bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebrospinal Fluid Penetration of Vancomycin During Continuous Infusion Therapy in Patients With Nosocomial Ventriculitis
Authors: Tuon Felipe Francisco , Yamada Carolina Hikari , Cieslinski Juliette , dos Santos Oliveira Dayana , Ribeiro Victoria Stadler Tasca , Gasparetto Juliano , Telles Joao Paulo 
Published: June 2021

Background:
This study aimed to evaluate the utility of a commercial kit used to measure serum vancomycin concentrations to determine vancomycin concentrations in cerebrospinal fluid (CSF) samples and evaluate CSF penetration when administered as a continuous high-dose infusion in patients with nosocomial ventriculitis.

Methods:
This study included patients with external ventricular drain infection who were admitted to the intensive care unit between January 2018 and September 2020. After validation, CSF samples from 33 patients were collected. All patients received 30 mg/kg of vancomycin as a loading dose followed by 60 mg/kg as a maintenance dose in continuous infusion; all CSF samples were collected at least 48 hours after the first dose.

Results:
Thirty-three patients were enrolled in this study. The median serum creatinine level was 0.66 mg/dL (0.5–0.92; n = 30), and median creatinine clearance was 119.2 mL/min (64.6–138.4; n = 13). The median serum vancomycin 24-hour area under the curve (AUC24h) was 838 mg*h/L (515–1010). The median CSF vancomycin concentration was 5.20 mg/L (1.95–12.4). Median serum vancomycin concentration was 34.9 mg/L (21.47–42.1), and median CSF/serum ratio was 18.6% (8.4–41.5). Acute renal injury occurred in 21% (n = 7) of the patients by the end of the therapy. In addition, the vancomycin CSF/serum ratio was positively correlated with the median serum creatinine level (r = 0.670; P = 0.004).

Conclusions:
Commercial vancomycin kits used to measure serum samples may be used to evaluate vancomycin concentrations in the CSF. Vancomycin penetration into CSF was 18.6%.
Lower ambulatory nocturnal SBP is associated with less cardiovascular and renal damage in normotensive hospitalized patients with chronic kidney disease
Authors: Zhang Jun , Song Jun , Zhou Liping , Zhou Wenying , Rao Jialing , Li Yuanqing , Wu Jianhao , Peng Hui , Lou Tanqi 
Published: June 2021

Objective:
The impact of nocturnal blood pressure (BP) on target organ damage (TOD) in chronic kidney disease (CKD) patients with normotension has not been established. In this study, we determined whether nocturnal BP is correlated with cardiovascular and renal damage independent of the 24-h BP in CKD patients with normotension or hypertension.

Methods:
A total of 1166 hospitalized patients with CKD not requiring dialysis were enrolled in this cross-sectional study, 421 and 745 of whom had normotension and hypertension, respectively. TOD was assessed by the left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR) and presence of proteinuria. Univariate and multivariable regression analyses were used to evaluate the relationships between nocturnal BP and TOD.

Results:
In the multivariable-adjusted models, including the 24-h BP, nocturnal SBP was independently associated with the LVMI, eGFR and proteinuria in patients with normotension (P < 0.05), while the nocturnal DBP was not correlated with proteinuria. The nocturnal SBP was associated with LVMI and proteinuria, but not the eGFR in patients with hypertension. We did not demonstrate an association between nocturnal DBP and TOD in these patients. When nocturnal SBP in patients with normotension was further divided into tertiles [tertile 1 (<104 mmHg), tertile 2 (104–114 mmHg) and tertile 3 (≥114 mmHg)], multivariate analysis showed that tertile 3 was independently associated with TOD.

Conclusion:
Nocturnal SBP was shown to be an independent risk factor for TOD in patients with normotension. Targeting a nocturnal ambulatory SBP to less than 114 mmHg or even less than 104 mmHg may help prevent TOD in patients with CKD.
Emtricitabine triphosphate in dried blood spots predicts future viremia in persons with HIV and identifies mismatch with self-reported adherence
Authors: Morrow Mary , MaWhinney Samantha , Coyle Ryan P. , Coleman Stacey S. , Zheng Jia-Hua , Ellison Lucas , Bushman Lane R. , Kiser Jennifer J. , Anderson Peter L. , Castillo-Mancilla Jose R. 
Published: June 2021

Objective:
Emtricitabine triphosphate (FTC-TP) in dried blood spots (DBS), a measure of short-term antiretroviral therapy (ART) adherence, is associated with viral suppression in persons with HIV (PWH). However, its ability to predict future viremia remains unknown.

