Novel Neuroprotective Agents to Treat Neonatal Hypoxic-Ischemic Encephalopathy: Inter-Alpha Inhibitor Proteins

Perinatal hypoxia-ischemia (HI) is a major cause of brain injury and mortality in neonates. Hypoxic-ischemic encephalopathy (HIE) predisposes infants to long-term cognitive deficits that influence their quality of life and place a large burden on society. The only approved treatment to protect the brain after HI is therapeutic hypothermia, which has limited effectiveness, a narrow therapeutic time window, and is not considered safe for treatment of premature infants. Alternative or adjunctive therapies are needed to improve outcomes of full-term and premature infants after exposure to HI. Inter-alpha inhibitor proteins (IAIPs) are immunomodulatory molecules that are proposed to limit the progression of neonatal inflammatory conditions, such as sepsis. Inflammation exacerbates neonatal HIE and suggests that IAIPs could attenuate HI-related brain injury and improve cognitive outcomes associated with HIE. Recent studies have shown that intraperitoneal treatment with IAIPs can decrease neuronal and non-neuronal cell death, attenuate glial responses and leukocyte invasion, and provide long-term behavioral benefits in neonatal rat models of HI-related brain injury. The present review summarizes these findings and outlines the remaining experimental analyses necessary to determine the clinical applicability of this promising neuroprotective treatment for neonatal HI-related brain injury.     

An Engineered E. coli Strain for Direct in Vivo Fluorination

Selectively fluorinated compounds are found frequently in pharmaceutical and agrochemical products where currently 25–30 % of optimised compounds emerge from development containing at least one fluorine atom. There are many methods for the site-specific introduction of fluorine, but all are chemical and they often use environmentally challenging reagents. Biochemical processes for C−F bond formation are attractive, but they are extremely rare. In this work, the fluorinase enzyme, originally identified from the actinomycete bacterium Streptomyces cattleya, is engineered into Escherichia coli in such a manner that the organism is able to produce 5′-fluorodeoxyadenosine (5′-FDA) from S-adenosyl-l -methionine (SAM) and fluoride in live E. coli cells. Success required the introduction of a SAM transporter and deletion of the endogenous fluoride efflux capacity in order to generate an E. coli host that has the potential for future engineering of more elaborate fluorometabolites.     

Supramolecular and Hybrid Bonding Polymers

Staudinger established a century ago the existence of covalent macromolecules, work that led to the development of transformative materials of great benefit to society and a “quantum leap” in our understanding of biological systems. Over the past few decades the concept of supramolecular polymers has emerged–chemical systems in which structural units bond strongly to each other non-covalently. These dynamic systems actually exist in the natural world and can create soft materials with structures, properties, and functions beyond the ones we know in Staudinger polymers. We reflect here on the potential of novel systems in which covalent and supramolecular polymers are chemically integrated and describe them as hybrid bonding polymers. This paper describes the concept with recent examples from the Stupp laboratory, and discusses their potential functions as robotic materials that mimic living matter and structures that offer new ideas on how to recycle and reuse soft materials.     

Material,Immunological, and Practical Perspectives on Eye Drop Formulation

Eye drops are the most common and inexpensive approach to topical ocular drug delivery. Eye drops offer a noninvasive treatment strategy; however, this can be detrimental to therapeutic efficacy when compared to invasive methods such as surgeries, implants, and injections. Improvements to the efficacy of the topical delivery of drugs to ocular tissues are currently being explored and much of this work centers on adjusting the formulation of the eye drops and prolonging the bioavailability of the therapeutic agent. This is often in preference to improving other patient‐focused or clinical factors. In this progress report, conventional, commercially available polymer eye drops are explored and the ability for current and future innovations to maintain the existing benefits of eye drops to the patient is assessed. The final materials and form of the drops (liquid, gel, or other) and the immunological implications for the user are explored. There is currently no consensus for how to most effectively improve the ocular retention and drug delivery capabilities of eye drops, but key issues are highlighted in the context of current methods under development, and potential questions and considerations for future innovations are raised.     

Vapour-liquid-solid growth of ternary Bi2Se2Te nanowires

High-density growth of single-crystalline Bi₂Se₂Te nanowires was achieved via the vapour-liquid-solid process. The stoichiometry of samples grown at various substrate temperatures is precisely determined based on energy-dispersive X-ray spectroscopy, X-ray diffraction, and Raman spectroscopy on individual nanowires. We discuss the growth mechanism and present insights into the catalyst-precursor interaction.     

3D Printing of Multifunctional Conductive Polymer Composite Hydrogels

Functional conductive hydrogels are widely used in various application scenarios, such as artificial skin, cell scaffolds, and implantable bioelectronics. However, their novel designs and technological innovations are severely hampered by traditional manufacturing approaches. Direct ink writing (DIW) is considered a viable industrial-production 3D-printing technology for the custom production of hydrogels according to the intended applications. Unfortunately, creating functional conductive hydrogels by DIW has long been plagued by complicated ink formulation and printing processes. In this study, a highly 3D printable poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS)-based ink made from fully commercially accessible raw materials is demonstrated. It is shown that complex structures can be directly printed with this ink and then precisely converted into high-performance hydrogels via a post-printing freeze–thawing treatment. The 3D-printed hydrogel exhibits high electrical conductivity of ≈2000 S m⁻¹, outstanding elasticity, high stability and durability in water, electromagnetic interference shielding, and sensing capabilities. Moreover, the hydrogel is biocompatible, showing great potential for implantable and tissue engineering applications. With significant advantages, the fabrication strategy is expected to open up a new route to create multifunctional hydrogels with custom features, and can bring new opportunities to broaden the applications of hydrogel materials.     

