bluuebunny/crossref_metadata_2025 huggingface dataset:
An efficient and accurate framework for calculating lattice thermal conductivity of solids: AFLOW—AAPL Automatic Anharmonic Phonon Library
Authors: Plata Jose J. , Nath Pinku , Usanmaz Demet , Carrete Jesús , Toher Cormac , de Jong Maarten , Asta Mark , Fornari Marco , Nardelli Marco Buongiorno , Curtarolo Stefano
Published: October 2017

One of the most accurate approaches for calculating lattice thermal conductivity, $$\kappa _\ell$$, is solving the Boltzmann transport equation starting from third-order anharmonic force constants. In addition to the underlying approximations of ab-initio parameterization, two main challenges are associated with this path: high computational costs and lack of automation in the frameworks using this methodology, which affect the discovery rate of novel materials with ad-hoc properties. Here, the Automatic Anharmonic Phonon Library (AAPL) is presented. It efficiently computes interatomic force constants by making effective use of crystal symmetry analysis, it solves the Boltzmann transport equation to obtain $$\kappa _\ell$$, and allows a fully integrated operation with minimum user intervention, a rational addition to the current high-throughput accelerated materials development framework AFLOW. An “experiment vs. theory” study of the approach is shown, comparing accuracy and speed with respect to other available packages, and for materials characterized by strong electron localization and correlation. Combining AAPL with the pseudo-hybrid functional ACBN0 is possible to improve accuracy without increasing computational requirements.
Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson’s disease
Authors: Sarkar Souvarish , Malovic Emir , Harishchandra Dilshan S. , Ghaisas Shivani , Panicker Nikhil , Charli Adhithiya , Palanisamy Bharathi N. , Rokad Dharmin , Jin Huajun , Anantharam Vellareddy , Kanthasamy Arthi , Kanthasamy Anumantha G.
Published: October 2017

The NLRP3 inflammasome signaling pathway is a major contributor to the neuroinflammatory process in the central nervous system. Oxidative stress and mitochondrial dysfunction are key pathophysiological processes of many chronic neurodegenerative diseases, including Parkinson’s disease (PD). However, the inter-relationship between mitochondrial defects and neuroinflammation is not well understood. In the present study, we show that impaired mitochondrial function can augment the NLRP3 inflammasome-driven proinflammatory cascade in microglia. Primary mouse microglia treated with the common inflammogen LPS increased NLRP3 and pro-IL-1β expression. Interestingly, exposure of LPS-primed microglial cells to the mitochondrial complex-I inhibitory pesticides rotenone and tebufenpyrad specifically potentiated the NLRP3 induction, ASC speck formation and pro-IL-1β processing to IL-1β in a dose-dependent manner, indicating that mitochondrial impairment heightened the NLRP3 inflammasome-mediated proinflammatory response in microglia. The neurotoxic pesticide-induced NLRP3 inflammasome activation was accompanied by bioenergetic defects and lysosomal dysfunction in microglia. Furthermore, the pesticides enhanced mitochondrial ROS generation in primary microglia, while amelioration of mitochondria-derived ROS by the mitochondria-targeted antioxidant mito-apocynin completely abolished IL-1β release, indicating mitochondrial ROS drives potentiation of the NLRP3 inflammasome in microglia. Exposure to conditioned media obtained from mitochondrial inhibitor-treated, LPS-primed microglial cells, but not unprimed cells, induced dopaminergic neurodegeneration in cultured primary mesencephalic and human dopaminergic neuronal cells (LUHMES). Notably, our in vivo results with chronic rotenone rodent models of PD further support the activation of proinflammatory NLRP3 inflammasome signaling due to mitochondrial dysfunction. Collectively, our results demonstrate that mitochondrial impairment in microglia can amplify NLRP3 inflammasome signaling, which augments the dopaminergic neurodegenerative process.
Neuronal replacement therapy: previous achievements and challenges ahead
Authors: Grade Sofia , Götz Magdalena
Published: October 2017

Lifelong neurogenesis and incorporation of newborn neurons into mature neuronal circuits operates in specialized niches of the mammalian brain and serves as role model for neuronal replacement strategies. However, to which extent can the remaining brain parenchyma, which never incorporates new neurons during the adulthood, be as plastic and readily accommodate neurons in networks that suffered neuronal loss due to injury or neurological disease? Which microenvironment is permissive for neuronal replacement and synaptic integration and which cells perform best? Can lost function be restored and how adequate is the participation in the pre-existing circuitry? Could aberrant connections cause malfunction especially in networks dominated by excitatory neurons, such as the cerebral cortex? These questions show how important connectivity and circuitry aspects are for regenerative medicine, which is the focus of this review. We will discuss the impressive advances in neuronal replacement strategies and success from exogenous as well as endogenous cell sources. Both have seen key novel technologies, like the groundbreaking discovery of induced pluripotent stem cells and direct neuronal reprogramming, offering alternatives to the transplantation of fetal neurons, and both herald great expectations. For these to become reality, neuronal circuitry analysis is key now. As our understanding of neuronal circuits increases, neuronal replacement therapy should fulfill those prerequisites in network structure and function, in brain-wide input and output. Now is the time to incorporate neural circuitry research into regenerative medicine if we ever want to truly repair brain injury.
Combined Microscopy, Calorimetry and X-ray Scattering Study of Fluorinated Dimesogens
Authors: Mandle Richard J. , Cowling Stephen J. , Goodby John W.
Published: October 2017

