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Fludarabine-based chemoimmunotherapy with rituximab is frequently used in patients with indolent and mantle-cell lymphomas who relapse after alkylating chemotherapy. We aimed to compare the efficacy and safety of rituximab with bendamustine or fludarabine in patients with relapsed, indolent, non-Hodgkin lymphoma and mantle-cell lymphoma. For this randomised, non-inferiority, open-label, phase 3 trial, we recruited patients from 55 centres in Germany, who were subsequently randomised centrally according to prespecified randomisation lists with permuted blocks of randomly variable block size to rituximab (375 mg/m2, day 1) plus either bendamustine (90 mg/m2, days 1 and 2) or fludarabine (25 mg/m2, days 1–3) every 28 days for a maximum of six 28-day cycles. Patients were aged 18 years or older with a WHO performance status of 0–2 and had relapsed or refractory indolent or mantle-cell lymphoma; patients refractory to regimens that included rituximab, bendamustine, or purine analogue drugs were excluded. Patients were stratified by histological subtypes of lymphoma and by their latest previous therapies. Treatment allocation was not masked. The primary endpoint was progression-free survival and the final analysis was completed per protocol. Non-inferiority of bendamustine plus rituximab versus fludarabine plus rituximab was defined as a difference of less than 15% in 1-year progression-free survival. The protocol was amended in July, 2006, after approval of rituximab maintenance (375 mg/m2 every 3 months for up to 2 years), which was then given to patients achieving a response to either trial treatment. This study is registered with ClinicalTrials.gov, number NCT01456351 (closed to enrolment, follow-up is ongoing). Between Oct 8, 2003, and Aug 5, 2010, we randomly assigned 230 patients to treatment groups (116 bendamustine plus rituximab, 114 fludarabine plus rituximab). 11 patients were excluded for protocol violations and were not followed up further (two in the bendamustine plus rituximab group and nine in the fludarabine plus rituximab group). Thus, 219 patients were included in the per-protocol analysis (114 bendamustine plus rituximab, 105 fludarabine plus rituximab). 1-year progression-free survival with bendamustine plus rituximab was 0·76 (95% CI 0·68–0·84) and 0·48 (0·39–0·58) with fludarabine plus rituximab (non-inferiority p<0·0001). At a median follow-up of 96 months (IQR 73·2–112·9), median progression-free survival with bendamustine plus rituximab was 34·2 months (95% CI 23·5–52·7) and 11·7 months (8·0–16·1) with fludarabine plus rituximab (hazard ratio [HR] 0·54 [95% CI 0·38–0·72], log-rank test p<0·0001). Safety outcomes were similar in both groups, with 46 serious adverse events recorded (23 in the bendamustine plus rituximab group and 23 in the fludarabine plus rituximab group), most commonly myelosuppression and infections. In combination with rituximab, bendamustine was more effective than fludarabine, suggesting that bendamustine plus rituximab may be the preferred treatment option for patients with relapsed indolent and mantle-cell lymphomas. Roche Pharma AG, Ribosepharm GmbH, Mundipharma GmbH, Studiengruppe indolente Lymphome (StiL).

