Saving Time and Making Cents: A Blueprint for Building Transit Better

Cities, states, and metropolitan areas across the United States are looking to invest in a range of public transit projects in order to connect people to jobs and economic opportunity, reduce greenhouse gas emissions from vehicles, and shape development patterns.  According to one estimate, the United States invested about $50 billion in new transit projects in just the last decade.1 These include underground subways in Los Angeles, commuter rail lines along the Front Range near Denver, a streetcar in downtown Atlanta, light rail lines in suburban Phoenix, and bus rapid transit in Richmond, Virginia, among many others.While these projects are as diverse as the country itself, they all have one thing in common: increased scrutiny over their costs and timelines to build. A few very visible projects have reinforced the narrative that rail transit investments have systemic issues that are endemic to the United States.This all begs the questions: Is this true? If so, why? And what should we do about it?These are precisely the questions Eno set out to answer through this research, policy, and communications project to analyze current and historical trends in public transit project delivery. We convened a set of advisors and conducted in-depth interviews with key stakeholders to understand the drivers behind mass transit construction, cost, and delivery in the United States. A comprehensive database of rail transit projects was created and curated to compare costs and timelines among U.S. cities and peer metropolitan areas in Western Europe and Canada. Through this quantitative and qualitative approach, we developed actionable recommendations for policy changes at all levels of government as well as best practices for the public and private sectors

ARAKNIPRINT: 3D Printing of Synthetic Spider Silk to Produce Biocompatible and Resorbable Biomaterials

At $3.07 billion in 2013, the 3D printing industry was projected to reach$12.8 billion in 2018 and exceed $21 billion by 2020 (Wohlers and Caffrey, 2013). A lucrative part of this expanding industry includes printing biocompatible medical implants, devices, and tissue scaffolds. A common problem encountered with traditional devices, implants, and tissue scaffolds is that they are not unique to the patient and lack the necessary strength and biocompatibility. To answer these demands, customizable devices are being produced from patient medical scans and CAD designs using 3D printers. These printers traditionally use thermoplastics because of the ease with which they are printed. These plastics are typically regarded as biocompatible but can degrade to less biocompatible forms in the body and leave the implant site, causing inflammatory and foreign body responses. Because of these problems, there has been a focus on developing new biomaterials for medical 3D printers. Spider silk is a natural protein polymer that is stronger than steel or Kevlar and more elastic than nylon. It has also been shown to be more biocompatible than many materials currently used in 3D printers. In previous animal studies, spider silk has proven to not cause an inflammatory response upon degradation which makes it a desired resorbable implant material (Lewis, 2006). A 3D printer system comprised of a synthetic spider silk resin and a modified 3D printer was developed. A fused filament 3D printer, purchased for under$600, was modified with a custom syringe pump design. This syringe pump allowed for the extrusion of spider silk proteins through a needle, producing defined structures. Cell studies were performed on these structures which showed favorable cell attachment and growth. Capable of entering various emerging industries, spider silk offers an alternative in 3D printed biomaterials

Fine-tuning of Substrate Affinity Leads to Alternative Roles of Mycobacterium tuberculosis Fe2+-ATPases

Little is known about iron efflux transporters within bacterial systems. Recently, the participation of Bacillus subtilis PfeT, a P1B4-ATPase, in cytoplasmic Fe(2+) efflux has been proposed. We report here the distinct roles of mycobacterial P1B4-ATPases in the homeostasis of Co(2+) and Fe(2+) Mutation of Mycobacterium smegmatis ctpJ affects the homeostasis of both ions. Alternatively, an M. tuberculosis ctpJ mutant is more sensitive to Co(2+) than Fe(2+), whereas mutation of the homologous M. tuberculosis ctpD leads to Fe(2+) sensitivity but no alterations in Co(2+) homeostasis. In vitro, the three enzymes are activated by both Fe(2+) and Co(2+) and bind 1 eq of either ion at their transport site. However, equilibrium binding affinities and activity kinetics show that M. tuberculosis CtpD has higher affinity for Fe(2+) and twice the Fe(2+)-stimulated activity than the CtpJs. These parameters are paralleled by a lower activation and affinity for Co(2+) Analysis of Fe(2+) and Co(2+) binding to CtpD by x-ray absorption spectroscopy shows that both ions are five- to six-coordinate, constrained within oxygen/nitrogen environments with similar geometries. Mutagenesis studies suggest the involvement of invariant Ser, His, and Glu residues in metal coordination. Interestingly, replacement of the conserved Cys at the metal binding pocket leads to a large reduction in Fe(2+) but not Co(2+) binding affinity. We propose that CtpJ ATPases participate in the control of steady state Fe(2+) levels. CtpD, required for M. tuberculosis virulence, is a high affinity Fe(2+) transporter involved in the rapid response to iron dyshomeostasis generated upon redox stress

