Cancer associated mutations in Sec61γ alter the permeability of the ER translocase

Translocation of secretory and integral membrane proteins across or into the ER membrane occurs via the Sec61 complex, a heterotrimeric protein complex possessing two essential sub-units, Sec61p/Sec61α and Sss1p/Sec61γ and the non-essential Sbh1p/Sec61β subunit. In addition to forming a protein conducting channel, the Sec61 complex maintains the ER permeability barrier, preventing flow of molecules and ions. Loss of Sec61 integrity is detrimental and implicated in the progression of disease. The Sss1p/Sec61γ C-terminus is juxtaposed to the key gating module of Sec61p/Sec61α and is important for gating the translocon. Inspection of the cancer genome database identifies six mutations in highly conserved amino acids of Sec61γ/Sss1p. We identify that five out of the six mutations identified affect gating of the ER translocon, albeit with varying strength. Together, we find that mutations in Sec61γ that arise in malignant cells result in altered translocon gating dynamics, this offers the potential for the translocon to represent a target in co-therapy for cancer treatment.     

The role of fire in terrestrial vertebrate richness patterns

Productivity is strongly associated with terrestrial species richness patterns, although the mechanisms underpinning such patterns have long been debated. Despite considerable consumption of primary productivity by fire, its influence on global diversity has received relatively little study. Here we examine the sensitivity of terrestrial vertebrate biodiversity (amphibians, birds and mammals) to fire, while accounting for other drivers. We analyse global data on terrestrial vertebrate richness, net primary productivity, fire occurrence (fraction of productivity consumed) and additional influences unrelated to productivity (i.e., historical phylogenetic and area effects) on species richness. For birds, fire is associated with higher diversity, rivalling the effects of productivity on richness, and for mammals, fire's positive association with diversity is even stronger than productivity; for amphibians, in contrast, there are few clear associations. Our findings suggest an underappreciated role for fire in the generation of animal species richness and the conservation of global biodiversity.     

Mechanisms and Risk Factors for Noncontact ACL Injury in Age Mature Athletes Who Engage in Field Or Court Sports: A Summary of the Literature Since 1980

ABSTRACT: Serpell, BG, Scarvell, JM, Ball, NB, and Smith, PN. Mechanisms and risk factors for noncontact ACL injury in age mature athletes who engage in field or court sports: A summary of literature since 1980. J Strength Cond Res 26(11): 3160-3176, 2012-Epidemiological data show that in the last 10 years alone the incidence and rate of anterior cruciate ligament (ACL) injuries have not changed appreciably. Furthermore, many ACL injuries appear to be noncontact in nature and sustained while engaging in some field or court sport. Thus, the need to investigate novel methods and adopt training strategies to prevent ACL injuries is paramount. To do so, however, requires an understanding of the mechanisms and risk factors for the injury. The aim of this review was to investigate the mechanisms and risk factors for noncontact ACL injuries in age mature athletes who compete in field or court sports. A search of the entire MEDLINE database for biomedicine was performed, and an iterative reference check was also conducted. A total of 87 articles disclosed met the eligibility criteria. Articles were grouped into 'themes'; 'anatomical and biomechanical mechanisms and risk factors,' 'intrinsic mechanisms and risk factors,' and 'extrinsic mechanisms and risk factors.' In this review, it is concluded that there are still a number of risk factors and mechanisms for noncontact ACL injury that are not well understood. However, the importance of dynamic knee joint stability is highlighted. It is also suggested that novel methods for preventing ACL injury be investigated and developed.     

Proteomic Strategy for Identifying Mollusc Shell Proteins Using Mild Chemical Degradation and Trypsin Digestion of Insoluble Organic Shell Matrix: A Pilot Study on Haliotis tuberculata

A successful strategy for the identification of shell proteins is based on proteomic analyses where soluble and insoluble fractions isolated from organic shell matrix are digested with trypsin with the aim of generating peptides, which are used to identify novel shell proteins contained in databases. However, using trypsin as a sole degradative agent is limited by the enzyme's cleavage specificity and is dependent upon the occurrence of lysine and arginine in the shell protein sequence. To bypass this limitation, we investigated the ability of trifluoroacetic acid (TFA), a low-specificity chemical degradative agent, to generate clusters of analyzable peptides from organic shell matrix, suitable for database annotation. Acetic acid-insoluble fractions from Haliotis tuberculata shell were processed by trypsin followed by TFA digestion. The hydrolysates were used to annotate an expressed sequence tag library constructed from the mantle tissue of Haliotis asinina, a tropical abalone species. The characterization of sequences with repeat motifs featured in some of the shell matrix proteins benefited from TFA-induced serial cutting, which can result in peptide ladder series. Using the degradative specificities of TFA and trypsin, we were able to identify five novel shell proteins. This pilot study indicates that a mild chemical digestion of organic shell matrix combined with trypsin generates peptides suitable for proteomic analysis for better characterization of mollusc shell matrix proteins.     

