When you first started looking at our program, you may have asked yourself why we are called the Fisher College of Business. Then you probably shrugged and forgot all about it. Well, I’m here to answer that burning question for you. Like many business schools, we are named after a benefactor who contributed a significant … Continue reading "Why is it called “Fisher” College of Business?"

TRB's “Tell Us ‘Our’ Story" challenge is now looking into the future. What impact do you hope to have on the world and how is the Transportation Research Board helping you make that impact? What is your vision for the Transportation Research Board 100 years from now? What are solutions that you have identified as a result of research you learned about through TRB? TRB welcomes all stories: small or large, profound or light-hearted, sobering or humorous. In addition to posting responses to these questions...

Issue 324 of TRB's magazine (November-December 2019) focuses on climate change resilience. Along with several explorations within that topic, a short history of TRB is offered as well as all the usual standing features of the magazine. TR News is TRB's bimonthly magazine featuring timely articles on innovative and state-of-the-art research and practice in all modes of transportation. It also includes brief news items of interest to the transportation community, research pays off articles , profiles of tr...

TRB 2021 Committee Paper Review will go on as scheduled. The submission site will open June 1 and the deadline is August 1. We have learned a lot during this year’s transition to the TRR Editorial Board workflow for publication papers and have listened to your feedback. Important improvements this year include: • Committee review comments will go to authors by October 31. • Full papers will be posted in the interactive program unless the authors “opt out” because they wish to publish the paper elsewhere....

As all aspects of transportation deal with the unfolding effects of the COVID-19 pandemic, there are research needs, gaps, and potential ways to leverage innovation revealing themselves across all modes, systems, and disciplines in transportation. In keeping with the mission of the National Academies of Sciences, Engineering, and Medicine to provide trusted, timely, impartial, and evidence-based information exchange and research, TRB is issuing an urgent and directed call for Research Needs Statements sp...

Are you looking for specific phrases in transportation research? When submitting keywords or keyword phrases as part of any search in TRID , those words are now highlighted in yellow in both the results list and in individual records. You can turn this feature off in the Advanced Search Filters with the toggle just below the Keywords field.

TRB's Transit Cooperative Research Program (TCRP) has issued a request for proposals to develop a comprehensive, evidenced-based guide for bus operator workforce management from pre-employment through retirement. The guide should present both best practices and innovative practices that enhance and sustain public transit and support bus operators who provide fixed-route, flexible-route, and on-demand services. Proposals are due August 11, 2020 at 5:00 PM Eastern.

Help those searching for transportation research on your site. If you have already implemented the TRIDGET (TRID Widget)  on your website or LibGuide, it will now take you to a result list in TRID based on the keyword(s) you entered into the TRIDGET keyword box.It is a widget that can be embedded on your own web platform and allows your customers to initiate a TRID search directly from your site. It is particularly easy to implement in LibGuides: just copy the TRIDGET code/markup into a Media/W...

The March-April 2020 issue of TR News (#326) - including a cover feature on TRB's "century of progress and foundation for the future" of transportation research - is available in hard copy and digital copy for subscribers. For those who are not subscribers, the table of contents is available. Other feature articles in the issue include ones on whether research processes can keep up, accessible rail sleeper compartments, drones and lasers for railroad bridges, implications of California wildfires, and muc...

According to Ken Murray, Sr. Landscape Architect, California Department of Transportation "TRB allows for expanding your influence and connections throughout the transportation world nationally. You're able to connect with fellow peers from different states and share experiences, discuss strategies for difficult situations, and solutions to issues that others may have already handled that you personally are dealing with. It expands your network that allows for more diverse information for other areas tha...

The National Academies/TRB Forum on Preparing for Automated Vehicles and Shared Mobility is hosting a webinar on Wednesday, May 13 at 2:00 – 3:30 PM Eastern to focus on the role of AV and Shared mobility in light of COVID-19. The online event is free and open to the public, but registration is required . Speakers include: Effect of COVID-19 on AVs , Annie Chang and Ed Straub of SAE International Effect of COVI19 on Shared Mobility , Susan Shaheen of University of California, Berkeley COVID-19 and New Par...

Been thinking about this blog and how a lot of the work I’ve been doing lately doesn’t always lend itself...

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From a friend: Please explain to me your enthusiasm for controlled digital lending. Please let me know what you think...

