LSR/angulin-1 is a tricellular tight junction protein involved in blood-brain barrier formation.

The blood-brain barrier (BBB) is a term used to describe the unique properties of central nervous system (CNS) blood vessels. One important BBB property is the formation of a paracellular barrier made by tight junctions (TJs) between CNS endothelial cells (ECs). Here, we show that Lipolysis-stimulated lipoprotein receptor (LSR), a component of paracellular junctions at points in which three cell membranes meet, is greatly enriched in CNS ECs compared with ECs in other nonneural tissues. We demonstrate that LSR is specifically expressed at tricellular junctions and that its expression correlates with the onset of BBB formation during embryogenesis. We further demonstrate that the BBB does not seal during embryogenesis in Lsr knockout mice with a leakage to small molecules. Finally, in mouse models in which BBB was disrupted, including an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and a middle cerebral artery occlusion (MCAO) model of stroke, LSR was down-regulated, linking loss of LSR and pathological BBB leakage

A Muscle’s Force Depends on the Recruitment Patterns of Its Fibers

Biomechanical models of whole muscles commonly used in simulations of musculoskeletal function and movement typically assume that the muscle generates force as a scaled-up muscle fiber. However, muscles are comprised of motor units that have different intrinsic properties and that can be activated at different times. This study tested whether a muscle model comprised of motor units that could be independently activated resulted in more accurate predictions of force than traditional Hill-type models. Forces predicted by the models were evaluated by direct comparison with the muscle forces measured in situ from the gastrocnemii in goats. The muscle was stimulated tetanically at a range of frequencies, muscle fiber strains were measured using sonomicrometry, and the activation patterns of the different types of motor unit were calculated from electromyographic recordings. Activation patterns were input into five different muscle models. Four models were traditional Hill-type models with different intrinsic speeds and fiber-type properties. The fifth model incorporated differential groups of fast and slow motor units. For all goats, muscles and stimulation frequencies the differential model resulted in the best predictions of muscle force. The in situ muscle output was shown to depend on the recruitment of different motor units within the muscle.Organismic and Evolutionary Biolog

Accuracy of gastrocnemius muscles forces in walking and running goats predicted by one-element and two-element Hill-type models

Hill-type models are commonly used to estimate muscle forces during human and animal movement —yet the accuracy of the forces estimated during walking, running, and other tasks remains largely unknown. Further, most Hill-type models assume a single contractile element, despite evidence that faster and slower motor units, which have different activation-deactivation dynamics, may be independently or collectively excited. This study evaluated a novel, two-element Hill-type model with “differential” activation of fast and slow contractile elements. Model performance was assessed using a comprehensive data set (including measures of EMG intensity, fascicle length, and tendon force) collected from the gastrocnemius muscles of goats during locomotor experiments. Muscle forces predicted by the new two-element model were compared to the forces estimated using traditional one-element models and to the forces measured in vivo using tendon buckle transducers. Overall, the two-element model resulted in the best predictions of in vivo gastrocnemius force. The coefficient of determination, r2, was up to 26.9% higher and the root mean square error, RMSE, was up to 37.4% lower for the two-element model than for the one-element models tested. All models captured salient features of the measured muscle force during walking, trotting, and galloping (r2 = 0.26 to 0.51), and all exhibited some errors (RMSE = 9.63 to 32.2% of the maximum in vivo force). These comparisons provide important insight into the accuracy of Hill-type models. The results also show that incorporation of fast and slow contractile elements within muscle models can improve estimates of time-varying, whole muscle force during locomotor tasks.Organismic and Evolutionary Biolog

Metabolic changes associated with adaptive resistance to daptomycin in Streptococcus mitis-oralis