Cognitive and neuroscientific perspectives of healthy ageing

With dementia incidence projected to escalate significantly within the next 25 years, the United Nations declared 2021–2030 the Decade of Healthy Ageing, emphasising cognition as a crucial element. As a leading discipline in cognition and ageing research, psychology is well-equipped to offer insights for translational research, clinical practice, and policy-making. In this comprehensive review, we discuss the current state of knowledge on age-related changes in cognition and psychological health. We discuss cognitive changes during ageing, including (a) heterogeneity in the rate, trajectory, and characteristics of decline experienced by older adults, (b) the role of cognitive reserve in age-related cognitive decline, and (c) the potential for cognitive training to slow this decline. We also examine ageing and cognition through multiple theoretical perspectives. We highlight critical unresolved issues, such as the disparate implications of subjective versus objective measures of cognitive decline and the insufficient evaluation of cognitive training programs. We suggest future research directions, and emphasise interdisciplinary collaboration to create a more comprehensive understanding of the factors that modulate cognitive ageing

Morning exercise mitigates the impact of prolonged sitting on cerebral blood flow in older adults

Preventing declines in cerebral blood flow is important for maintaining optimal brain health with aging. We compared the effects of a morning bout of moderate-intensity exercise, with and without subsequent light-intensity walking breaks from sitting, on cerebral blood velocity over 8 h in older adults. In a randomized crossover trial, overweight/obese older adults (n = 12, 70 ± 7 yr; 30.4 ± 4.3 kg/m2), completed three acute conditions (6-day washout); SIT: prolonged sitting (8 h, control); EX+SIT: sitting (1 h), moderate-intensity walking (30 min), followed by uninterrupted sitting (6.5 h); and EX + BR: sitting (1 h), moderate-intensity walking (30 min), followed by sitting (6.5 h) interrupted with 3 min of light-intensity walking every 30 min. Bilateral middle cerebral artery velocities (MCAv) were determined using transcranial Doppler at 13 time points across the day. The temporal pattern and average MCAv over 8 h was determined. The pattern of MCAv over 8 h was a negative linear trend in SIT (P < 0.001), but a positive quadratic trend in EX + SIT (P < 0.001) and EX + BR (P < 0.01). Afternoon time points in SIT were lower than baseline within condition (P ≤ 0.001 for all). A morning dip in MCAv was observed in EX + SIT and EX + BR (P < 0.05 relative to baseline), but afternoon time points were not significantly lower than baseline. The average MCAv over 8 h was higher in EX + SIT than SIT (P = 0.007) or EX + BR (P = 0.024). Uninterrupted sitting should be avoided, and moderate-intensity exercise should be encouraged for the daily maintenance of cerebral blood flow in older adults. The clinical implications of maintaining adequate cerebral blood flow include the delivery of vital oxygen and nutrients to the brain

Silkworms with Spider Silklike Fibers Using Synthetic Silkworm Chow Containing Calcium Lignosulfonate, Carbon Nanotubes, and Graphene

Silkworm silk has become increasingly relevant for material applications. However, the industry as a whole is retracting because of problems with mass production. One of the key problems is the inconsistent properties of the silk. A means by which to improve the silk material properties is through enhanced sericulture techniques. One possible technique is altering the feed of the silkworms to include single-wall carbon nanotubes (SWNTs) or graphene (GR). Recently published results have demonstrated substantial improvement in fiber mechanical properties. However, the effect of the surfactant used to incorporate those materials into the feed on the fiber mechanical properties in comparison to normal silkworm silk has not been studied or reported. Thus, the total effect of feeding the SWNT and GR in the presence of surfactants on silkworms is not understood. Our study focuses on the surfactant [calcium lignosulfonate (LGS)] and demonstrates that it alone results in appreciable improvement of mechanical properties in comparison to nontreated silkworm silk. Furthermore, our study demonstrates that mixing the LGS, SWNT, and GR directly into the artificial diet of silkworms yields improved mechanical properties without decline below the control silk at high doses of SWNT or GR. Combined, we present evidence that mixing surfactants, in this case LGS, directly with the diet of silkworms creates a high-quality fiber product that can exceed 1 GPa in tensile strength. With the addition of nanocarbons, either SWNT or GR, the improvement is even greater and consistently surpasses control fibers. However, feeding LGS alone is a more economical and practical choice to consistently improve the mechanical properties of silkworm fiber

