bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and Safety of Multiband Mucosectomy Versus Cap-assisted Endoscopic Resection For Early Esophageal Cancer and Precancerous Lesions: A Systematic Review and Meta-Analysis
Authors: Dan Xiang , Lv Xiu-He , San Zhi-Jie , Geng Sang , Wang Yan-Qiang , Li Shao-Hua , Xie Hua-Hong
Published: August 2019

Background:

The effectiveness of multiband mucosectomy (MBM) for early esophageal cancer and precancerous lesions is still in uncertainty. We aimed to evaluate the efficacy and safety of this procedure and to compare it with cap-assisted endoscopic resection (EMR-cap).

Methods:

A systematic search of both English and Chinese databases was performed from inception to April 30, 2019. Complete resection rate, local recurrence rate, and procedure time were considered the primary outcome measures. Prevalence of complications was considered the secondary outcome measure. All data analyses were performed using Review Manager Software.

Results:

Two randomized controlled trials (RCTs) and 3 non-RCTs were included in the final meta-analysis. When compared with the EMR-cap technique, MBM had a similar complete resection rate [odds ratio (OR)=2.09, 95% confidence interval (CI): 0.78-5.60, P=0.14], a similar local recurrence rate (OR=0.50, 95% CI: 0.09-2.67, P=0.42), a shorter resection time (mean difference: −9.08, 95% CI: −13.86 to −4.30, P=0.0002), a shorter procedure time (mean difference: −13.36, 95% CI: −17.85 to −8.86, P<0.00001), a lower bleeding rate (OR=0.45, 95% CI: 0.24-0.83, P=0.01), a similar perforation rate (OR=0.55, 95% CI: 0.15-2.06, P=0.37), and a similar stricture rate (OR=0.77, 95% CI: 0.10-5.84, P=0.80). The results of non-RCTs were consistent with those of RCTs.

Conclusions:

MBM is similar to EMR-cap in terms of efficacy and safety for endoscopic resection of early cancer and precancerous lesions of the esophagus. However, MBM is less time-consuming.
Microbe Profile: Thermococcus kodakarensis: the model hyperthermophilic archaeon
Authors: Atomi Haruyuki , Reeve John
Published: August 2019

Thermococcus kodakarensis

is a hyperthermophilic Euryarchaeon that grows well under laboratory conditions and, being naturally competent for genetic transformation, it has become a widely studied experimental model species. With the genome sequence available since 2004, combining genetic, enzymological and structural biochemical approaches has revealed previously unknown and unanticipated features of archaeal molecular biology and metabolism.

T. kodakarensis

DNA polymerase is already commercialized and with the details of metabolism and hydrogenase available, generating H2 from biopolymers solubilized at high temperatures, most notably chitin, now seems a very attractive possibility as a renewable energy bioprocess.
Ion-networks: a sparse data format capturing full data integrity of data independent acquisition mass spectrometry
Authors: Willems Sander , Daled Simon , Van Puyvelde Bart , De Clerck Laura , Vande Casteele Sofie , Van Nieuwerburgh Filip , Deforce Dieter , Dhaenens Maarten
Published: August 2019

Data-independent acquisition (DIA) mass spectrometry (MS) has introduced deter-ministic, periodic and simultaneous acquisition of all fragment ions. Despite the chimeric side-effects associated with this unprecedented data integrity, DIA data analysis approaches still use conventional spectra and extracted ion chromatograms (XICs) that represent individual precursors and fragments. Here, we introduce ion-networks, an alternative data format wherein nodes correspond to reproducible fragment ions from multiple runs and edges correspond to consistent co-elution. Each ion-network represents a complete experiment and computationally eliminates chimericy based on reproducibility without sacrificing data integrity.
Systemic Commitments of the Context-Dependency; Basics of Elementary Coordination in Circadian Cycles
Authors: Park Chulwook
Published: August 2019

The present study was attempted to measure whether the dynamics of elementary coordination is influenced by an overarching temporal structure that is embedded in circadian rhythms (part 1) as well as the systemic proof associated with the intelligent capabilities (part 2). For part 1, evidence of entrainment or any influence of the embedding rhythm were examined on the stability or attractor location. The estimations from the dynamics of the relative phase between the two oscillations show that while (i) circadian effects under the artificially perturbed manipulation were not straightforward along the day-night temperature cycle, (ii) the circadian effect divided by the ordinary circadian seems to be constant along the day-night cycle. Corresponding to this evidence related to performance consequences depending on the organism and environmental interaction, the part 2 determined the impact of circadian (mis)alignment on biological functions and raised the possibility that the disruption of circadian systems may contribute to physical complications. The observations entail rules that self-attunement of current performance may develop not at a single component but across many nested, inter-connected scales. These inter-dependencies from different object phase may allow a potential context-dependent explanation for goal-oriented movements and the emergent assumption of a principle of organisms embedded into their environmental contexts.
Frequency specific network effective connectivity: ERP analysis of recognition memory process by directed connectivity estimators
Authors: Bayazi Mohammad Javad Darvishi , Nasrabadi Ali Motie , Curran Tim
Published: August 2019

