Curved-crease origami face shields for infection control

The COVID-19 pandemic has created enormous global demand for personal protective equipment (PPE). Face shields are an important component of PPE for front-line workers in the context of the COVID-19 pandemic, providing protection of the face from splashes and sprays of virus-containing fluids. Existing face shield designs and manufacturing procedures may not allow for production and distribution of face shields in sufficient volume to meet global demand, particularly in Low and Middle-Income countries. This paper presents a simple, fast, and cost-effective curved-crease origami technique for transforming flat sheets of flexible plastic material into face shields for infection control. It is further shown that the design could be produced using a variety of manufacturing methods, ranging from manual techniques to high-volume die-cutting and creasing. This demonstrates the potential for the design to be applied in a variety of contexts depending on available materials, manufacturing capabilities and labour. An easily implemented and flexible physical-digital parametric design methodology for rapidly exploring and refining variations on the design is presented, potentially allowing others to adapt the design to accommodate a wide range of ergonomic and protection requirements

Curved-crease origami face shields for infection control

The COVID-19 pandemic has created enormous global demand for personal protective equipment (PPE). Face shields are an important component of PPE for front-line workers in the context of the COVID-19 pandemic, providing protection of the face from splashes and sprays of virus-containing fluids. Existing face shield designs and manufacturing procedures may not allow for production and distribution of face shields in sufficient volume to meet global demand, particularly in Low and Middle-Income countries. This paper presents a simple, fast, and cost-effective curved-crease origami technique for transforming flat sheets of flexible plastic material into face shields for infection control. It is further shown that the design could be produced using a variety of manufacturing methods, ranging from manual techniques to high-volume die-cutting and creasing. This demonstrates the potential for the design to be applied in a variety of contexts depending on available materials, manufacturing capabilities and labour. An easily implemented and flexible physical-digital parametric design methodology for rapidly exploring and refining variations on the design is presented, potentially allowing others to adapt the design to accommodate a wide range of ergonomic and protection requirements

Applications of Field-Theoretic Renormalization Group Methods to Reaction-Diffusion Problems

We review the application of field-theoretic renormalization group (RG) methods to the study of fluctuations in reaction-diffusion problems. We first investigate the physical origin of universality in these systems, before comparing RG methods to other available analytic techniques, including exact solutions and Smoluchowski-type approximations. Starting from the microscopic reaction-diffusion master equation, we then pedagogically detail the mapping to a field theory for the single-species reaction k A -> l A (l < k). We employ this particularly simple but non-trivial system to introduce the field-theoretic RG tools, including the diagrammatic perturbation expansion, renormalization, and Callan-Symanzik RG flow equation. We demonstrate how these techniques permit the calculation of universal quantities such as density decay exponents and amplitudes via perturbative eps = d_c - d expansions with respect to the upper critical dimension d_c. With these basics established, we then provide an overview of more sophisticated applications to multiple species reactions, disorder effects, L'evy flights, persistence problems, and the influence of spatial boundaries. We also analyze field-theoretic approaches to nonequilibrium phase transitions separating active from absorbing states. We focus particularly on the generic directed percolation universality class, as well as on the most prominent exception to this class: even-offspring branching and annihilating random walks. Finally, we summarize the state of the field and present our perspective on outstanding problems for the future.Comment: 10 figures include

Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia:a descriptive genomic study

BACKGROUND: Since June, 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has, worldwide, caused 104 infections in people including 49 deaths, with 82 cases and 41 deaths reported from Saudi Arabia. In addition to confirming diagnosis, we generated the MERS-CoV genomic sequences obtained directly from patient samples to provide important information on MERS-CoV transmission, evolution, and origin. METHODS: Full genome deep sequencing was done on nucleic acid extracted directly from PCR-confirmed clinical samples. Viral genomes were obtained from 21 MERS cases of which 13 had 100%, four 85-95%, and four 30-50% genome coverage. Phylogenetic analysis of the 21 sequences, combined with nine published MERS-CoV genomes, was done. FINDINGS: Three distinct MERS-CoV genotypes were identified in Riyadh. Phylogeographic analyses suggest the MERS-CoV zoonotic reservoir is geographically disperse. Selection analysis of the MERS-CoV genomes reveals the expected accumulation of genetic diversity including changes in the S protein. The genetic diversity in the Al-Hasa cluster suggests that the hospital outbreak might have had more than one virus introduction. INTERPRETATION: We present the largest number of MERS-CoV genomes (21) described so far. MERS-CoV full genome sequences provide greater detail in tracking transmission. Multiple introductions of MERS-CoV are identified and suggest lower R0 values. Transmission within Saudi Arabia is consistent with either movement of an animal reservoir, animal products, or movement of infected people. Further definition of the exposures responsible for the sporadic introductions of MERS-CoV into human populations is urgently needed. FUNDING: Saudi Arabian Ministry of Health, Wellcome Trust, European Community, and National Institute of Health Research University College London Hospitals Biomedical Research Centre

Inter-domain Communication Mechanisms in an ABC Importer: A Molecular Dynamics Study of the MalFGK2E Complex

