Background Ascending thoracic aortic aneurysm (ATAA) predisposes patients to aortic dissection and has been associated with diminished tensile strength and disruption of collagen. Ascending thoracic ...aortic aneurysms arising in patients with bicuspid aortic valve (BAV) develop earlier than in those with tricuspid aortic valves (TAV) and have a different risk of dissection. The purpose of this study was to compare aortic wall tensile strength between BAV and TAV ATAAs and determine whether the collagen content of the ATAA wall is associated with tensile strength and valve phenotype. Methods Longitudinally and circumferentially oriented strips of ATAA tissue obtained during elective surgery were stretched to failure, and collagen content was estimated by hydroxyproline assay. Experimental stress-strain data were analyzed for failure strength and elastic mechanical variables: α, β, and maximal tangential stiffness. Results The circumferential and longitudinal tensile strengths were higher for BAV ATAAs when compared with TAV ATAAs. The α and β were lower for BAV ATAAs when compared with TAV ATAAs. The maximal tangential stiffness was higher for circumferential when compared with longitudinal orientation in both BAV and TAV ATAAs. The amount of hydroxyproline was equivalent in BAV and TAV ATAA specimens. Although there was a moderate correlation between the collagen content and tensile strength for TAV, this correlation is not present in BAV. Conclusions The increased tensile strength and decreased values of α and β in BAV ATAAs despite uniform collagen content between groups indicate that microstructural changes in collagen contribute to BAV-associated aortopathy.
In all tailed phages, the packaging of the double-stranded genome into the head by a terminase motor complex is an essential step in virion formation. Despite extensive research, there are still ...major gaps in the understanding of this highly dynamic process and the mechanisms responsible for DNA translocation. Over the last fifteen years, single-molecule fluorescence technologies have been applied to study viral nucleic acid packaging using the robust and flexible T4 in vitro packaging system in conjunction with genetic, biochemical, and structural analyses. In this review, we discuss the novel findings from these studies, including that the T4 genome was determined to be packaged as an elongated loop via the colocalization of dye-labeled DNA termini above the portal structure. Packaging efficiency of the TerL motor was shown to be inherently linked to substrate structure, with packaging stalling at DNA branches. The latter led to the design of multiple experiments whose results all support a proposed torsional compression translocation model to explain substrate packaging. Evidence of substrate compression was derived from FRET and/or smFRET measurements of stalled versus resolvase released dye-labeled Y-DNAs and other dye-labeled substrates relative to motor components. Additionally, active in vivo T4 TerS fluorescent fusion proteins facilitated the application of advanced super-resolution optical microscopy toward the visualization of the initiation of packaging. The formation of twin TerS ring complexes, each expected to be ~15 nm in diameter, supports a double protein ring-DNA synapsis model for the control of packaging initiation, a model that may help explain the variety of ring structures reported among
site phages. The examination of the dynamics of the T4 packaging motor at the single-molecule level in these studies demonstrates the value of state-of-the-art fluorescent tools for future studies of complex viral replication mechanisms.
The development of subunit vaccine platforms has been of considerable interest due to their good safety profile and ability to be adapted to new antigens, compared to other vaccine typess. ...Nevertheless, subunit vaccines often lack sufficient immunogenicity to fully protect against infectious diseases. A wide variety of subunit vaccines have been developed to enhance antigen immunogenicity by increasing antigen multivalency, as well as stability and delivery properties, via presentation of antigens on protein nanoparticles. Increasing multivalency can be an effective approach to provide a potent humoral immune response by more strongly engaging and clustering B cell receptors (BCRs) to induce activation, as well as increased uptake by antigen presenting cells and their subsequent T cell activation. Proper orientation of antigen on protein nanoparticles is also considered a crucial factor for enhanced BCR engagement and subsequent immune responses. Therefore, various strategies have been reported to decorate highly repetitive surfaces of protein nanoparticle scaffolds with multiple copies of antigens, arrange antigens in proper orientation, or combinations thereof. In this review, we describe different chemical bioconjugation methods, approaches for genetic fusion of recombinant antigens, biological affinity tags, and enzymatic conjugation methods to effectively present antigens on the surface of protein nanoparticle vaccine scaffolds.