Various processes occur in memory retrieval in recognition memory and it is necessary to investigate memory brain function. Most of the research in past decades have focused on particular brain region function, but the interaction between these has a major role in human cognition. In this study, we used the memory retrieval task to investigate the underlying mechanism of recognition memory. The connectivity between brain regions is estimated from scalp electroencephalography signals that were recorded from twenty-three healthy subject participated in recognition memory task to correctly classify old/new words. Multivariate autoregressive models (MVAR) are used for the determination of Granger causality to estimate the effective connectivity in the time-frequency domain. We use GPDC and dDTF methods because they have almost resolved the previous problems in estimations. Results show that brain regions in the old condition have greater global connectivity in the theta and gamma band compared to the new words retrieval. Connectivity within and between the brain’s hemisphere may be related to correct rejection. The left frontal has a crucial role in recollection. theta and gamma specific connectivity pattern between temporal, parietal and frontal cortex may disclose the retrieval mechanism. old/new comparison resulted in the different patterns of network connection. These results and other evidence emphasize the role of frequency of causal network interactions in the memory process.
A Targeted Mass Spectrometry Approach to detect and quantify Oxidised Phospholipids in plasma samples of Diabetic patients
Authors: Thakker Alpesh , Spickett Corinne M , Pitt Andrew
Published: August 2019

Phospholipid oxidation by adventitious damage generates a wide variety of products with potentially novel biological activities that can modulate inflammatory processes associated with various diseases such as atherosclerosis, acute Pancreatitis and Type 2 diabetes. To understand the biological importance of oxidised phospholipids (OxPL) and their potential role as disease biomarkers requires precise information about the abundance of these compounds in cells and tissues. There are many chemiluminescence and spectroscopic assays available for detecting oxidised phospholipids, but they all have some limitations. Mass spectrometry coupled with liquid chromatography is a powerful and sensitive approach but its application to complex biological samples remains challenging.

The aim of this work was to develop improved methods for detection of OxPLs, specifically by using targeted mass spectrometry approaches (precursor ion [PIS] and neutral loss [NL] scanning), high resolution mass spectrometry and alternative chromatographic approaches. Initial experiments were carried out using oxidation products generated in vitro from a commercially available phosphatidylcholine (PC) and phosphatidylethanolamine (PE) mixture in order to optimise the chromatography separation parameters and mass spectrometry parameters. The chromatographic separation of oxidised phosphatidylcholines (OxPCs) and oxidised phosphatidylethanolamines (OXPEs) was evaluated using C8, C18 and C30 reverse phase, polystyrene – divinylbenzene based monolithic and mixed – mode hydrophilic interaction (HILIC) columns, interfaced with mass spectrometry. Our results suggest that the divinylbenzene based reverse phase monolithic column gave best separation of short chain OxPCs and OxPEs from long chain oxidised and native PCs and PEs.

Targeted mass spectrometric approaches for the selective identification of short chain OxPCs using PIS for m/z 184 Da and NL for m/z 34 Da for identification of hydroperoxides were tested on OxPC mixture, it enabled identification of low abundant oxidation products such as: γ-hydroxy alkenals and alkenoates and saturated aldehydes collectively termed as “short - chain oxidation products” such as PONPC, POVPC and HOOA-PC. The combination of these chromatographic and MS methods allowed identification of several oxidised molecular species in plasma of diabetic patients. Quantitative differences in oxidised products were observed in diabetic samples and the trend showed high abundance of oxidised phosphatidylcholine species in diabetic samples, compared to healthy plasma samples. However, the difference in abundance was statistically not significant when the samples were analysed using Progenesis QI software, performing global normalisation and ANOVA analysis because of inherent biological variability observed for OxPC species in samples.
Co-catabolism of arginine and succinate drives symbiotic nitrogen fixation
Authors: Flores-Tinoco Carlos Eduardo , Christen Matthias , Christen Beat
Published: August 2019

Biological nitrogen fixation emerging from the symbiosis between bacteria and crop plants holds a significant promise to increase the sustainability of agriculture. One of the biggest hurdles for the engineering of nitrogen-fixing organisms is to identify the metabolic blueprint for symbiotic nitrogen fixation. Here, we report on the CATCH-N cycle, a novel metabolic network based on co-catabolism of plant-provided arginine and succinate to drive the energy-demanding process of symbiotic nitrogen fixation in endosymbiotic rhizobia. Using systems biology, isotope labeling studies and transposon sequencing in conjunction with biochemical characterization, we uncovered highly redundant network components of the CATCH-N cycle including transaminases that interlink the co-catabolism of arginine and succinate. The CATCH-N cycle shares aspects with plant mitochondrial arginine degradation path-way. However, it uses N2 as an additional sink for reductant and therefore delivers up to 25% higher yields of nitrogen than classical arginine catabolism — two alanines and three ammonium ions are secreted for each input of arginine and succinate. We argue that the CATCH-N cycle has evolved as part of a specific mechanism to sustain bacterial metabolism in the microoxic and acid environment of symbiosomes. In sum, our systems-level findings provide the theoretical framework and enzymatic blueprint for the rational design of plants and plant-associated organisms with new properties for improved nitrogen fixation.