Subtitled: What’s the Yahoo! Internet Life for this generation? From a friend: A nice older lady asked for advice on...

I was wondering if you might give my little women’s (boomers) some guidance as to a beginning graphic novel for...

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I recently travelled to Pittsburgh, USA, to present the paper “From Playing Games to Committing Crimes: A Multi-Technique Approach to Predicting Key Actors on an Online Gaming Forum” at eCrime 2019, co-authored with Ben Collier and Alice Hutchings. The accepted version of the paper can be accessed here. The structure and content of various underground … Continue reading From Playing Games to Committing Crimes: A Multi-Technique Approach to Predicting Key Actors on an Online Gaming Forum →

In this paper (winner of the eCrime 2019 Best Paper award), we consider the types of things that can go wrong when you intend to make things better and more secure. Consider this scenario. You are browsing through Internet and see a news headline on one of the presidential candidates. You are unsure if the … Continue reading Identifying Unintended Harms of Cybersecurity Countermeasures →

I’m at Financial Cryptography 2020 and will try to liveblog some of the talks in followups to this post. The keynote was given by Allison Nixon, Chief Research Officer of Unit221B, on “Fraudsters Taught Us that Identity is Broken”. Allison started by showing the Mitchell and Webb clip. In a world where even Jack Dorsey … Continue reading FC 2020 →

In this reboot of the Three Paper Thursdays, back after a hiatus of almost eight years, I consider the many different ways in which programs can be sanitised to detect, or mitigated to prevent the use of, the many programmer errors that can introduce security vulerabilities in low-level languages such as C and C++. We … Continue reading Three Paper Thursday: Sanitisers and Mitigators →

The platforms, providers, and infrastructures which together make up the contemporary Internet play an increasingly central role in the business of governing human societies. Although the software engineers, administrators, business professionals, and other staff working at these organisations may not have the institutional powers of state organisations such as law enforcement or the civil service, … Continue reading Three Paper Thursday: The role of intermediaries, platforms, and infrastructures in governing crime and abuse →

There have recently been several proposals for pseudonymous contact tracing, including from Apple and Google. To both cryptographers and privacy advocates, this might seem the obvious way to protect public health and privacy at the same time. Meanwhile other cryptographers have been pointing out some of the flaws. There are also real systems being built … Continue reading Contact Tracing in the Real World →

Recent advancements in Machine Learning (ML) have taught us two main lessons: a large proportion of things that humans do can actually be automated, and that a substantial part of this automation can be done with minimal human supervision. One no longer needs to select features for models to use; in many cases people are … Continue reading Three Paper Thursday: Adversarial Machine Learning, Humans and everything in between →

People have tried to develop many different attack vectors on cryptocurrencies, from codebase flaws, cryptographic algorithms, mining processes, consensus protocols and block propagation mechanisms to the underlying network layer. Most attacks could be patched quickly by modifying the source code, but preventing attacks that exploit the network layer remains a non-trivial problem as the network … Continue reading Three Paper Thursday: Attacking the Bitcoin Peer-to-Peer Network →

Just as in other types of victimization, victims of cybercrime can experience serious consequences, emotional or not. First of all, a repeat victim of a cyber-attack might face serious financial or emotional hardship. These victims are also more likely to require medical attention as a consequence of online fraud victimization. This means repeat victims have a … Continue reading Three Paper Thursday: Exploring the Impact of Online Crime Victimization →

Software Guard eXtensions (SGX) represents Intel’s latest foray into trusted computing. Initially intended as a means to secure cloud computation, it has since been employed for DRM and secure key storage in production systems. SGX differs from its competitors such as TrustZone in its focus on reducing the volume of trusted code in its “secure … Continue reading Three Paper Thursday: What’s Intel SGX Good For? →

OED Word of the Day: time-ridden, adj. Afflicted by the effects of time; time-worn

OED Word of the Day: simony, n. The buying or selling of ecclesiastical or spiritual benefits; esp. the sale or purchase of preferment or office in the church

OED Word of the Day: femina, n. The long pale feathers from the wing tips of a female ostrich, used as decorative plumes

OED Word of the Day: mural, adj.1 Designating a crown or (later also) a garland, wreath, etc., conferred as a mark of honour (originally by the ancient Romans) on the first soldier to scale the walls of a besieged town

