bluuebunny/crossref_metadata_2025 huggingface dataset:
11C-4DST PET/CT Imaging of Cardiac Sarcoidosis
Authors: Hotta Masatoshi , Minamimoto Ryogo , Kubota Shuji , Awaya Toru , Hiroi Yukio
Published: March 2018

A 75-year-old woman with a history of sarcoidosis presenting with low cardiac output and complete right bundle-branch block underwent 4′-[methyl-11C]-thiothymidine (4DST) PET/CT after cardiac MRI and FDG PET/CT for the evaluation of suspected cardiac sarcoidosis (CS) before treatment. Cardiac MRI revealed late gadolinium enhancement on the anterior-to-lateral and posterior wall, indicating CS. FDG uptake was shown on the anterior-to-lateral wall, but not on the posterior wall. In contrast, 4DST uptake was demonstrated on both anterior-to-lateral and posterior walls. Use of 4DST appears promising for detecting CS without dietary restriction, due to the lack of physiological uptake in myocardium.
Crossed Cerebellar Tracer Uptake on Acute-Stage 123I-Iomazenil SPECT Imaging Predicts 3-Month Functional Outcome in Patients With Nonfatal Hypertensive Putaminal or Thalamic Hemorrhage
Authors: Kojima Daigo , Komoribayashi Nobukazu , Omama Shinichi , Oikawa Kohki , Fujiwara Shunrou , Kobayashi Masakazu , Kubo Yoshitaka , Terasaki Kazunori , Ogasawara Kuniaki
Published: March 2018

Purpose

Whereas SPECT images obtained 180 minutes after administration of 123I-iomazenil (IMZ) (late images) are proportional to the distribution of central benzodiazepine receptor–binding potential, SPECT images obtained within 30 minutes after 123I-IMZ administration (early images) correlate with regional brain perfusion. The aim of the present study was to determine whether crossed cerebellar tracer uptake on acute-stage 123I-IMZ SPECT imaging predicts 3-month functional outcome in patients with nonfatal hypertensive putaminal or thalamic hemorrhage.

Methods

Forty-six patients underwent early and late SPECT imaging with 123I-IMZ within 7 days after the onset of hemorrhage. A region of interest was automatically placed in the bilateral cerebellar hemispheres using a 3-dimensional stereotaxic region-of-interest template, and the ratio of the value in the cerebellar hemisphere contralateral to the affected side to that in the ipsilateral cerebellar hemisphere (ARcbl) was calculated in each patient. Each patient's physical function was measured using the modified Rankin scale (mRS) score 3 months after onset.

Results

The ARcbl on early (ρ = −0.511, P = 0.0003) and late (ρ = −0.714, P < 0.0001) images correlated with the mRS 3 months after the onset of hemorrhage. Multivariate analysis showed that only a low ARcbl in late images was significantly associated with a poor functional outcome (mRS score ≥3 at 3 months after onset) (95% confidence interval, 0.001–0.003; P = 0.0212).

Conclusions

Crossed cerebellar tracer uptake on acute-stage 123I-IMZ SPECT imaging predicts 3-month functional outcome in patients with nonfatal hypertensive putaminal or thalamic hemorrhage.
Interventional vitamin C: A strategy for attenuation of coagulopathy and inflammation in a swine multiple injuries model
Authors: Reynolds Penny S. , Fisher Bernard J. , McCarter Jacquelyn , Sweeney Christopher , Martin Erika J. , Middleton Paul , Ellenberg Matthew , Fowler Evan , Brophy Donald F. , Fowler Alpha A. , Spiess Bruce D. , Natarajan Ramesh
Published: March 2018

BACKGROUND

Coagulopathy and inflammation induced by hemorrhagic shock and traumatic injury are associated with increased mortality and morbidity. Vitamin C (VitC) is an antioxidant with potential protective effects on the proinflammatory and procoagulant pathways. We hypothesized that high-dose VitC administered as a supplement to fluid resuscitation would attenuate inflammation, coagulation dysfunction, and end-organ tissue damage in a swine model of multiple injuries and hemorrhage.

METHODS

Male Sinclair swine (n = 24; mean body weight, 27 kg) were anesthetized, intubated, mechanically ventilated, and instrumented for physiologic monitoring. Following stabilization, swine were subjected to shock/traumatic injury (hypothermia, liver ischemia and reperfusion, comminuted femur fracture, hemorrhagic hypotension), resuscitated with 500 mL of hydroxyethyl starch, and randomized to receive either intravenous normal saline (NS), low-dose VitC (50 mg/kg; LO), or high-dose VitC (200 mg/kg; HI). Hemodynamics, blood chemistry, hematology, and coagulation function (ROTEM) were monitored to 4 hours postresuscitation. Histological and molecular analyses were obtained for liver, kidney, and lung.

RESULTS

Compared with VitC animals, NS swine showed significant histological end-organ damage, elevated acute lung injury scores, and increased mRNA expression of tissue proinflammatory mediators (IL-1β, IL-8, TNFα), plasminogen activation inhibitor-1 and tissue factor. There were no statistically significant differences between treatment groups on mean arterial pressure or univariate measures of coagulation function; however, NS showed impaired multivariate clotting function at 4 hours.

CONCLUSION

Although correction of coagulation dysfunction was modest, intravenous high-dose VitC may mitigate the proinflammatory/procoagulant response that contributes to multiple organ failure following acute severe multiple injuries.