Significance Statement

Symbiotic bacteria assimilate nitrogen from the air and fix it into a form that can be used by plants in a process known as biological nitrogen fixation. In agricultural systems, this process is restricted mainly to legumes, yet there is considerable interest in exploring whether similar symbioses can be developed in non-legumes including cereals and other important crop plants. Here we present systems-level findings on the minimal metabolic function set for biological nitrogen fixation that provides the theoretical framework for rational engineering of novel organisms with improved nitrogen-fixing capabilities.
Phosphoinositide-binding proteins mark, shape and functionally modulate highly-diverged endocytic compartments in the parasitic protistGiardia lamblia
Authors: Cernikova Lenka , Faso Carmen , Hehl Adrian B.
Published: August 2019

Phosphorylated derivatives of phosphatidylinositol (PIPs), are key membrane lipid residues involved in clathrin-mediated endocytosis (CME). CME relies on PI(4,5)P2 to mark endocytic sites at the plasma membrane (PM) associated to clathrin-coated vesicle (CCV) formation. The highly diverged parasitic protistGiardia lambliapresents disordered and static clathrin assemblies at PM invaginations, contacting specialized endocytic organelles called peripheral vacuoles (PVs). The role for clathrin assemblies in fluid phase uptake and their link to internal membranes via PIP-binding adaptors is unknown.

Here we provide evidence for a robust link between clathrin assemblies and fluid-phase uptake inG. lambliamediated by proteins carrying predicted PX, FYVE and NECAP1 PIP-binding modules. We show that chemical and genetic perturbation of PIP-residue binding and turnover elicits novel uptake and organelle-morphology phenotypes. A combination of co-immunoprecipitation andin silicoannotation techniques expands the initial PIP-binding network with addition of new members. Our data indicate that, despite the partial conservation of lipid markers and protein cohorts known to play important roles in dynamic endocytic events in well-characterized model systems, theGiardialineage presents a strikingly divergent clathrin-centered network. This includes several PIP-binding modules, often associated to domains of currently unknown function that shape and modulate fluid-phase uptake at PVs.
fMRI detects bilateral brain network activation following unilateral chemogenetic activation of direct striatal projection neurons
Authors: Nakamura Yuki , Nakamura Yukari , Pelosi Assunta , Djemai Boucif , Debacker Clément , Hervé Denis , Girault Jean-Antoine , Tsurugizawa Tomokazu
Published: August 2019

Although abnormal structural and functional connectivity in the striatum during neurological disorders has been reported using functional magnetic resonance imaging (fMRI), the effects of cell-type specific neuronal stimulation on fMRI and related behavioral alterations are not well understood. In this study, we successfully combined DREADD-technology with fMRI (chemo-fMRI) to investigate the alterations of spontaneous neuronal activity induced by the unilateral activation of dopamine D1 receptor-expressing neurons (D1-neurons) in the mouse dorsal striatum (DS). We compared the effects of two different DREADD ligands, clozapine (CLZ) and clozapine-N-oxide (CNO), on behavior and fMRI. We found that the effects of CLZ on behavior were more rapid than those of CNO. In fMRI, both systemic CLZ and CNO administrations, which evoked unilateral activations of D1-neurons in DS, increased the fractional amplitude of low frequency fluctuations (fALFF) in the thalamus and bilateral cortex. In addition, we found the increased gamma-band of local field potentials in DS and bilateral cortex after CLZ-evoked unilateral activation of D1-neuron in the striatum. These results provide bases for better interpretation of cell type-specific activity changes in fMRI.
Leveraging shared connectivity to aggregate heterogeneous datasets into a common response space
Authors: Nastase Samuel A. , Liu Yun-Fei , Hillman Hanna , Norman Kenneth A. , Hasson Uri
Published: August 2019

Connectivity hyperalignment can be used to estimate a single shared response space across disjoint datasets. We develop a connectivity-based shared response model that factorizes aggregated fMRI datasets into a single reduced-dimension shared connectivity space and subject-specific topographic transformations. These transformations resolve idiosyncratic functional topographies and can be used to project response time series into shared space. We evaluate this algorithm on a large collection of heterogeneous, naturalistic fMRI datasets acquired while subjects listened to spoken stories. Projecting subject data into shared space dramatically improves between-subject story time-segment classification and increases the dimensionality of shared information across subjects. This improvement generalizes to subjects and stories excluded when estimating the shared space. We demonstrate that estimating a simple semantic encoding model in shared space improves between-subject forward encoding and inverted encoding model performance. The shared space estimated across all datasets is distinct from the shared space derived from any particular constituent dataset; the algorithm leverages shared connectivity to yield a consensus shared space conjoining diverse story stimuli.

Highlights

Connectivity SRM estimates a single shared space across subjects and stimuli

Topographic transformations resolve idiosyncrasies across individuals

Shared connectivity space enhances spatiotemporal intersubject correlations

Semantic model-based encoding and decoding improves across subjects

Transformations project into a consensus space conjoining diverse stimuli
Evoked and spontaneous pain assessment during tooth pulp injury
Authors: Rossi Heather Lynn , See Lily Pachanin , Foster William , Pitake Saumitra , Gibbs Jennifer , Schmidt Brian , Mitchell Claire H. , Abdus-Saboor Ishmail
Published: August 2019