The material FDO11DFCB3 (compound 2 in this work) remains the only example of a liquid-crystalline material to exhibit a phase transition from the heliconical twist-bend phase into a lamellar smectic A mesophase, additionally this material exhibits a previously unidentified mesophase. We have prepared and characterised several homologues of this compound, with each material subjected to an in-depth analysis by optical microscopy, calorimetry and small angle X-ray scattering studies. Despite FDO11DFCB3 being similar in chemical structure to the novel materials presented herein its liquid-crystalline behaviour is rather different, indicating an unexpected sensitivity of the twist-bend phase to molecular structure.
Worsening calcification propensity precedes all-cause and cardiovascular mortality in haemodialyzed patients
Authors: Lorenz Georg , Steubl Dominik , Kemmner Stephan , Pasch Andreas , Koch-Sembdner Wilhelm , Pham Dang , Haller Bernhard , Bachmann Quirin , Mayer Christopher C. , Wassertheurer Siegfried , Angermann Susanne , Lech Maciej , Moog Philipp , Bauer Axel , Heemann Uwe , Schmaderer Christoph
Published: October 2017

A novel in-vitro test (T50-test) assesses ex-vivo serum calcification propensity which predicts mortality in HD patients. The association of longitudinal changes of T50 with all-cause and cardiovascular mortality has not been investigated. We assessed T50 in paired sera collected at baseline and at 24 months in 188 prevalent European HD patients from the ISAR cohort, most of whom were Caucasians. Patients were followed for another 19 [interquartile range: 11–37] months. Serum T50 exhibited a significant decline between baseline and 24 months (246 ± 64 to 190 ± 68 minutes; p < 0.001). With serum Δ-phosphate showing the strongest independent association with declining T50 (r = −0.39; p < 0.001) in multivariable linear regression. The rate of decline of T50 over 24 months was a significant predictor of all-cause (HR = 1.51 per 1SD decline, 95% CI: 1.04 to 2.2; p = 0.03) and cardiovascular mortality (HR = 2.15; 95% CI: 1.15 to 3.97; p = 0.02) in Kaplan Meier and multivariable Cox-regression analysis, while cross-sectional T50 at inclusion and 24 months were not. Worsening serum calcification propensity was an independent predictor of mortality in this small cohort of prevalent HD patients. Prospective larger scaled studies are needed to assess the value of calcification propensity as a longitudinal parameter for risk stratification and monitoring of therapeutic interventions.
MiR-302b Suppresses Osteosarcoma Cell Migration and Invasion by Targeting Runx2
Authors: Xie Yuanlong , Sun Wenchao , Deng Zhouming , Zhu Xiaobin , Hu Chao , Cai Lin
Published: October 2017

Osteosarcoma patients with lung metastasis and local invasion remain challenging to treat despite the significant contribution of the combination of surgery and neo-adjuvant chemotherapy. Our previous microarray study demonstrated that miR-302b had significantly lower expression in osteosarcoma cell lines than in osteoblast cell lines. In the present study, we further elucidated the role of miR-302b in regulating the migration and invasiveness of osteosarcoma. MiR-302b expression was markedly down-regulated in osteosarcoma cell lines and clinical tumour tissues. Lower levels of miR-302b expression were significantly associated with metastasis and high pathological grades. A functional study demonstrated that over-expression of miR-302b suppressed tumour cell proliferation, invasion and migration in vitro and in vivo. Runx2 was identified as a direct target gene for miR-302b by bioinformatics analysis and dual-luciferase reporter gene assay. Moreover, over-expression of miR-302b induced down-regulation of Runx2, OPN, MMP-2, MMP-9, MMP-12, MMP-14, and VEGF in 143B cells. Exogenous expression of Runx2 partially rescued the inhibitory effect of miR-302b on the invasion and migration activity of 143B osteosarcoma cells. Taken together, our results indicate that miR-302b functions as a tumour repressor in the invasion and migration of osteosarcoma by directly downregulating Runx2 expression and may be a potential therapeutic target for osteosarcoma.
Diagonal Earlobe Crease is a Visible Sign for Cerebral Small Vessel Disease and Amyloid-β
Authors: Lee Jin San , Park Seongbeom , Kim Hee Jin , Kim Yeshin , Jang Hyemin , Kim Ko Woon , Rhee Hak Young , Yoon Sung Sang , Hwang Kyoung Jin , Park Key-Chung , Moon Seung Hwan , Kim Sung Tae , Lockhart Samuel N. , Na Duk L. , Seo Sang Won
Published: October 2017

We investigated the frequency and clinical significance of diagonal earlobe crease (DELC) in cognitively impaired patients using imaging biomarkers, such as white matter hyperintensities (WMH) on MRI and amyloid-β (Aβ) PET. A total of 471 cognitively impaired patients and 243 cognitively normal (CN) individuals were included in this study. Compared with CN individuals, cognitively impaired patients had a greater frequency of DELC (OR 1.6, 95% CI 1.1–2.2, P = 0.007). This relationship was more prominent in patients with dementia (OR 1.8, 95% CI 1.2–2.7, P = 0.002) and subcortical vascular cognitive impairment (OR 2.4, 95% CI 1.6–3.6, P < 0.001). Compared with Aβ-negative cognitively impaired patients with minimal WMH, Aβ-positive patients with moderate to severe WMH were significantly more likely to exhibit DELC (OR 7.3, 95% CI 3.4–16.0, P < 0.001). We suggest that DELC can serve as a useful supportive sign, not only for the presence of cognitive impairment, but also for cerebral small vessel disease (CSVD) and Aβ-positivity. The relationship between DELC and Aβ-positivity might be explained by the causative role of CSVD in Aβ accumulation.
Postnatal Development of the Murine Notochord Remnants Quantified by High-resolution Contrast-enhanced MicroCT
Authors: Bhalla Sameer , Lin Kevin H. , Tang Simon Y.
Published: October 2017