LEVEL OF EVIDENCE

Prospective randomized controlled blinded trial study, Preclinical (animal-based).
Mapping areas with concentrated risk of trauma mortality: A first step toward mitigating geographic and socioeconomic disparities in trauma
Authors: Jarman Molly P. , Haut Elliott R. , Curriero Frank C. , Castillo Renan C.
Published: March 2018

BACKGROUND

Many rural, low-income, and historically underrepresented minority communities lack access to trauma center services, including surgical care and injury prevention efforts. Along with features of the built and social environment at injury incident locations, geographic barriers to trauma center services may contribute to injury disparities. This study sought to classify injury event locations based on features of the built and social environment at the injury scene, and to examine patterns in individual patient demographics, injury characteristics, and mortality by location class.

METHODS

Data from the 2015 Maryland Adult Trauma Registry and associated prehospital records (n = 16,082) were used in a latent class analysis of characteristics of injury event locations, including trauma center distance, trauma center characteristics, land use, community-level per capita income, and community-level median age. Mortality effects of location class were estimated with logistic regression, with and without adjustment for individual patient demographics and injury characteristics.

RESULTS

Eight classes were identified: rural, exurban, young suburban, aging suburban, inner suburban, urban fringe, high-income urban core, and low-income urban core. Patient characteristics and odds of death varied across classes. Compared with inner suburban locations, adjusted odds of death were highest at rural (odds ratio [OR], 1.98; 95% confidence interval [CI], 1.36–2.88), young suburb (OR, 1.57; 95% CI, 1.14–2.17), aging suburb (OR, 1.36; 95% CI, 1.04–1.78), and low-income urban core (OR, 1.38; 95% CI, 1.04–1.83) locations.

CONCLUSION

Injury incident locations can be categorized into distinguishable classes with varying mortality risk. Identification of location classes may be useful for targeted primary prevention and treatment interventions, both by identifying geographic areas with the highest risk of injury mortality and by identifying patterns of individual risk within location classes.

LEVEL OF EVIDENCE

Prognostic and epidemiological, level III.
Indications and outcomes of extracorporeal life support in trauma patients
Authors: Swol Justyna , Brodie Daniel , Napolitano Lena , Park Pauline K. , Thiagarajan Ravi , Barbaro Ryan P. , Lorusso Roberto , McMullan David , Cavarocchi Nicholas , Hssain Ali Ait , Rycus Peter , Zonies David
Published: March 2018

BACKGROUND

The use of extracorporeal life support (ECLS) in the trauma population remains controversial and has been reported only in small cohort studies. Recent ECLS technical advances have increased its use as an advanced critical care option in trauma. Given the degree of resource utilization, costs, and expertise required to provide ECLS support in trauma patients, we sought to perform a multi-institutional study to assess the indications and outcomes of ECLS in trauma.

METHODS

A retrospective review of adult (≥16 years) trauma patients receiving ECLS support in the Extracorporeal Life Support Organization (ELSO) registry (1989–2016) was performed. Standardized data from the contributing ELSO centers includes patient demographics, diagnoses, and ECLS technique and procedures. Additionally, baseline characteristics, precannulation and postcannulation physiologic data, complications, and outcomes were recorded. Survival was categorized both by transition off ECLS support and survival to hospital discharge.

RESULTS

Two hundred seventy-nine trauma patients were identified (0.92% of 30,273 adult ECLS patients). Extracorporeal life support increased significantly in the last 5 years (173 in 2011–2016, 62%) compared with 106 in the prior 18 years. Trauma patients were predominantly male (78%), with a mean age of 34.8 ± 15.4 years (range, 16–88 years). Thoracic injury was the most common diagnosis; acute respiratory distress syndrome was the most common indication. Extracorporeal life support was venovenous for respiratory failure (89%), VA for cardiac failure (7%), and VA for ECLS-assisted cardiopulmonary resuscitation (CPR) (E-CPR) (4%). Extracorporeal life support duration was 8.8 ± 9.5 days (longest 83 days), and was longer for respiratory support (9.3 ± 9.3 days) vs. cardiac support (4.1 ± 4.5 days) and E-CPR (6.5 ± 16.8 days). Overall survival from ECLS was 70% and survival to hospital discharge was 61% in the total cohort (63% respiratory, 50% cardiac, 25% E-CPR), similar to survival rates in other ELSO registry cohorts. More than 80% of patients had a reported complication during ECLS support. The most common complication was cardiovascular (51%) followed by a bleeding complication (29%). Multiple organ failure was the most common cause of death (15.4%).

CONCLUSION

Data from the largest registry of critically ill trauma patients receiving ECLS support demonstrates reasonable survival. With growing experience and improved safety profile, trauma should not be considered a contraindication for ECLS. Further analysis of the ELSO registry regarding trauma-specific risk factors and ECLS-specific practices may identify best candidates and improve trauma ECLS outcomes.