Injury of the tooth pulp is excruciatingly painful and yet the receptors and neural circuit mechanisms that transmit this form of pain remain poorly defined in both the clinic and preclinical rodent models. Easily quantifiable behavioral assessment in the rodent orofacial area remains a major bottleneck in uncovering molecular mechanisms that govern inflammatory pain in the tooth. Here we use a dental pulp injury model in the mouse and expose the tooth pulp to the outside environment, a procedure we have previously shown produces pulpal inflammation. We demonstrate here with RNAscope technology in the trigeminal ganglion of injured mice, an upregulation of genes that contribute to the inflammatory pain state. Using both evoked and spontaneous measures of pain in the orofacial area, including application of von Frey Hair filaments and pain feature detection with the mouse grimace scale, we reveal a differential timeline of induction of spontaneous pain versus mechanical allodynia following pulpal injury. This work demonstrates that tooth pain can be easily assessed in freely behaving mice using approaches common for other types of pain assessment. Harnessing these assays in the orofacial area during gene manipulation should assist in uncovering mechanisms for tooth pulp inflammation and other forms of trigeminal pain.
Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations
Authors: Zampaglione Erin , Kinde Benyam , Place Emily M. , Navarro-Gomez Daniel , Maher Matthew , Jamshidi Farzad , Nassiri Sherwin , Mazzone J. Alex , Finn Caitlin , Schlegel Dana , Comander Jason , Pierce Eric A. , Bujakowska Kinga M.
Published: August 2019

Purpose

Current sequencing strategies can genetically solve 55-60% of inherited retinal degeneration (IRD) cases, despite recent progress in sequencing. This can partially be attributed to elusive pathogenic variants (PVs) in known IRD genes, including copy number variations (CNVs), which we believe are a major contributor to unsolved IRD cases.

Methods

Five hundred IRD patients were analyzed with targeted next generation sequencing (NGS). The NGS data was used to detect CNVs with ExomeDepth and gCNV and the results were compared to CNV detection with a SNP-Array. Likely causal CNV predictions were validated by quantitative (q)PCR.

Results

Likely disease-causing single nucleotide variants (SNVs) and small indels were found in 55.8% of subjects. PVs in USH2A (11.6%), RPGR (4%) and EYS (4%) were the most common. Likely causal CNVs were found in an additional 8.8% of patients. Of the three CNV detection methods, gCNV showed the highest accuracy. Approximately 30% of unsolved subjects had a single likely PV in a recessive IRD gene.

Conclusions

CNV detection using NGS-based algorithms is a reliable method that greatly increases the genetic diagnostic rate of IRDs. Experimentally validating CNVs helps estimate the rate at which IRDs might be solved by a CNV plus a more elusive variant.
Depolarizing GABA Transmission Restrains Activity-Dependent Glutamatergic Synapse Formation in the Developing Hippocampal Circuit
Authors: Salmon Christopher K. , Pribiag Horia , Farmer W. Todd , Cameron Scott , Jones Emma V. , Mahadevan Vivek , Stellwagen David , Woodin Melanie A. , Murai Keith K.
Published: August 2019

GABA is the main inhibitory neurotransmitter in the mature brain but has the paradoxical property of depolarizing neurons during early development. Depolarization provided by GABAA transmission during this early phase regulates neural stem cell proliferation, neural migration, neurite outgrowth, synapse formation, and circuit refinement, making GABA a key factor in neural circuit development. Importantly, depending on the context, depolarizing GABAA transmission can either drive neural activity, or inhibit it through shunting inhibition. The varying roles of depolarizing GABAA transmission during development, and its ability to both drive and inhibit neural activity, makes it a difficult developmental cue to study. This is particularly true in the later stages of development, when the majority of synapses form and GABAA transmission switches from depolarizing to hyperpolarizing. Here we addressed the importance of depolarizing but inhibitory (or shunting) GABAA transmission in glutamatergic synapse formation in hippocampal CA1 pyramidal neurons. We first showed that the developmental depolarizing-to-hyperpolarizing switch in GABAA transmission is recapitulated in organotypic hippocampal slice cultures. Based on the expression profile of K+-Cl- co-transporter 2 (KCC2) and changes in the GABA reversal potential, we pinpointed the timing of the switch from depolarizing to hyperpolarizing GABAA transmission in CA1 neurons. We found that blocking depolarizing but shunting GABAA transmission increased excitatory synapse number and strength, indicating that depolarizing GABAA transmission can restrain glutamatergic synapse formation. The increase in glutamatergic synapses was activity-dependent, but independent of BDNF signalling. Importantly, the elevated number of synapses was stable for more than a week after GABAA inhibitors were washed out. Together these findings point to the ability of immature GABAergic transmission to restrain glutamatergic synapse formation and suggest an unexpected role for depolarizing GABAA transmission in shaping excitatory connectivity during neural circuit development.
Benchmarking tomographic acquisition schemes for high-resolution structural biology
Authors: Turoňová Beata , Hagen Wim J. H. , Obr Martin , Kräusslich Hans-Georg , Beck Martin
Published: August 2019

Cryo electron tomography with subsequent subtomogram averaging is a powerful technique to structurally analyze macromolecular complexes in their native context. Although close to atomic resolution, in principle, can be obtained, it is not clear how individual experimental parameters contribute to the attainable resolution. Here, we have used immature HIV-1 lattice as a benchmarking sample to optimize the attainable resolution for subtomogram averaging. We systematically tested various experimental parameters such as the order of projections, different angular increments and the use of the Volta phase plate. We find that although any of the prominently used acquisition schemes is sufficient to obtain subnanometer resolution, dose-symmetric acquisition provides considerably better outcome. We discuss our findings in order to provide guidance for data acquisition. Our data is publicly available at EMPIAR-10277 as well as EMD-10207 and might be used to further develop processing routines.
Privatization of biofilm matrix in structurally heterogeneous biofilms
Authors: Otto Simon B. , Martin Marivic , Schäfer Daniel , Hartmann Raimo , Drescher Knut , Brix Susanne , Dragoš Anna , Kovács Ákos T.
Published: August 2019

