Comprehensive characterization of molecular interactions based on nanomechanics

Molecular interaction is a key concept in our understanding of the biological mechanisms of life. Two physical properties change when one molecular partner binds to another. Firstly, the masses combine and secondly, the structure of at least one binding partner is altered, mechanically transducing the binding into subsequent biological reactions. Here we present a nanomechanical micro-array technique for bio-medical research, which not only monitors the binding of effector molecules to their target but also the subsequent effect on a biological system in vitro. This label-free and real-time method directly and simultaneously tracks mass and nanomechanical changes at the sensor interface using micro-cantilever technology. To prove the concept we measured lipid vesicle (approximately 748*10(6) Da) adsorption on the sensor interface followed by subsequent binding of the bee venom peptide melittin (2840 Da) to the vesicles. The results show the high dynamic range of the instrument and that measuring the mass and structural changes simultaneously allow a comprehensive discussion of molecular interactions

Improving Transferability Case Studies: \u27Building a Better Bridge to the Bachelor\u27s\u27

Many Virginians aspiring to earn a four-year degree intentionally begin their journey at one of the 23 community colleges within the Virginia Community College System (VCCS). In concert with those aspirations, the VCCS is committed to providing its residents an affordable and accessible program of study that prepares them to transfer and earn a bachelor’s degree at any one of Virginia’s colleges and universities. The establishment of an affordable and accessible pathway was one of the emanating purposes of the community college (Mellow & Heelan, 2015). The dream of affordable transfer education is one of three key legislative efforts of the VCCS, and statute 23.1-907 of the Commonwealth of Virginia mandates transfer agreements between the institutions. With at least 38 transfer agreements and more than 300 articulation agreements developed between the VCCS and the four-year colleges and universities, the State Council of Higher Education for Virginia (SCHEV) states that up to 32% of transfer students do so under the auspices of guaranteed admission agreements (Joint Legislative Audit and Review Commission, 2017). Transfer pathway must be accessible and easily achieved in the least amount of time, with the least amount of required credits, and the least amount of cost and debt. To build a better bridge to the bachelor’s degree, Virginia must examine the current situation, consider best practices within the Commonwealth and across the nation, and seek to enact policies and procedures that achieve that goal

Toll-Like Receptors and Dectin-1, a C-Type Lectin Receptor, Trigger Divergent Functions in CNS Macrophages

Spinal cord injury (SCI) activates macrophages, endowing them with both reparative and pathological functions. The mechanisms responsible for these divergent functions are unknown but are likely controlled through stochastic activation of different macrophage receptor subtypes. Various danger-associated molecular patterns released from dying cells in the injured spinal cord likely activate distinct subtypes of macrophage pattern recognition receptors, including bacterial toll-like receptors (TLRs) and fungal C-type lectin receptors (e.g., dectin-1). To determine the in vivo consequences of activating these receptors, ligands specific for TLR2 or dectin-1 were microinjected, alone or in combination, into intact spinal cord. Both ligands elicit a florid macrophage reaction; however, only dectin-1 activation causes macrophage-mediated demyelination and axonal injury. Coactivating TLR2 reduced the injurious effects of dectin-1 activation. When injected into traumatically injured spinal cord, TLR2 agonists enhance the endogenous macrophage reaction while conferring neuroprotection. Indeed, dieback of axons was reduced, leading to smaller lesion volumes at the peak of the macrophage response. Moreover, the density of NG2+ cells expressing vimentin increased in and near lesions that were enriched with TLR2-activated macrophages. In dectin-1-null mutant (knock-out) mice, dieback of corticospinal tract axons also is reduced after SCI. Collectively, these data support the hypothesis that the ability of macrophages to create an axon growth-permissive microenvironment or cause neurotoxicity is receptor dependent and it may be possible to exploit this functional dichotomy to enhance CNS repair. SIGNIFICANCE STATEMENT: There is a growing appreciation that macrophages exert diverse functions in the injured and diseased CNS. Indeed, both macrophage-mediated repair and macrophage-mediated injury occur, and often these effector functions are elicited simultaneously. Understanding the mechanisms governing the reparative and pathological properties of activated macrophages is at the forefront of neuroscience research. In this report, using in vitro and in vivo models of relevance to traumatic spinal cord injury (SCI), new data indicate that stochastic activation of toll-like and c-type lectin receptors on macrophages causes neuroprotection or neurotoxicity, respectively. Although this manuscript focuses on SCI, these two innate immune receptor subtypes are also involved in developmental processes and become activated in macrophages that respond to various neurological diseases