LEVEL OF EVIDENCE

Therapeutic study, level III.
Multicenter study of crystalloid boluses and transfusion in pediatric trauma—When to go to blood?
Authors: Polites Stephanie F. , Nygaard Rachel M. , Reddy Pooja N. , Zielinski Martin D. , Richardson Chad J. , Elsbernd Terri A. , Petrun Branden M. , Weinberg Sean L. , Murphy Sherrie , Potter Donald D. , Klinkner Denise B. , Moir Christopher R.
Published: March 2018

BACKGROUND

The 9th edition of Advanced Trauma Life Support recommends up to three crystalloid boluses in pediatric trauma patients with consideration of transfusion after the second bolus; however, this approach is debated. We aimed to determine if requirement of more than one fluid bolus predicts the need for transfusion.

METHODS

The 2010 to 2016 highest tier activation patients younger than 15 years from two ACS Level I pediatric trauma centers were identified from prospectively maintained trauma databases. Those with a shock index (heart rate/systolic blood pressure) greater than 0.9 were included. Crystalloid boluses (20 ± 10 mL/kg) and transfusions administered prehospital and within 12 hours of hospital arrival were determined. Univariate and multivariable analyses were conducted to determine association between crystalloid volume and transfusion.

RESULTS

Among 208 patients, the mean age was 5 ± 4 years (60% male), 91% sustained blunt injuries, and median (interquartile range) Injury Severity Score was 11 (6,25). Twenty-nine percent received one bolus, 17% received two, and 10% received at least three. Transfusion of any blood product occurred in 50 (24%) patients; mean (range) red blood cells was 23 (0–89) mL/kg, plasma 8 (0–69), and platelets 1 (0–18). The likelihood of transfusion increased logarithmically from 11% to 43% for those requiring 2 or more boluses (Fig. 1). This relationship persisted on multivariable analysis that adjusted for institution, age, and shock index with good discrimination (Area under the Receiver Operating Characteristic, 0.84). Shock index was also strongly associated with transfusion.

CONCLUSION

Almost half of pediatric trauma patients with elevated shock index require transfusion following two crystalloid boluses and the odds of requiring a transfusion plateau at this point in resuscitation. This supports consideration of blood with the second bolus in conjunction with shock index though prospective studies are needed to confirm this and its impact on outcomes.

LEVEL OF EVIDENCE

Therapeutic study, level IV.
Early Midlife Pulmonary Function and Dementia Risk
Authors: Gilsanz Paola , Mayeda Elizabeth Rose , Flatt Jason , Glymour M. Maria , Quesenberry Charles P. , Whitmer Rachel A.
Published: March 2018

Background:

Poor pulmonary function (PPF) is associated with increased risk of dementia, yet it is unclear if PPF in early adulthood to midlife increases risk, independent of smoking and subsequent vascular disease.

Objective:

This study evaluated the association between multiple markers of PPF in early adulthood to midlife and long-term risk of dementia.

Methods:

We evaluated 27,387 members of an integrated health care system with forced expiratory volume in 1, 2 seconds, and vital capacity collected from 1964 to 1973 (mean age=41.8±4.2 y). Associations of PPF with dementia diagnoses from January 1, 1996 to September 30, 2015 were evaluated with Cox proportional hazards models adjusted for demographics, height, body mass index, hypertension, smoking status, diabetes, stroke, and heart failure.

Results:

In total, 7519 individuals (27%) were diagnosed with dementia. In fully adjusted Cox proportional hazards models, for all PPF measures each liter decrease was associated with a 13% to 14% higher risk of dementia. Compared with the highest quintile, the first quintile of PPF measures were associated with a 24% to 28% increased risk of dementia; second to fourth quintiles showed strong dose-dependent associations. Results were similar when stratified by smoking status.

Conclusions:

In this large, diverse cohort, multiple measures of PPF in early adulthood to midlife were associated with dementia risk independent of smoking and vascular comorbidities.
Temporal and spatial changes in wall shear stress during atherosclerotic plaque progression in mice
Authors: Xing R. , Moerman A. M. , Ridwan Y. , Daemen M. J. , van der Steen A. F. W. , Gijsen F. J. H. , van der Heiden K.
Published: March 2018

Wall shear stress (WSS) is involved in atherosclerotic plaque initiation, yet its role in plaque progression remains unclear. We aimed to study (i) the temporal and spatial changes in WSS over a growing plaque and (ii) the correlation between WSS and plaque composition, using animal-specific data in an atherosclerotic mouse model. Tapered casts were placed around the right common carotid arteries (RCCA) of ApoE
−/−
mice. At 5, 7 and 9 weeks after cast placement, RCCA geometry was reconstructed using contrast-enhanced micro-CT. Lumen narrowing was observed in all mice, indicating the progression of a lumen intruding plaque. Next, we determined the flow rate in the RCCA of each mouse using Doppler Ultrasound and computed WSS at all time points. Over time, as the plaque developed and further intruded into the lumen, absolute WSS significantly decreased. Finally at week 9, plaque composition was histologically characterized. The proximal part of the plaque was small and eccentric, exposed to relatively lower WSS. Close to the cast a larger and concentric plaque was present, exposed to relatively higher WSS. Lower WSS was significantly correlated to the accumulation of macrophages in the eccentric plaque. When pooling data of all animals, correlation between WSS and plaque composition was weak and no longer statistically significant. In conclusion, our data showed that in our mouse model absolute WSS strikingly decreased during disease progression, which was significantly correlated to plaque area and macrophage content. Besides, our study demonstrates the necessity to analyse individual animals and plaques when studying correlations between WSS and plaque composition.
Colorimetric detection of hydrogen peroxide by dioxido-vanadium(V) complex containing hydrazone ligand: synthesis and crystal structure
Authors: Kurbah Sunshine D. , Syiemlieh Ibanphylla , Lal Ram A.
Published: March 2018