The self-produced biofilm provides beneficial protection for the enclosed cells, but the costly production of matrix components makes producer cells susceptible to cheating by non-producing individuals. Despite detrimental effects of non-producers, biofilms can be heterogeneous, with isogenic non-producers being a natural consequence of phenotypic differentiation processes. For instance, inBacillus subtilisbiofilm cells differ in the two major matrix components production, the amyloid fiber protein TasA and exopolysaccharides (EPS), demonstrating different expression levels of corresponding matrix genes. This raises questions regarding matrix gene expression dynamics during biofilm development and the impact of phenotypic non-producers on biofilm robustness. Here, we show that biofilms are structurally heterogeneous and can be separated into strongly and weakly associated clusters. We reveal that spatiotemporal changes in structural heterogeneity correlate with matrix gene expression, with TasA playing a key role in biofilm integrity and timing of development. We show that the matrix remains partially privatized by the producer subpopulation, where cells tightly stick together even when exposed to shear stress. Our results support previous findings on the existence of ‘weak points’ in seemingly robust biofilms as well as on the key role of linkage proteins in biofilm formation. Furthermore, we provide a starting point for investigating the privatization of common goods within isogenic populations.

IMPORTANCE

Biofilms are communities of bacteria protected by a self-produced extracellular matrix. The detrimental effects of non-producing individuals on biofilm development raises questions about the dynamics between community members, especially when isogenic non-producers exist within wild-type populations. We asked ourselves whether phenotypic non-producers impact biofilm robustness, and where and when this heterogeneity of matrix gene expression occurs. Based on our results we propose that the matrix remains partly privatized by the producing subpopulation, since producing cells stick together when exposed to shear stress. The important role of linkage proteins in robustness and development of the structurally heterogeneous biofilm provides an entry into studying the privatization of common goods within isogenic populations.
RNA-seq analysis of a zebrafish tlr2 mutant shows a broad function of this Toll-like receptor in transcriptional and metabolic control and defense to Mycobacterium marinum infection
Authors: Yang Shuxin , Hu Wanbin , Shimada Yasuhito , Münch Magnus , Marín-Juez Rubén , Meijer Annemarie H. , Spaink Herman P.
Published: August 2019

Background

The function of Toll-like receptor 2 (TLR2) in host defense against pathogens, especially Mycobacterium tuberculosis (Mtb) is poorly understood. To investigate the role of TLR2 during mycobacterial infection, we analyzed the response of tlr2 zebrafish mutant larvae to infection with Mycobacterium marinum (Mm), a close relative to Mtb, as a model for tuberculosis. We measured infection burdens and transcriptome responses using RNA deep sequencing in mutant and control larvae.

Results

tlr2 mutant embryos at 2 dpf do not show morphological alterations or differences in the number of macrophages and neutrophils when compared to control embryos. However, we found substantial changes in gene expression in these mutants, particularly in developmental and metabolic pathways, when compared with the heterozygote tlr2+/− control. After Mm infection, bacterial burden was six to ten fold higher in tlr2−/− larvae than in tlr2+/−, or tlr2+/+ larvae, indicating that Tlr2 acts as a protective factor in zebrafish host defense. RNAseq analysis of infected tlr2−/− versus tlr2+/− shows that the number of up-regulated and down-regulated genes in response to infection was greatly diminished in tlr2 mutants by at least 2 fold and 10 fold, respectively. Analysis of the transcriptome data and qPCR validation shows that Mm infection of tlr2 mutants leads to decreased mRNA levels of genes involved in inflammation and immune responses, including il1b, tnfb, cxcl11aa/ac, fosl1a, and cebpb. Furthermore, RNAseq analyses revealed that the expression of genes for Maf family transcription factors, vitamin D receptors, and Dicps proteins is significantly altered in tlr2 mutants with or without infection. In addition, the data indicate a function of Tlr2 in the control of induction of cytokines and chemokines, such as the CXCR3-CXCL11 signaling axis.

Conclusion

The transcriptome and infection burden analyses give support for a function of TLR2 in host defense against mycobacteria. Transcriptome analysis revealed tlr2-specific pathways involved in Mm infection, which are related to responses to Mtb infection in human macrophages. Considering its dominant function in control of transcriptional processes that govern defense responses and metabolism, the TLR2 protein can be expected to be also of importance for other infectious diseases and interactions with the microbiome.
Health behaviors among male and female university students in Cambodia: a cross-sectional survey
Authors: Sok Say , Pal Khuondyla , Tuot Sovannary , Yi Rosa , Chhoun Pheak , Yi Siyan
Published: August 2019

Background

Students go through a transition when they enter university, which involves major individual and contextual changes in every domain of life that may lead to several behavioral and health problems. This paper describes a wide range of health behaviors among male and female university students in Cambodia.

Methods

A cross-sectional survey was conducted in 2015 among students randomly selected from the Royal University of Phnom Penh and University of Battambang. Health-related behaviors in different domains were collected using a structured questionnaire. Chi-square test, Fisher’s exact test, or independent Student’s t-test was used as appropriate to describe and compare the variables among male and female students.