Multi‐model comparison highlights consistency in predicted effect of warming on a semi‐arid shrub

A number of modeling approaches have been developed to predict the impacts of climate change on species distributions, performance, and abundance. The stronger the agreement from models that represent different processes and are based on distinct and independent sources of information, the greater the confidence we can have in their predictions. Evaluating the level of confidence is particularly important when predictions are used to guide conservation or restoration decisions. We used a multi‐model approach to predict climate change impacts on big sagebrush (Artemisia tridentata), the dominant plant species on roughly 43 million hectares in the western United States and a key resource for many endemic wildlife species. To evaluate the climate sensitivity of A. tridentata, we developed four predictive models, two based on empirically derived spatial and temporal relationships, and two that applied mechanistic approaches to simulate sagebrush recruitment and growth. This approach enabled us to produce an aggregate index of climate change vulnerability and uncertainty based on the level of agreement between models. Despite large differences in model structure, predictions of sagebrush response to climate change were largely consistent. Performance, as measured by change in cover, growth, or recruitment, was predicted to decrease at the warmest sites, but increase throughout the cooler portions of sagebrush's range. A sensitivity analysis indicated that sagebrush performance responds more strongly to changes in temperature than precipitation. Most of the uncertainty in model predictions reflected variation among the ecological models, raising questions about the reliability of forecasts based on a single modeling approach. Our results highlight the value of a multi‐model approach in forecasting climate change impacts and uncertainties and should help land managers to maximize the value of conservation investments.     

Morphometric and molecular variation in concert: taxonomy and genetics of the reticulate Pyrenean and Iberian alpine spiny fescues (Festuca eskia complex,Poaceae)

The Iberian mountain spiny fescues are a reticulate group of five diploid grass taxa consisting of three parental species and two putative hybrids: F. × souliei (F. eskia × F. quadriflora) and F. × picoeuropeana (F. eskia × F. gautieri). Phenotypic and molecular studies were conducted with the aim of determining the taxonomic boundaries and genetic relationships of the five taxa and disentangling the origins of the two hybrids. Statistical analyses of 31 selected phenotypic traits were conducted on individuals from 159 populations and on nine type specimens. Molecular analyses of random amplified polymorphic DNA (RAPD) markers were performed on 29 populations. The phenotypic analyses detected significant differences between the five taxa and demonstrated the overall intermediacy of the F. × picoeuropeana and F. × souliei between their respective parents. The RAPD analysis corroborated the genetic differentiation of F. eskia, F. gautieri and F. quadriflora and the intermediate nature of the two hybrids; however, they also detected genetic variation within F. × picoeuropeana. These results suggest distinct origins for F. × picoeuropeana in the Cantabrian and Pyrenean mountains, with the sporadic Pyrenean populations having potentially resulted from recent hybridizations and the stabilized Cantabrian ones from older events followed by potential displacements of the parents. © 2013 The Linnean Society of London, Botanical Journal of the Linnean Society, 2013, 173 , 676–706.     

First record of non-marine ostracods from the Paleogene “hamadian deposits” of Méridja area,west of Bechar (southwestern Algeria)

A new non-marine ostracod fauna from the Paleogene “hamadian deposits” outcropping west of Bechar (southwestern Algeria) has been recovered from lacustrine to fluvial deposits of the Oued Méridja section and fluvial deposits on the southern edge of the Hamada de Méridja section. Recently, these sections have been dated as late Thanetian – early Ypresian (latest Paleocene to earliest Eocene) and Ypresian – earliest Lutetian (early to earliest middle Eocene), respectively, based on charophytes. The associated ostracod fauna recovered consists of relatively mostly moderately to badly preserved specimens and comprises 14 taxa, none of which could be identified to species level in view of its poor state of preservation; we have nevertheless been able to identify and describe the following taxa: Herpetocypris sp., Cyprinotus? sp., Heterocypris? sp. 1 and sp. 2, Cypris? sp., Ilyocypris sp., Cytheroidea indet. sp. 1 and sp. 2, Limnocytheridae indet. sp. 1, Cypridoidea indet. sp. 1, Cyprididae indet. sp. 1, and Ostracoda indet. sp. 1, 2 and 3. Only Heterocypris sp. 1 occurs in both sections. Although the fauna can as yet not be related to the few other contemporaneous faunas reported from the wider palaeogeographic area, it adds important new information to our poor knowledge on Eocene non-marine ostracods in North Africa and southern Europe. The Méridja sections and area are promising regarding the discovery of more, better preserved material and further studies, and one main limitation to the correlation of the fauna is the hitherto insufficient taxonomic knowledge on many faunal elements of Eocene non-marine ostracods to which our section contributes considerably.     

Longer lifespan in male mice treated with a weakly estrogenic agonist,an antioxidant,an α‐glucosidase inhibitor or a Nrf2‐inducer

The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin – the latter with and without rapamycin, and two drugs previously examined: 17‐α‐estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17‐α‐estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male‐specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α‐glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.     

Molecular insights into RBR E3 ligase ubiquitin transfer mechanisms

RING‐in‐between‐RING (RBR) ubiquitin (Ub) ligases are a distinct class of E3s, defined by a RING1 domain that binds E2 Ub‐conjugating enzyme and a RING2 domain that contains an active site cysteine similar to HECT‐type E3s. Proposed to function as RING/HECT hybrids, details regarding the Ub transfer mechanism used by RBRs have yet to be defined. When paired with RING‐type E3s, E2s perform the final step of Ub ligation to a substrate. In contrast, when paired with RBR E3s, E2s must transfer Ub onto the E3 to generate a E3~Ub intermediate. We show that RBRs utilize two strategies to ensure transfer of Ub from the E2 onto the E3 active site. First, RING1 domains of HHARI and RNF144 promote open E2~Ubs. Second, we identify a Ub‐binding site on HHARI RING2 important for its recruitment to RING1‐bound E2~Ub. Mutations that ablate Ub binding to HHARI RING2 also decrease RBR ligase activity, consistent with RING2 recruitment being a critical step for the RBR Ub transfer mechanism. Finally, we demonstrate that the mechanism defined here is utilized by a variety of RBRs.