Dioxido-vanadium(V) complex has been synthesized in good yield, the complex was characterized by IR, UV–visible and
1
H NMR spectroscopy. Single crystal X-ray crystallography techniques were used to assign the structure of the complex. Complex crystallized with monoclinic
P
2
1
/c
space group with cell parameters
a
(Å) = 39.516(5),
b
(Å) = 6.2571(11),
c
(Å) = 17.424(2),
α
(°) = 90,
β
(°) = 102.668(12) and
γ
(°) = 90. The hydrazone ligand is coordinate to metal ion in tridentate fashion through –ONO– donor atoms forming a distorted square pyramidal geometry around the metal ion.
Pseudo-enantiomeric chiral components and formation of the helical micro- and nanostructures in charge-transfer complexes
Authors: Langer Jerzy J. , Hreczycho Grzegorz
Published: March 2018

Helical organic micro- and nanostructures are formed by a charge-transfer complex, cinchonidine-TCNQ. These unusual forms result from the chirality, the steric structure and specific interactions of cinchonidine molecules. These materials are semiconductors (10−4 S cm−1), with the typical absorption spectra in IR and UV-vis, but also have a characteristic of CD spectrum. Surprisingly, conductive micro and nano helices are not formed in pseudo-enantiomeric cinchonine, i.e. the complex of cinchonine and TCNQ.
Graph analysis of cell clusters forming vascular networks
Authors: Alves A. P. , Mesquita O. N. , Gómez-Gardeñes J. , Agero U.
Published: March 2018

This manuscript describes the experimental observation of vasculogenesis in chick embryos by means of network analysis. The formation of the vascular network was observed in the
area opaca
of embryos from 40 to 55 h of development. In the
area opaca
endothelial cell clusters self-organize as a primitive and approximately regular network of capillaries. The process was observed by bright-field microscopy in control embryos and in embryos treated with Bevacizumab (Avastin
®
), an antibody that inhibits the signalling of the vascular endothelial growth factor (VEGF). The sequence of images of the vascular growth were thresholded, and used to quantify the forming network in control and Avastin-treated embryos. This characterization is made by measuring vessels density, number of cell clusters and the largest cluster density. From the original images, the topology of the vascular network was extracted and characterized by means of the usual network metrics such as: the degree distribution, average clustering coefficient, average short path length and assortativity, among others. This analysis allows to monitor how the largest connected cluster of the vascular network evolves in time and provides with quantitative evidence of the disruptive effects that Avastin has on the tree structure of vascular networks.
Preparation, characterization and luminescence properties of core–shell ternary terbium composites SiO
2(600)
@Tb(MABA-Si)•L
Authors: Ma Yang-Yang , Li Wen-Xian , Zheng Yu-Shan , Bao Jin-Rong , Li Yi-Lian , Feng Li-Na , Yang Kui-Suo , Qiao Yan , Wu An-Ping
Published: March 2018

Two novel core–shell structure ternary terbium composites SiO
2(600)
@Tb(MABA-Si)·L(L:dipy/phen) nanometre luminescence materials were prepared by ternary terbium complexes Tb(MABA-Si)·L
2
·(ClO
4
)
3
·2H
2
O shell grafted onto the surface of SiO
2
microspheres. And corresponding ternary terbium complexes were synthesized using (CONH(CH
2
)
3
Si(OCH
2
CH
3
)
3
)
2
(denoted as MABA-Si) as first ligand and L as second ligand coordinated with terbium perchlorate. The as-synthesized products were characterized by means of IR spectra,
1
HNMR, element analysis, molar conductivity, SEM and TEM. It was found that the first ligand MABA-Si of terbium ternary complex hydrolysed to generate the Si–OH and the Si–OH condensate with the Si–OH on the surface of SiO
2
microspheres; then ligand MABA-Si grafted onto the surface of SiO
2
microspheres. The diameter of SiO
2
core of SiO
2(600)
@Tb(MABA-Si)·L was approximately 600 nm. Interestingly, the luminescence properties demonstrate that the two core–shell structure ternary terbium composites SiO
2(600)
Tb(MABA-Si)·L(dipy/phen) exhibit strong emission intensities, which are 2.49 and 3.35 times higher than that of the corresponding complexes Tb(MABA-Si)·L
2
·(ClO
4
)
3
·2H
2
O, respectively. Luminescence decay curves show that core–shell structure ternary terbium composites have longer lifetime. Excellent luminescence properties enable the core–shell materials to have potential applications in medicine, industry, luminescent fibres and various biomaterials fields.
Amphotericin B-conjugated polypeptide hydrogels as a novel innovative strategy for fungal infections
Authors: Shu Chang , Li Tengfei , Yang Wen , Li Duo , Ji Shunli , Ding Li
Published: March 2018

