Distribution of Entocytheridae (Crustacea: Ostracoda) in the northern prairies of North America and reports of opportunistic clitellate annelids on crayfish hosts

Northern crayfish, Orconectes virilis (Hagen, 1870), were collected from 89 sites across Alberta, Saskatchewan, Manitoba, Montana, North Dakota, and Minnesota. The entocytherid ostracod Thermastrocythere riojai (Hoff, 1943) was found on O. virilis at 45 of the 89 sites, distributed primarily in the eastern and southern portion of the study area. These observations of T. riojai greatly extend the known range of the species. The widespread distribution of T. riojai suggests that the dearth of entocytherid records from other parts of Canada is a result of nontargeted sampling rather than true absence. In addition, we report on observations of 3 noteworthy associations of oligochaetes with their crayfish hosts. Se colectaron especímenes del acocil Orconectes virilis (Hagen, 1870) en 89 sitios a lo largo de Alberta, Saskatchewan, Manitoba, Montana, North Dakota y Minnesota. Encontramos el ostracódo entocitérido Thermastrocythere riojai (Hoff, 1943) en O. virilis en 45 de los 89 sitios, distribuidos principalmente en la parte sur y la parte este del área de estudio. Estas observaciones de T. riojai amplían considerablemente el área de distribución conocida de esta especie. La distribución extensa de T. riojai sugiere que la escasez de registros de entocitéridos en otras partes de Canadá es el resultado del muestreo inespecífico y no de una ausencia verdadera. Además, reportamos observaciones de 3 asociaciones sobresalientes entre los oligoquetos y los acociles huéspedes.     

The patterns and dynamics of genomic instability in metastatic pancreatic cancer

Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.     

Oscillatory dependence of current-driven magnetic domain wall motion on current pulse length

Magnetic domain walls, in which the magnetization direction varies continuously from one direction to another, have long been objects of considerable interest. New concepts for devices based on such domain walls are made possible by the direct manipulation of the walls using spin-polarized electrical current through the phenomenon of spin momentum transfer. Most experiments to date have considered the current-driven motion of domain walls under quasi-static conditions, whereas for technological applications, the walls must be moved on much shorter timescales. Here we show that the motion of domain walls under nanosecond-long current pulses is surprisingly sensitive to the pulse length. In particular, we find that the probability of dislodging a domain wall, confined to a pinning site in a permalloy nanowire, oscillates with the length of the current pulse, with a period of just a few nanoseconds. Using an analytical model and micromagnetic simulations, we show that this behaviour is connected to a current-induced oscillatory motion of the domain wall. The period is determined by the wall's mass and the slope of the confining potential. When the current is turned off during phases of the domain wall motion when it has enough momentum, the domain wall is driven out of the confining potential in the opposite direction to the flow of spin angular momentum. This dynamic amplification effect could be exploited in magnetic nanodevices based on domain wall motion.     

Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.     

S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration

Stress proteins located in the cytosol or endoplasmic reticulum (ER) maintain cell homeostasis and afford tolerance to severe insults. In neurodegenerative diseases, several chaperones ameliorate the accumulation of misfolded proteins triggered by oxidative or nitrosative stress, or of mutated gene products. Although severe ER stress can induce apoptosis, the ER withstands relatively mild insults through the expression of stress proteins or chaperones such as glucose-regulated protein (GRP) and protein-disulphide isomerase (PDI), which assist in the maturation and transport of unfolded secretory proteins. PDI catalyses thiol-disulphide exchange, thus facilitating disulphide bond formation and rearrangement reactions. PDI has two domains that function as independent active sites with homology to the small, redox-active protein thioredoxin. During neurodegenerative disorders and cerebral ischaemia, the accumulation of immature and denatured proteins results in ER dysfunction, but the upregulation of PDI represents an adaptive response to protect neuronal cells. Here we show, in brains manifesting sporadic Parkinson's or Alzheimer's disease, that PDI is S-nitrosylated, a reaction transferring a nitric oxide (NO) group to a critical cysteine thiol to affect protein function. NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leads to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. S-nitrosylation also abrogates PDI-mediated attenuation of neuronal cell death triggered by ER stress, misfolded proteins or proteasome inhibition. Thus, PDI prevents neurotoxicity associated with ER stress and protein misfolding, but NO blocks this protective effect in neurodegenerative disorders through the S-nitrosylation of PDI.