Background: Viridans group streptococci of the Streptococcus mitis-oralis subgroup are important endovascular pathogens. They can rapidly develop high-level and durable non-susceptibility to daptomycin both in vitro and in vivo upon exposure to daptomycin. Two consistent genetic adaptations associated with this phenotype (i.e., mutations in cdsA and pgsA) lead to the depletion of the phospholipids, phosphatidylglycerol and cardiolipin, from the bacterial membrane. Such alterations in phospholipid biosynthesis will modify carbon flow and change the bacterial metabolic status. To determine the metabolic differences between daptomycin-susceptible and non- susceptible bacteria, the physiology and metabolomes of S. mitis-oralis strains 351 (daptomycin-susceptible) and 351-D10 (daptomycin non-susceptible) were analyzed. S. mitis-oralis strain 351-D10 was made daptomycin non- susceptible through serial passage in the presence of daptomycin. Background: Viridans group streptococci of the Streptococcus mitis-oralis subgroup are important endovascular pathogens. They can rapidly develop high-level and durable non-susceptibility to daptomycin both in vitro and in vivo upon exposure to daptomycin. Two consistent genetic adaptations associated with this phenotype (i.e., mutations in cdsA and pgsA) lead to the depletion of the phospholipids, phosphatidylglycerol and cardiolipin, from the bacterial membrane. Such alterations in phospholipid biosynthesis will modify carbon flow and change the bacterial metabolic status. To determine the metabolic differences between daptomycin-susceptible and non- susceptible bacteria, the physiology and metabolomes of S. mitis-oralis strains 351 (daptomycin-susceptible) and 351-D10 (daptomycin non-susceptible) were analyzed. S. mitis-oralis strain 351-D10 was made daptomycin non- susceptible through serial passage in the presence of daptomycin. Conclusions: S. mitis-oralis metabolism is altered in daptomycin non-susceptible bacteria relative to the daptomycin susceptible parent strain. As demonstrated in Staphylococcus aureus, inhibiting the metabolic changes that facilitate the transition from a daptomycin susceptible state to a non-susceptible one, inhibits daptomycin non- susceptibility. By preventing these metabolic adaptations in S. mitis-oralis, it should be possible to deter the formation of daptomycin non-susceptibility

Human coronaviruses and other respiratory infections in young adults on a university campus: Prevalence, symptoms, and shedding

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145532/1/irv12563.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145532/2/irv12563_am.pd

Origin and Control of Chemoselectivity in Cytochrome c Catalyzed Carbene Transfer into Si–H and N–H bonds

A cytochrome c heme protein was recently engineered to catalyze the formation of carbon–silicon bonds via carbene insertion into Si–H bonds, a reaction that was not previously known to be catalyzed by a protein. High chemoselectivity toward C–Si bond formation over competing C–N bond formation was achieved, although this trait was not screened for during directed evolution. Using computational and experimental tools, we now establish that activity and chemoselectivity are modulated by conformational dynamics of a protein loop that covers the substrate access to the iron–carbene active species. Mutagenesis of residues computationally predicted to control the loop conformation altered the protein’s chemoselectivity from preferred silylation to preferred amination of a substrate containing both N–H and Si–H functionalities. We demonstrate that information on protein structure and conformational dynamics, combined with knowledge of mechanism, leads to understanding of how non-natural and selective chemical transformations can be introduced into the biological world

Provider-Level Variation in Smoking Cessation Assistance Provided in the Cardiology Clinics: Insights From the NCDR PINNACLE Registry