Virological outcome of patients with HIV drug resistance attending an urban out-patient clinic in Uganda: a need for structured adherence counselling and third line treatment options

BACKGROUND HIV drug resistance and suboptimal adherence are the main reasons for treatment failure among HIV-infected individuals. As genotypic resistance testing is not routinely available in resource-limited settings such as Uganda, data on transmitted and acquired resistance is sparse. METHODS This observational follow-up study assessed the virological outcomes of patients diagnosed with virological failure or transmitted HIV drug resistance in 2015 at the adults' out-patient clinic of the Infectious Diseases Institute in Kampala, Uganda. Initially, 2430 patients on antiretroviral therapy (ART) underwent virological monitoring, of which 190 had virological failure and were subsequently eligible for this follow-up study. Nine patients diagnosed with transmitted drug resistance were eligible. In patients with a viral load > 1000 copies/mL genotypic resistance testing was done. RESULTS Of 190 eligible patients, 30 (15.8%) had either died or were lost to follow-up. A total of 148 (77.9%) were included, of which 98 had had a change of ART regimen, and 50 had received adherence counselling only. The majority was now on 2-line ART (N=130, 87.8%). The median age was 39 years (interquartile range: 32-46) and 109 (73.6%) were female. Virological failure was diagnosed in 29 (19.6%) patients, of which 24 (82.8%) were on 2-line ART. Relevant drug resistance was found in 25 (86.2%) cases, of which 12 (41.3%) carried dual and 7 (24.1%) triple drug resistance. CONCLUSION Two years after initial virological failure, most patients followed up by this study had a successful virological outcome. However, a significant proportion either continued to fail or died or was lost to follow-up

Oligodendrocytes contribute to motor neuron death in ALS via SOD1 dependent mechanism

Oligodendrocytes have recently been implicated in the pathophysiology of ALS. Here we show that, in vitro, mutant SOD1 mouse oligodendrocytes induce wild-type motor neuron hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls, sporadic and familial ALS patients using two different reprogramming methods. All ALS oligodendrocyte lines induced motor neuron death through conditioned medium and in co-culture. Conditioned medium-mediated motor neuron death was associated with decreased lactate production and release, while toxicity in co-culture was lactate independent, demonstrating that motor neuron survival is not only mediated by soluble factors. Remarkably, human SOD1 shRNA treatment resulted in motor neuron rescue in both mouse and human cultures when knockdown was achieved in progenitor cells, while it was ineffective in differentiated oligodendrocytes. Early SOD1 knockdown, in fact, rescued lactate impairment and cell toxicity in all lines tested with exclusion of samples carrying C9orf72 repeat expansions. These did not respond to SOD1 knockdown nor showed lactate release impairment. Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type some damage might be irreversible. In addition, we demonstrate that C9ORF72 patients represent an independent patient group that might not respond to the same treatment

Critical quantum chaos and the one dimensional Harper model

We study the quasiperiodic Harper's model in order to give further support for a possible universality of the critical spectral statistics. At the mobility edge we numerically obtain a scale-invariant distribution of the bands $S$, which is closely described by a semi-Poisson $P(S)=4S \exp(-2S)$ curve. The $\exp (-2S)$ tail appears when the mobility edge is approached from the metal while $P(S)$ is asymptotically log-normal for the insulator. The multifractal critical density of states also leads to a sub-Poisson linear number variance $\Sigma_{2}(E)\propto 0.041E$.Comment: 4 pages, 4 eps figure

Variability and Predictors of Urinary Bisphenol A Concentrations during Pregnancy