OED Word of the Day: sinistrorse, adj. Designating spiral mollusc shells that coil to the left (anticlockwise), and molluscs having such shells

OED Word of the Day: Padawan, n. In the fictional universe of the Star Wars films: an apprentice Jedi. In extended and allusive use: a youthful, naive, or untrained person

OED Word of the Day: microfinance, n. The provision of loans and other financial services to low-income individuals and communities for the creation of small businesses…

We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. White adipose tissue of HFD-fed Asxl2ΔLysM mice also exhibited none of the pathological remodeling extant in their control counterparts. Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity. Thus, ASXL2 controlled the response of macrophages to dietary factors to regulate metabolic homeostasis, suggesting modulation of the cells’ inflammatory phenotype may impact obesity and its complications.

Hearing loss caused by the death of sensory hair cells of the inner ear is an unfortunate side effect for many patients treated with aminoglycoside antibiotics or platinum-containing chemotherapy agents. In animal models, induction of heat shock confers substantial otoprotection against aminoglycoside- and cisplatin-induced hair cell death. In this issue of the JCI, Breglio et al. demonstrate that inner ear tissue released exosomes carrying heat shock protein 70 (HSP70) in response to heat stress. HSP70 acted by a paracrine mechanism that engaged the Toll-like receptor 4 (TLR4) on hair cells to protect them from death. Exosomes and the HSP70/TLR4 pathway could thus provide treatment targets for the protection of hair cells from chemically induced death or from other insults, such as noise.

Levodopa-induced dyskinesia (LID) poses a significant health care challenge for Parkinson’s disease (PD) patients. Amantadine is currently the only drug proven to alleviate LID. Although its efficacy in treating LID is widely assumed to be mediated by blockade of N-methyl-D-aspartate (NMDA) glutamate receptors, our experiments demonstrate that at therapeutically relevant concentrations, amantadine preferentially blocks inward-rectifying K+ channel type 2 (Kir2) channels in striatal spiny projection neurons (SPNs) — not NMDA receptors. In so doing, amantadine enhances dendritic integration of excitatory synaptic potentials in SPNs and enhances — not antagonizes — the induction of long-term potentiation (LTP) at excitatory, axospinous synapses. Taken together, our studies suggest that the alleviation of LID in PD patients is mediated by diminishing the disparity in the excitability of direct- and indirect-pathway SPNs in the on state, rather than by disrupting LTP induction. This insight points to a pharmacological approach that could be used to effectively ameliorate LID and improve the quality of life for PD patients.

Hair cells, the mechanosensory receptors of the inner ear, are responsible for hearing and balance. Hair cell death and consequent hearing loss are common results of treatment with ototoxic drugs, including the widely used aminoglycoside antibiotics. Induction of heat shock proteins (HSPs) confers protection against aminoglycoside-induced hair cell death via paracrine signaling that requires extracellular heat shock 70-kDa protein (HSP70). We investigated the mechanisms underlying this non–cell-autonomous protective signaling in the inner ear. In response to heat stress, inner ear tissue releases exosomes that carry HSP70 in addition to canonical exosome markers and other proteins. Isolated exosomes from heat-shocked utricles were sufficient to improve survival of hair cells exposed to the aminoglycoside antibiotic neomycin, whereas inhibition or depletion of exosomes from the extracellular environment abolished the protective effect of heat shock. Hair cell–specific expression of the known HSP70 receptor TLR4 was required for the protective effect of exosomes, and exosomal HSP70 interacted with TLR4 on hair cells. Our results indicate that exosomes are a previously undescribed mechanism of intercellular communication in the inner ear that can mediate nonautonomous hair cell survival. Exosomes may hold potential as nanocarriers for delivery of therapeutics against hearing loss.

Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPNs). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPNs suggests that vascular function is altered. The consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice resulting from a disturbed endothelial NO pathway and increased endothelial oxidative stress. This response was reproduced in WT mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for their effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes suppressed their effect on oxidative stress. Antioxidants such as simvastatin and N-acetyl cysteine improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPNs are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears to be a promising therapeutic strategy in this setting.