Design:
Prospective, observational cohort (up to three visits in 48 weeks).

Methods:
PWH receiving TDF/FTC-based ART had DBS and HIV viral load obtained at routine clinical visits. FTC-TP in DBS was dichotomized into quantifiable vs. below the limit of quantification (BLQ). The adjusted odds ratio (aOR) of future viremia (≥20 copies/ml at next study visit) was estimated according to FTC-TP at the current visit. To assess for possible interactions, additional models adjusted for tenofovir diphosphate (TFV-DP) in DBS and 3-day self-reported adherence.

Results:
Data from 433 PWH (677 paired DBS/HIV viral load samples) were analyzed. The aOR [95% confidence interval (CI)] for future viremia for BLQ vs. quantifiable FTC-TP was 3.4 (1.8--6.5; P = 0.0002). This diminished after adjusting for TFV-DP [aOR 1.9 (0.9--4.1); P = 0.090]. Among PWH reporting 100% 3-day adherence, the odds of future viremia were 6.0 times higher [(1.8--20.3); P = 0.001] when FTC-TP was BLQ vs. quantifiable. Among participants (n = 75) reporting less than 100% adherence, BLQ FTC-TP in DBS was not predictive of future viremia [aOR 1.3 (0.4--4.6); P = 0.96].

Conclusion:
Nonquantifiable FTC-TP in DBS predicts future viremia and is particularly informative in PWH reporting perfect adherence. As point-of-care adherence measures become available, mismatches between objective and subjective measures, such as FTC-TP in DBS and self-report, could help clinicians identify individuals at an increased risk of future viremia.
Broadly neutralizing antibody responses in the longitudinal primary HIV-1 infection Short Pulse Anti-Retroviral Therapy at Seroconversion cohort
Authors: Granger Luke A. , Huettner Isabella , Debeljak Franka , Kaleebu Pontiano , Schechter Mauro , Tambussi Giuseppe , Weber Jonathan , Miro Jose M. , Phillips Rodney , Babiker Abdel , Cooper David A. , Fisher Martin , Ramjee Gita , Fidler Sarah , Frater John , Fox Julie , Doores Katie J. 
Published: June 2021

Objective:
Development of immunogens that elicit an anti-HIV-1 broadly neutralizing antibody (bnAb) response will be a key step in the development of an effective HIV-1 vaccine. Although HIV-1 bnAb epitopes have been identified and mechanisms of action studied, current HIV-1 envelope-based immunogens do not elicit HIV-1 bnAbs in humans or animal models. A better understanding of how HIV-1 bnAbs arise during infection and the clinical factors associated with bnAb development may be critical for HIV-1 immunogen design efforts.

Design and methods:
Longitudinal plasma samples from the treatment-naive control arm of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) primary HIV-1 infection cohort were used in an HIV-1 pseudotype neutralization assay to measure the neutralization breadth, potency and specificity of bnAb responses over time.

Results:
In the SPARTAC cohort, development of plasma neutralization breadth and potency correlates with duration of HIV infection and high viral loads, and typically takes 3–4 years to arise. bnAb activity was mostly directed to one or two bnAb epitopes per donor and more than 60% of donors with the highest plasma neutralization having bnAbs targeted towards glycan-dependent epitopes.