Fungi associated with photosynthetic organisms are major determinants of terrestrial biomass, nutrient cycling, and ecosystem productivity from the poles to the equator. Whereas most fungi are known because of their fruit bodies (e.g., saprotrophs), symptoms (e.g., pathogens), or emergent properties as symbionts (e.g., lichens), the majority of fungal diversity is thought to occur among species that rarely manifest their presence with visual cues on their substrate (e.g., the apparently hyperdiverse fungal endophytes associated with foliage of plants). Fungal endophytes are ubiquitous among all lineages of land plants and live within overtly healthy tissues without causing disease, but the evolutionary origins of these highly diverse symbionts have not been explored. Here, we show that a key to understanding both the evolution of endophytism and the diversification of the most species-rich phylum of Fungi (Ascomycota) lies in endophyte-like fungi that can be isolated from the interior of apparently healthy lichens. These “endolichenic” fungi are distinct from lichen mycobionts or any other previously recognized fungal associates of lichens, represent the same major lineages of Ascomycota as do endophytes, largely parallel the high diversity of endophytes from the arctic to the tropics, and preferentially associate with green algal photobionts in lichen thalli. Using phylogenetic analyses that incorporate these newly recovered fungi and ancestral state reconstructions that take into account phylogenetic uncertainty, we show that endolichenism is an incubator for the evolution of endophytism. In turn, endophytism is evolutionarily transient, with endophytic lineages frequently transitioning to and from pathogenicity. Although symbiotrophic lineages frequently give rise to free-living saprotrophs, reversions to symbiosis are rare. Together, these results provide the basis for estimating trophic transition networks in the Ascomycota and provide a first set of hypotheses regarding the evolution of symbiotrophy and saprotrophy in the most species-rich fungal phylum. [Ancestral state reconstruction; Ascomycota; Bayesian analysis; endolichenic fungi; fungal endophytes; lichens; pathogens; phylogeny; saprotrophy; symbiotrophy; trophic transition network.]

After a short historical overview of past systematic studies on Cantharellus , discussing delimitation and species diversity of the genus as well as previous, morphology-based, infrageneric classifications, this paper presents the first molecularly-based infrageneric classification of this genus using a multigene phylogenetic approach (nucLSU, mitSSU, RPB2 and tef-1 ) on a dataset that covers approximately halve of the described chanterelles worldwide, including many type specimens. Six subgenera are recognized and the recognition of subgenus Afrocantharellus as a separate genus is not accepted. The taxonomic value of individual morphological features is discussed as challenged by this new multigene phylogeny which comprises five new sections, one new subgenus and many emendations for previously recognized infrageneric groups. The paper discusses the observed discrepancy in biodiversity of Cantharellus when comparing between studies that focus either on below- or above-ground presence. A preliminary biogeographic hypothesis suggests an ‘out of Africa’ Gondwanan origin as a result of vicariance and subsequent migrations.

Parmelioid lichens are a diverse and ubiquitous group of foliose lichens. Generic delimitation in parmelioid lichens has been in a state of flux since the late 1960s with the segregation of the large, heterogeneous genus Parmelia into numerous smaller genera. Recent molecular phylogenetic studies have demonstrated that some of these new genera were monophyletic, some were not, and others, previously believed to be unrelated, fell within single monophyletic groups, indicating the need for a revision of the generic delimitations. This study aims to give an overview of current knowledge of the major clades of all parmelioid lichens. For this, we assembled a dataset of 762 specimens, including 31 of 33 currently accepted parmelioid genera (and 63 of 84 accepted genera of Parmeliaceae). We performed maximum likelihood and Bayesian analyses of combined datasets including two, three and four loci. Based on these phylogenies and the correlation of morphological and chemical characters that characterize monophyletic groups, we accept 27 genera within nine main clades. We re-circumscribe several genera and reduce Parmelaria to synonymy with Parmotrema. Emodomelanelia Divakar & A. Crespo is described as a new genus (type: E. masonii). Nipponoparmelia (Kurok.) K.H. Moon, Y. Ohmura & Kashiw. ex A. Crespo & al. is elevated to generic rank and 15 new combinations are proposed (in the genera Flavoparmelia, Parmotrema, Myelochroa, Melanelixia and Nipponoparmelia). A short discussion of the accepted genera is provided and remaining challenges and areas requiring additional taxon sampling are identified.