The present work is focused on the design and development of novel amphotericin B (AmB)-conjugated biocompatible and biodegradable polypeptide hydrogels to improve the antifungal activity. Using three kinds of promoting self-assembly groups (2-naphthalene acetic acid (Nap), naproxen (Npx) and dexamethasone (Dex)) and polypeptide sequence (Phe-Phe-Asp-Lys-Tyr, FFDKY), we successfully synthesized the Nap-FFDK(AmB)Y gels, Npx-FFDK(AmB)Y gels and Dex-FFDK(AmB)Y gels. The AmB-conjugated hydrogelators are highly soluble in different aqueous solutions. The cryo-transmission electron microscopy and scanning electron microscopy micrographs of hydrogels afford nanofibres with a width of 20–50 nm. Powder X-ray diffraction analyses demonstrate that the crystalline structures of the AmB and Dex are changed into amorphous structures after the formation of hydrogels. Circular dichroism spectra of the solution of blank carriers and the corresponding drug deliveries further help elucidate the molecular arrangement in gel phase, indicating the existence of turn features. The
in vitro
drug releases suggest that the AmB-conjugated hydrogels are suitable as drug-controlled release vehicles for hydrophobic drugs. The antifungal effect of AmB-conjugated hydrogels significantly exhibits the antifungal activity against
Candida albicans
. The results of the present study indicated that the AmB-conjugated hydrogels are suitable carriers for poorly water soluble drugs and for enhancement of therapeutic efficacy of antifungal drugs.
Synthesis of diketopyrrolopyrrole-based polymers with polydimethylsiloxane side chains and their application in organic field-effect transistors
Authors: Ohnishi Inori , Hashimoto Kazuhito , Tajima Keisuke
Published: March 2018

Linear polydimethylsiloxane (PDMS) was investigated as a solubilizing group for π-conjugated polymers with the aim of combining high solubility in organic solvents with the molecular packing in solid films that is advantageous for charge transport. Diketopyrrolopyrrole-based copolymers with different contents and substitution patterns of the PDMS side chains were synthesized and evaluated for application in organic field-effect transistors. The PDMS side chains greatly increased the solubility of the polymers and led to shorter
d
-spacings of the π-stacking in the thin films compared with polymers containing conventional branched alkyl side chains.
In vitro and in vivo phasor analysis of stoichiometry and pharmacokinetics using near-infrared dyes
Authors: Chen Sez-Jade , Sinsuebphon Nattawut , Rudkouskaya Alena , Barroso Margarida , Intes Xavier , Michalet Xavier
Published: March 2018

1

We introduce a simple new approach for time-resolved multiplexed analysis of complex systems using near-infrared (NIR) dyes, applicable to in vitro and in vivo studies. We first show that fast and precise in vitro quantification of NIR fluorophores lifetime and stoichiometry can be done using phasor analysis, a computationally efficient and user-friendly representation of complex fluorescence intensity decays obtained with pulsed laser excitation. We apply this approach to the study of binding equilibria by Förster resonant energy transfer (FRET), using two different model systems: primary/secondary antibody binding in vitro and ligand/receptor binding in cell cultures. We then extend our demonstration to dynamic imaging of the pharmacokinetics of transferrin binding to the transferrin receptor in live mice, elucidating the kinetic of differential transferrin accumulation in specific organs, straightforwardly differentiating specific from non-specific binding. Our method, implemented in a freely-available software package, has all the advantages of time-resolved NIR imaging, including better tissue penetration and background-free imaging, but simplifies and considerably speeds up data processing and interpretation, while remaining quantitative. These advances make this method attractive and of broad applicability for in vitro and in vivo molecular imaging, and could be extended to applications as diverse as image guided-surgery or optical tomography.
Ordino: a visual cancer analysis tool for ranking and exploring genes, cell lines, and tissue samples
Authors: Streit Marc , Gratzl Samuel , Stitz Holger , Wernitznig Andreas , Zichner Thomas , Haslinger Christian
Published: March 2018

Ordino is a web-based analysis tool for cancer genomics that allows users to flexibly rank, filter, and explore genes, cell lines, and tissue samples based on pre-loaded data, including The Cancer Genome Atlas (TCGA), the Cancer Cell Line Encyclopedia (CCLE), and manually uploaded information. Interactive tabular data visualization that facilitates the user-driven prioritization process forms a core component of Ordino. Detail views of selected items complement the exploration. Findings can be stored, shared, and reproduced via the integrated session management.

Availability and Implementation

Ordino is publicly available at https://ordino.caleydoapp.org. The source code is released at https://github.com/Caleydo/ordino under the Mozilla Public License 2.0.

Contact

marc.streit@jku.at
Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment
Authors: Sliz Eeva , Kettunen Johannes , Holmes Michael V , Oliver-Williams Clare , Boachie Charles , Wang Qin , Männikkö Minna , Sebert Sylvain , Walters Robin , Lin Kuang , Millwood Iona Y , Clarke Robert , Li Liming , Rankin Naomi , Welsh Paul , Delles Christian , Jukema J. Wouter , Trompet Stella , Ford Ian , Perola Markus , Salomaa Veikko , Järvelin Marjo-Riitta , Chen Zhengming , Lawlor Debbie A , Ala-Korpela Mika , Danesh John , Smith George Davey , Sattar Naveed , Butterworth Adam , Würtz Peter
Published: March 2018

Background

Both statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial, and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial.

Methods

228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) usingPCSK9rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors.

Results

Scaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid balance were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 showed weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C;P=2 × 10−7for heterogeneity). Genetic inhibition of PCSK9 showed no robust effects on amino acids, ketones, and a marker of inflammation (GlycA); in contrast, statin treatment lowered GlycA levels.