Abstract Statement of problem No studies have evaluated the internal adaptation of pressed and milled ceramic crowns made from digital impressions. Purpose The purpose of this in vitro study was to ...evaluate the internal fit of pressed and milled ceramic crowns made from digital and conventional impressions. Material and methods Thirty polyvinyl siloxane (PVS) impressions and 30 Lava COS impressions made of a prepared dentoform tooth (master die) were fabricated. Thirty crowns were pressed in lithium disilicate (IPS e.max Press), and 30 crowns were milled from lithium disilicate blocks (IPS e.max CAD) (15/impression technique) with the E4D scanner and milling engine. The master die and the intaglio of the crowns were digitized with a 3-dimensional laser coordinate measurement machine. The digital master die and intaglio of each crown were merged. The distance between the die and the intaglio surface of the crown was measured at 3 standardized points. One-way ANOVA was used for statistical analysis (α=.05). Results One-way ANOVA revealed that the internal gap obtained from the Lava/press group (0.211 mm, ±SD 0.041) was significantly greater than that obtained from the other groups ( P <.001), while no significant differences were found among PVS/press (0.111 mm ±SD 0.047), PVS/CAD/CAM (0.116 mm ±SD 0.02), and Lava/CAD/CAM (0.145 mm ±SD 0.024). Conclusions The combination of the digital impression and pressed crown produced the least accurate internal fit.
Synthetic cannabinoids are manufactured clandestinely with little quality control and are distributed as herbal "spice" for smoking or as bulk compound for mixing with a solvent and inhalation via ...electronic vaporizers. Intoxication with synthetic cannabinoids has been associated with seizure, excited delirium, coma, kidney damage, and other disorders. The chemical alterations produced by heating these structurally novel compounds for consumption are largely unknown. Here, we show that heating synthetic cannabinoids containing tetramethylcyclopropyl-ring substituents produced thermal degradants with pharmacological activity that varied considerably from their parent compounds. Moreover, these degradants were formed under conditions simulating smoking. Some products of combustion retained high affinity at the cannabinoid 1 (CB
) and CB
receptors, were more efficacious than (-)-cis-3-2-hydroxy-4-(1,1-dimethylheptyl)phenyl-trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940) in stimulating CB
receptor-mediated guanosine 5'-O-(3-thiotriphosphate) (GTPγS) binding, and were potent in producing Δ
-tetrahydrocannabinol-like effects in laboratory animals, whereas other compounds had low affinity and efficacy and were devoid of cannabimimetic activity. Degradants that retained affinity and efficacy also substituted in drug discrimination tests for the prototypical synthetic cannabinoid 1-pentyl-3-(1-naphthoyl)indole (JWH-018), and are likely to produce psychotropic effects in humans. Hence, it is important to take into consideration the actual chemical exposures that occur during use of synthetic cannabinoid formulations to better comprehend the relationships between dose and effect.