We examined genetic structure and long-distance gene flow in two lichenized ascomycetes, Flavocetraria cucullata and Flavocetraria nivalis, which are widespread in arctic and alpine tundra. Circumpolar North. DNA sequences were obtained for 90 specimens (49 for F. cucullata and 41 for F. nivalis) collected from various locations in Europe, Asia and North America. Sequences of the nuclear internal transcribed spacer (ITS) + 5.8S ribosomal subunit gene region were generated for 89 samples, and supplemented by beta-tubulin (BTUB) and translation elongation factor 1-alpha gene (EF1) sequences for a subset of F. cucullata specimens. Phylogenetic, nonparametric permutation methods and coalescent analyses were used to assess population divergence and to estimate the extent and direction of migration among continents. Both F. cucullata and F. nivalis were monophyletic, supporting their morphology-based delimitation, and had high and moderately high intraspecific genetic diversity, respectively. Clades within each species contained specimens from both North America and Eurasia. We found only weak genetic differentiation among North American and Eurasian populations, and evidence for moderate to high transoceanic gene flow. Our results suggest that both F. cucullata and F. nivalis have been able to migrate over large distances in response to climatic fluctuations. The high genetic diversity observed in the Arctic indicates long-term survival at high latitudes, whereas the estimated migration rates and weak geographic population structure suggest a continuing long-distance gene flow between continents that has prevented pronounced genetic differentiation. The mode of long-distance dispersal is unknown, but wind dispersal of conidia and/or ascospores is probably important in the open arctic landscapes. The high genetic diversity and efficient long-distance dispersal capability of F. cucullata and F. nivalis suggest that these species, and perhaps other arctic lichens as well, will be able to track their potential niche in the changing Arctic.

Parmelioid lichens form a species-rich group of predominantly foliose and fruticose lichenized fungi encompassing a broad range of morphological and chemical diversity. Using a multilocus approach, we reconstructed a phylogeny including 323 OTUs of parmelioid lichens and employed ancestral character reconstruction methods to understand the phenotypical evolution within this speciose group of lichen-forming fungi. Specifically, we were interested in the evolution of growth form, epicortex structure, and cortical chemistry. Since previous studies have shown that results may differ depending on the reconstruction method used, here we employed both maximum-parsimony and maximum-likelihood approaches to reconstruct ancestral character states. We have also implemented binary and multistate coding of characters and performed parallel analyses with both coding types to assess for potential coding-based biases. We reconstructed the ancestral states for nine well-supported major clades in the parmelioid group, two higher-level sister groups and the ancestral character state for all parmelioid lichens. We found that different methods for coding phenotypical characters and different ancestral character state reconstruction methods mostly resulted in identical reconstructions but yield conflicting inferences of ancestral states, in some cases. However, we found support for the ancestor of parmelioid lichens having been a foliose lichen with a non-pored epicortex and pseudocyphellae. Our data suggest that some traits exhibit patterns of evolution consistent with adaptive radiation.

YidC/Oxa/Alb3 family proteins catalyze the insertion of integral membrane proteins in bacteria, mitochondria, and chloroplasts, respectively. Unlike gram-negative organisms, gram-positive bacteria express 2 paralogs of this family, YidC1/SpoIIIJ and YidC2/YgjG. In Streptococcus mutans, deletion of yidC2 results in a stress-sensitive phenotype similar to that of mutants lacking the signal recognition particle (SRP) protein translocation pathway, while deletion of yidC1 has a less severe phenotype. In contrast to eukaryotes and gram-negative bacteria, SRP-deficient mutants are viable in S. mutans; however, double SRP-yidC2 mutants are severely compromised. Thus, YidC2 may enable loss of the SRP by playing an independent but overlapping role in cotranslational protein insertion into the membrane. This is reminiscent of the situation in mitochondria that lack an SRP pathway and where Oxa1 facilitates cotranslational membrane protein insertion by binding directly to translation-active ribosomes. Here, we show that OXA1 complements a lack of yidC2 in S. mutans. YidC2 also functions reciprocally in oxa1-deficient Saccharomyces cerevisiae mutants and mediates the cotranslational insertion of mitochondrial translation products into the inner membrane. YidC2, like Oxa1, contains a positively charged C-terminal extension and associates with translating ribosomes. Our results are consistent with a gene-duplication event in gram-positive bacteria that enabled the specialization of a YidC isoform that mediates cotranslational activity independent of an SRP pathway.