Conclusions

Genetic inhibition of PCSK9 results in similar metabolic effects as statin therapy across a detailed lipid and metabolite profile. However, for the same lowering of LDL-C, PCSK9 inhibitors are predicted to be less efficacious than statins at lowering VLDL lipids, which could potentially translate into subtle differences in cardiovascular risk reduction.
Inferring synaptic inputs from spikes with a conductance-based neural encoding model
Authors: Latimer Kenneth W. , Rieke Fred , Pillow Jonathan W.
Published: March 2018

A popular approach to the study of information processing in the nervous system is to char-acterize neural responses in terms of a cascade of linear and nonlinear stages: a linear filter to describe the neuron’s stimulus integration properties, followed by a rectifying nonlinearity to convert filter output to spike rate. However, real neurons integrate stimuli via the modula-tion of nonlinear excitatory and inhibitory synaptic conductances. Here we introduce a bio-physically inspired point process model with conductance-based inputs. The model provides a novel interpretation of the popular Poisson generalized linear model (GLM) as a special kind of conductance-based model, where excitatory and inhibitory conductances are modulated in a “push-pull” manner so that total conductance remains constant. We relax this constraint to obtain a more general and flexible “conductance-based encoding model” (CBEM), which can exhibit stimulus-dependent fluctuations in gain and dynamics. We fit the model to spike trains of macaque retinal ganglion cells and show that, remarkably, we can accurately infer underlying inhibitory and excitatory conductances, using comparisons to intracellularly measured conductances. Using extracellular data, we corroborate the intracellular finding that synaptic excitation temporally precedes inhibition in retina. We show that the CBEM outperforms the classic GLM at predicting retinal ganglion cell responses to full-field stimuli, generalizes better across contrast levels, and captures inhibition-dependent response properties to spatially structured stimuli. The CBEM provides a powerful tool for gaining insights into the intracellular variables governing spiking, and forges an important link between extracellular characterization methods and biophysically detailed response models.
Time-dependent mnemonic vulnerability induced by new-learning
Authors: Shen Fengtao , Ku Yixuan , Wu Jue , Cui Yue , Li Jianqi , Wang Zhaoxin , Wang Huimin , Kwok Sze Chai
Published: March 2018

Reactivation renders consolidated memory labile again, and the ensuing temporary reconsolidation process is highly susceptible to mnemonic modification. Here, we show that memories in such an unstable state could be reprogrammed by sheer behavioral means, bypassing the need for pharmacological intervention. In two experiments using a “face-location associationc” paradigm in which participants experienced a “Learning – New-learning – Final-test” programme, we demonstrate that reactivated memory traces were robustly hampered when the new learning was strategically administered within a critical 20-minute time window. Using fMRI, we further advance our theoretical understanding that this lability can be mechanistically explained by the differential activation in the hippocampal-amygdala memory system implicated by the new-learning whereas the mnemonic intrusion caused by newly learned memories is efficaciously reconciled by the left inferior frontal gyrus. Our findings provide important implications for educational and clinical practices in devising effective strategies for memory integration.
Physiological Significance of R-fMRI Indices: Can Functional Metrics Differentiate Structural Lesions (Brain Tumors)?
Authors: Fan Zhen , Chen Xiao , Qi Zeng-Xin , Li Le , Lu Bin , Jiang Cong-Lin , Zhu Ren-Qing , Chen Liang , Yan Chao-Gan
Published: March 2018

Resting-state functional MRI (R-fMRI) research has recently entered the era of “big data”, however, few studies have provided a rigorous validation of the physiological underpinnings of R-fMRI indices. Although studies have reported that various neuropsychiatric disorders exhibit abnormalities in R-fMRI measures, these “biomarkers” have not been validated in differentiating structural lesions (brain tumors) as a concept proof. We enrolled 60 patients with intracranial tumors located in the unilateral cranial cavity and 60 matched normal controls to test whether R-fMRI indices can differentiate tumors, which represents a prerequisite for adapting such indices as biomarkers for neuropsychiatric disorders. Common R-fMRI indices of tumors and their counterpart control regions, which were defined as the contralateral normal areas (for amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo) and degree centrality (DC)) and ipsilateral regions surrounding the tumors (for voxel-mirrored homotopic connectivity (VMHC)), were comprehensively assessed. According to paired t-tests with a Bonferroni correction, only ALFF (both with and without Z-standardization) and VMHC (Fisher’s r-to-z transformed) could successfully differentiate substantial tumors from their counterpart normal regions in patients. And DC was not able to differentiate tumor from normal unless employed Z-standardization. To validate the lower power in the between-subject design than in the within-subject design, each metric was calculated in a matched control group, and two-sample t-tests were used to compare the patient tumors and the normal controls at the same area. Only ALFF (and that with Z-standardization) along with VMHC succeeded in differentiating significant differences between tumors and the sham tumors areas of normal controls. This study tested the premise of R-fMRI biomarkers for differentiating lesions, and brings a new understanding to physical significance of the Z-standardization.
Grammars of action in human behavior and evolution
Authors: Stout Dietrich , Chaminade Thierry , Thomik Andreas , Apel Jan , Faisal Aldo
Published: March 2018