BackgroundPrenatal bisphenol A (BPA) exposure may be associated with developmental toxicity, but few studies have examined the variability and predictors of urinary BPA concentrations during pregnancy.ObjectiveOur goal was to estimate the variability and predictors of serial urinary BPA concentrations taken during pregnancy.MethodsWe measured BPA concentrations during pregnancy and at birth in three spot urine samples from 389 women. We calculated the intraclass correlation coefficient (ICC) to assess BPA variability and estimated associations between log10-transformed urinary BPA concentrations and demographic, occupational, dietary, and environmental factors, using mixed models.ResultsGeometric mean (GM) creatinine-standardized concentrations (micrograms per gram) were 1.7 (16 weeks), 2.0 (26 weeks), and 2.0 (birth). Creatinine-standardized BPA concentrations exhibited low reproducibility (ICC = 0.11). By occupation, cashiers had the highest BPA concentrations (GM: 2.8 μg/g). Consuming canned vegetables at least once a day was associated with higher BPA concentrations (GM = 2.3 μg/g) compared with those consuming no canned vegetables (GM = 1.6 μg/g). BPA concentrations did not vary by consumption of fresh fruits and vegetables, canned fruit, or store-bought fresh and frozen fish. Urinary high-molecular-weight phthalate and serum tobacco smoke metabolite concentrations were positively associated with BPA concentrations.ConclusionsThese results suggest numerous sources of BPA exposure during pregnancy. Etiological studies may need to measure urinary BPA concentrations more than once during pregnancy and adjust for phthalates and tobacco smoke exposures

Prenatal Tobacco Smoke Exposure and Early Childhood BMI

Maternal smoking during pregnancy is associated with increased risk of childhood overweight body mass index (BMI). Less is known about the association between prenatal secondhand tobacco smoke (SHS) exposure and childhood BMI. We followed 292 mother-child dyads from early pregnancy to 3 years of age. Prenatal tobacco smoke exposure during pregnancy was quantified using self-report and serum cotinine biomarkers. We used linear mixed models to estimate the association between tobacco smoke exposure and BMI at birth, 4 weeks, and 1, 2, and 3 years. During pregnancy, 15% of women reported SHS exposure and 12% reported active smoking, but 51% of women had cotinine levels consistent with SHS exposure and 10% had cotinine concentrations indicative of active smoking. After adjustment for confounders, children born to active smokers had higher BMI at 2 and 3 years of age (self-report or serum cotinine), compared to unexposed children. Children born to women with prenatal serum cotinine concentrations indicative of SHS exposure had higher BMI at 2 (Mean Difference [MD]:0.3; 95% confidence interval [CI]:−0.1, 0.7) and 3 (MD:0.4; [0, 0.8]) years compared to unexposed children. Using self-reported prenatal exposure resulted in non-differential exposure misclassification of SHS exposures that attenuated the association between SHS exposure and BMI compared to serum cotinine concentrations. These findings suggest active and secondhand prenatal tobacco smoke exposure may be related to an important public health problem in childhood and later life. In addition, accurate quantification of prenatal secondhand tobacco smoke exposures is essential to obtaining valid estimates

Performance of the X-Calibur Hard X-Ray Polarimetry Mission during its 2018/19 Long-Duration Balloon Flight

X-Calibur is a balloon-borne telescope that measures the polarization of high-energy X-rays in the 15--50keV energy range. The instrument makes use of the fact that X-rays scatter preferentially perpendicular to the polarization direction. A beryllium scattering element surrounded by pixellated CZT detectors is located at the focal point of the InFOC{\mu}S hard X-ray mirror. The instrument was launched for a long-duration balloon (LDB) flight from McMurdo (Antarctica) on December 29, 2018, and obtained the first constraints of the hard X-ray polarization of an accretion-powered pulsar. Here, we describe the characterization and calibration of the instrument on the ground and its performance during the flight, as well as simulations of particle backgrounds and a comparison to measured rates. The pointing system and polarimeter achieved the excellent projected performance. The energy detection threshold for the anticoincidence system was found to be higher than expected and it exhibited unanticipated dead time. Both issues will be remedied for future flights. Overall, the mission performance was nominal, and results will inform the design of the follow-up mission XL-Calibur, which is scheduled to be launched in summer 2022.Comment: 19 pages, 31 figures, submitted to Astropart. Phy

Lipopeptides: from self-assembly to bioactivity

This Feature Article discusses several classes of lipopeptide with important biomedical applications as antimicrobial and antifungal agents, in immune therapies and in personal care applications among others. Two main classes of lipopeptide are considered: (i) bacterially-expressed lipopeptides with a cyclic peptide headgroup and (ii) linear lipopeptides (with one or more lipid chains) based on bio-derived and bio-inspired amino acid sequences with current clinical applications. The applications are briefly summarized, and the biophysical characterization of the molecules is reviewed, with a particular focus on self-assembly. For several of these types of biomolecule, the formation of micelles above a critical micelle concentration has been observed while others form bilayer structures, depending on conditions of pH and temperature. As yet, there are few studies on the possible relationship between self-assembly into structures such as micelles and bioactivity of this class of molecule although this is likely to attract further attention