Results

This study included 1359 students, of whom 50.8% were male, and the mean age was 21.3 years (SD= 2.3). Of the total, 79.5% reported not having any vigorous-intensity activities, 25.9% not having moderate-intensity activities, and 33.5% not having walked continuously for 10 minutes during the past seven days. The prevalence of substance use was low with 38.3% currently drinking alcohol, 1.1% smoking tobacco, and 0.4% using an illicit drug during the past 12 months. About one in ten (10.6%) reported having sexual intercourse, with a mean number of partners of 2.1 (SD= 2.4) during the past 12 months, and 42.4% not using a condom in the last intercourse. Only 7.1% reported having been diagnosed with a sexually transmitted infection in the past 12 months; of whom, 60% sought for treatment. About one-third (33.6%) reported eating fast food once or twice, and 5.3% having it three times or more over the last week. More than half (55.6%) had one to two servings of fruits and vegetables daily, and 9.9% did not eat any fruits and vegetables over the last week.

Conclusions

We found that the prevalence of sexual risk behaviors and substance use was plausibly low among university students in this study. However, the rates of inactive lifestyle and unhealthy food consumption were concerning. Public policy and universities should promote healthy behaviors among the students. The interventions may take advantage of and expend upon the good health behaviors and consider gender differences.
Adaptational lags during periods of environmental change
Authors: Van Dooren Tom J. M.
Published: August 2019

Effects of climate change can be handled by means of mitigation and adaptation. In the biological sciences, adaptations are solutions which evolved when organisms needed to match an ecological challenge. Based on Adaptive Dynamics theory, a definition is proposed of adapted states and adaptational lags applicable during periods with environmental change of any speed. Adaptation can thus be studied when it emerges from complex eco-evolutionary processes or when targets for adaptation are not defined a priori. The approach is exemplified with a model for delayed germination in an annual plant. Plasticity and maternal effects are often presumed to be adaptive and added to the model to investigate lags in these modes of trait determination. Adaptational lags can change sign and to understand their dynamics, effects of trait space boundaries and characteristics of years with large numbers of recruits had to be considered. Adaptational lags can be crucial elements of adaptive control strategies for managed ecosystems. To demonstrate their practical relevance, examples from pest management show that evolutionary adaptation has been used to infer targets of control. Adaptational lags then serve as measures of the distance to the control target and become integral elements of strategies for adaptive pest population management.
Mesoscale computational protocols for the design of highly cooperative bivalent macromolecules
Authors: Saurabh S. , Piazza F.
Published: August 2019

The last decade has witnessed a swiftly increasing interest in the design and production of novel multivalent molecules as powerful alternatives for conventional antibodies in the fight against cancer and infectious diseases. However, while it is widely accepted that large-scale flexibility (10 − 100 nm) and free/constrained dynamics (100 ns −µs) control the activity of such novel molecules, computational strategies at the mesoscale still lag behind experiments in optimizing the design of crucial features, such as the binding cooperativity (a.k.a. avidity).

In this study, we introduced different coarse-grained models of a polymer-linked, two-nanobody composite molecule, with the aim of laying down the physical bases of a thorough computational drug design protocol at the mesoscale. We show that the calculation of suitable potentials of mean force allows one to apprehend the nature, range and strength of the thermodynamic forces that govern the motion of free and wall-tethered molecules. Furthermore, we develop a simple computational strategy to quantify the encounter/dissociation dynamics between the free end of a wall-tethered molecule and the surface, at the roots of binding cooperativity. This procedure allows one to pinpoint the role of internal flexibility and weak non-specific interactions on the kinetic constants of the NB-wall encounter and dissociation. Finally, we quantify the role and weight of rare events, which are expected to play a major role in real-life situations, such as in the immune synapse, where the binding kinetics is likely dominated by fluctuations.

SIGNIFICANCE

Multivalent and multispecific molecules composed of polymer-linked nanobodies have gained interest as engineered alternatives to conventional antibodies. These therapeutic molecules have a larger reach due to their smaller size and promise substantial and tunable gains in avidity. This paper studies a model diabody to lay the bases of a multi-scale computational design of the structural and dynamical determinants of binding cooperativity, rooted in a blend of atomistic and coarse-grained MD simulations and concepts from statistical mechanics.
Pdm3 directs sleep circuit development to control sleep maturation
Authors: Dilley Leela Chakravarti , Szuperak Milan , Williams Charlette E. , Saldana Ricardo Linares , Gong Naihua N. , Garbe David S. , Syed Mubarak H. , Jain Rajan , Kayser Matthew S.
Published: August 2019

Across species, sleep in young animals is critical for normal brain maturation. In contrast to mature adult sleep, the molecular determinants of early life sleep remain unknown. Through an RNAi-based screen, we identified a gene, pdm3, required for sleep maturation in Drosophila. Pdm3, a transcription factor, acts during nervous system development to coordinate the ingrowth of wake-promoting dopaminergic neurites to a sleep-promoting region. Loss of PDM3 prematurely increases dopaminergic inhibition of the sleep center, abolishing the juvenile sleep state. RNA-Seq/ChIP-Seq and a subsequent modifier screen reveal that pdm3 regulates expression of the synaptogenesis gene Msp300 to control sleep ontogeny. These studies define the molecular cues governing sleep behavioral and circuit development, and suggest sleep disorders may be of neurodevelopmental origin.
A transient amphipathic helix in PCSK9’s prodomain facilitates low-density lipoprotein binding
Authors: Sarkar Samantha K. , Foo Alexander C.Y. , Matyas Angela , Kosenko Tanja , Goto Natalie K. , Vergara-Jaque Ariela , Lagace Thomas A.
Published: August 2019

