Demixing signals in transcranial videos of neuronal calcium flux across the cerebral hemispheres is a key step before mapping features of cortical organization. Here we demonstrate that independent ...component analysis can optimally recover neural signal content in widefield recordings of neuronal cortical calcium dynamics captured at a minimum sampling rate of 1.5×106 pixels per one-hundred millisecond frame for seventeen minutes with a magnification ratio of 1:1. We show that a set of spatial and temporal metrics obtained from the components can be used to build a random forest classifier, which separates neural activity and artifact components automatically at human performance. Using this data, we establish functional segmentation of the mouse cortex to provide a map of ~115 domains per hemisphere, in which extracted time courses maximally represent the underlying signal in each recording. Domain maps revealed substantial regional motifs, with higher order cortical regions presenting large, eccentric domains compared with smaller, more circular ones in primary sensory areas. This workflow of data-driven video decomposition and machine classification of signal sources can greatly enhance high quality mapping of complex cerebral dynamics.
The vertebrate PPP1R15 family consists of the proteins GADD34 (growth arrest and DNA damage-inducible protein 34, the product of the PPP1R15A gene) and CReP (constitutive repressor of eIF2α ...phosphorylation, the product of the PPP1R15B gene), both of which function as targeting/regulatory subunits for protein phosphatase 1 (PP1) by regulating subcellular localization, modulating substrate specificity and assembling complexes with target proteins. The primary cellular function of these proteins is to facilitate the dephosphorylation of eukaryotic initiation factor 2-alpha (eIF2α) by PP1 during cell stress. In this review, we will provide a comprehensive overview of the cellular function, biochemistry and pharmacology of GADD34 and CReP, starting with a brief introduction of eIF2α phosphorylation via the integrated protein response (ISR). We discuss the roles GADD34 and CReP play as feedback inhibitors of the unfolded protein response (UPR) and highlight the critical function they serve as inhibitors of the PERK-dependent branch, which is particularly important since it can mediate cell survival or cell death, depending on how long the stressful stimuli lasts, and GADD34 and CReP play key roles in fine-tuning this cellular decision. We briefly discuss the roles of GADD34 and CReP homologs in model systems and then focus on what we have learned about their function from knockout mice and human patients, followed by a brief review of several diseases in which GADD34 and CReP have been implicated, including cancer, diabetes and especially neurodegenerative disease. Because of the potential importance of GADD34 and CReP in aspects of human health and disease, we will discuss several pharmacological inhibitors of GADD34 and/or CReP that show promise as treatments and the controversies as to their mechanism of action. This review will finish with a discussion of the biochemical properties of GADD34 and CReP, their regulation and the additional interacting partners that may provide insight into the roles these proteins may play in other cellular pathways. We will conclude with a brief outline of critical areas for future study.
The most common pathogens in surgical site infections after total hip and knee arthroplasty are methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and ...coagulase-negative staphylococci. Patients colonized with MSSA or MRSA have an increased risk for a staphylococcal infection at the site of a total hip or knee arthroplasty. Most colonized individuals who develop a staphylococcal infection at the site of a total hip or total knee arthroplasty have molecularly identical S. aureus isolates in their nares and wounds. Screening and nasal decolonization of S. aureus can potentially reduce the rates of staphylococcal surgical site infection after total hip and total knee arthroplasty.
In refractory cardiac arrest, with cardiopulmonary resuscitation (CPR) for more than 30 min, chances of survival are small. Extracorporeal cardiopulmonary resuscitation (ECPR) is an option for ...certain patients with cardiac arrest. The aim of this study was to evaluate characteristics of patients selected for ECPR.
Anonymised data of adult patients suffering refractory cardiac arrest, transported with ongoing CPR to an ED of a tertiary care centre between 2002 and 2012 were analysed. Outcome measure was the selection for ECPR. Secondary outcome was 180 days survival in good neurological condition.
Overall, 239 patients fulfilled the inclusion criteria. ECPR was initiated in seven patients. Patients treated with ECPR were younger (46 vs 60 years; p=0.04), had shorter intervals before CPR was started (0 vs 1 min; p=0.013), faster admissions at the ED (38 vs 56 min; p=0.31) and lower blood glucose levels on admission (14 vs 21 mmol/L; p=0.018). Survival to discharge in good neurological condition was achieved in 14 (6%) of all patients. One patient in the ECPR group survived in excellent neurological condition. Age was independently associated with the selection for ECPR (OR 0.07; 95% CI 0.01 to 0.85; p=0.037).
Emergency extracorporeal life support was used for a highly selected group of patients in refractory cardiac arrest. Several parameters were associated with the decision, but only age was independently associated with the selection for ECPR. The patient selection resulting in a survival of one patient out of seven treated seems reasonable. Randomised controlled trials evaluating the age limit as selection criteria are urgently needed to confirm these findings.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)-a subtype of Hodgkin lymphoma (HL)-is characterized by a low content of tumor cells, the lymphocyte predominant (LP) cells. Transformation into ...diffuse large B-cell lymphoma (DLBCL) occurs in about 10% of patients. We performed whole-genome mutation analysis of the DLBCL components from two composite lymphomas consisting of clonally related NLPHL and DLBCL as a means to identify candidate tumor suppressor genes and oncogenes in NLPHL. The analysis of LP cells for selected mutations of the DLBCL revealed that most mutations are also present in the LP cells, indicating a close relationship between the two components. The analysis of 62 selected genes in NLPHL by targeted ultra-deep sequencing revealed three novel highly recurrently mutated genes (each mutated in ~50% of cases), that is, DUSP2, SGK1 and JUNB. SGK1 was expressed in the LP cells of primary NLPHL cases and in the NLPHL cell line DEV. Administration of an SGK1 inhibitor induced apoptosis in the NLPHL cell line DEV and the DLBCL cell line Farage, suggesting a pathogenetic role of SGK1 in the LP and DLBCL cells. In summary, the present study identifies SGK1, DUSP2 and JUNB as novel key players in the pathogenesis of NLPHL.
