Analysis of intrachip electrical and optical fanout

We examine the benefits of electrical isolation in intrachip optical signaling. We calculate the delay and energy metrics of an optical interconnect with fanout driving an electrical load. By examining fanout and including load drivers into delay equations, we make a shift from the general trend of looking at optical interconnects as a replacement for long parasitic wires. Our calculations show that optical fanout provides a large improvement in an Etau2 (energy delay squared) metric and improves performance even at very short intrachip distances. The break-even length corresponds to the wiring length of 250 minimum-size inverters that are compactly laid out. These results provide a compelling reason to further examine the implementation of optical interconnects.     

Lipid and Phospholipid Profiling of Biological Samples Using MALDI Fourier Transform Mass Spectrometry

Here we describe a study of the feasibility of lipid and phospholipid (PL) profiling using matrix assisted laser desorption/ionization (MALDI) Fourier transform mass spectrometry (FTMS) for two different applications. In this work PL profiles of different mammalian tissues as well as those of whole cell organisms were examined. In particular, comparative analysis of lipid and PL profiles of tissues from mice fed different diets was done and, in another application, MALDI FTMS was used to analyze PL profiles of genetically modified Saccharomyces cerevisiae. Computational sorting of the observed ions was done in order to group the lipid and PL ions from complex MALDI spectra. The PL profiles of liver tissues from mice fed different diets showed a cross correlation coefficient of 0.2580, indicating significant dissimilarity, and revealed more than 30 significantly different peaks at the 99.9% confidence level. Histogram plots derived from the spectra of wild type and genetically modified yeast resulted in a cross correlation coefficient 0.8941 showing greater similarity, but still revealing a number of significantly different peaks. Based on these results, it appears possible to use MALDI FTMS to identify PLs as potential biomarkers for metabolic processes in whole cells and tissues.     

Manual patient transfers: factors that influence decisions and kinematic strategies employed by nursing aides

While extensive literature has characterised factors that influence the acceptable mass of ‘boxes’ during MMH tasks, less is known about these factors when moving ‘people’ in healthcare settings. This study examined factors that influence decisions/approaches employed during manual patient transfers. Sixteen nursing aides manually-transferred a standardised ‘patient’; patient mass was adjusted (using a weight vest) to determine a maximum acceptable patient mass for this task (mass_max). Grip strength was the only worker characteristic significantly associated with mass_max (r?=?0.48). Older worker age was associated with smaller peak trunk flexion (r?= ?0.58) and shoulder abduction (r?= ?0.59), and greater trunk axial twist (r?=?0.52). Workers emphasised that patient characteristics (e.g. physical/cognitive status) influenced their decisions when performing transfers. These findings extend previous literature by suggesting that grip strength is a useful predictor of perceived work capacity, older workers adapt protective postural strategies during patient transfers and worker-patient dynamics are crucial during this high-risk occupational task.

Practitioner Summary: This study examined manual patient transfers performed by nursing aides. Worker grip strength (but not age or size) was associated with perceptions of maximum acceptable patient mass. Kinematic changes suggested more conservative strategies used by older workers. Workers emphasised that patient characteristics substantially influenced their decisions when performing transfer tasks.     

The impact response of motorcycle helmets at different impact severities

Helmets reduce the frequency and severity of head and brain injuries over a range of impact severities broader than those covered by the impact attenuation standards. Our goal was to document the impact attenuation performance of common helmet types over a wide range of impact speeds. Sixty-five drop tests were performed against the side of 10 different helmets onto a flat anvil at impact speeds of 0.9–10.1 m/s (energy = 2–260 J; equivalent drop heights of 0.04–5.2 m). Three non-approved beanie helmets performed poorly, with the worst helmet reaching a peak headform acceleration of 852g at 29 J. Three full-face and one open-face helmet responded similarly from about 100g at 30 J to between 292g and 344g at 256–260 J. Three shorty style helmets responded like the full-face helmets up to 150 J, above which varying degrees of foam densification appeared to occur. Impact restitution values varied from 0.19 to 0.46. A three-parameter model successfully captured the plateau and densification responses exhibited by the various helmets (R² = 0.95–0.99). Helmet responses varied with foam thickness, foam material and possibly shell material, with the largest response differences consistent with either the presence/absence of a foam liner or the densification of the foam liner.     

Design Principles for Cationic,Astrocyte-Targeted Probes

The brain's astrocytes play key roles in normal and pathological brain processes. Targeting small molecules to astrocytes in the presence of the many other cell types in the brain will provide useful tools for their visualization and manipulation. Herein, we explore the functional consequences of synthetic modifications to a recently described astrocyte marker composed of a bright rhodamine-based fluorophore and an astrocyte-targeting moiety. We altered the nature of the targeting moiety to probe the dependence of astrocyte targeting on hydrophobicity, charge, and pK_a when exposed to astrocytes and neurons isolated from the mouse cortex. We found that an overall molecular charge of +2 and a targeting moiety with a heterocyclic aromatic amine are important requirements for specific and robust astrocyte labeling. These results provide a basis for engineering astrocyte-targeted molecular tools with unique properties, including metabolite sensing or optogenetic control.     