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a ligand of low-density lipoprotein receptor (LDLR) that promotes LDLR degradation in late endosomes/lysosomes. In human plasma, 30-40% of PCSK9 is bound to LDL particles; however, the physiological significance of this interaction remains unknown. LDL bindingin vitrorequires a disordered N-terminal region in PCSK9’s prodomain. Here we report that peptides corresponding to a predicted amphipathic α-helix in the prodomain N-terminus adopted helical structure in a membrane-mimetic environment; this effect was greatly enhanced by an R46L substitution representing an athero-protectivePCSK9loss-of-function mutation. A helix-disrupting proline substitution within the putative α-helical motif in full-length PCSK9 lowered LDL binding affinity >5-fold. Modeling studies suggested the transient α-helix aligns multiple polar residues to interact with positive-charged residues in the C-terminal domain. Gain-of-functionPCSK9mutations associated with familial hypercholesterolemia (FH) and clustered at the predicted interdomain interface (R469W, R496W, F515L) inhibited LDL binding, which was abolished for the R496W variant. These studies inform on allosteric conformational changes in PCSK9 required for high-affinity binding to LDL particles. Moreover, we report the initial identification of FH-associated mutations that diminish the ability of PCSK9 to bind LDL, supporting that LDL association in the circulation inhibits PCSK9 activity.
Paclitaxel-induced peripheral neuropathy is caused by epidermal ROS and mitochondrial damage through conserved MMP-13 activation
Authors: Cirrincione Anthony M. , Pellegrini Adriana D. , Dominy Jessica R. , Benjamin Marisa E. , Utkina-Sosunova Irina , Lotti Francesco , Jergova Stanislava , Sagen Jacqueline , Rieger Sandra
Published: August 2019

Paclitaxel is a chemotherapeutic agent that causes peripheral neuropathy (PIPN) as a side effect of cancer treatment. Severely affected patients need to terminate chemotherapy, diminishing their chance of survival. The underlying causes of PIPN are unclear, but epidermal, unmyelinated axons have been shown to be the first to degenerate. We previously utilized a zebrafish in vivo model to show that the epidermal matrix-metalloproteinase 13 (MMP-13) induces degeneration of unmyelinated axons, whereas pharmacological inhibition of MMP-13 prevented axon degeneration. The precise functions by which MMP-13 is regulated and affects axons, however, remained elusive. In this study, we assessed mitochondrial damage and reactive oxygen species (ROS) formation as possible inducers of MMP-13, and we analyzed MMP-13-dependent damage. We show that the small ROS, H2O2, is increased in keratinocytes following treatment with paclitaxel. Epidermal mitochondrial damage appears to be a source of ROS leading to cytoplasmic H2O2 elevation, upregulation of MMP-13, and increased matrix degradation. Intriguingly, although axonal mitochondria also show aberrant morphologies and are vacuolized, as shown in other neuropathies, these axonal mitochondria do not produce increased H2O2 levels. We suggest that mitochondrial vacuolization occurs independently of axonal damage given that MMP-13 inhibition prevents axon degeneration, though vacuoles persist. We further show that MMP-13 dysregulation also underlies PIPN in rodent paclitaxel models, and that this function appears to be DRG neuron-extrinsic. These findings suggest that vacuolization is not a cause of paclitaxel-induced neuropathy, and that epidermal MMP-13 is a strong candidate for therapeutic interventions in cancer patients with neuropathy.
Extradomain-B Fibronectin is a molecular marker of invasive breast cancer cells
Authors: Vaidya Amita M. , Wang Helen , Qian Victoria , Lu Zheng-Rong
Published: August 2019

Breast tumor heterogeneity is a major impediment to oncotherapy. Tumor cells undergo rapid clonal evolution, thereby acquiring significant growth and invasive advantages. The absence of specific markers of these high-risk tumors precludes efficient therapeutic and diagnostic management of breast cancer. Given the critical function of tumor microenvironment in the oncogenic circuitry, we sought to determine the role of the extracellular matrix oncoprotein, extradomain-B fibronectin (EDB-FN), as a molecular marker of aggressive cancers. High-risk invasive cell lines generated from relatively less invasive MCF7 and MDA-MB-468 breast cancer cells by long-term TGF-β treatment and chemoresistance demonstrated hybrid epithelial-mesenchymal phenotype, enhanced motility, and significantly elevated EDB-FN levels in 2D- and 3D-cultures. To determine if EDB-FN could serve as a therapy-predictive marker, the invasive cell lines were treated with MK2206-HCl, a pan-AKT inhibitor. Phospho-AKT depletion reduced EMT and invasion of the populations, with a concomitant decrease in EDB-FN expression, partly through the phosphoAKT-SRp55 pathway, demonstrating that EDB-FN expression is strongly associated with high-risk breast cancer. EDB-FN is a promising molecular marker for accurate detection, differential diagnosis, and non-invasive therapeutic surveillance of aggressive breast cancer.