ATP-Binding Cassette transporters are ubiquitous membrane proteins that convert the energy from ATP-binding and hydrolysis into conformational changes of the transmembrane region to allow the translocation of substrates against their concentration gradient. Despite the large amount of structural and biochemical data available for this family, it is still not clear how the energy obtained from ATP hydrolysis in the ATPase domains is “transmitted” to the transmembrane domains. In this work, we focus our attention on the consequences of hydrolysis and inorganic phosphate exit in the maltose uptake system (MalFGK2E) from Escherichia coli. The prime goal is to identify and map the structural changes occurring during an ATP-hydrolytic cycle. For that, we use extensive molecular dynamics simulations to study three potential intermediate states (with 10 replicates each): an ATP-bound, an ADP plus inorganic phosphate-bound and an ADP-bound state. Our results show that the residues presenting major rearrangements are located in the A-loop, in the helical sub-domain, and in the “EAA motif” (especially in the “coupling helices” region). Additionally, in one of the simulations with ADP we were able to observe the opening of the NBD dimer accompanied by the dissociation of ADP from the ABC signature motif, but not from its corresponding P-loop motif. This work, together with several other MD studies, suggests a common communication mechanism both for importers and exporters, in which ATP-hydrolysis induces conformational changes in the helical sub-domain region, in turn transferred to the transmembrane domains via the “coupling helices”

Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors.

Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies

Drug Discovery Using Chemical Systems Biology: Weak Inhibition of Multiple Kinases May Contribute to the Anti-Cancer Effect of Nelfinavir

Nelfinavir is a potent HIV-protease inhibitor with pleiotropic effects in cancer cells. Experimental studies connect its anti-cancer effects to the suppression of the Akt signaling pathway, but the actual molecular targets remain unknown. Using a structural proteome-wide off-target pipeline, which integrates molecular dynamics simulation and MM/GBSA free energy calculations with ligand binding site comparison and biological network analysis, we identified putative human off-targets of Nelfinavir and analyzed the impact on the associated biological processes. Our results suggest that Nelfinavir is able to inhibit multiple members of the protein kinase-like superfamily, which are involved in the regulation of cellular processes vital for carcinogenesis and metastasis. The computational predictions are supported by kinase activity assays and are consistent with existing experimental and clinical evidence. This finding provides a molecular basis to explain the broad-spectrum anti-cancer effect of Nelfinavir and presents opportunities to optimize the drug as a targeted polypharmacology agent

Was Wright Right? The Canonical Genetic Code is an Empirical Example of an Adaptive Peak in Nature; Deviant Genetic Codes Evolved Using Adaptive Bridges

The canonical genetic code is on a sub-optimal adaptive peak with respect to its ability to minimize errors, and is close to, but not quite, optimal. This is demonstrated by the near-total adjacency of synonymous codons, the similarity of adjacent codons, and comparisons of frequency of amino acid usage with number of codons in the code for each amino acid. As a rare empirical example of an adaptive peak in nature, it shows adaptive peaks are real, not merely theoretical. The evolution of deviant genetic codes illustrates how populations move from a lower to a higher adaptive peak. This is done by the use of “adaptive bridges,” neutral pathways that cross over maladaptive valleys by virtue of masking of the phenotypic expression of some maladaptive aspects in the genotype. This appears to be the general mechanism by which populations travel from one adaptive peak to another. There are multiple routes a population can follow to cross from one adaptive peak to another. These routes vary in the probability that they will be used, and this probability is determined by the number and nature of the mutations that happen along each of the routes. A modification of the depiction of adaptive landscapes showing genetic distances and probabilities of travel along their multiple possible routes would throw light on this important concept

Dual Triumphalist Heritage Narrative And The Sungai Buloh Leprosy Settlement

Unlike other heritage movements in Malaysia, which are largely ethnicbased and culture obsessed (Cartier 1996; Worden 2001), the preservation movement of the Sungai Bulah Leprosy Settlement (SBLS thereafter), also widely referred to as the "Valley of Hope", 1 is concerned with the conservation of a site that is associated with a socially stigmatised disease. Built at a jungle fringe in Selangor in 1930, SBLS was constructed as a place for the treatment, and forced isolation from wider society, of people suffering from leprosy. Although leprosy knows no racial boundaries as people of any background can be afflicted with the disease, nearly eighty per cent of the patients admitted to SBLS have been ethnic Chinese. Of the rest, about fifteen per cent were ethnic Malays with ethnic Indians making up five per cent. Former patients who were cured but left with differing degrees of disfigurement and disability are also residents of the SBLS today.2 SBLS's population reached its peal<. with 2400 people in 1958, but today their number is just slightly over one hundred (JoshuaRaghavar 1983; Wong and Phang 2006)

Genetic modification of primary human B cells to model high-grade lymphoma

Abstract: Sequencing studies of diffuse large B cell lymphoma (DLBCL) have identified hundreds of recurrently altered genes. However, it remains largely unknown whether and how these mutations may contribute to lymphomagenesis, either individually or in combination. Existing strategies to address this problem predominantly utilize cell lines, which are limited by their initial characteristics and subsequent adaptions to prolonged in vitro culture. Here, we describe a co-culture system that enables the ex vivo expansion and viral transduction of primary human germinal center B cells. Incorporation of CRISPR/Cas9 technology enables high-throughput functional interrogation of genes recurrently mutated in DLBCL. Using a backbone of BCL2 with either BCL6 or MYC, we identify co-operating genetic alterations that promote growth or even full transformation into synthetically engineered DLBCL models. The resulting tumors can be expanded and sequentially transplanted in vivo, providing a scalable platform to test putative cancer genes and to create mutation-directed, bespoke lymphoma models