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The global surge in demand for metals such as cobalt and nickel has created unprecedented interest in deep-sea habitats with mineral resources. The largest area of activity is a 6 million km2 region known as the Clarion-Clipperton Zone (CCZ) in the central and eastern Pacific, regulated by the International Seabed Authority (ISA). Baseline biodiversity knowledge of the region is crucial to effective management of environmental impact from potential deep-sea mining activities, but until recently this has been almost completely lacking. The rapid growth in taxonomic outputs and data availability for the region over the last decade has allowed us to conduct the first comprehensive synthesis of CCZ benthic metazoan biodiversity for all faunal size classes. Here we present the CCZ Checklist, a biodiversity inventory of benthic metazoa vital to future assessments of environmental impacts. An estimated 92% of species identified from the CCZ are new to science (436 named species from a total of 5,578 recorded). This is likely to be an overestimate owing to synonyms in the data but is supported by analysis of recent taxonomic studies suggesting that 88% of species sampled in the region are undescribed. Species richness estimators place total CCZ metazoan benthic diversity at 6,233 (+/−82 SE) species for Chao1, and 7,620 (+/−132 SE) species for Chao2, most likely representing lower bounds of diversity in the region. Although uncertainty in estimates is high, regional syntheses become increasingly possible as comparable datasets accumulate. These will be vital to understanding ecological processes and risks of biodiversity loss.

Mitochondria are dynamic, interactive organelles that connect cellular signaling and whole-cell homeostasis. This "mitochatting" allows the cell to receive information about the mitochondria's condition before accommodating energy demands. Mitofusin 2 (Mfn2), an outer mitochondrial membrane fusion protein specializes in mediating mitochondrial homeostasis. Early studies defined the biological significance of Mfn2, while latter studies highlighted its role in substrate metabolism. However, determining Mfn2 potential to contribute to energy homeostasis needs study. This review summarizes current literature on mitochondrial metabolic processes, dynamics, and evidence of interactions among Mfn2 and regulatory processes that may link Mfn2's role in maintaining mitochondrial function and substrate metabolism.

The HIV-1 Envelope glycoprotein (Env) is the sole target for broadly neutralizing antibodies (bnAbs). Env is heavily glycosylated with host-derived N-glycans, and many bnAbs bind to, or are dependent upon, Env glycans for neutralization. Although glycan-binding bnAbs are frequently detected in HIV-infected individuals, attempts to elicit them have been unsuccessful because of the poor immunogenicity of Env N-glycans. Here, we report cross-reactivity of glycan-binding bnAbs with self- and non-self N-glycans and glycoprotein antigens from different life-stages of Schistosoma mansoni. Using the IAVI Protocol C HIV infection cohort, we examine the relationship between S. mansoni seropositivity and development of bnAbs targeting glycan-dependent epitopes. We show that the unmutated common ancestor of the N332/V3-specific bnAb lineage PCDN76, isolated from an HIV-infected donor with S. mansoni seropositivity, binds to S. mansoni cercariae while lacking reactivity to gp120. Overall, these results present a strategy for elicitation of glycan-reactive bnAbs which could be exploited in HIV-1 vaccine development.

Mass drug administration with praziquantel (PZQ) monotherapy is considered the mainstay for control and elimination of the parasites causing schistosomiasis in humans. This drug shows imperfect cure rates in the field, and parasites showing reduced PZQ response can be selected in the laboratory, but the extent of resistance in Schistosoma mansoni populations is unknown. We examined the genetic basis of the variation in response in a PZQ-selected S. mansoni population (SmLE-PZQ-R) in which 35% of the parasitic worms survive high-dose PZQ (73 micrograms per milliliter) treatment. We used genome-wide association to map loci underlying PZQ response and identified a transient receptor potential (Sm.TRPMPZQ) channel (Smp_246790) within the major chromosome 3 peak that is activated by nanomolar concentrations of PZQ. The PZQ response showed recessive inheritance and marker-assisted selection of parasites at a single Sm.TRPMPZQ SNP that produced populations of PZQ-enriched resistant (PZQ-ER) and PZQ-enriched sensitive (PZQ-ES) parasites, exhibiting >377-fold difference in PZQ response. The PZQ-ER parasites survived treatment in rodents at higher frequencies compared with PZQ-ES, and resistant parasites exhibited 2.25-fold lower expression of Sm.TRPMPZQ relative to sensitive parasites. Specific chemical blockers of Sm.TRPMPZQ enhanced PZQ resistance, whereas Sm.TRPMPZQ activators increased sensitivity. We surveyed Sm.TRPMPZQ sequence variations in 259 parasites from different global sites and identified one nonsense mutation that resulted in a truncated protein with no PZQ binding site. Our results demonstrate that Sm.TRPMPZQ underlies variation in PZQ responses in S. mansoni and provides an approach for monitoring emerging PZQ-resistant alleles in schistosome elimination programs.

Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p.E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29-14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate

Mesenteric infection by the parasitic blood fluke Schistosoma bovis is a common veterinary problem in Africa and the Middle East and occasionally in the Mediterranean Region. The species also has the ability to form interspecific hybrids with the human parasite S. haematobium with natural hybridisation observed in West Africa, presenting possible zoonotic transmission. Additionally, this exchange of alleles between species may dramatically influence disease dynamics and parasite evolution. We have generated a 374 Mb assembly of the S. bovis genome using Illumina and PacBio-based technologies. Despite infecting different hosts and organs, the genome sequences of S. bovis and S. haematobium appeared strikingly similar with 97% sequence identity. The two species share 98% of protein-coding genes, with an average sequence identity of 97.3% at the amino acid level. Genome comparison identified large continuous parts of the genome (up to several 100 kb) showing almost 100% sequence identity between S. bovis and S. haematobium. It is unlikely that this is a result of genome conservation and provides further evidence of natural interspecific hybridization between S. bovis and S. haematobium. Our results suggest that foreign DNA obtained by interspecific hybridization was maintained in the population through multiple meiosis cycles and that hybrids were sexually reproductive, producing viable offspring. The S. bovis genome assembly forms a highly valuable resource for studying schistosome evolution and exploring genetic regions that are associated with species-specific phenotypic traits.

Existing and emerging methods in computational mechanics are rarely validated against problems with an unknown outcome. For this reason, Sandia National Laboratories, in partnership with US National Science Foundation and Naval Surface Warfare Center Carderock Division, launched a computational challenge in mid-summer, 2012. Researchers and engineers were invited to predict crack initiation and propagation in a simple but novel geometry fabricated from a common off-the-shelf commercial engineering alloy. The goal of this international Sandia Fracture Challenge was to benchmark the capabilities for the prediction of deformation and damage evolution associated with ductile tearing in structural metals, including physics models, computational methods, and numerical implementations currently available in the computational fracture community. Thirteen teams participated, reporting blind predictions for the outcome of the Challenge. The simulations and experiments were performed independently and kept confidential. The methods for fracture prediction taken by the thirteen teams ranged from very simple engineering calculations to complicated multiscale simulations. The wide variation in modeling results showed a striking lack of consistency across research groups in addressing problems of ductile fracture. While some methods were more successful than others, it is clear that the problem of ductile fracture prediction continues to be challenging. Specific areas of deficiency have been identified through this effort. Also, the effort has underscored the need for additional blind prediction-based assessments.

Studies to evaluate the interaction of the synthetic cannabinoid WIN55,212-2 (WIN2) and ionizing radiation have led to preliminary results implicating a novel site of action of WIN2 in the MCF-7 breast cancer model. In previous reports, WIN2 was found to stereoselectively inhibit the growth of breast cancer cells in a dose-dependent but cannabinoid receptor-independent mechanism. Experiments described in this report evaluated antiproliferative mechanisms of WIN2 treatment both alone and in combination with ionizing radiation (IR). Evaluation of autophagy, apoptosis and necrotic mechanism failed to indicate that WIN2 promoted death of the tumor cells. Autophagy was induced both for radiation alone, WIN2 alone and WIN2 + radiation, but did not appear to be involved in the antiproliferative mechanisms of either treatment. Senescence, quantified by β-galactosidase staining, and DNA damage, quantified by γH2AX formation, confirmed that radiation treatment induced senescent growth arrest both alone and in combination with WIN2; however, WIN2 was unable to alter the magnitude of senescent growth arrest induced by IR. Comparison of γH2AX levels at 1 and 24 h also showed that WIN2 did not alter the rate of DNA repair after radiation treatment. These data assessing cell death and senescence combined with additional temporal cell count studies indicated that WIN2 induces growth arrest but not cell death. It was further concluded that augmentation of IR induced antiproliferative effects by WIN2 occur from the parallel induction of both senescent and classical growth arrest responses in the breast tumor cells.

Work looking at the interaction of the synthetic cannabinoid WIN55,212-2 and ionizing radiation has led to preliminary results implicating a novel site of action in the MCF-7 breast cancer model. WIN55,212-2 has been shown previously to dose dependently, and potentially more importantly stereoselectively, inhibit the growth of breast cancer cells. Interestingly, when selective cannabinoid receptor antagonists AM251 and AM630 were administered, we see a failure to antagonize WIN55,212-2 s antiproliferative effects. This despite the observation the MCF-7 cells express mRNA for the cannabinoid receptor CB2, which WIN55,212-2 has been shown to act on in other breast cancer cell lines. Further studies were conducted that pharmacologically excluded the involvement of members of the PPAR receptor system, known to be reactive to WIN55,212-2. TRPV1 is reported to be sensitive to some cannabinoids as well, and subsequently was evaluated and then excluded based on similar pharmacological experiments. Studies from a colleague have implicated the involvement of sphingosine-1-phosphate receptors as a potential site of action for WIN55,212-2 in the brain. Our work has since shown WIN55,212-2 to be able to antagonize this sphingosine-1-phosphate receptor system, and it s known importance to MCF-7 cell growth gives a potential mechanism of action. This interaction has not previously been reported and suggests a novel site of action that could be exploited with future research., The original document contains color images.