Liquefaction Resistance of Soils: Summary Report from the 1996 NCEER and 1998 NCEER∕NSF Workshops on Evaluation of Liquefaction Resistance of Soils

Following disastrous earthquakes in Alaska and in Niigata, Japan in 1964, Professors H. B. Seed and I. M. Idriss developed and published a methodology termed the “simplified procedure” for evaluating liquefaction resistance of soils. This procedure has become a standard of practice throughout North America and much of the world. The methodology which is largely empirical, has evolved over years, primarily through summary papers by H. B. Seed and his colleagues. No general review or update of the procedure has occurred, however, since 1985, the time of the last major paper by Professor Seed and a report from a National Research Council workshop on liquefaction of soils. In 1996 a workshop sponsored by the National Center for Earthquake Engineering Research (NCEER) was convened by Professors T. L. Youd and I. M. Idriss with 20 experts to review developments over the previous 10 years. The purpose was to gain consensus on updates and augmentations to the simplified procedure. The following topics were reviewed and recommendations developed: (1) criteria based on standard penetration tests; (2) criteria based on cone penetration tests; (3) criteria based on shear-wave velocity measurements; (4) use of the Becker penetration test for gravelly soil; (4) magnitude scaling factors; (5) correction factors for overburden pressures and sloping ground; and (6) input values for earthquake magnitude and peak acceleration. Probabilistic and seismic energy analyses were reviewed but no recommendations were formulated.     

Do patient‐reported measures of symptoms and health status predict mortality in hemodialysis? An assessment of POS‐S Renal and EQ‐5D

Introduction Experience with the use of patient‐reported outcome measures such as EQ‐5D and the symptom module of the Palliative care Outcome Scale—Renal Version (POS‐S Renal) as mortality prediction tools in hemodialysis is limited. Methods A prospective survival study of people receiving hemodialysis (N = 362). The EQ‐5D and the POS‐S Renal were used to assess symptom burden and self‐rated health (with a self‐rated component). Participants were followed from instrument completion to death or study end. Competing risks survival analysis was used to evaluate associations with time to death, with renal transplant as a competing risk. Findings 32% (N = 116) of participants died over a median (25th–75th centile) of 2.6 (1.41–3.38) years. Factors most notably associated with mortality adjusted hazard ratio (95%CI) included: lower EQ VAS score 2.7 (1.4, 5.2) P = 0.004 (lowest tertile), higher POS‐S Renal score 2.4 (1.3, 4.3) P = 0.004 (highest tertile), and lower EQ‐5D score 2.6 (1.3, 5.3) P = 0.01 (lowest tertile) as well as the presence of: “problems with mobility?” 2 (1.1, 3.3) P = 0.01, or “problems with usual activities?” 2.1 (1.4, 3.3), P < 0.001. After age adjustment area under the receiver operating curves (AUC) (95%CI) for mortality were: 0.71 (0.62, 0.79) for EQ VAS score, 0.71 (0.63, 0.80) for POS‐S Renal‐S Renal score, and 0.76 (0.68, 0.84) for EQ‐5D score. AUC 95%CI was highest for our fourth model at 0.79 (0.72, 0.86) comprised of individual elements from both instruments and established risk factors. Discussion EQ VAS scores and predictive models based on combinations of elements from the POS‐S Renal and EQ‐5D instruments may aid in mortality discrimination and possibly in the delivery of supportive care services.     

Bridging, Patching and Keeping the Work Flowing: Defect Resolution in Distributed Software Development

This paper reports on results from a long-term field study of globally distributed software development projects within a multinational organization. The research explores the issues involved in performing global software development, utilizing a perspective informed by CSCW research concerning the local organization of work practices and the key role of workers in being able to intervene in the ‘flow of work’ where necessary. The paper also raises some more general questions concerning the field of Global Software Development (GSD), in terms of the concepts and methods being used in the area. Our contribution is in the form of a CSCW-informed empirical study of the use of defect (or ‘bug’) tracking systems—systems which support the identification, classification and resolution of defects in the emerging software. In one case, the team persisted with a defect tracking system that they had used for years and maintained it in parallel with a system used by co-workers in other countries—all the while attempting to implement a bridge between the two. In the other, we report on how local software patches were created to allow for local work to proceed while not interfering with the existing coordination mechanisms between the local site and remote co-workers who were responsible for creating daily builds according to the overall project plan. In both cases, local practices were shaped by the necessity to keep work flowing across the whole project, even if this involved what might, at first sight, seem to go against project-wide practice. We discuss implications of these findings in terms of a key distinction between externally-prescribed ‘workflow’ and internally-managed ‘flow of work’ activities. We also explore how a heterogeneous ‘assembly’ of variably coupled systems may be the most appropriate image for technological support of distributed teams as they keep the work flowing in an orderly fashion. Overall, our work suggests that studies of global software development can profit from the CSCW tradition of workplace studies both conceptually and methodologically.     

A (somewhat) new solution to the variable binding problem

To perform automatic, unconscious inference, the human brain must solve the binding problem by correctly grouping properties with objects. Temporal binding models like SHRUTI already suggest much of how this might be done in a connectionist and localist way by using temporal synchrony. We propose a set of alternatives to temporal synchrony mechanisms that instead use short signatures. This serves two functions: it allows us to explore an additional biologically plausible alternative, and it allows us to extend and improve the capabilities of these models. These extensions model the human ability to both perform unification and handle multiple instantiations of logical terms. To verify our model's feasibility, we simulate it with a computer system modeling simple, neuron-like computations.