The notochord gives rise to spinal segments during development, and it becomes embedded within the nucleus pulposus of the intervertebral disc (IVD) during maturation. The disruption of the notochord band has been observed with IVD degeneration. Since the mechanical competence of the IVD relies on its structural constituents, defining the structure of the notochord during aging is critical for investigations relating to IVD function and homeostasis. The assessment and imaging of the notochord has classically relied on histological techniques, which introduces sectioning artifacts during preparation and spatial biases. Magnetic resonance imaging (MRI) does not offer sufficient resolution to discriminate the notochord from the surrounding the nucleus pulposus, especially in murine models. Current X-ray based computed tomography systems provide imaging resolutions down to the single- and sub- micron scales, and when coupled with contrast-enhancing agents, enable the high-resolution three-dimensional imaging of relatively small features. Utilizing phosphomolybdic acid to preferentially bind to collagen cationic domains, we describe the structure of the notochord remnants with aging in the lumbar IVDs of BALB/c mice. These results provide a highly quantitative and sensitive approach to monitoring the IVD during postnatal development.
Progesterone Via its Type-A Receptor Promotes Myometrial Gap Junction Coupling
Authors: Nadeem Lubna , Shynlova Oksana , Mesiano Sam , Lye Stephen
Published: October 2017

Effective labour contractions require synchronization of myometrial cells through gap junctions (GJs). Clasically, progesterone (P4) is known to inhibit the expression of connexin-43 (Cx43, major component of GJs) and GJ formation in myometrium. Our current study is based on a striking observation that challenges this dogma. We observed conspicuous differences in the intracellular localization of Cx43 protein in PRA versus PRB expressing myocytes. Thus in P4 stimulated PRA cells Cx43 protein forms GJs, whereas in PRB cells the forward trafficking of Cx43 and GJ formation is inhibited even when Cx43 is overexpressed. We found that P4, via PRA/B, differentially regulates Cx43 translation to generate a Cx43-20 K isoform, which facilitates the transport of full length Cx43 to plasma membrane. The P4 mediated regulation of Cx43 trafficking and GJ formation occurs via non-genomic pathway and involves the regulation of mTOR signaling since inhibition of this pathway restored the Cx43 trafficking defect in PRB cells. We propose that PRA is a master regulator of Cx43 expression, GJ formation and myocyte connectivity/synchronization for labour.
Dynamic photo-switching in light-responsive JUC-62 for CO
2

capture
Authors: Prasetya Nicholaus , Ladewig Bradley P.
Published: October 2017

In this paper, we demonstrate the highly efficient photo-switching ability of a Cu-azobenzene tetracarboxylate MOF (JUC-62) for low-energy CO2 capture. Under UV light irradiation, both at 273 and 298 K, JUC-62 showed 51% and 34% lower CO2 uptake, respectively, than when UV light was off. Its dynamic CO2 uptake also matched well with its static condition. Storing it at ambient condition was also found not to destroy its framework structure and its dynamic photoswitching property could still be maintained.
Role of the Qinghai-Tibetan Plateau uplift in the Northern Hemisphere disjunction: evidence from two herbaceous genera of Rubiaceae
Authors: Deng Tao , Zhang Jian-Wen , Meng Ying , Volis Sergei , Sun Hang , Nie Ze-Long
Published: October 2017

To assess the role of the Qinghai-Tibetan Plateau uplift in shaping the intercontinental disjunction in Northern Hemisphere, we analyzed the origin and diversification within a geological timeframe for two relict herbaceous genera,TheligonumandKelloggia(Rubiaceae). Phylogenetic relationships within and betweenTheligonumandKelloggiaas well as their relatives were inferred using five chloroplast markers with parsimony, Bayesian and maximum-likelihood approaches. Migration routes and evolution of these taxa were reconstructed using Bayesian relaxed molecular clock and ancestral area reconstruction. Our results suggest the monophyly of eachTheligonumandKelloggia. Eastern Asian and North American species ofKelloggiadiverged at ca.18.52 Mya and the Mediterranean species ofTheligonumdiverged from eastern Asian taxa at ca.13.73 Mya. BothKelloggiaandTheligonumare Tethyan flora relicts, and their ancestors might have been occurred in warm tropical to subtropical environments along the Tethys coast. The Qinghai-Tibetan Plateau separated the eastern and western Tethyan area may contribute significantly to the disjunct distributions ofTheligonum, and the North Atlantic migration appears to be the most likely pathway of expansion ofKelloggiato North America. Our results highlight the importance role of the QTP uplift together with corresponding geological and climatic events in shaping biodiversity and biogeographic distribution in the Northern Hemisphere.
Silica precipitation potentially controls earthquake recurrence in seismogenic zones
Authors: Saishu Hanae , Okamoto Atsushi , Otsubo Makoto
Published: October 2017

Silica precipitation is assumed to play a significant role in post-earthquake recovery of the mechanical and hydrological properties of seismogenic zones. However, the relationship between the widespread quartz veins around seismogenic zones and earthquake recurrence is poorly understood. Here we propose a novel model of quartz vein formation associated with fluid advection from host rocks and silica precipitation in a crack, in order to quantify the timescale of crack sealing. When applied to sets of extensional quartz veins around the Nobeoka Thrust of SW Japan, an ancient seismogenic splay fault, our model indicates that a fluid pressure drop of 10–25 MPa facilitates the formation of typical extensional quartz veins over a period of 6.6 × 100–5.6 × 101years, and that 89%–100% of porosity is recovered within ~3 × 102years. The former and latter sealing timescales correspond to the extensional stress period (~3 × 101years) and the recurrence interval of megaearthquakes in the Nankai Trough (~3 × 102years), respectively. We therefore suggest that silica precipitation in the accretionary wedge controls the recurrence interval of large earthquakes in subduction zones.
Comparative analysis of molecular and physiological traits between perennial Arabis alpina Pajares and annual Arabidopsis thaliana Sy-0
Authors: Park Jong-Yoon , Kim Hoyeun , Lee Ilha
Published: October 2017

