The rockefeller university

Molecular motors walk along filaments until they detach stochastically with a force-dependent unbinding rate. Here, we show how this unbinding rate can be obtained from the analysis of experimental data of molecular motors moving in stationary optical traps. Two complementary methods are presented, based on the analysis of the distribution for the unbinding forces and of the motor's force traces. In the first method, analytically derived force distributions for slip bonds, slip-ideal bonds, and catch bonds are used to fit the cumulative distributions of the unbinding forces. The second method is based on the statistical analysis of the observed force traces. We validate both methods with stochastic simulations and apply them to experimental data for kinesin-1.

Developmental lead (Pb) exposure alters brain function through mechanisms that are not yet understood. A previous study showed that early lead exposure reduced microglia number in the dentate gyrus region of the hippocampus. Given the critical role of microglia in brain development, it is important to determine whether these differences are unique to the dentate gyrus, or occur throughout the hippocampus. Unbiased stereology was used to quantify microglia mean cell body number in total hippocampus, and compare the proportion of microglia in the ventral vs. dorsal regions. Total hippocampal volume was also measured and compared. The study included brain tissue from 30 pre-adolescent C57BL/6 J mice, exposed to 30 ppm Pb acetate (n = 10, mean BLL 3.4 mu g/dL at sacrifice), 330 ppm Pb acetate (n = 10, mean BLL 14.1 mu g/dL at sacrifice), or 0 ppm Pb acetate (n = 10, negative controls). In lead exposed animals, microglia mean cell body number was reduced in total hippocampus; total hippocampal volume was reduced. Importantly, effects in low-and high-dose exposure groups did not differ. Contrary to study hypotheses, the distribution of hippocampal microglia in the ventral vs. dorsal hippocampal regions did not differ. Overall, lowest and higher levels of lead exposure during development had strikingly similar disruptive effects in the neuroimmune system. Studies are needed to determine the immune and other mechanisms responsible for these effects. Future studies would benefit from larger samples to determine whether in fact there is a group by sex interaction driving the effects of early lead exposure on microglia.

A search is presented for a heavy spin- 1 resonance Z decaying to a top quark and a vector- like top quark partner T in the lepton + jets final state. The search is performed using a data set of pp collisions at a centre- of- mass energy of 13 TeV corresponding to an integrated luminosity of 35.9 fb - 1 as recorded by the CMS experiment at the CERN LHC in the year 2016. The analysis is optimised for final states arising from the T decay modes to a top quark and a Higgs or Z boson ( T. Ht, Zt). The event selection makes use of resolved and merged top quark decay products, as well as decays of boosted Higgs bosons and Z and W bosons using jet substructure techniques. No significant deviation from the standard model background expectation is observed. Exclusion limits on the product of the cross section and branching fraction for Z . tT, T. Ht, Zt, Wb are presented for various combinations of the Z resonance mass and the vector- like T quark mass. These results represent the most stringent limits to date for the decay mode Z . tT. tHt. In a benchmark model with extra dimensions, invoking a heavy spin- 1 resonance G *, masses of the G * between 1.5 and 2.3 TeV and between 2.0 and 2.4 TeV are excluded for T masses of 1.2 and 1.5 TeV, respectively.

The effects on the vasculature produced by ethanol withdrawal include both vasodilatation and hypocontractility, although a detailed biochemical understanding of these processes is yet to be accomplished. Here, we sought to investigate some of the mechanisms underlying vascular hypocontractility induced by ethanol withdrawal. Male Wistar rats were treated with increasing doses of 3-9% ethanol (v/v) for 21 days and the impact of ethanol withdrawal on the vascular function was assessed 48 h after immediate ethanol suspension. Endothelium-denuded rat aortic rings showed a reduced contractile response to phenylephrine, angiotensin II, serotonin and KC1 after ethanol withdrawal, but the same phenomenon was not observed in endothelium-intact rings. Indomethacin, but not L-NAME, tiron, PEG-catalase and SC560, restored the contractile response to phenylephrine of endothelium-denuded aortas from abstinent rats. Hyporeactivity to phenylephrine induced by ethanol withdrawal was reversed by SC236, a selective cyclooxygenase (COX)-2 inhibitor. Similarly, Ro1138452, a selective prostacyclin IP receptor antagonist, reversed vascular hypocontractility induced by ethanol withdrawal. Increased concentrations of 6-keto-prostaglandin (PG)F-1(alpha), a stable product of PGI(2), was detected in endothelium-denuded aortas from abstinent rats, and this response was prevented by indomethacin. However, no changes in aortic PGE(2) levels were detected after ethanol withdrawal. In situ quantification of hydrogen peroxide (H2O2 ) and nitric oxide (NO) using fluorescent dyes revealed that ethanol withdrawal decreased the levels of these two compounds in the tunica media. Our studies show that the vascular hypocontractility induced by ethanol withdrawal is independent of the endothelium and it is mediated by PGI(2) derived from COX-2.