Distinctive human behaviors from tool-making to language are thought to rely on a uniquely evolved capacity for hierarchical action sequencing. Unfortunately, testing of this idea has been hampered by a lack of objective, generalizable methods for measuring the structural complexity of real-world behaviors. Here we present a data-driven approach for quantifying hierarchical structure by extracting action grammars from basic ethograms. We apply this method to the evolutionarily-relevant behavior of stone tool-making by comparing sequences from the experimental replication of ˜2.5 Mya Oldowan vs. more recent ˜0.5 Mya Achuelean tools. Results show that, while using the same “alphabet” of elementary actions, Acheulean sequences are structurally more complex. Beyond its specific evolutionary implications, this finding illustrates the broader applicability of our method to investigate the structure of naturalistic human behaviors and cognition. We demonstrate one application by using our complexity measures to re-analyze data from an fMRI study of tool-making action observation.
Novel role of Lin28 signaling in regulation of mammalian PNS and CNS axon regeneration
Authors: Wang Xue-Wei , Liu Chang-Mei , Hall Philip A. , Jiang Jing-Jing , Katchis Christopher D. , Kang Sehwa , Dong Bryan C. , Li Shuxin , Zhou Feng-Quan
Published: March 2018

Several signaling molecules involved in cellular reprogramming have been shown to regulate mammalian axon regeneration. We hypothesized that reprogramming factors are key regulators of axon regeneration. Here we investigated the role of Lin28, an important reprogramming factor, in the regulation of axon regeneration. We found that Lin28a and Lin28b and their regulatory partners, let-7 microRNAs (miRNAs), were both necessary and sufficient in regulating mature sensory axon regeneration in vivo. More importantly, overexpression of either Lin28a or Lin28b in mature retinal ganglion cells (RGCs) promoted robust and sustained optic nerve regeneration. Additionally, combined overexpression of Lin28a and downregulation of PTEN in RGCs acted additively to promote optic nerve regeneration by reducing the backward turning of regenerating RGC axons. Our findings not only identified a novel molecule promoting optic nerve regeneration but also suggested that reprogramming factors may play vital roles in regulating axon regeneration in mammals.
Timing of ESCRT-III protein recruitment and membrane scission during HIV-1 assembly
Authors: Johnson Daniel S. , Bleck Marina , Simon Sanford M.
Published: March 2018

The Endosomal Sorting Complexes Required for Transport III (ESCRT-III) proteins are critical for cellular membrane scission processes with topologies inverted relative to clathrin-mediated endocytosis. Some viruses appropriate ESCRT-IIIs for their release. By imaging single assembling viral-like particles of HIV-1, we observed that ESCRT-IIIs and the ATPase VPS4 arrive after most of the virion membrane is bent, linger for tens of seconds, and depart ∼20 seconds before scission. These observations suggest ESCRT-IIIs are recruited by a combination of membrane curvature and the late domains of the HIV-1 Gag protein. ESCRT-IIIs may pull the neck into a narrower form but must leave to allow scission. If scission does not occur within minutes of ESCRT departure, ESCRT-III and VPS4 are recruited again. This mechanistic insight is likely relevant for other ESCRT dependent scission processes including cell division, endosome tubulation, multivesicular body and nuclear envelope formation, and secretion of exosomes and ectosomes.
Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes
Authors: Altanerova Ursula , Jakubechova Jana , Benejova Katarina , Priscakova Petra , Pesta Martin , Pitule Pavel , Topolcan Ondrej , Kausitz Juraj , Zdurjencikova Martina , Repiska Vanda , Altaner Cestmir
Published: March 2018

Human tumor trophic mesenchymal stem cells (MSCs) isolated from various tissues and MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase suicide fusion gene (yCD::UPRT‒MSCs) released exosomes in conditional medium (CM). Exosomes from all tissue specific yCD::UPRT‒MSCs contained mRNA of the suicide gene in the exosome’s cargo. When the CM was applied to tumor cells, the exosomes were internalized by recipient tumor cells and in the presence of the prodrug 5‒fluorocytosine (5‒FC) effectively triggered dose‒dependent tumor cell death by endocytosed exosomes via an intracellular conversion of the prodrug 5‒FC to 5‒fluorouracil. Exosomes were found to be responsible for the tumor inhibitory activity. MSCs transduced with the Herpes simplex virus thymidine kinase gene released exosomes causing death of tumor cells in the presence of ganciclovir. The presence of microRNAs in exosomes produced from naive MSCs and corresponding transgene transduced MSCs did not differ significantly. microRNAs from yCD::UPRT‒MSCs were not associated with therapeutic effect. MSC suicide gene exosomes represent a new class of tumor cell targeting drug acting intracellular with curative potential.
Testing an Optimally Weighted Combination of Common and/or Rare Variants with Multiple Traits
Authors: Wang Zhenchuan , Sha Qiuying , Zhang Kui , Zhang Shuanglin
Published: March 2018

