Discrete vibro-tactile feedback prevents object slippage in hand prostheses more intuitively than other modalities

In the case of a hand amputation, the affected can use myoelectric prostheses to substitute the missing limb and regain motor functionality. Unfortunately, these prostheses do not restore sensory feedback, thus users are forced to rely on vision to avoid object slippage. This is cognitively taxing, as it requires continuous attention to the task. Thus, providing functionally effective sensory feedback is pivotal to reduce the occurrence of slip events and reduce the users’ cognitive burden. However, only a few studies investigated which kind of feedback is the most effective for this purpose, mostly using unrealistic experimental scenarios. Here we attempt a more realistic simulation of involuntary hand opening and subsequent recovery of a stable grasp of the slipping object using a robotic hand operated by the subjects through a standard myoelectric control interface. We compared three stimulation modalities (vision, continuous grip force feedback and discrete slip feedback) and found that the discrete feedback allowed subjects to have higher success rates (close to 100%) in terms of objects recovered from slippage, basically requiring no learning. These results suggest that this simple yet effective feedback can be used to reduce grasp failures in prosthetic users, increasing their confidence in the device

Neural feedback strategies to improve grasping coordination in neuromusculoskeletal prostheses

Conventional prosthetic arms suffer from poor controllability and lack of sensory feedback. Owing to the absence of tactile sensory information, prosthetic users must rely on incidental visual and auditory cues. In this study, we investigated the effect of providing tactile perception on motor coordination during routine grasping and grasping under uncertainty. Three transhumeral amputees were implanted with an osseointegrated percutaneous implant system for direct skeletal attachment and bidirectional communication with implanted neuromuscular electrodes. This neuromusculoskeletal prosthesis is a novel concept of artificial limb replacement that allows to extract control signals from electrodes implanted on viable muscle tissue, and to stimulate severed afferent nerve fibers to provide somatosensory feedback. Subjects received tactile feedback using three biologically inspired stimulation paradigms while performing a pick and lift test. The grasped object was instrumented to record grasping and lifting forces and its weight was either constant or unexpectedly changed in between trials. The results were also compared to the no-feedback control condition. Our findings confirm, in line with the neuroscientific literature, that somatosensory feedback is necessary for motor coordination during grasping. Our results also indicate that feedback is more relevant under uncertainty, and its effectiveness can be influenced by the selected neuromodulation paradigm and arguably also the prior experience of the prosthesis user

Isoprenoid Pathway Optimization for Taxol Precursor Overproduction in Escherichia coli

Author Manuscript February 6, 2011Taxol (paclitaxel) is a potent anticancer drug first isolated from the Taxus brevifolia Pacific yew tree. Currently, cost-efficient production of Taxol and its analogs remains limited. Here, we report a multivariate-modular approach to metabolic-pathway engineering that succeeded in increasing titers of taxadiene—the first committed Taxol intermediate—approximately 1 gram per liter (~15,000-fold) in an engineered Escherichia coli strain. Our approach partitioned the taxadiene metabolic pathway into two modules: a native upstream methylerythritol-phosphate (MEP) pathway forming isopentenyl pyrophosphate and a heterologous downstream terpenoid–forming pathway. Systematic multivariate search identified conditions that optimally balance the two pathway modules so as to maximize the taxadiene production with minimal accumulation of indole, which is an inhibitory compound found here. We also engineered the next step in Taxol biosynthesis, a P450-mediated 5α-oxidation of taxadiene to taxadien-5α-ol. More broadly, the modular pathway engineering approach helped to unlock the potential of the MEP pathway for the engineered production of terpenoid natural products

Yielded to Christ or conformed to this world? Postwar Mennonite responses to labour activism

This is the accepted version of the manuscript.The urbanization of North American Mennonites after the Second World War necessitated a reconsideration of Mennonite religious beliefs. Post-war concerns for social justice led to a greater emphasis on non-violence and agape at the expense of Gelassenheit. The tenor of Mennonite church conference resolutions regarding labour union membership changed; while skepticism remained regarding the wisdom of union involvement, the door was left open for participation in unions. The labour militancy of the 1970s led Manitoba Mennonites to re-examine their engagement with the labour movement, a process that has continued to the present day. Without further research on Mennonite workplaces, it cannot be known exactly how the change in religious emphases has affected Mennonite identity.https://journals.sagepub.com/doi/abs/10.1177/00084298070360020

BCL11A enhancer edited hematopoietic stem cells persist in rhesus monkeys without toxicity

Gene editing of the erythroid-specific BCL11A enhancer in hematopoietic stem and progenitor cells (HSPCs) from sickle cell disease (SCD) patients induces fetal hemoglobin (HbF) without detectable toxicity as assessed by mouse xenotransplant. Here, we evaluated autologous engraftment and HbF induction potential of erythroid-specific BCL11A enhancer edited HSPCs in four non-human primates. We utilized a single guide RNA (sgRNA) with identical human and rhesus target sequences to disrupt a GATA1 binding site at the BCL11A +58 erythroid enhancer. Cas9 protein and sgRNA ribonucleoprotein complex (RNP) was electroporated into rhesus HSPCs, followed by autologous infusion after myeloablation. We found that gene edits persisted in peripheral blood (PB) and bone marrow (BM) for up to 101 weeks similarly for BCL11A enhancer or control locus (AAVS1) targeted cells. Biallelic BCL11A enhancer editing resulted in robust gamma-globin induction, with the highest levels observed during stress erythropoiesis. Indels were evenly distributed across PB and BM lineages. Off-target edits were not observed. Non-homologous end-joining repair alleles were enriched in engrafting HSCs. In summary, we find that edited HSCs can persist for at least 101 weeks post-transplant, and biallelic edited HSCs provide substantial HbF levels in PB red blood cells, together supporting further clinical translation of this approach

Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology

Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations

Searching for VHE gamma-ray emission associated with IceCube neutrino alerts using FACT, H.E.S.S., MAGIC, and VERITAS

The realtime follow-up of neutrino events is a promising approach to searchfor astrophysical neutrino sources. It has so far provided compelling evidencefor a neutrino point source: the flaring gamma-ray blazar TXS 0506+056 observedin coincidence with the high-energy neutrino IceCube-170922A detected byIceCube. The detection of very-high-energy gamma rays (VHE, $\mathrm{E} >100\,\mathrm{GeV}$) from this source helped establish the coincidence andconstrained the modeling of the blazar emission at the time of the IceCubeevent. The four major imaging atmospheric Cherenkov telescope arrays (IACTs) -FACT, H.E.S.S., MAGIC, and VERITAS - operate an active follow-up program oftarget-of-opportunity observations of neutrino alerts sent by IceCube. Thisprogram has two main components. One are the observations of known gamma-raysources around which a cluster of candidate neutrino events has been identifiedby IceCube (Gamma-ray Follow-Up, GFU). Second one is the follow-up of singlehigh-energy neutrino candidate events of potential astrophysical origin such asIceCube-170922A. GFU has been recently upgraded by IceCube in collaborationwith the IACT groups. We present here recent results from the IACT follow-upprograms of IceCube neutrino alerts and a description of the upgraded IceCubeGFU system.<br