Annual plants complete life cycle in a year while perennial plants maintain growth for several years. Arabis alpina, a polycarpic perennial, is a close relative of monocarpic annual Arabidopsis. Pajares is an accession of A. alpina requiring vernalization, a long-term cold for flowering. Arabidopsis shows holistic flowering whereas Pajares shows idiographic flowering, producing axillary branches under variable developmental phases from juvenile, adult vegetative to reproductive phases. To understand the molecular mechanism behind diverse phases of axillary branches, we analyzed the levels of primary miR156 expressions because miR156-SPL module is a key regulator for developmental phase transition. We found that in Pajares, miR156 levels were highly variable among the axillary branches, which causes differential sensitivity to vernalization. Thus, the axillary branches expressing high levels of miR156 remain in juvenile phase even after vernalization, whereas the axillary branches expressing low levels of miR156 produce flowers after vernalization. In contrast, every axillary branches of Arabidopsis winter annual Sy-0 expressed similar levels of miR156 and synchronously responded to vernalization, which causes holistic flowering. Therefore, we suggest that variable miR156 expression levels and the resulting differential response to vernalization among axillary branches are distinctive features determining polycarpic perenniality of A. alpina Pajares.
Prokaryotic Community Distribution along an Ecological Gradient of Salinity in Surface and Subsurface Saline Soils
Authors: Xie Kehui , Deng Yong , Zhang Shaocun , Zhang Wenhao , Liu Jianrong , Xie Yulong , Zhang Xuze , Huang He
Published: October 2017

Salinity effects on microbial communities in saline soils is still unclear, and little is known about subsurface soil microbial communities especially in saline or hypersaline ecosystems. Here we presented the survey of the prokaryotic community in saline soils along a salinity gradient (17.3–148.3 dS/m) in surface (0–10 cm) and subsurface (15–30 cm) saline soils of Qarhan Salt Lake, China. Moreover, we compared them with three paired nonsaline normal soils. Using the high-throughput sequencing technology and several statistical methods, we observed no significant community difference between surface soils and subsurface soils. For environmental factors, we found that TOC was the primary driver of the prokaryotic community distribution in surface saline soils, so was pH in subsurface saline soils. Salinity had more effects on the prokaryotic community in subsurface saline soils than in surface saline soils and played a less important role in saline soils than in saline waters or saline sediments. Our research provided references for the prokaryotic community distribution along a salinity gradient in both surface and subsurface saline soils of arid playa areas.
Novel Application of Magnetic Protein: Convenient One-Step Purification and Immobilization of Proteins
Authors: Jiang Min , Zhang Lujia , Wang Fengqing , Zhang Jie , Liu Guosong , Gao Bei , Wei Dongzhi
Published: October 2017

Recently, a magnetic protein was discovered, and a multimeric magnetosensing complex was validated, which may form the basis of magnetoreception. In this study, the magnetic protein was firstly used in biotechnology application, and a novel convenient one-step purification and immobilization method was established. A universal vector and three linker patterns were developed for fusion expression of magnetic protein and target protein. The magnetic protein was absorbed by iron beads, followed by target protein aggregation, purification, and immobilization. GFP, employed as a reporter protein, was successfully purified from cell lysate. Subsequently, three enzymes (lipase, α-L-arabinofuranosidase, pullulanase) with different molecular sizes testified the versatility of this magnetic-based approach. The specific activities of the purified enzymes were distinctly higher than those of the traditionally purified enzymes using affinity chromatography. The lipase immobilized on iron beads presented improved thermostability and enhanced pH tolerance compared to the free enzyme. The immobilized lipase could be easily recovered and reused for maximum utilization. After 20 cycles of reutilization, the magnetically immobilized lipase retained 71% of its initial activity. This investigation may help introduce magnetic protein into biotechnology applications, and the one-step purification and immobilization method may serve to illustrate an economically viable process for industry.
Carnosine scavenging of glucolipotoxic free radicals enhances insulin secretion and glucose uptake
Authors: Cripps Michael J. , Hanna Katie , Lavilla Charlie , Sayers Sophie R. , Caton Paul W. , Sims Craig , De Girolamo Luigi , Sale Craig , Turner Mark D.
Published: October 2017

The worldwide prevalence of diabetes has risen to 8.5% among adults, which represents a staggering rise in prevalence from 4.7% in 1980. Whilst some treatments work by increasing insulin secretion, over time their effectiveness decreases. We aim to increase insulin secretion by developing strategies that work through mechanisms independent of current treatment options. Isolated CD1 mouse islets, INS-1 pancreatic β-cells, or C2C12 mouse myotubes were incubated in standard tissue culture media, or media supplemented with 28 mM glucose, 200 μM palmitic acid, and 200 μM oleic acid as a cellular model of diabetic glucolipotoxicity. Intracellular reactive species content was assayed using 2′,7′-dichlorofluorescein diacetate dye, inducible nitric oxide synthase levels determined by Western blot, 3-nitrotyrosine and 4-hydrpxnonenal both assayed by ELISA, insulin secretion quantified using ELISA or radioimmunoassay, and glucose uptake determined through 2-deoxy glucose 6 phosphate luminescence. Our data indicate that carnosine, a histidine containing dipeptide available through the diet, is an effective scavenger of each of the aforementioned reactive species. This results in doubling of insulin secretion from isolated mouse islets or INS-1 β-cells. Crucially, carnosine also reverses glucolipotoxic inhibition of insulin secretion and enhances glucose uptake into skeletal muscle cells. Thus, carnosine, or non-hydrolysable carnosine analogs, may represent a new class of therapeutic agent to fight type 2 diabetes.
Diffusion tensor image features predict IDH genotype in newly diagnosed WHO grade II/III gliomas
Authors: Eichinger Paul , Alberts Esther , Delbridge Claire , Trebeschi Stefano , Valentinitsch Alexander , Bette Stefanie , Huber Thomas , Gempt Jens , Meyer Bernhard , Schlegel Juergen , Zimmer Claus , Kirschke Jan S. , Menze Bjoern H. , Wiestler Benedikt
Published: October 2017