IMPORTANCE: The late effects of traumatic brain injury (TBI) are of great interest, but studies characterizing these effects are limited. OBJECTIVE: To determine whether TBI with loss of ...consciousness (LOC) is associated with an increased risk for clinical and neuropathologic findings of Alzheimer disease (AD), Parkinson disease (PD), and other dementias. DESIGN, SETTING, AND PARTICIPANTS: This study analyzed data from the Religious Orders Study (ROS), Memory and Aging Project (MAP), and Adult Changes in Thought study (ACT). All ROS and MAP participants and a subset of ACT participants consent to autopsy. Studies performed annual (ROS and MAP) or biennial (ACT) cognitive and clinical testing to identify incident cases of dementia and AD. The 7130 participants included members of a Seattle-area health care delivery system (ACT), priests and nuns living in orders across the United States (ROS), and Chicago-area adults in retirement communities (MAP). Of these, 1589 underwent autopsy. Primary hypothesis was that TBI with LOC would be associated with increased risk for AD and neurofibrillary tangles. Data were accrued from 1994 to April 1, 2014. EXPOSURES: Self-reported TBI when the participant was free of dementia, categorized as no more than 1 vs more than 1 hour of LOC. MAIN OUTCOMES AND MEASURES: Clinical outcomes included incident all-cause dementia, AD, and PD in all studies and incident mild cognitive impairment and progression of parkinsonian signs in ROS and MAP. Neuropathologic outcomes included neurofibrillary tangles, neuritic plaques, microinfarcts, cystic infarcts, Lewy bodies, and hippocampal sclerosis in all studies. RESULTS: Of 7130 participants (2879 40.4% men; overall mean SD age, 79.9 6.9 years), 865 reported a history of TBI with LOC. In 45 190 person-years of follow-up, 1537 incident cases of dementia and 117 of PD were identified. No association was found between TBI with LOC and incident dementia (ACT: HR for TBI with LOC ≤1 hour, 1.03; 95% CI, 0.83-1.27; HR for TBI with LOC >1 hour, 1.18; 95% CI, 0.77-1.78; ROS and MAP: HR for TBI with LOC ≤1 hour, 0.87; 95% CI, 0.58-1.29; HR for TBI with LOC >1 hour, 0.84; 95% CI, 0.44-1.57) or AD (findings similar to those for dementia). Associations were found for TBI with LOC and incident PD in ACT (HR for TBI with LOC >1 hour, 3.56; 95% CI, 1.52-8.28) and progression of parkinsonian signs in ROS and MAP (odds ratio OR for TBI with LOC ≤1 hour, 1.65; 95% CI, 1.23-2.21; OR for TBI with LOC >1 hour, 2.23; 95% CI, 1.16-4.29). Traumatic brain injury with LOC was associated with Lewy bodies (any Lewy body in ACT: RR for TBI with LOC >1 hour, 2.64; 95% CI, 1.40-4.99; Lewy bodies in substantia nigra and/or locus ceruleus in ACT: RR for TBI with LOC >1 hour, 3.30; 95% CI, 1.71-6.38; Lewy bodies in frontal or temporal cortex in ACT: RR for TBI with LOC >1 hour, 5.73; 95% CI, 2.18-15.0; ROS and MAP: RR for TBI with LOC ≤1 hour, 1.64; 95% CI, 1.00-2.70; pooled RR for TBI with LOC ≤1 hour, 1.59; 95% CI, 1.06-2.39) and microinfarcts (any cortical microinfarct in ROS and MAP: RR for TBI with LOC >1 hour, 2.12; 95% CI, 1.12-4.01; pooled RR for TBI with LOC >1 hour, 1.58; 95% CI, 1.06-2.35). CONCLUSIONS AND RELEVANCE: Pooled clinical and neuropathologic data from 3 prospective cohort studies indicate that TBI with LOC is associated with risk for Lewy body accumulation, progression of parkinsonism, and PD, but not dementia, AD, neuritic plaques, or neurofibrillary tangles.
ABSTRACTClinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential ...biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective forunderstanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.
To determine the incidence of burnout among American surgeons and evaluate personal and professional characteristics associated with surgeon burnout.
: Burnout is a syndrome of emotional exhaustion ...and depersonalization that leads to decreased effectiveness at work. A limited amount of information exists about the relationship between specific demographic and practice characteristics with burnout among American surgeons.
Members of the American College of Surgeons (ACS) were sent an anonymous, cross-sectional survey in June 2008. The survey evaluated demographic variables, practice characteristics, career satisfaction, burnout, and quality of life (QOL). Burnout and QOL were measured using validated instruments.