Conclusion:
This study highlights the SPARTAC cohort as an important resource for more in-depth analysis of bnAb developmental pathways.
Ketamine for the multivariate effect of PTSD: Systematic review and meta-analysis
Authors: Du Rui , Niu Kun , Lu Guofang , Shang Yulong 
Published: June 2021

SummaryThe aim of this systematic review and meta-analysis was to examine the efficacy, anti-effect of ketamine (intervention) for post-traumatic stress disorder (PTSD) patients during analgesia proceeding and mental illness treatment methods, in comparison with control (midazolam, opioid, saline or placebo). The bibliographic databases Cochrane, Embase, Pubmed and Web of Science were searched from inception to 23 May 2021 for randomized controlled trials, case-control and cohort studies included. For continuous and dichotomous outcomes, respectively, we calculated the mean difference using the inverse-variance method and the risk ratio with the Mantel–Haenszel method. In all, ten trials with 705 patients were included. Confirmed by meta-analysis, ketamine didn’t increase the prevalence of PTSD by a risk ratio (95 % CI) of 0.86 (0.61 to 1.20), p = 0.38 in 3 trials with 503 patients. Evidence of a difference was found in the PTSD-scales taken between ketamine and control during short durations (months), with a mean difference (95 % CI) of 2.45 (1.33 to 3.58), p < 0.001 in three trials with 65 patients. Another evidence is shown in chronic PTSD (years), with a mean difference (95 % CI) of −3.66 (−7.05 to −0.27), p = 0.03 in three trials with 91 patients. Sub-group analysis underlined the increased benefit of ketamine administration for those in whom the procedure was more than one week in the chronic PTSD group. The adoption of ketamine for the short duration of PTSD is in avoidance, but for chronic PTSD is recommended and, in the opinion of the authors, should be considered as a new therapy in view of its potential to ameliorate arousal, avoidance and dissociative symptoms, neuroticism after trauma needing more animal research and clinical trials.
Mechanosensory trichome cells evoke a mechanical stimuli–induced immune response in plants
Authors: Matsumura Mamoru , Nomoto Mika , Itaya Tomotaka , Aratani Yuri , Iwamoto Mizuki , Matsuura Takakazu , Hayashi Yuki , Kinoshita Toshinori , Mori Izumi C , Suzuki Takamasa , Betsuyaku Shigeyuki , Spoel Steven H , Toyota Masatsugu , Tada Yasuomi 
Published: June 2021

AbstractPerception of pathogen-derived ligands by corresponding host receptors is a pivotal strategy in eukaryotic innate immunity. In plants, this is complemented by circadian anticipation of infection timing, promoting basal resistance even in the absence of pathogen threat. Here, we report that trichomes, hair-like structures on the epidermis, directly sense external mechanical forces caused by raindrops to anticipate waterborne infections in Arabidopsis thaliana. Exposure of leaf surfaces to mechanical stimuli initiates the concentric propagation of intercellular calcium waves away from trichomes to induce defence-related genes. Propagating calcium waves enable effective immunity against pathogenic microbes through the calmodulin-binding transcription activator 3 (CAMTA3) and mitogen-activated protein kinases. We propose a novel layer of plant immunity in which trichomes function as mechanosensory cells to detect potential risks.
TDAExplore: quantitative image analysis through topology-based machine learning
Authors: Edwards Parker , Skruber Kristen , Milićević Nikola , Heidings James B. , Read Tracy-Ann , Bubenik Peter , Vitriol Eric A. 
Published: June 2021

AbstractMachine learning has greatly expanded the ability to classify images. However, many machine learning classifiers require thousands of images for training and lack quantitative descriptors of how images were grouped. We overcome these limitations with a machine learning approach based on topological data analysis, where a data set of 20-30 images is sufficient to accurately train the classifier. Our method quantifies differences between groups and identifies subcellular regions with the largest dissimilarities.
MorphVAE: Generating Neural Morphologies from 3D-Walks using a Variational Autoencoder with Spherical Latent Space
Authors: Laturnus Sophie , Berens Philipp 
Published: June 2021

AbstractFor the past century, the anatomy of a neuron has been considered one of its defining features: The shape of a neuron’s dendrites and axon fundamentally determines what other neurons it can connect to. These neurites have been described using mathematical tools e.g. in the context of cell type classification, but generative models of these structures have only rarely been proposed and are often computationally inefficient. Here we propose MorphVAE, a sequence-to-sequence variational autoencoder with spherical latent space as a generative model for neural morphologies. The model operates on walks within the tree structure of a neuron and can incorporate expert annotations on a subset of the data using semi-supervised learning. We develop our model on artificially generated toy data and evaluate its performance on dendrites of excitatory cells and axons of inhibitory cells of mouse motor cortex (M1) and dendrites of retinal ganglion cells. We show that the learned latent feature space allows for better cell type discrimination than other commonly used features. By sampling new walks from the latent space we can easily construct new morphologies with a specified degree of similarity to their reference neuron, providing an efficient generative model for neural morphologies.
Live Imaging Reveals the Cellular Events Downstream of SARM1 Activation
Authors: Ko Kwang Woo , Milbrandt Jeffrey , DiAntonio Aaron 
Published: June 2021