Joint analysis of multiple traits has recently become popular since it can increase statistical power to detect genetic variants and there is increasing evidence showing that pleiotropy is a widespread phenomenon in complex diseases. Currently, most of existing methods test the association between multiple traits and a single common variant. However, the variant-by-variant methods for common variant association studies may not be optimal for rare variant association studies due to the allelic heterogeneity as well as the extreme rarity of individual variants. In this article, we developed a statistical method by testing an optimally weighted combination of variants with multiple traits (TOWmuT) to test the association between multiple traits and a weighted combination of variants (rare and/or common) in a genomic region. TOWmuT is robust to the directions of effects of causal variants and is applicable to different types of traits. Using extensive simulation studies, we compared the performance of TOWmuT with the following five existing methods: gene association with multiple traits (GAMuT), multiple sequence kernel association test (MSKAT), adaptive weighting reverse regression (AWRR), single-TOW, and MANOVA. Our results showed that, in all of the simulation scenarios, TOWmuT has correct type I error rates and is consistently more powerful than the other five tests. We also illustrated the usefulness of TOWmuT by analyzing a whole-genome genotyping data from a lung function study.
Population genetics ofParameciummitochondrial genomes: recombination, mutational spectrum, and efficacy of selection
Authors: Johri Parul , Marinov Georgi K. , Doak Thomas G. , Lynch Michael
Published: March 2018

The evolution of mitochondrial genomes and their population-genetic environment among unicellular eukaryotes are understudied. Ciliate mitochondrial genomes exhibit a unique combination of characteristics, including a linear organization and the presence of multiple genes with no known function or detectable homologs in other eukaryotes. Here we study the variation of ciliate mitochondrial genomes both within and across thirteen highly divergedParameciumspecies, including multiple species from theP. aureliaspecies complex, with four outgroup species:P. caudatum,P. multimicronucleatum, and two strains that may represent novel related species. We observe extraordinary conservation of gene order and protein-coding content inParameciummitochondria across species. In contrast, significant differences are observed in tRNA content and copy number, which is highly conserved in species belonging to theP. aureliacomplex but variable among and even within the otherParameciumspecies. There is an increase in GC content from ~20% to ~40% on the branch leading to theP. aureliacomplex. Patterns of polymorphism in population-genomic data and mutation-accumulation experiments suggest that the increase in GC content is primarily due to changes in the mutation spectra in theP. aureliaspecies. Finally, we find no evidence of recombination inParameciummitochondria and find that the mitochondrial genome appears to experience either similar or stronger efficacy of purifying selection than the nucleus.
A network of MAP-Kinase pathways and transcription factors regulates cell-to-cell communication and cell wall integrity inNeurospora crassa
Authors: Fischer Monika S. , Wu Vincent W. , Lee Ji E. , O’Malley Ronan C. , Glass N. Louise
Published: March 2018

Maintenance of cell integrity and cell-to-cell communication are fundamental biological processes. Filamentous fungi, such asNeurospora crassa, depend on communication to locate compatible cells, coordinate cell fusion, and establish a robust hyphal network. Two MAP-Kinase pathways are essential for communication and cell fusion inN. crassa; the Cell Wall Integrity/MAK-1 pathway and the MAK-2 (signal response) pathway. Previous studies have demonstrated several points of cross talk between the MAK-1 and MAK-2 pathways, which is likely necessary for oordinating chemotropic growth toward an extracellular signal, and then mediating cell fusion. Canonical MAP-Kinase pathways begin with signal reception and end with a transcriptional response. Two transcription factors, ADV-1 and PP-1, are essential for communication and cell fusion. PP-1 is the conserved target of MAK-2, while it is unclear what targets ADV-1. We did RNAseq onΔadv-1, Δpp-1, and wild-type cells and found that ADV-1 and PP-1 have a shared regulon including many genes required for communication, cell fusion, growth, development, and stress response. We identified ADV-1 and PP-1 binding sites across the genome by adapting thein vitromethod of DNA-Affinity Purification sequencing (DAP-seq) forN. crassa. To elucidate the regulatory network, we misexpressed each transcription factor in each upstream MAPK deletion mutant. Misexpression ofadv-1was sufficient to fully suppress the phenotype of theΔpp-1mutant and partially suppress the phenotype of theΔmak-1mutant. Collectively, our data demonstrate that the MAK-1-ADV-1 and MAK-2- PP-1 pathways form a tight regulatory network that maintains cell integrity and mediates communication and cell fusion.
Prosody perception in children: studying individual differences with novel brain and behavioral approaches
Authors: Myers Brett , Vaughan Chloe , Soman Uma , Blain Scott , Korsnack Kylie , Camarata Stephen , Gordon Reyna L.
Published: March 2018

A sizeable literature has shown that perception of prosodic elements bolsters speech comprehension across developmental stages; recent work also suggests that variance in musical aptitude predicts individual differences in prosody perception in adults. The current study investigates brain and behavioral methods of assessing prosody perception and tests the relationship with musical rhythm perception in 35 school-aged children (age range: 5;5 to 8;0 years, M = 6;7 years, SD = 10 months; 18 females). We applied stimulus reconstruction, a technique for analyzing EEG data by fitting a temporal response function that maps the neural response back to the sensory stimulus. In doing so, we obtain a measure of neural encoding of the speech envelope in passive listening to continuous narratives. We also present a behavioral prosody assessment that requires holistic judgments of filtered speech. The results from these typically developing children revealed that individual differences in stimulus reconstruction in the delta band, indexing neural synchrony to the speech envelope, are significantly related to individual differences in behavioral measurement of prosody perception. In addition, both of these measures are moderately to strongly correlated with musical rhythm perception skills. Results support a domain-general mechanism for cognitive processing of speech and music.

Graphical Abstract