Immune checkpoint inhibitors targeting the interaction between programmed cell death-1 (PD-1) and its ligand PD-L1 induce tumor regression in a subset of non-small cell lung cancer patients. However, ...clinical response rates are less than 25%. Evaluation of combinations of immunotherapy with existing therapies requires appropriate preclinical animal models. In this study, murine lung cancer cells (CMT167 and LLC) were implanted either orthotopically in the lung or subcutaneously in syngeneic mice, and response to anti-PD-1/PD-L1 therapy was determined. Anti-PD-1/PD-L1 therapy inhibited CMT167 orthotopic lung tumors by 95%. The same treatments inhibited CMT167 subcutaneous tumors by only 30% and LLC orthotopic lung tumors by 35%. CMT167 subcutaneous tumors had more Foxp3
CD4
T cells and fewer PD-1
CD4
T cells compared with CMT167 orthotopic tumors. Flow cytometric analysis also demonstrated increased abundance of PD-L1
cells in the tumor microenvironment in CMT167 tumor-bearing lungs compared with CMT167 subcutaneous tumors or LLC tumor-bearing lungs. Silencing PD-L1 expression in CMT167 cells resulted in smaller orthotopic tumors that remained sensitive to anti-PD-L1 therapy, whereas implantation of CMT167 cells into PD-L1
mice blocked orthotopic tumor growth, indicating a role for PD-L1 in both the cancer cell and the microenvironment. These findings indicate that the response of cancer cells to immunotherapy will be determined by both intrinsic properties of the cancer cells and specific interactions with the microenvironment. Experimental models that accurately recapitulate the lung tumor microenvironment are useful for evaluation of immunotherapeutic agents.
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The vascular adventitia is a complex layer of the vessel wall consisting of vasa vasorum microvessels, nerves, fibroblasts, immune cells, and resident progenitor cells. Adventitial progenitors ...express the stem cell markers, Sca1 and CD34 (adventitial sca1-positive progenitor cells AdvSca1), have the potential to differentiate in vitro into multiple lineages, and potentially contribute to intimal lesions in vivo.
Although emerging data support the existence of AdvSca1 cells, the goal of this study was to determine their origin, degree of multipotency and heterogeneity, and contribution to vessel remodeling.
Using 2 in vivo fate-mapping approaches combined with a smooth muscle cell (SMC) epigenetic lineage mark, we report that a subpopulation of AdvSca1 cells is generated in situ from differentiated SMCs. Our data establish that the vascular adventitia contains phenotypically distinct subpopulations of progenitor cells expressing SMC, myeloid, and hematopoietic progenitor-like properties and that differentiated SMCs are a source to varying degrees of each subpopulation. SMC-derived AdvSca1 cells exhibit a multipotent phenotype capable of differentiating in vivo into mature SMCs, resident macrophages, and endothelial-like cells. After vascular injury, SMC-derived AdvSca1 cells expand in number and are major contributors to adventitial remodeling. Induction of the transcription factor Klf4 in differentiated SMCs is essential for SMC reprogramming in vivo, whereas in vitro approaches demonstrate that Klf4 is essential for the maintenance of the AdvSca1 progenitor phenotype.
We propose that generation of resident vascular progenitor cells from differentiated SMCs is a normal physiological process that contributes to the vascular stem cell pool and plays important roles in arterial homeostasis and disease.
Domestic goats are raised for meat, milk and hair production, in herds for rangeland weed control, and as pack animals. Domestic sheep, goats and wild bighorn sheep are all susceptible to a ...multifactorial pneumonia. We sampled 43 herd goats from 7 herds and 48 pack goats from 11 herds for viral and bacterial serology, parasitology, and Pasteurellaceae microbiology. The goats in this study were in generally good health, although most goats did harbor various pathogens and parasites including several bacteria, specifically Pasteurellaceae, which have been associated with pneumonia in free-ranging bighorn sheep. It is not known if domestic goats can transmit the Pasteurellaceae or other pathogens found in this study readily to wild bighorn sheep. However, due the possibility of transmission, domestic goats in areas in or near bighorn sheep habitat should be managed to minimize the risk of spreading disease agents to bighorn sheep.
Memristors are novel devices, useful as memory at all hierarchies. These devices can also behave as logic circuits. In this paper, the IMPLY logic gate, a memristor-based logic circuit, is described. ...In this memristive logic family, each memristor is used as an input, output, computational logic element, and latch in different stages of the computing process. The logical state is determined by the resistance of the memristor. This logic family can be integrated within a memristor-based crossbar, commonly used for memory. In this paper, a methodology for designing this logic family is proposed. The design methodology is based on a general design flow, suitable for all deterministic memristive logic families, and includes some additional design constraints to support the IMPLY logic family. An IMPLY 8-bit full adder based on this design methodology is presented as a case study.
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