AbstractSARM1 is an inducible NAD+ hydrolase that triggers axon loss and neuronal cell death in the injured and diseased nervous system. While SARM1 activation and enzyme function are well defined, the cellular events downstream of SARM1 activity but prior to axonal demise are much less well understood. Defects in calcium, mitochondria, ATP, and membrane homeostasis occur in injured axons, but the relationships among these events have been difficult to disentangle because prior studies analyzed large collections of axons in which cellular events occur asynchronously. Here we used live imaging with single axon resolution to investigate the cellular events downstream of SARM1 activity. Our studies support a model in which SARM1 NADase activity leads to an ordered sequence of events from loss of cellular ATP, to defects in mitochondrial movement and depolarization, followed by calcium influx, externalization of phosphatidylserine, and loss of membrane permeability prior to catastrophic axonal self-destruction.
Genetic and chemical inhibition of autophagy in zebrafish induced myeloproliferation
Authors: Hasan Kazi Md Mahmudul , Chen Xiang-Ke , Yi Zhen-Ni , Lau Jack Jark-Yin , Ma Alvin Chun-Hang 
Published: June 2021

AbstractAutophagy is an evolutionary conserved and dynamic lysosomal degradation process for cellular homeostasis and remodelling, which is essential for the development and maintenance of different hematopoietic fates. However, the roles of autophagy in definitive hematopoiesis remain elusive. Here, we exploited zebrafish (Danio rerio) to investigate the effect of knocking-out unc-51 like autophagy activating kinase 1b and 2 (ulk1b and ulk2), homologous of human ULK1 and ULK2, respectively, on definitive hematopoiesis. Upon ulk1b or ulk2 mutation, autophagosome formation was blocked in zebrafish embryos. More importantly, pan-leukocytes (lcp1), common myeloid progenitors (spi1b), neutrophils (mpx), and macrophages (mpeg1.1) significantly elevated, while the hematopoietic stem and progenitor cell (HSPC) (myb), erythroid progenitors (gata1), and embryonic hemoglobin (hbae1.1) significantly reduced in the caudal hematopoietic tissue (CHT) of ulk1b or ulk2 mutant zebrafish embryos. On the other hand, chemically modulated autophagy induction by calpeptin, a downstream autophagy inducer for ulk complex, was insufficient to ameliorate dysregulated hematopoiesis in both ulk1b and ulk2 mutants. Conversely, autophagy inhibitor 3-Methyladenine functioned parallelly with the ulk mutants to maintain defective hematopoiesis. These observations raised a link between autophagy and definitive hematopoiesis and potentiates the fact that autophagy deficiency incorporates with myeloproliferation and anemia, which warrants the significance of autophagy in regulating definitive hematopoiesis.
Analyzing the differences in olfactory bulb mitral cell spiking with ortho- and retronasal stimulation
Authors: Craft Michelle F. , Barreiro Andrea K. , Gautam Shree Hari , Shew Woodrow L. , Ly Cheng 
Published: June 2021