ObjectivesEarly melanoma detection decreases morbidity and mortality. Early detection classically involves dermoscopy to identify suspicious lesions for which biopsy is indicated. Biopsy and histological examination then diagnose benign nevi, atypical nevi, or cancerous growths. With current methods, a considerable number of unnecessary biopsies are performed as only 11% of all biopsied, suspicious lesions are actually melanomas. Thus, there is a need for more advanced noninvasive diagnostics to guide the decision of whether or not to biopsy. Artificial intelligence can generate screening algorithms that transform a set of imaging biomarkers into a risk score that can be used to classify a lesion as a melanoma or a nevus by comparing the score to a classification threshold. Melanoma imaging biomarkers have been shown to be spectrally dependent in Red, Green, Blue (RGB) color channels, and hyperspectral imaging may further enhance diagnostic power. The purpose of this study was to use the same melanoma imaging biomarkers previously described, but over a wider range of wavelengths to determine if, in combination with machine learning algorithms, this could result in enhanced melanoma detection. MethodsWe used the melanoma advanced imaging dermatoscope (mAID) to image pigmented lesions assessed by dermatologists as requiring a biopsy. The mAID is a 21-wavelength imaging device in the 350-950nm range. We then generated imaging biomarkers from these hyperspectral dermoscopy images, and, with the help of artificial intelligence algorithms, generated a melanoma Q-score for each lesion (0=nevus, 1=melanoma). The Q-score was then compared to the histopathologic diagnosis. ResultsThe overall sensitivity and specificity of hyperspectral dermoscopy in detecting melanoma when evaluated in a set of lesions selected by dermatologists as requiring biopsy was 100% and 36%, respectively. ConclusionWith widespread application, and if validated in larger clinical trials, this non-invasive methodology could decrease unnecessary biopsies and potentially increase life-saving early detection events. Lasers Surg. Med. 51:214-222, 2019. (c) 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Cerebral blood flow (CBF) reductions in Alzheimer's disease patients and related mouse models have been recognized for decades, but the underlying mechanisms and resulting consequences for Alzheimer's disease pathogenesis remain poorly understood. In APP/PS1 and 5xFAD mice we found that an increased number of cortical capillaries had stalled blood flow as compared to in wild-type animals, largely due to neutrophils that had adhered in capillary segments and blocked blood flow. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to both an immediate increase in CBF and rapidly improved performance in spatial and working memory tasks. This study identified a previously uncharacterized cellular mechanism that explains the majority of the CBF reduction seen in two mouse models of Alzheimer's disease and demonstrated that improving CBF rapidly enhanced short-term memory function. Restoring cerebral perfusion by preventing neutrophil adhesion may provide a strategy for improving cognition in Alzheimer's disease patients.

The nucleus accumbens, a key brain reward region, receives synaptic inputs from a range of forebrain and brainstem regions. Many of these projections have been established using electrophysiology or fluorescent tract tracing. However, more recently developed viral tracing techniques have allowed for fluorescent labeling of synaptic afferents in a cell type-specific manner. Since the NAc is comprised of multiple cell types, these methods have enabled the delineation of the cell type-specific connectivity of principal medium spiny neurons in the region. The synaptic connectivity of somatostatin interneurons, which account for <5% of the neurons in the region, has been inferred from electrophysiological and immunohistochemical data, but has not yet been visualized using modern viral tracing techniques. Here, we use the pseudorabies virus (PRV)-Introvert-GFP virus, an alphaherpes virus previously shown to label synaptic afferents in a cell type-specific manner, to label first order afferents to NAc somatostatin interneurons. While we find GFP(+) labeling in several well established projections to the NAc, we also observe that several known projections to NAc did not contain GFP(+) cells, suggesting they do not innervate somatostatin interneurons in the region. A subset of the GFP(+) afferents are c-FOS(+) following acute administration of cocaine, showing that NAc somatostatin interneurons are innervated by some cells that respond to rewarding stimuli. These results provide a foundation for future studies aimed toward elucidating the cell type-specific connectivity of the NAc, and identify specific circuits that warrant future functional characterization.

Spatial synchrony is defined by related fluctuations through time in population abundances measured at different locations. The degree of relatedness typically declines with increasing distance between sampling locations. Standard approaches for assessing synchrony assume isotropy in space and uniformity across timescales of analysis, but it is now known that spatial variability and timescale structure in population dynamics are common features. We tested for spatial and timescale structure in the patterns of synchrony of freshwater plankton in Kentucky Lake, U.S.A. We also evaluated whether different mechanisms may drive synchrony and its spatial structure on different timescales. Using wavelet techniques and matrix regression, we analyzed phytoplankton biomass and abundances of seven zooplankton taxa at 16 locations sampled from 1990 to 2015. We found that zooplankton abundances and phytoplankton biomass exhibited synchrony at multiple timescales. Timescale structure in the potential mechanisms of synchrony was revealed primarily through networks of relationships among zooplankton taxa, which differed by timescale. We found substantial interspecific variability in geographic structures of synchrony and their causes: all mechanisms we considered strongly explained geographic structure in synchrony for at least one species, while Euclidean distance between sampling locations was generally less well supported than more mechanistic explanations. Geographic structure in synchrony and its underlying mechanisms also depended on timescale for a minority of the taxa tested. Overall, our results show substantial and complex but interpretable variation in structures of synchrony across three variables: space, timescale, and taxon. It seems likely these aspects of synchrony are important general features of freshwater systems.

We engineered and employed a chaperone-like amyloid-binding protein Nucleobindin 1 (NUCB1) to stabilize human islet amyloid polypeptide (hIAPP) protofibrils for use as immunogen in mice. We obtained multiple monoclonal antibody (mAb) clones that were reactive against hIAPP protofibrils. A secondary screen was carried out to identify clones that cross-reacted with amyloid beta-peptide (A beta 42) protofibrils, but not with A beta 40 monomers. These mAbs were further characterized in several in vitro assays, in immunohistological studies of a mouse model of Alzheimer's disease (AD) and in AD patient brain tissue. We show that mAbs obtained by immunizing mice with the NUCB1-hIAPP complex cross-react with A beta 42, specifically targeting protofibrils and inhibiting their further aggregation. In line with conformation-specific binding, the mAbs appear to react with an intracellular antigen in diseased tissue, but not with amyloid plaques. We hypothesize that the mAbs we describe here recognize a secondary or quaternary structural epitope that is common to multiple amyloid protofibrils. In summary, we report a method to create mAbs that are conformation-sensitive and sequence-independent and can target more than one type of protofibril species.