0.05 and 0.13 respectively, and constrain the sum of the neutrino masses, Σ mν, to 39 meV (1 sigma). The wide frequency coverage of CORE, 60-600 GHz, will enable measurement of the relativistic thermal SZE by stacking clusters. Contamination by dust emission from the clusters, however, makes constraining the temperature of the intracluster medium difficult. The kinetic SZE pairwise momentum will be extracted with 0S/N=7 in the foreground-cleaned CMB map. Measurements of TCMB(z) using CORE clusters will establish competitive constraints on the evolution of the CMB temperature: (1+z)1−β, with an uncertainty of σβ lesssim 2.7× 10−3 at low redshift (z lesssim 1). The wide frequency coverage also enables clean extraction of a map of the diffuse SZE signal over the sky, substantially reducing contamination by foregrounds compared to the Planck SZE map extraction. Our analysis of the one-dimensional distribution of Compton-y values in the simulated map finds an order of magnitude improvement in constraints on σ8 over the Planck result, demonstrating the potential of this cosmological probe with CORE.
Epilepsy is a common outcome of traumatic brain injury (TBI), but the mechanisms of posttraumatic epileptogenesis are poorly understood. One clue is the occurrence of selective hippocampal cell death ...after fluid-percussion TBI in rats, consistent with the reported reduction of hippocampal volume bilaterally in humans after TBI and resembling hippocampal sclerosis, a hallmark of temporal-lobe epilepsy. Other features of temporal-lobe epilepsy, such as long-term seizure susceptibility, persistent hyperexcitability in the dentate gyrus (DG), and mossy fiber synaptic reorganization, however, have not been examined after TBI. To determine whether TBI induces these changes, we used a well studied model of TBI by weight drop on somatosensory cortex in adult rats. First, we confirmed an early and selective cell loss in the hilus of the DG and area CA3 of hippocampus, ipsilateral to the impact. Second, we found persistently enhanced susceptibility to pentylenetetrazole-induced convulsions 15 weeks after TBI. Third, by applying GABA(A) antagonists during field-potential and optical recordings in hippocampal slices 3 and 15 weeks after TBI, we unmasked a persistent, abnormal APV-sensitive hyperexcitability that was bilateral and localized to the granule cell and molecular layers of the DG. Finally, using Timm histochemistry, we detected progressive sprouting of mossy fibers into the inner molecular layers of the DG bilaterally 2-27 weeks after TBI. These findings are consistent with the development of posttraumatic epilepsy in an animal model of impact head injury, showing a striking similarity to the enduring behavioral, functional, and structural alterations associated with temporal-lobe epilepsy.
Mutations within cytotoxic T lymphocyte (CTL) epitopes impair T cell recognition, but escape mutations arising in flanking regions that alter antigen processing have not been defined in natural human ...infections. In human histocompatibility leukocyte antigen (HLA)-B57+ HIV-infected persons, immune selection pressure leads to a mutation from alanine to proline at Gag residue 146 immediately preceding the NH2 terminus of a dominant HLA-B57-restricted epitope, ISPRTLNAW. Although N-extended wild-type or mutant peptides remained well-recognized, mutant virus-infected CD4 T cells failed to be recognized by the same CTL clones. The A146P mutation prevented NH2-terminal trimming of the optimal epitope by the endoplasmic reticulum aminopeptidase I. These results demonstrate that allele-associated sequence variation within the flanking region of CTL epitopes can alter antigen processing. Identifying such mutations is of major relevance in the construction of vaccine sequences.
Pain self-efficacy and anxiety have each been shown to contribute substantially to pain intensity and pain-related disability. Although adult attachment theory has been related separately to chronic ...pain, anxiety, and self-efficacy, it has not before been investigated with either
pain self-efficacy or anxiety in the context of chronic pain. This study investigated the interrelations between these aspects of the chronic pain experience and their relative contributions towards pain intensity and disability. A clinical sample of 152 chronic pain patients participated in this study, completing self-report measures of attachment, self-efficacy, pain intensity, and disability, prior to attending a multidisciplinary pain clinic. Results revealed that fearful and preoccupied (anxious) attachment categories were associated with low pain self-efficacy, while high scores on the attachment dimension of comfort with closeness were linked with high pain self-efficacy, particularly for males. Insecure attachment (whether defined in terms of categories or dimensions) was related to higher levels of anxiety. Pain self-efficacy proved a stronger predictor of pain intensity than did anxiety and was a stronger predictor of disability than pain intensity or anxiety. In addition, comfort with closeness moderated the associations between pain self-efficacy and disability, pain self-efficacy and pain intensity, and anxiety and disability. Together, these findings support the value of adopting an attachment theoretical approach in the context of chronic pain. Treatment considerations and future research directions are considered.
V(D)J joining is mediated by RAG recombinase during early B-lymphocyte development in the bone marrow (BM). Activation-induced deaminase initiates isotype switching in mature B cells of secondary ...lymphoid structures. Previous studies questioned the strict ontological partitioning of these processes. We show that pro-B cells undergo robust switching to a subset of immunoglobulin H (IgH) isotypes. Chromatin studies reveal that in pro-B cells, the spatial organization of the Igh locus may restrict switching to this subset of isotypes. We demonstrate that in the BM, V(D)J joining and switching are interchangeably inducible, providing an explanation for the hyper-IgE phenotype of Omenn syndrome.
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