Biological soil crusts (BSCs) are communities of cryptogamic organisms, occurring in arid and semiarid regions all over the world. Based on both morphological identification and genetic analyses, we established a first cyanobacterial inventory using the biphasic approach for BSCs within two major biomes of southern Africa. The samples were collected at two different sites in the Succulent Karoo and one in the Nama Karoo. After cultivation and morphological identification, the 16S rRNA gene was sequenced from the cyanobacterial cultures. From the soil samples, the DNA was extracted, and the 16S rRNA gene sequenced. All the sequences of the clone libraries from soil and cultures were compared with those of the public databases. Forty-five different species were morphologically identified in the samples of the Succulent Karoo (observatories of Soebatsfontein and Goedehoop). Based on the genetic analyses, 60 operational taxonomic units (OTUs) were identified for the Succulent Karoo and 43 for the Nama Karoo (based on 95 % sequence similarity). The cloned sequences corresponded well with the morphologically described taxa in cultures and sequences in the public databases. Besides known species of typical crust-forming cyanobacterial genera (Microcoleus, Phormidium, Tolypothrix and Scytonema), we found sequences of so far undescribed species of the genera Leptolyngbya, Pseudanabaena, Phormidium, Oscillatoria, Schizothrix and Microcoleus. Most OTUs were restricted to distinct sites. Grazed soils showed lower taxa numbers than undisturbed soils, implying the presence of early successional crust types and reduced soil surface protection. Our combined approach of morphological identification and genetic analyses allowed both a taxa inventory and the analysis of species occurring under specific habitat conditions.

This revision of Cantharellus in Madagascar deals with species that are associated with strictly endemic host trees and shrubs. Based on morphological differences and molecular sequence data of the tef-1 gene, five new species are proposed ( C. albidolutescens , C. ambohitantelyensis , C. ibityensis , C. paucifurcatus and C. sebosus ), as well as one new subspecies, C. subincarnatus ssp. rubrosalmoneus , whereas C. decolorans and C. platyphyllus ssp. bojeriensis are epitypified. A key is provided to all Cantharellus that grow with native vegetation in Madagascar.

We present a 6-gene, 420-species maximum-likelihood phylogeny of Ascomycota, the largest phylum of Fungi. This analysis is the most taxonomically complete to date with species sampled from all 15 currently circumscribed classes. A number of superclass-level nodes that have previously evaded resolution and were unnamed in classifications of the Fungi are resolved for the first time. Based on the 6-gene phylogeny we conducted a phylogenetic informativeness analysis of all 6 genes and a series of ancestral character state reconstructions that focused on morphology of sporocarps, ascus dehiscence, and evolution of nutritional modes and ecologies. A gene-by-gene assessment of phylogenetic informativeness yielded higher levels of informativeness for protein genes (RPB1, RPB2, and TEF1) as compared with the ribosomal genes, which have been the standard bearer in fungal systematics. Our reconstruction of sporocarp characters is consistent with 2 origins for multicellular sexual reproductive structures in Ascomycota, once in the common ancestor of Pezizomycotina and once in the common ancestor of Neolectomycetes. This first report of dual origins of ascomycete sporocarps highlights the complicated nature of assessing homology of morphological traits across Fungi. Furthermore, ancestral reconstruction supports an open sporocarp with an exposed hymenium (apothecium) as the primitive morphology for Pezizomycotina with multiple derivations of the partially (perithecia) or completely enclosed (cleistothecia) sporocarps. Ascus dehiscence is most informative at the class level within Pezizomycotina with most superclass nodes reconstructed equivocally. Character-state reconstructions support a terrestrial, saprobic ecology as ancestral. In contrast to previous studies, these analyses support multiple origins of lichenization events with the loss of lichenization as less frequent and limited to terminal, closely related species.