We hypothesized that machine learning analysis based on texture information from the preoperative MRI can predict IDH mutational status in newly diagnosed WHO grade II and III gliomas. This retrospective study included in total 79 consecutive patients with a newly diagnosed WHO grade II or III glioma. Local binary pattern texture features were generated from preoperative B0 and fractional anisotropy (FA) diffusion tensor imaging. Using a training set of 59 patients, a single hidden layer neural network was then trained on the texture features to predict IDH status. The model was validated based on the prediction accuracy calculated in a previously unseen set of 20 gliomas. Prediction accuracy of the generated model was 92% (54/59 cases; AUC = 0.921) in the training and 95% (19/20; AUC = 0.952) in the validation cohort. The ten most important features were comprised of tumor size and both B0 and FA texture information, underlining the joint contribution of imaging data to classification. Machine learning analysis of DTI texture information and tumor size reliably predicts IDH status in preoperative MRI of gliomas. Such information may increasingly support individualized surgical strategies, supplement pathological analysis and highlight the potential of radiogenomics.
Placenta-specific1 (PLAC1) is a potential target for antibody-drug conjugate-based prostate cancer immunotherapy
Authors: Nejadmoghaddam Mohammad-Reza , Zarnani Amir-Hassan , Ghahremanzadeh Ramin , Ghods Roya , Mahmoudian Jafar , Yousefi Maryam , Nazari Mahboobeh , Ghahremani Mohammad Hossein , Abolhasani Maryam , Anissian Ali , Mahmoudi Morteza , Dinarvand Rassoul
Published: October 2017

Our recent findings strongly support the idea of PLAC1 being as a potential immunotherapeutic target in prostate cancer (PCa). Here, we have generated and evaluated an anti-placenta-specific1 (PLAC1)-based antibody drug conjugate (ADC) for targeted immunotherapy of PCa. Prostate cancer cells express considerable levels of PLAC1. The Anti-PLAC1 clone, 2H12C12, showed high reactivity with recombinant PLAC1 and selectivity recognized PLAC1 in prostate cancer cells but not in LS180 cells, the negative control. PLAC1 binding induced rapid internalization of the antibody within a few minutes which reached to about 50% after 15 min and almost completed within an hour. After SN38 conjugation to antibody, a drug-antibody ratio (DAR) of about 5.5 was achieved without apparent negative effect on antibody affinity to cell surface antigen. The ADC retained intrinsic antibody activity and showed enhanced and selective cytotoxicity with an IC50 of 62 nM which was about 15-fold lower compared to free drug. Anti-PLAC1-ADC induced apoptosis in human primary prostate cancer cells and prostate cell lines. No apparent cytotoxic effect was observed inin vivoanimal safety experiments. Our newly developed anti-PLAC1-based ADCs might pave the way for a reliable, efficient, and novel immunotherapeutic modality for patients with PCa.
Portable biosensor for monitoring cortisol in low-volume perspired human sweat
Authors: Kinnamon David , Ghanta Ramesh , Lin Kai-Chun , Muthukumar Sriram , Prasad Shalini
Published: October 2017

A non-faradaic label-free cortisol biosensor was demonstrated using MoS2 nanosheets integrated into a nanoporous flexible electrode system. Low volume (1–5 μL) sensing was achieved through use of a novel sensor stack design comprised of vertically aligned metal electrodes confining semi-conductive MoS2 nanosheets. The MoS2 nanosheets were surface functionalized with cortisol antibodies towards developing an affinity biosensor specific to the physiological relevant range of cortisol (8.16 to 141.7 ng/mL) in perspired human sweat. Sensing was achieved by measuring impedance changes associated with cortisol binding along the MoS2 nanosheet interface using electrochemical impedance spectroscopy. The sensor demonstrated a dynamic range from 1–500 ng/mL with a limit of detection of 1 ng/mL. A specificity study was conducted using a metabolite expressed in human sweat, Ethyl Glucuronide. Continuous dosing studies were performed during which the sensor was able to discriminate between four cortisol concentration ranges (0.5, 5, 50, 500 ng/mL) for a 3+ hour duration. Translatability of the sensor was shown with a portable form factor device, demonstrating a comparable dynamic range and limit of detection for the sensor. The device demonstrated a R2 correlation value of 0.998 when comparing measurements to the reported impedance values of the benchtop instrumentation.
Long-term Cyclability of Substoichiometric Silicon Nitride Thin Film Anodes for Li-ion Batteries
Authors: Ulvestad Asbjørn , Andersen Hanne Flåten , Mæhlen Jan Petter , Prytz Øystein , Kirkengen Martin
Published: October 2017

