Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity.

The majority of chimeric antigen receptor (CAR) T-cell research has focused on attacking cancer cells. Here, we show that targeting the tumor-promoting, nontransformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single-chain Fv FAP [monoclonal antibody (mAb) 73.3] with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-γ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAP(hi) stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8(+) T-cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T-cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective, suggesting that further clinical development of anti-human FAP-CAR is warranted

OpenSep: A generalizable open source pipeline for SOFA score calculation and Sepsis-3 classification

EHR-based sepsis research often uses heterogeneous definitions of sepsis leading to poor generalizability and difficulty in comparing studies to each other. We have developed OpenSep, an open-source pipeline for sepsis phenotyping according to the Sepsis-3 definition, as well as determination of time of sepsis onset and SOFA scores. The Minimal Sepsis Data Model was developed alongside the pipeline to enable the execution of the pipeline to diverse sources of electronic health record data. The pipeline\u27s accuracy was validated by applying it to the MIMIC-IV version 1.0 data and comparing sepsis onset and SOFA scores to those produced by the pipeline developed by the curators of MIMIC. We demonstrated high reliability between both the sepsis onsets and SOFA scores, however the use of the Minimal Sepsis Data model developed for this work allows our pipeline to be applied to more broadly to data sources beyond MIMIC

Social distancing during the COVID-19 pandemic: quantifying the practice in Michigan - a hotspot state early in the pandemic - using a volunteer-based online survey

BACKGROUND: Public Health policies related to social distancing efforts during the COVID-19 pandemic helped slow the infection rate. However, individual-level factors associated with social distancing are largely unknown. We sought to examine social distancing during the COVID-19 pandemic in Michigan, an infection hotspot state in the United States early in the pandemic. METHODS: Two surveys were distributed to Michigan residents via email lists and social media following COVID-19 related state mandates in March; 45,691 adults responded to the first survey and 8512 to the second. Staying home ≥ 3 out of 5 previous days defined having more social distancing. Logistic regression models were used to examine potential factors associated with more social distancing. RESULTS: Most respondents were women (86% in Survey 1, 87% in Survey 2). In Survey 1, 63% reported more social distancing, increasing to 78% in Survey 2. Female sex and having someone (or self) sick in the home were consistently associated with higher social distancing, while increasing age was positively associated in Survey 1 but negatively associated in Survey 2. Most respondents felt social distancing policies were important (88% in Survey 1; 91% in Survey 2). CONCLUSIONS: Michiganders responding to the surveys were both practicing and supportive of social distancing. State-level executive orders positively impacted behaviors early in the COVID-19 pandemic in Michigan. Additional supports are needed to help vulnerable populations practice social distancing, including older individuals

A Recurrent Network in the Lateral Amygdala: A Mechanism for Coincidence Detection

Synaptic changes at sensory inputs to the dorsal nucleus of the lateral amygdala (LAd) play a key role in the acquisition and storage of associative fear memory. However, neither the temporal nor spatial architecture of the LAd network response to sensory signals is understood. We developed a method for the elucidation of network behavior. Using this approach, temporally patterned polysynaptic recurrent network responses were found in LAd (intra-LA), both in vitro and in vivo, in response to activation of thalamic sensory afferents. Potentiation of thalamic afferents resulted in a depression of intra-LA synaptic activity, indicating a homeostatic response to changes in synaptic strength within the LAd network. Additionally, the latencies of thalamic afferent triggered recurrent network activity within the LAd overlap with known later occurring cortical afferent latencies. Thus, this recurrent network may facilitate temporal coincidence of sensory afferents within LAd during associative learning

Synthesis of Biological Reports on Juvenile Fish Passage and Survival at Bonneville Dam through 2005

This report describes a review of available literature on juvenile salmonid passage at Bonneville Dam from 1939 through 2005. Studies of interest included project-wide fish-passage efficiency (FPE) studies by radio telemetry and fixed-aspect hydroacoustics, fish survival studies (direct and indirect), FGE studies, powerhouse and unit (by netting, hydroacoustics, and radio telemetry), predation studies in the forebay and tailrace, behavioral studies on forebay approach and egress, and surface-bypass studies. The FPE effort will include a review of available distribution data (horizontal, diel, and vertical) for juvenile salmon. This study does not repeat the results of previous review and synthesis studies but cites them. Where no previous review exists for a subject area, all reports were reviewed and synthesized. The report includes an annotated bibliography summarizing each of the documents reviewed and a DVD disk containing all of the original papers and reports along with an HTML index to the documents

Prusa 3-D Printer Position Error: Conceptualization and Testbed Design

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Automatic Network Fingerprinting through Single-Node Motifs

Complex networks have been characterised by their specific connectivity patterns (network motifs), but their building blocks can also be identified and described by node-motifs---a combination of local network features. One technique to identify single node-motifs has been presented by Costa et al. (L. D. F. Costa, F. A. Rodrigues, C. C. Hilgetag, and M. Kaiser, Europhys. Lett., 87, 1, 2009). Here, we first suggest improvements to the method including how its parameters can be determined automatically. Such automatic routines make high-throughput studies of many networks feasible. Second, the new routines are validated in different network-series. Third, we provide an example of how the method can be used to analyse network time-series. In conclusion, we provide a robust method for systematically discovering and classifying characteristic nodes of a network. In contrast to classical motif analysis, our approach can identify individual components (here: nodes) that are specific to a network. Such special nodes, as hubs before, might be found to play critical roles in real-world networks.Comment: 16 pages (4 figures) plus supporting information 8 pages (5 figures

Oblique Corrections To The W Width

The lowest-order expression for the partial $W$ width to $e \nu ,~\Gamma (W \to e \nu) = G_\mu M_W^3 /(6 \pi \sqrt{2})$, has no oblique radiative corrections from new physics if the measured $W$ mass is used. Here $G_\mu = (1.16639 \pm 0.00002) \times 10^{-5}$ GeV/$c^2$ is the muon decay constant. For the present value of $M_W = (80.14 \pm 0.27)$ GeV/$c^2$, and with $m_t = 140$ GeV$/c^2$, one expects $\Gamma (W \to e \nu) = (224.4 \pm 2.3)$ MeV. The total width $\Gamma_{\rm tot}(W)$ is also expected to lack oblique corrections from new physics, so that $\Gamma_{\rm tot} (W)/ \Gamma (W \to e \nu) = 3 + 6 [1 + \{\alpha_s (M_W)/\pi \}]$. Present data are consistent with this prediction.Comment: 15 pages (LaTeX), one PostScript figure not included (available upon request