AbstractThe majority of olfaction studies focus on orthonasal stimulation where odors enter via the front nasal cavity, while retronasal olfaction, where odors enter the rear of the nasal cavity during feeding, is understudied. The processing of retronasal odors via coordinated spiking of neurons in the olfactory bulb (OB) is largely unknown. To this end, we use multi-electrode array in vivo recordings of rat OB mitral cells (MC) in response to a food odor with both modes of stimulation, and find significant differences in evoked firing rates and spike count covariances (i.e., noise correlations). To better understand these differences, we develop a single-compartment biophysical OB model that is able to reproduce key properties of important OB cell types. Prior experiments in olfactory receptor neurons (ORN) showed retro stimulation yields slower and spatially smaller ORN inputs than with ortho, yet whether this is consequential for OB activity remains unknown. Indeed with these specifications for ORN inputs, our OB model captures the trends in our OB data. We also analyze how first and second order ORN input statistics dynamically transfer to MC spiking statistics with a phenomenological linear-nonlinear filter model, and find that retro inputs result in larger temporal filters than ortho inputs. Finally, our models show that the temporal profile of ORN is crucial for capturing our data and is thus a distinguishing feature between ortho and retro stimulation, even at the OB. Using data-driven modeling, we detail how ORN inputs result in differences in OB dynamics and MC spiking statistics. These differences may ultimately shape how ortho and retro odors are coded.Author summaryOlfaction is a key sense for many cognitive and behavioral tasks, and is particularly unique because odors can naturally enter the nasal cavity from the front or rear, i.e., ortho- and retro-nasal, respectively. Yet little is known about the differences in coordinated spiking in the olfactory bulb with ortho versus retro stimulation, let alone how these different modes of olfaction may alter coding of odors. We simultaneously record many cells in rat olfactory bulb to assess the differences in spiking statistics, and develop a biophysical olfactory bulb network model to study the reasons for these differences. Using theoretical and computational methods, we find that the olfactory bulb transfers input statistics differently for retro stimulation relative to ortho stimulation. Furthermore, our models show that the temporal profile of inputs is crucial for capturing our data and is thus a distinguishing feature between ortho and retro stimulation, even at the olfactory bulb. Understanding the spiking dynamics of the olfactory bulb with both ortho and retro stimulation is a key step for ultimately understanding how the brain codes odors with different modes of olfaction.
Mapping the Genetic Landscape of DNA Double-strand Break Repair
Authors: Hussmann Jeffrey A. , Ling Jia , Ravisankar Purnima , Yan Jun , Cirincione Ann , Xu Albert , Simpson Danny , Yang Dian , Bothmer Anne , Cotta-Ramusino Cecilia , Weissman Jonathan S. , Adamson Britt 
Published: June 2021

SUMMARYCells repair DNA double-strand breaks (DSBs) through a complex set of pathways that are critical for maintaining genomic integrity. Here we present Repair-seq, a high-throughput screening approach that measures the effects of thousands of genetic perturbations on the distribution of mutations introduced at targeted DNA lesions. Using Repair-seq, we profiled DSB repair outcomes induced by two programmable nucleases (Cas9 and Cas12a) after knockdown of 476 genes involved in DSB repair or associated processes in the presence or absence of oligonucleotides for homology-directed repair (HDR). The resulting data enabled principled, data-driven inference of DSB end joining and HDR pathways and demonstrated that repair outcomes with superficially similar sequence architectures can have markedly different genetic dependencies. Systematic interrogation of these dependencies then uncovered unexpected relationships among DSB repair genes and isolated incompletely characterized repair mechanisms. This work provides a foundation for understanding the complex pathways of DSB repair and for optimizing genome editing across modalities.
CENP-N promotes the compaction of centromeric chromatin
Authors: Zhou Keda , Gebala Magdalena , Woods Dustin , Sundararajan Kousik , Edwards Garrett , Krzizike Dan , Wereszczynski Jeff , Straight Aaron F. , Luger Karolin 
Published: June 2021

AbstractThe histone variant CENP-A is the epigenetic determinant for the centromere, where it is interspersed with canonical H3 to form a specialized chromatin structure that nucleates the kinetochore. The arrangement of nucleosomes at the centromere into higher order structure is unknown. Here we demonstrate that the CENP-A interacting protein CENP-N promotes the stacking of CENP-A containing mono-nucleosomes and nucleosomal arrays through a previously undefined interaction between the α6 helix of CENP-N with the DNA of a neighboring nucleosome. We describe the cryoEM structures and biophysical characterization of such CENP-N mediated nucleosome stacks and nucleosomal arrays and demonstrate that this interaction is responsible for the formation of densely packed chromatin at the centromere in the cell. Our results provide first evidence that CENP-A, together with CENP-N, promotes specific chromatin higher order structure at the centromere.One-Sentence SummaryThe centromere-associated protein CENP-N promotes centromere-specific nucleosome stacking and higher order structures in vitro and in the cell.