The usefulness of CD64, other monocyte-associated antigens, and CD45 gating in the subclassification of acute myeloid leukemias with monocytic differentiation

Immunophenotyping by flow cytometry is widely used in the diagnosis and subclassification of acute myeloid leukemia (AML). CD14 is the monocyte-associated antigen most widely used to identify AML with monocytic differentiation (French-American-British classes M4 and M5); however, we observed that CD14 expression is frequently diminished or absent in such cases. To identify monocyte-associated antigens that might improve recognition of AML M4 and M5, we used 3-color flow cytometry and a panel of antibodies reported to distinguish cells of monocytic lineage in 44 cases of AML. In addition, CD45 vs logarithmic side scatter plots were analyzed in all cases. As expected, CD14 was highly specific but was only moderately sensitive for monocytic differentiation. CD64 had the best-combined sensitivity and specificity for AML M4 and M5. CD45 vs logarithmic side scatter analysis showed a higher percentage of monocytes in AML M4 and M5 compared with nonmonocytic AML. CD64 was expressed in 5 of 5 cases of acute promyelocytic leukemia (AML M3), but the intensity of staining was significantly less in AML M3 than in AML M4 and M5. Our findings show that addition of CD64 and CD45 vs logarithmic side scatter analysis to CD14 greatly improves flow cytometric detection of AML with monocytic differentiation and that CD64, also expressed in AML M3, may help distinguish AML M3 from other subtypes.     

Cloning and sequence of ADP-ribosylation factor 1 (ARF1) from Schizosaccharomyces pombe

A gene encoding a homologue of the ADP-ribosylation factor (ARF) family of small GTP binding proteins was cloned from a Schizosaccharomyces pombe cDNA library by a functional screen of suppressors of sensitivity to 3-aminotriazole in a gcn3 null strain of Saccharomyces cerevisiae. Two independent isolates each contained the full coding region of the ARF1 gene. The encoded SpARF1 protein has a predicted molecular weight of 20 618 and is 88% and 79% identical to human and S. cerevisiae ARF1 proteins, respectively. As independent isolates were obtained, this effect of the SpARF1 appears to be a real phenomenon, but cannot currently be easily understood within the context of the evidence for a role(s) for ARF proteins in the protein secretory pathway.     

A Combination of Chemotherapy and Oncolytic Virotherapy Sensitizes Colorectal Adenocarcinoma to Immune Checkpoint Inhibitors in a cDC1-Dependent Manner

Immune checkpoint therapy has shown great promise in the treatment of cancers with a high mutational burden, such as mismatch repair-deficient colorectal carcinoma (dMMR CRC). However, many patients fail to respond to immune checkpoint therapy. Using a mouse model of dMMR CRC, we demonstrated that tumors can be further sensitized to immune checkpoint therapy by using a combination of low-dose chemotherapy and oncolytic HSV-1. This combination induced the infiltration of CD8⁺ and CD4⁺ T cells into the tumor and the upregulation of gene signatures associated with the chemoattraction of myeloid cell subsets. When combined with immune checkpoint therapy, the combination promoted the infiltration of activated type 1 conventional dendritic cells (cDC1s) into the tumor. Furthermore, we found this combination strategy to be dependent on cDC1s, and its therapeutic efficacy to be abrogated in cDC1-deficient Batf3^−/− mice. Thus, we demonstrated that the adjuvanticity of dMMR CRCs can be improved by combining low-dose chemotherapy and oncolytic HSV-1 in a cDC1-dependent manner.     

The Neonatal Fc Receptor Is Elevated in Monocyte-Derived Immune Cells in Pancreatic Cancer

The neonatal Fc receptor (FcRn) is responsible for recycling of IgG antibodies and albumin throughout the body. This mechanism has been exploited for pharmaceutic delivery across an array of diseases to either enhance or diminish this function. Monoclonal antibodies and albumin-bound nanoparticles are examples of FcRn-dependent anti-cancer therapeutics. Despite its importance in drug delivery, little is known about FcRn expression in circulating immune cells. Through time-of-flight mass cytometry (CyTOF) we were able to characterize FcRn expression in peripheral blood mononuclear cell (PBMC) populations of pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer donors. Furthermore, we were able to replicate these findings in an orthotopic murine model of PDAC. Altogether, we found that in both patients and mice with PDAC, FcRn was elevated in migratory and resident classical dendritic cell type 2 (cDC2) as well as monocytic and granulocytic myeloid-derived suppressor cell (MDSC) populations compared to tumor-free controls. Furthermore, PBMCs from PDAC patients had elevated monocyte, dendritic cells and MDSCs relative to non-cancer donor PBMCs. Future investigations into FcRn activity may further elucidate possible mechanisms of poor efficacy of antibody immunotherapies in patients with PDAC.