Clinical Characteristics, Racial Inequities, and Outcomes in Patients with Breast Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Cohort Study

BACKGROUND: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. METHODS: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. RESULTS: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. CONCLUSIONS: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. FUNDING: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. CLINICAL TRIAL NUMBER: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701

The Dynamic Nature And Biophysical Characterization Of Isu1, Fe-S Cluster Assembly Scaffold Protein In Saccharomyces Cerevisiae, And Its Significance To Human Disease

Mitochondrial Fe-S cluster biosynthesis is accomplished within yeast utilizing the biophysical characteristics of the “Isu1” scaffold protein. As a member of a highly homologous protein family, Isu1 has sequence conservation with orthologs and a conserved ability to assemble [2Fe-2S] clusters. Regardless of species, scaffold orthologs can exist in both “disordered” and “structured” conformations and is directly related to conformations utilized during Fe-cofactor assembly. During assembly, the scaffold directs the delivery and the utilization of both Fe(II) and sulfide substrates in order to produce [2Fe-2S] clusters, however Zn(II) binding can alter the activity of the scaffold with stabilizing the protein in the structured state. Understanding the interplay between Fe(II) and Zn(II) binding in vitro may help clarify metal loading events that occur during Fe-S cluster assembly in vivo. Here we determine the metal:protein stoichiometry for Isu1 Zn and Fe binding is 1:1 and 2:1, respectively. As expected, while Zn binding shifts the Isu1 to its structured state, folding is not influenced by Fe(II) binding alone. X-ray absorption spectroscopy (XAS) confirms Zn(II) binds to the scaffold’s cysteine rich cluster assembly active site and Fe(II) binds at a location distinct from the active site. XAS results show Isu1 binding of either Fe(II) or Zn(II) does not perturb the structure of the alternatively bound metal. XAS and Mössbauer spectroscopies combined confirm that several scaffold orthologs bind iron as high-spin Fe(II) at a site composed of ca 6 oxygen and nitrogen only nearest neighbor ligands. Finally, Zn binding dramatically reduces the Fe-S cluster assembly activity of Isu1, even in the presence of frataxin. Given the metal binding activity of Isu1, a mechanism for Fe(II) transport during cluster assembly and a possible role for Zn for the protein have been considered in this report. We also present evidence for the significance of the C-terminal alpha helix of Isu1. Despite the importance of the pathway, very little is known about the molecular details of Isu1, especially in the protein’s C-terminal helical region. Data shows that a loss of the 10 C-terminal residues in Isu1 causes a complete loss of cluster assembly activity and impairs cellular growth without while the proteins structure and iron binding activity remain unchanged. One possible role for the C-terminus is that it provides structural anchor which positions the LPPVK domain and active site to make contacts with key ISC members. This report shows the C-terminus is essential for cluster assembly emphasizing a direct relationship to the pathogenesis of ISCU myopathy

Producing Spider Silk Fibers

Millions of years of evolution have turned proteins into incredible biomaterials. Among protein superstars is dragline spider silk. Excreted by spiders as a lifeline, it is the strongest biomaterial known to man. Millions of years of evolution have also made spiders highly independent (in other words; territorial and cannibalistic), which poses major barriers to farming. Genetic engineering has provided an alternative to this problem via production of this protein in other organisms. The focus of this research is optimizing the mechanical spinning of proteins produced by transgenic goats. In order to bring the strength of synthetic fibers up to par with those produced by spiders, testing has been done with varying parameters for this spinning e.g. speed, stretch, temperature, additives, solvents, etc.. In addition to optimizing properties this research plans to design, build, and test spinning systems that integrate these treatments and maximize the speed of silk production for commercial use. The hope is to match the properties of native spider silk in tensile strength and elasticity. The results from previous experiments and plans for future experiments will be presented