Summary Statement

Dynamic changes in invasive properties of breast cancer cells directly influence extradomain-B fibronectin levels, suggesting its potential role as a molecular marker for active surveillance and therapeutic monitoring of breast cancer.
Cables2 Is a Novel Smad2-Regulatory Factor Essential for Early Embryonic Development in Mice
Authors: Dinh Tra Thi Huong , Iseki Hiroyoshi , Mizuno Seiya , Iijima-Mizuno Saori , Tanimoto Yoko , Daitoku Yoko , Kato Kanako , Hamada Yuko , Hasan Ammar Shaker Hamed , Suzuki Hayate , Murata Kazuya , Muratani Masafumi , Ema Masatsugu , Kim Jun-dal , Ishida Junji , Fukamizu Akiyoshi , Kato Mitsuyasu , Takahashi Satoru , Yagami Ken-ichi , Wilson Valerie , Arkell Ruth M. , Sugiyama Fumihiro
Published: August 2019

CDK5 and Abl enzyme substrate 2 (Cables2), a member of the Cables family that has a C-terminal cyclin box-like domain, is widely expressed in adult mouse tissues. However, the physiological role of Cables2in vivois unknown. We show here thatCables2-deficiency causes post-gastrulation embryonic lethality in mice. The mutant embryos progress to gastrulation, but then arrest, and fail to grow. Analysis of gene expression patterns reveals that formation of the anterior visceral endoderm and the primitive streak is impaired inCables2-deficient embryos. Tetraploid complementation analyses support the critical requirement of Cables2 in both the epiblast and visceral endoderm for progression of embryogenesis. In addition, we show that Cables2 physically interacts with a key mediator of the canonical Nodal pathway, Smad2, and augments its transcriptional activity. These findings provide novel insights into the essential role of Cables2 in the early embryonic development in mice.
Regionalized tissue fluidization by an actomyosin cable is required for epithelial gap closure during insect gastrulation
Authors: Jain A. , Ulman V. , Mukherjee A. , Prakash M. , Pimpale L. , Muenster S. , Haase R. , Panfilio K.A. , Jug F. , Grill S.W. , Tomancak P. , Pavlopoulos A.
Published: August 2019

Many animal embryos pull and close an epithelial sheet around the spherical or ellipsoidal egg surface during a gastrulation process known as epiboly. The ovoidal geometry dictates that the epithelial sheet first expands and subsequently compacts. Moreover, the epithelial sheet spreading over the sphere is mechanically stressed and this stress needs to be released. Here we show that during extraembryonic tissue (serosa) epiboly in the red flour beetle Tribolium castaneum, the non-proliferative serosa becomes regionalized into two distinct territories: a dorsal region under higher tension away from the leading edge with larger non-rearranging cells, and a more fluid ventral region under lower tension surrounding the leading edge with smaller cells undergoing cell intercalation. Our results suggest that fluidization of the leading edge is caused by a heterogeneous actomyosin cable that drives sequential eviction and intercalation of individual cells away from the serosa margin. Since this developmental solution utilized during epiboly resembles the mechanism of wound healing in other systems, we propose actomyosin cable-driven local tissue fluidization as a conserved morphogenetic module for closure of epithelial gaps.
Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach
Authors: Polykretis Panagis , Luchinat Enrico , Bonucci Alessio , Giachetti Andrea , Graewert Melissa A. , Svergun Dmitri I. , Banci Lucia
Published: August 2019

The X-chromosome-linked inhibitor of apoptosis protein (XIAP) is a multidomain protein whose main function is to block apoptosis by caspase inhibition. XIAP is also involved in other signalling pathways, including NF-κB activation and copper homeostasis. XIAP is overexpressed in tumours, potentiating cell survival and resistance to chemotherapeutics, and has therefore become an important target for the treatment of malignancy. Despite the fact that the structure of each single domain is known, the conformation of the full-length protein has never been determined. Here, the first structural model of the full-length XIAP dimer, determined by an integrated approach using nuclear magnetic resonance, small-angle X-ray scattering and electron paramagnetic resonance data, is presented. It is shown that XIAP adopts a compact and relatively rigid conformation, implying that the spatial arrangement of its domains must be taken into account when studying the interactions with its physiological partners and in developing effective inhibitors.
Absolute structure of (3aS,5S,7aS,7bS,9aR,10R,12aR,12bS)-7b-hydroxy-4,4,7a,9a,12a-pentamethyl-10-[(2′R)-6-methylheptan-2-yl]-2,8,9-trioxooctadecahydrobenzo[d]indeno[4,5-b]azepin-5-yl acetate from 62-year-old crystals
Authors: Suescun Leopoldo , Heinzen Horacio
Published: August 2019

The structure of the title compound, C32H51NO6, was determined from 62-year-old crystals at room temperature and refined with 100 K data in a monoclinic (C2) space group. This compound with a triterpenoid structure, now confirmed by this study, played an important role in the determination of the structure of lanosterol. The molecules pack in linear O—H...O hydrogen-bonded chains along the short axis (b), while parallel chains display weak van der Waals interactions that explain the needle-shaped crystal morphology. The structure exhibits disorder of the flexible methylheptane chain at one end of the main molecule with a small void around it. Crystals of the compounds were resistant to data collection for decades with the available cameras and Mo Kα radiation single-crystal diffractometer in our laboratory until a new instrument with Cu Kα radiation operating at 100 K allowed the structure to be solved and refined.