Silicon has been the subject of an extensive research effort aimed at developing new anode materials for lithium ion batteries due to its large specific and volumetric capacity. However, commercial use is limited by a number of degradation problems, many of which are related to the large volume change the material undergoes during cycling in combination with limited lithium-diffusivity. Silicon rich silicon oxides (SiOx), which converts into active silicon and inactive lithium oxide during the initial lithiation, have attracted some attention as a possible solution to these issues. In this work we present an investigation of silicon rich amorphous silicon nitride (a-SiNx) as an alternative convertible anode material. Amorphous SiN0.89 thin films deposited by plasma enhanced chemical vapour deposition show reversible reactions with lithium when cycled between 0.05 and 1.0 V vs. Li+/Li. This material delivers a reversible capacity of approximately 1,200 mAh/g and exhibits excellent cycling stability, with 41 nm a-SiN0.89 thin film electrodes showing negligible capacity degradation over more than 2,400 cycles.
MG-132 reduces virus release in Bovine herpesvirus-1 infection
Authors: Fiorito Filomena , Iovane Valentina , Cantiello Antonietta , Marullo Annarosaria , De Martino Luisa , Iovane Giuseppe
Published: October 2017

Bovine herpesvirus 1 (BoHV-1) can provoke conjunctivitis, abortions and shipping fever. BoHV-1 infection can also cause immunosuppression and increased susceptibility to secondary bacterial infections, leading to pneumonia and occasionally to death. Herein, we investigated the influence of MG-132, a proteasome inhibitor, on BoHV-1 infection in bovine kidney (MDBK) cells. Infection of MDBK cells with BoHV-1 induces apoptotic cell death that enhances virus release. Whereas, MG-132 inhibited virus-induced apoptosis and stimulated autophagy. Protein expression of viral infected cell protein 0 (bICP0), which is constitutively expressed during infection and is able to stimulate Nuclear factor kappa B (NF-κB), was completely inhibited by MG-132. These results were accompanied by a significant delay in the NF-κB activation. Interestingly, the efficient virus release provoked by BoHV-1-induced apoptosis was significantly reduced by MG-132. Overall, this study suggests that MG-132, through the activation of autophagy, may limit BoHV-1 replication during productive infection, by providing an antiviral defense mechanism.
The Role of Chromatin Density in Cell Population Heterogeneity during Stem Cell Differentiation
Authors: Golkaram Mahdi , Jang Jiwon , Hellander Stefan , Kosik Kenneth S. , Petzold Linda R.
Published: October 2017

We incorporate three-dimensional (3D) conformation of chromosome (Hi-C) and single-cell RNA sequencing data together with discrete stochastic simulation, to explore the role of chromatin reorganization in determining gene expression heterogeneity during development. While previous research has emphasized the importance of chromatin architecture on activation and suppression of certain regulatory genes and gene networks, our study demonstrates how chromatin remodeling can dictate gene expression distribution by folding into distinct topological domains. We hypothesize that the local DNA density during differentiation accentuate transcriptional bursting due to the crowding effect of chromatin. This phenomenon yields a heterogeneous cell population, thereby increasing the potential of differentiation of the stem cells.
Ultrasensitive, high-dynamic-range and broadband strain sensing by time-of-flight detection with femtosecond-laser frequency combs
Authors: Lu Xing , Zhang Shuangyou , Chen Xing , Kwon Dohyeon , Jeon Chan-Gi , Zhang Zhigang , Kim Jungwon , Shi Kebin
Published: October 2017

Ultrahigh-resolution optical strain sensors provide powerful tools in various scientific and engineering fields, ranging from long-baseline interferometers to civil and aerospace industries. Here we demonstrate an ultrahigh-resolution fibre strain sensing method by directly detecting the time-of-flight (TOF) change of the optical pulse train generated from a free-running passively mode-locked laser (MLL) frequency comb. We achieved a local strain resolution of 18 pε/Hz1/2 and 1.9 pε/Hz1/2 at 1 Hz and 3 kHz, respectively, with large dynamic range of >154 dB at 3 kHz. For remote-point sensing at 1-km distance, 80 pε/Hz1/2 (at 1 Hz) and 2.2 pε/Hz1/2 (at 3 kHz) resolution is demonstrated. While attaining both ultrahigh resolution and large dynamic range, the demonstrated method can be readily extended for multiple-point sensing as well by taking advantage of the broad optical comb spectra. These advantages may allow various applications of this sensor in geophysical science, structural health monitoring, and underwater science.
Switching to PegIFNα-2b leads to HBsAg loss in patients with low HBsAg levels and HBV DNA suppressed by NAs
Authors: Huang Jing , Zhang Ka , Chen Wenli , Liao Jinyao , Luo Xiaodan , Chen Ren
Published: October 2017

Patients with low hepatitis B surface antigen (HBsAg) levels and hepatitis B virus (HBV) DNA suppression by nucleos(t)ide analogues (NAs) achieve high rate of HBsAg loss through switching to PegIFNα in pre-registration study. The aim of this study was to achieve higher rate of HBsAg loss through extended PegIFN treatment. 98 patients with HBsAg < 2,000 IU/ml and HBV DNA < 20 IU/ml were randomized to receive PegIFNα-2b or continuing NA therapy for 60 weeks. At the end of treatment (EOT) and end of follow-up (EOF), only patients who switched to PegIFNα-2b achieved HBsAg loss (32.6%) and HBsAg seroconversion (27.9% and 25.6%). Patients who switched to PegIFNα-2b also achieved higher HBeAg seroconversion rates (65.1%) and HBeAg loss (81.4% and 90.7%) than those who continued NAs treatment. On-treatment HBsAg declines predicted the responses at EOT, and HBsAg declines at post-baseline times predicted the responses at EOF. The rates of responses were not increased through extended PegIFNα treatment. For patients with low HBsAg and HBV suppression with NAs, switching to PegIFNα-2b significantly increased the rates of HBsAg loss and HBsAg seroconversion. HBsAg decline can predict the response of switching to PegIFNα-2b following from NAs.
High resolution, high speed, long working distance, large field of view confocal fluorescence microscope
Authors: Pacheco Shaun , Wang Chengliang , Chawla Monica K. , Nguyen Minhkhoi , Baggett Brend K. , Utzinger Urs , Barnes Carol A. , Liang Rongguang
Published: October 2017