Of the approximately 24,922 surgeons sampled, 7905 (32%) returned surveys. Responders had been in practice 18 years, worked 60 hours per week, and were on call 2 nights/wk (median values). Overall, 40% of responding surgeons were burned out, 30% screened positive for symptoms of depression, and 28% had a mental QOL score >1/2 standard deviation below the population norm. Factors independently associated with burnout included younger age, having children, area of specialization, number of nights on call per week, hours worked per week, and having compensation determined entirely based on billing. Only 36% of surgeons felt their work schedule left enough time for personal/family life and only 51% would recommend their children pursue a career as a physician/surgeon.
Burnout is common among American surgeons and is the single greatest predictor of surgeons' satisfaction with career and specialty choice. Additional research is needed to identify individual, organizational, and societal interventions that preserve and promote the mental health of American surgeons.
Faecal microbiota transplant (FMT) effectively treats recurrent
infection (rCDI), but its mechanisms of action remain poorly defined. Certain bile acids affect
germination or vegetative growth. We ...hypothesised that loss of gut microbiota-derived bile salt hydrolases (BSHs) predisposes to CDI by perturbing gut bile metabolism, and that BSH restitution is a key mediator of FMT's efficacy in treating the condition.
Using stool collected from patients and donors pre-FMT/post-FMT for rCDI, we performed 16S rRNA gene sequencing, ultra performance liquid chromatography mass spectrometry (UPLC-MS) bile acid profiling, BSH activity measurement, and qPCR of
/
CD genes involved in bile metabolism. Human data were validated in
batch cultures and a C57BL/6 mouse model of rCDI.
From metataxonomics, pre-FMT stool demonstrated a reduced proportion of BSH-producing bacterial species compared with donors/post-FMT. Pre-FMT stool was enriched in taurocholic acid (TCA, a potent
germinant); TCA levels negatively correlated with key bacterial genera containing BSH-producing organisms. Post-FMT samples demonstrated recovered BSH activity and
/
CD gene copy number compared with pretreatment (p<0.05). In batch cultures, supernatant from engineered
-expressing
and naturally BSH-producing organisms (
and
) reduced TCA-mediated
germination relative to culture supernatant of wild-type (BSH-negative)
total viable counts were ~70% reduced in an rCDI mouse model after administration of
expressing highly active BSH relative to mice administered BSH-negative
(p<0.05).
Restoration of gut BSH functionality contributes to the efficacy of FMT in treating rCDI.
Synthetic cannabinoids are a class of novel psychoactive substances that exhibit high affinity at the cannabinoid type-1 (CB
) receptor and produce effects similar to those of ...Δ-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. Illicit drug manufacturers are continually circumventing laws banning the sale of synthetic cannabinoids by synthesizing novel structures and doing so with little regard for the potential impact on pharmacological and toxicological effects. Synthetic cannabinoids produce a wide range of effects that include cardiotoxicity, seizure activity, and kidney damage, and they can cause death. Six synthetic cannabinoids, recently detected in illicit preparations, MMB-FUBINACA, MDMB-FUBINACA, CUMYL-PICA, 5F-CUMYL-PICA, NNEI, and MN-18 were assessed for: 1) receptor binding affinity at the human CB
and human CB
receptors, 2) function in
SGTP
S and cAMP signaling, and 3) THC-like effects in a mouse drug discrimination assay. All six synthetic cannabinoids exhibited high affinity for human cannabinoid receptors type-1 and type-2 and produced greater maximal effects than THC in
SGTP
S and cAMP signaling. Additionally, all six synthetic cannabinoids substituted for THC in drug discrimination, suggesting they probably possess subjective effects similar to those of cannabis. Notably, MDMB-FUBINACA, a methylated analog of MMB-FUBINACA, had higher affinity for CB
than the parent, showing that minor structural modifications being introduced can have a large impact on the pharmacological properties of these drugs. This study demonstrates that novel structures being sold and used illicitly as substitutes for cannabis are retaining high affinity at the CB
receptor, exhibiting greater efficacy than THC, and producing THC-like effects in models relevant to subjective effects in humans.
PDF
