Adventure Mode: A Speculative Rideshare Design

Most smart city projections presume efficiency, predictability, and control as core design principles for smart transportation. Adventure Mode is a speculative design proposal developed as part of a research project with a major automotive company that proposes uses and interactions for Autonomous Vehicles (AVs) and rideshare advancements that defy these normative presumptions. Adventure Mode reframes the focus of moving vehicles from destination-based experiences to journey-based ones. Adventure Mode pushes the probabilities for unexpected encounters and anonymous play in increasingly predictable and predicted urban environments. It embraces the submission to algorithmic decision and chance as a ludic modality in human-computer interactions and urban artificial intelligence

The realtionship between common patterns of prenatal alcohol exposure and the neurodevelopment of two-year old children

Background: Around 60% of women drink some alcohol while pregnant. There is conflicting evidence on the effect on the fetus of common patterns of prenatal alcohol exposure (PAE) e.g. low level or sporadic drinking. Guidelines recommend abstinence as the safest option, creating problems for those advising women who drink at these levels before pregnancy recognition or beyond. The Asking QUestions about Alcohol (AQUA) study aimed to accurately measure PAE and account for important cofactors, to reduce uncertainty about child outcomes. Method: Detailed data on PAE were prospectively collected in a pre-birth cohort of over 1500 mother/child dyads. There was also extensive data collection of predictors of child development at one and two-year's post-partum. A sub-group of children was followed up at two years of age with a neurodevelopmental assessment (Bayley III). Two-step multivariable regression analyses of an effect of PAE accounted for independent risk factors that related to 1) pregnancy, including sociodemographic, psychologic and lifestyle variables such as diet and supplement use, and 2) the postnatal care-giving environment, including breastfeeding and maternal psychological wellbeing. Results: Adjustment for independent risk factors ameliorated any putative associations between PAE and cognitive, language and motor development in 554 two year-old children spread evenly across six PAE groups. Conclusions: Assessing neurodevelopmental outcomes associated with PAE is strongly influenced by other modifiable and non-modifiable risk factors. Although we found no adverse neurodevelopmental outcomes at two years of age, follow-up will be necessary in these children when complex higher-level cognitive, language and motor skills are required

Prenatal alcohol exposure and facial shape of one-year old children: no amount of alcohol is without consequence

Background: Children with Fetal Alcohol Spectrum Disorder (FASD) can have a characteristic facial appearance in addition to neurodevelopmental impairment. We do not know if there is a gradient of effects on the face of children with prenatal alcohol exposure (PAE). Method: This is an analysis of 3D craniofacial images of 415 one year-old Caucasian children with detailed, prospectively collected PAE data. Analysis involved objective, holistic craniofacial phenotyping applying partial least-square regression to dense-surface models of the facial images. Results: We saw a significant association between craniofacial shape and PAE, whether exposure occurred only in trimester one, or throughout pregnancy. Regions of difference (p < 0.05) were concentrated around the mid-face, nose, lips and eyes. Directional visualisation showed these corresponded to general recession of the midface and superior displacement of the nose, especially the tip of the nose, indicating shortening of the nose and upturning of the nose tip. Significant differences existed between groups with no exposure and groups with low exposure in trimester one (forehead), moderate/high exposure in trimester one (eyes, midface, chin, parietal region) and binge level exposure in trimester one (chin). Conclusion: PAE, even at low levels, can influence craniofacial development. The observed differences were subtle, but are typical of dysmorphic features often seen in children with FASD. Although facial development is complex and each person's face is unique, it is sensitive to some influences at critical stages of development. Our study shows that alcohol contributes to how the face is formed in the womb

Quaternary Structure Defines a Large Class of Amyloid-β Oligomers Neutralized by Sequestration

SummaryThe accumulation of amyloid-β (Aβ) as amyloid fibrils and toxic oligomers is an important step in the development of Alzheimer’s disease (AD). However, there are numerous potentially toxic oligomers and little is known about their neurological effects when generated in the living brain. Here we show that Aβ oligomers can be assigned to one of at least two classes (type 1 and type 2) based on their temporal, spatial, and structural relationships to amyloid fibrils. The type 2 oligomers are related to amyloid fibrils and represent the majority of oligomers generated in vivo, but they remain confined to the vicinity of amyloid plaques and do not impair cognition at levels relevant to AD. Type 1 oligomers are unrelated to amyloid fibrils and may have greater potential to cause global neural dysfunction in AD because they are dispersed. These results refine our understanding of the pathogenicity of Aβ oligomers in vivo

Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer.

Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity

Three-Dimensional Cell Entrapment as a Function of the Weight Percent of Peptide-Amphiphile Hydrogels

The design of scaffolds which mimic the stiffness, nanofiber structure, and biochemistry of the native extracellular matrix (ECM) has been a major objective for the tissue engineering field. Furthermore, mimicking the innate three-dimensional (3D) environment of the ECM has been shown to significantly altered cellular response compared to that of traditional two-dimensional (2D) culture. We report the development of a self-assembling, fibronectin-mimetic, peptide-amphiphile nanofiber scaffold for 3D cell culture. To form such a scaffold, 5 mol % of a bioactive PR_g fibronectin-mimetic peptide-amphiphile was mixed with 95 mol % of a diluent peptide-amphiphile (E2) whose purpose was to neutralize electrostatic interactions, increase the gelation kinetics, and promote cell survival. Atomic force microscopy verified the fibrilar structure of the gels, and the mechanical properties were characterized for various weight percent (wt %) formulations of the 5 mol % PR_g–95 mol % E2 peptide-amphiphile mixture. The 0.5 wt % formulations had an elastic modulus of 429.0 ± 21.3 Pa whereas the 1.0 wt % peptide-amphiphile hydrogels had an elastic modulus of 808.6 ± 38.1 Pa. The presence of entrapped cells in the gels decreased the elastic modulus, and the decrease was a function of cell loading. Although both formulations supported cell proliferation, the 0.5 wt % gels supported significantly greater NIH3T3/GFP fibroblast cell proliferation throughout the gels than the 1.0 wt % gels. However, compared to the 0.5 wt % formulations, the 1.0 wt % hydrogels promoted greater increases in mRNA expression and the production of fibronectin and type IV collagen ECM proteins. This study suggests that this fibronectin-mimetic scaffold holds great promise in the advancement of 3D culture applications and cell therapies

Simian Immunodeficiency Virus–Induced Intestinal Cell Apoptosis Is the Underlying Mechanism of the Regenerative Enteropathy of Early Infection

The enteropathic manifestations of the human immunodeficiency virus (HIV) and the simian immunodeficiency virus (SIV) in late infection are usually due to infection by other microbes, but in early infection the viruses themselves cause an enteropathy by heretofore undetermined mechanisms. Here we report that SIV induces massive apoptosis of intestinal epithelial cells lining the small and large bowel, thus identifying apoptosis as the driving force behind the regenerative pathology of early infection. We found that apoptosis of gut epithelium paralleled the previously documented apoptosis and massive depletion of CD4 T cells in gut lamina propria, triggered by established mechanisms of gut epithelial cell apoptosis and, at peak, possibly by virus interactions with GPR15/Bob, an intestinal epithelial cell–associated alternative coreceptor for SIV and HIV-1. Apoptosis in early SIV infection is thus the common theme of the pathological processes that quickly afflict the innate as well as adaptive arms of the gut immune system