Confocal fluorescence microscopy is often used in brain imaging experiments, however conventional confocal microscopes are limited in their field of view, working distance, and speed for high resolution imaging. We report here the development of a novel high resolution, high speed, long working distance, and large field of view confocal fluorescence microscope (H2L2-CFM) with the capability of multi-region and multifocal imaging. To demonstrate the concept, a 0.5 numerical aperture (NA) confocal fluorescence microscope is prototyped with a 3 mm × 3 mm field of view and 12 mm working distance, an array of 9 beams is scanned over the field of view in 9 different regions to speed up the acquisition time by a factor of 9. We test this custom designed confocal fluorescence microscope for future use with brain clarification methods to image large volumes of the brain at subcellular resolution. This multi-region and multi-spot imaging method can be used in other imaging modalities, such as multiphoton microscopes, and the field of view can be extended well beyond 12 mm × 12 mm.
Fabrication of AO/LDH fluorescence composite and its detection of Hg2+ in water
Authors: Liu Meng , Lv Guocheng , Mei Lefu , Wei Yanke , Liu Jieyuan , Li Zhaohui , Liao Libing
Published: October 2017

Divalent mercury ion (Hg2+) is one of the most common pollutants in water with high toxicity and significant bioaccumulation, for which sensitive and selective detection methods are highly necessary to carry out its detection and quantification. Fluorescence detection by organic dyes is a simple and rapid method in pollutant analyses and is limited because of quenching caused by aggregation dye molecules. Hydrotalcite (LDH) is one of the most excellent carrier materials. In this study, an organic dye acridine orange (AO) was successfully loaded on the LDH layers, which significantly inhibited fluorescence quenching of AO. The composite AO/LDH reaches the highest fluorescence intensity when the AO initial concentration is 5 mg/L. With its enhanced fluorescent property, the composite powder was fabricated to fluorescence test papers. The maximal fluorescence intensity was achieved with a pulp to AO/LDH ratio of 1:5 which can be used to detect Hg2+ in water by naked eyes. Hg2+ in aqueous solution can be detected by instruments in the range of 0.5 to 150 mM. The novelty of this study lies on both the development of a new type of mineral-dye composite material, as well as its practical applications for fast detection.
Therapy of corneal endothelial dysfunction with corneal endothelial cell-like cells derived from skin-derived precursors
Authors: Shen Lin , Sun Peng , Zhang Canwei , Yang Le , Du Liqun , Wu Xinyi
Published: October 2017

Corneal endothelial dysfunction occurs when corneal endothelial cells (CECs) are dramatically lost and eventually results in vision loss. Corneal transplantation is the only solution at present. However, corneal transplantation requires a fresh human cornea and there is a worldwide shortage of donors. Therefore, finding new functional CECs to replace human CECs is urgent. Skin-derived precursors (SKPs) can be easily acquired and have multiple differential potential. We co-cultured human SKPs with B4G12 cells in serum-free medium and obtained abundant CEC-like cells which had similar morphology and characteristic to human CECs. CEC-like cells exerted excellent therapeutic effect when they were transplanted into rabbit and monkey corneal endothelial dysfunction models by injection method. This protocol enables efficient production of CEC-like cells from SKPs. The renewable cell source, novel derivation method and simple treatment strategy may lead to potential applications in cell replacement therapy for corneal endothelial dysfunction.
Herpud1 negatively regulates pathological cardiac hypertrophy by inducing IP3 receptor degradation
Authors: Torrealba Natalia , Navarro-Marquez Mario , Garrido Valeria , Pedrozo Zully , Romero Diego , Eura Yuka , Villalobos Elisa , Roa Juan Carlos , Chiong Mario , Kokame Koichi , Lavandero Sergio
Published: October 2017

Cardiac hypertrophy is an adaptive response triggered by pathological stimuli. Regulation of the synthesis and the degradation of the Ca2+ channel inositol 1,4,5-trisphosphate receptor (IP3R) affects progression to cardiac hypertrophy. Herpud1, a component of the endoplasmic reticulum-associated degradation (ERAD) complex, participates in IP3R1 degradation and Ca2+ signaling, but the cardiac function of Herpud1 remains unknown. We hypothesize that Herpud1 acts as a negative regulator of cardiac hypertrophy by regulating IP3R protein levels. Our results show that Herpud1-knockout mice exhibit cardiac hypertrophy and dysfunction and that decreased Herpud1 protein levels lead to elevated levels of hypertrophic markers in cultured rat cardiomyocytes. In addition, IP3R levels were elevated both in Herpud1-knockout mice and Herpud1 siRNA-treated rat cardiomyocytes. The latter treatment also led to elevated cytosolic and nuclear Ca2+ levels. In summary, the absence of Herpud1 generates a pathological hypertrophic phenotype by regulating IP3R protein levels. Herpud1 is a novel negative regulator of pathological cardiac hypertrophy.
Surface Decoration of Pt Nanoparticles via ALD with TiO2 Protective Layer on Polymeric Nanofibers as Flexible and Reusable Heterogeneous Nanocatalysts
Authors: Celebioglu Asli , Ranjith Kugalur Shanmugam , Eren Hamit , Biyikli Necmi , Uyar Tamer
Published: October 2017