Background: Studies show suboptimal provision of smoking cessation assistance (counseling or pharmacotherapy) for current smokers attempting to quit. We aimed to identify smoking cessation assistance patterns in US cardiology practices. Methods and Results: Among 328 749 current smokers seen between January 1, 2013, and March 31, 2016, in 348 NCDR (National Cardiovascular Data Registry) PINNACLE (Practice Innovation and Clinical Excellence)-affiliated cardiology practices, we measured the rates of cessation assistance. We used multivariable hierarchical logistic regression models to determine provider-, practice-, and patient-level predictors of cessation assistance. We measured provider variation in cessation assistance using median rate ratio (the likelihood that the same patient would receive the same assistance at by any given provider; \u3e 1.2 suggests significant variation). Smoking cessation assistance was documented in only 34% of encounters. Despite adjustment of provider, practice, and patient characteristics, there was large provider-level variation in cessation assistance (median rate ratio, 6 [95% CI , 5.76-6.32]). Practice location in the South region (odds ratio [OR], 0.48 [0.37-0.63] versus West region) and rural or suburban location (OR, 0.92 [0.88-0.95] for rural; OR, 0.94 [0.91-0.97] for suburban versus urban) were associated with lower rates of cessation assistance. Similarly, older age (OR, 0.88 [0.88-0.89] per 10-year increase), diabetes mellitus (OR, 0.84 [0.82-0.87]), and atrial fibrillation (OR, 0.93 [0.91-0.96]) were associated with lower odds of receiving cessation assistance. Conclusions: In a large contemporary US registry, only 1 in 3 smokers presenting for a cardiology visit received smoking cessation assistance. Our findings suggest the presence of a large deficit and largely idiosyncratic provider-level variation in the provision of smoking cessation assistance

Facemasks, Hand Hygiene, and Influenza among Young Adults: A Randomized Intervention Trial

Limited vaccine availability and the potential for resistance to antiviral medications have led to calls for establishing the efficacy of non-pharmaceutical measures for mitigating pandemic influenza. Our objective was to examine if the use of face masks and hand hygiene reduced rates of influenza-like illness (ILI) and laboratory-confirmed influenza in the natural setting. A cluster-randomized intervention trial was designed involving 1,178 young adults living in 37 residence houses in 5 university residence halls during the 2007–2008 influenza season. Participants were assigned to face mask and hand hygiene, face mask only, or control group during the study. Discrete-time survival models using generalized estimating equations to estimate intervention effects on ILI and confirmed influenza A/B infection over a 6-week study period were examined. A significant reduction in the rate of ILI was observed in weeks 3 through 6 of the study, with a maximum reduction of 75% during the final study week (rate ratio [RR] = 0.25, [95% CI, 0.07 to 0.87]). Both intervention groups compared to the control showed cumulative reductions in rates of influenza over the study period, although results did not reach statistical significance. Generalizability limited to similar settings and age groups. Face masks and hand hygiene combined may reduce the rate of ILI and confirmed influenza in community settings. These non-pharmaceutical measures should be recommended in crowded settings at the start of an influenza pandemic

Epidural Hematoma Following Cervical Spine Surgery.

STUDY DESIGN: A multicentered retrospective case series. OBJECTIVE: To determine the incidence and circumstances surrounding the development of a symptomatic postoperative epidural hematoma in the cervical spine. METHODS: Patients who underwent cervical spine surgery between January 1, 2005, and December 31, 2011, at 23 institutions were reviewed, and all patients who developed an epidural hematoma were identified. RESULTS: A total of 16 582 cervical spine surgeries were identified, and 15 patients developed a postoperative epidural hematoma, for a total incidence of 0.090%. Substantial variation between institutions was noted, with 11 sites reporting no epidural hematomas, and 1 site reporting an incidence of 0.76%. All patients initially presented with a neurologic deficit. Nine patients had complete resolution of the neurologic deficit after hematoma evacuation; however 2 of the 3 patients (66%) who had a delay in the diagnosis of the epidural hematoma had residual neurologic deficits compared to only 4 of the 12 patients (33%) who had no delay in the diagnosis or treatment (P = .53). Additionally, the patients who experienced a postoperative epidural hematoma did not experience any significant improvement in health-related quality-of-life metrics as a result of the index procedure at final follow-up evaluation. CONCLUSION: This is the largest series to date to analyze the incidence of an epidural hematoma following cervical spine surgery, and this study suggest that an epidural hematoma occurs in approximately 1 out of 1000 cervical spine surgeries. Prompt diagnosis and treatment may improve the chance of making a complete neurologic recovery, but patients who develop this complication do not show improvements in the health-related quality-of-life measurements