Although CEACAM1 (CC1) glycoprotein resides at the interface of immune liver injury and metabolic homeostasis, its role in orthotopic liver transplantation (OLT) remains elusive. We aimed to determine whether/how CEACAM1 signaling may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. In the mouse, donor liver CC1 null mutation augmented IRI-OLT (CC1-KO→WT) by enhancing ROS expression and HMGB1 translocation during cold storage, data supported by in vitro studies where hepatic flush from CC1-deficient livers enhanced macrophage activation in bone marrow–derived macrophage cultures. Although hepatic CC1 deficiency augmented cold stress–triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI and improved OLT survival by suppressing p-p38 upregulation, ROS induction, and HMGB1 translocation (CC1-KO→WT), whereas ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in 60 human donor liver biopsies correlated negatively with activation of the ASK1/p-p38 axis, whereas low CC1 levels associated with increased ROS and HMGB1 translocation, enhanced innate and adaptive immune responses, and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of the independent predictors for early allograft dysfunction (EAD) in human OLT patients. Thus, as a checkpoint regulator of IR stress and sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.

Whether mutations in cancer driver genes directly affect cancer immune phenotype and T cell immunity remains a standing question. ARID1A is a core member of the polymorphic BRG/BRM-associated factor chromatin remodeling complex. ARID1A mutations occur in human cancers and drive cancer development. Here, we studied the molecular, cellular, and clinical impact of ARID1A aberrations on cancer immunity. We demonstrated that ARID1A aberrations resulted in limited chromatin accessibility to IFN-responsive genes, impaired IFN gene expression, anemic T cell tumor infiltration, poor tumor immunity, and shortened host survival in many human cancer histologies and in murine cancer models. Impaired IFN signaling was associated with poor immunotherapy response. Mechanistically, ARID1A interacted with EZH2 via its carboxyl terminal and antagonized EZH2-mediated IFN responsiveness. Thus, the interaction between ARID1A and EZH2 defines cancer IFN responsiveness and immune evasion. Our work indicates that cancer epigenetic driver mutations can shape cancer immune phenotype and immunotherapy.

The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP syndrome, transplant-associated thrombotic microangiopathy, antiphospholipid antibody syndrome, myasthenia gravis, and neuromyelitis optica. Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review of (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology), and (d) the potential future of precision medicine. Better understanding of complement diagnostics and therapeutics will not only facilitate physicians treating patients in clinical practice but also provide the basis for future research toward precision medicine in this field.

Tumor-associated peptide–human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface–expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents.

Organ shortage continues to limit the lives of patients who require liver transplantation. While extending criteria for liver organs provides a needed resource, tissue damage from prolonged ischemic injury can result in early allograft dysfunction and consequent rejection. In this issue of the JCI, Nakamura et al. used a mouse transplantation model with prolonged ex vivo cold storage to explore liver graft protection. The authors found that liver grafts with absent carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) exhibited increased ischemia-reperfusion injury inflammation and decreased function in wild-type recipients. The authors went on to correlate CEACAM1 levels with postreperfusion damage in human liver transplant recipients. Notably, this study identified a potential biomarker for liver transplant donor graft quality.

Chronic pancreatitis (CP) is considered an irreversible fibroinflammatory pancreatic disease. Despite numerous animal model studies, questions remain about local immune characteristics in human CP. We profiled pancreatic immune cell characteristics in control organ donors and CP patients including those with hereditary and idiopathic CP undergoing total pancreatectomy with islet autotransplantation. Flow cytometric analysis revealed a significant increase in the frequency of CD68+ macrophages in idiopathic CP. In contrast, hereditary CP samples showed a significant increase in CD3+ T cell frequency, which prompted us to investigate the T cell receptor β (TCRβ) repertoire in the CP and control groups. TCRβ sequencing revealed a significant increase in TCRβ repertoire diversity and reduced clonality in both CP groups versus controls. Interestingly, we observed differences in Vβ-Jβ gene family usage between hereditary and idiopathic CP and a positive correlation of TCRβ rearrangements with disease severity scores. Immunophenotyping analyses in hereditary and idiopathic CP pancreases indicate differences in innate and adaptive immune responses, which highlights differences in immunopathogenic mechanisms of disease among subtypes of CP. TCR repertoire analysis further suggests a role for specific T cell responses in hereditary versus idiopathic CP pathogenesis, providing insights into immune responses associated with human CP.