Coupling the functional nanoheterostructures over the flexible polymeric nanofibrous membranes through electrospinning followed by the atomic layer deposition (ALD), here we presented a high surface area platform as flexible and reusable heterogeneous nanocatalysts. Here, we show the ALD of titanium dioxide (TiO2) protective nanolayer onto the electrospun polyacrylonitrile (PAN) nanofibrous web and then platinum nanoparticles (Pt-NP) decoration was performed by ALD onto TiO2 coated PAN nanofibers. The free-standing and flexible Pt-NP/TiO2-PAN nanofibrous web showed the enhancive reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP) within 45 seconds though the hydrogenation process with the degradation rate of 0.1102 s−1. The TiO2 protective layer on the PAN polymeric nanofibers was presented as an effective route to enhance the attachment of Pt-NP and to improve the structure stability of polymeric nanofibrous substrate. Commendable enhancement in the catalytic activity with the catalytic dosage and the durability after the reusing cycles were investigated over the reduction of 4-NP. Even after multiple usage, the Pt-NP/TiO2-PAN nanofibrous webs were stable with the flexible nature with the presence of Pt and TiO2 on its surface.
The protein phosphatase 1 regulator NIPP1 is essential for mammalian spermatogenesis
Authors: Ferreira Mónica , Boens Shannah , Winkler Claudia , Szekér Kathelijne , Verbinnen Iris , Van Eynde Aleyde , Fardilha Margarida , Bollen Mathieu
Published: October 2017

NIPP1 is one of the major nuclear interactors of protein phosphatase PP1. The deletion of NIPP1 in mice is early embryonic lethal, which has precluded functional studies in adult tissues. Hence, we have generated an inducible NIPP1 knockout model using a tamoxifen-inducible Cre recombinase transgene. The inactivation of the NIPP1 encoding alleles (Ppp1r8) in adult mice occurred very efficiently in testis and resulted in a gradual loss of germ cells, culminating in a Sertoli-cell only phenotype. Before the overt development of this phenotype Ppp1r8
−/−
testis showed a decreased proliferation and survival capacity of cells of the spermatogenic lineage. A reduced proliferation was also detected after the tamoxifen-induced removal of NIPP1 from cultured testis slices and isolated germ cells enriched for undifferentiated spermatogonia, hinting at a testis-intrinsic defect. Consistent with the observed phenotype, RNA sequencing identified changes in the transcript levels of cell-cycle and apoptosis regulating genes in NIPP1-depleted testis. We conclude that NIPP1 is essential for mammalian spermatogenesis because it is indispensable for the proliferation and survival of progenitor germ cells, including (un)differentiated spermatogonia.
The polyglutamine protein ataxin-3 enables normal growth under heat shock conditions in the methylotrophic yeast Pichia pastoris
Authors: Bonanomi Marcella , Roffia Valentina , De Palma Antonella , Lombardi Alessio , Aprile Francesco Antonio , Visentin Cristina , Tortora Paolo , Mauri Pierluigi , Regonesi Maria Elena
Published: October 2017

The protein ataxin-3 carries a polyglutamine stretch close to the C-terminus that triggers a neurodegenerative disease in humans when its length exceeds a critical threshold. A role as a transcriptional regulator but also as a ubiquitin hydrolase has been proposed for this protein. Here, we report that, when expressed in the yeast Pichia pastoris, full-length ataxin-3 enabled almost normal growth at 37 °C, well above the physiological optimum of 30 °C. The N-terminal Josephin domain (JD) was also effective but significantly less, whereas catalytically inactive JD was completely ineffective. Based on MudPIT proteomic analysis, we observed that the strain expressing full-length, functional ataxin-3 displayed persistent upregulation of enzymes involved in mitochondrial energy metabolism during growth at 37 °C compared with the strain transformed with the empty vector. Concurrently, in the transformed strain intracellular ATP levels at 37 °C were even higher than normal ones at 30 °C. Elevated ATP was also paralleled by upregulation of enzymes involved in both protein biosynthesis and biosynthetic pathways, as well as of several stress-induced proteins. A similar pattern was observed when comparing a strain expressing JD with another expressing its catalytically inactive counterpart. We suggest that such effects mostly result from mechanisms of transcriptional regulation.
A novel quantification-driven proteomic strategy identifies an endogenous peptide of pleiotrophin as a new biomarker of Alzheimer’s disease
Authors: Skillbäck Tobias , Mattsson Niklas , Hansson Karl , Mirgorodskaya Ekaterina , Dahlén Rahil , van der Flier Wiesje , Scheltens Philip , Duits Floor , Hansson Oskar , Teunissen Charlotte , Blennow Kaj , Zetterberg Henrik , Gobom Johan
Published: October 2017

We present a new, quantification-driven proteomic approach to identifying biomarkers. In contrast to the identification-driven approach, limited in scope to peptides that are identified by database searching in the first step, all MS data are considered to select biomarker candidates. The endopeptidome of cerebrospinal fluid from 40 Alzheimer’s disease (AD) patients, 40 subjects with mild cognitive impairment, and 40 controls with subjective cognitive decline was analyzed using multiplex isobaric labeling. Spectral clustering was used to match MS/MS spectra. The top biomarker candidate cluster (215% higher in AD compared to controls, area under ROC curve = 0.96) was identified as a fragment of pleiotrophin located near the protein’s C-terminus. Analysis of another cohort (n = 60 over four clinical groups) verified that the biomarker was increased in AD patients while no change in controls, Parkinson’s disease or progressive supranuclear palsy was observed. The identification of the novel biomarker pleiotrophin 151–166 demonstrates that our quantification-driven proteomic approach is a promising method for biomarker discovery, which may be universally applicable in clinical proteomics.