bluuebunny/crossref_metadata_2025 huggingface dataset:
A Description of Deaths Following Emergency Abdominal Surgery
Authors: Wolsted Henrik , Møller Ann Merete , Tolstrup Mai‐Britt , Vester‐Andersen Morten
Published: July 2017

Objective

Emergency major abdominal surgery carries a high mortality rate. The aim of this present study was to characterize a population of deceased abdominal surgical patients, to examine how many died unexpectedly and how many were subject to treatment limitations.

Materials and methods

We included adult emergency abdominal surgical patients who died within 30 days postoperatively. We collected data from January 1, 2013, to December 31, 2014, in a Danish tertiary care hospital (Herlev).

Results

A total of 138 patients were included which corresponded to a crude mortality rate of 16.5% in the population. Four percent (5 of 138) of the patients died unexpectedly without any prior signs of deterioration and 46% (65 of 138) experienced a complicated treatment course, 67% of which was treated in the intensive care unit (ICU). The remaining 50% (68 of 138) had treatment limitations, applied pre‐ or postoperatively, of which 4% were treated in the ICU ward.

Conclusions

In the present study, we found a high number of patients with treatment limitations, offering one explanation to why so relatively few high‐risk surgical patients are admitted to the ICU ward. Whether intermediary wards could serve as a viable alternative for these patients, securing a sufficient level of treatment without taking up scarce beds in the intensive care unit, remains an important question for future studies. Furthermore, five patients died unexpectedly, without any clear cause of death, proving that continual strides toward improving the overall process of postoperative care are still demanded.
Esophageal stenosis and the Glasgow Prognostic Score as independent factors of poor prognosis for patients with locally advanced unresectable esophageal cancer treated with chemoradiotherapy (exploratory analysis of JCOG0303)
Authors: Okuno Tatsuya , Wakabayashi Masashi , Kato Ken , Shinoda Masayuki , Katayama Hiroshi , Igaki Hiroyasu , Tsubosa Yasuhiro , Kojima Takashi , Okabe Hiroshi , Kimura Yusuke , Kawano Tatsuyuki , Kosugi Shinichi , Toh Yasushi , Kato Hoichi , Nakamura Kenichi , Fukuda Haruhiko , Ishikura Satoshi , Ando Nobutoshi , Kitagawa Yuko ,   Japan Esophageal Oncology Group/Japan Clinical Oncology Group
Published: July 2017

Background

The aim of this study was to investigate the possible prognostic factors and predictive accuracy of the Glasgow Prognostic Score (GPS) for patients with unresectable locally advanced esophageal squamous cell carcinoma (LAESCC) treated with chemoradiotherapy.

Methods

One hundred forty-two patients were enrolled in JCOG0303 and assigned to the standard cisplatin and 5-fluorouracil (PF)-radiotherapy (RT) group or the low-dose PF-RT group. One hundred thirty-one patients with sufficient data were included in this analysis. A Cox regression model was used to analyze the prognostic factors of patients with unresectable LAESCC treated with PF-RT. The GPS was classified based on the baseline C-reactive protein (CRP) and serum albumin levels. Patients with CRP ≤1.0 mg/dL and albumin ≥3.5 g/dL were classified as GPS0. If only CRP was increased or only albumin was decreased, the patients were classified as GPS1, and the patients with CRP >1.0 mg/dL and albumin <3.5 g/dL were classified as GPS2.

Results

The patients’ backgrounds were as follows: median age (range), 62 (37–75); male/female, 119/12; ECOG PS 0/1/2, 64/65/2; and clinical stage (UICC 5th) IIB/III/IVA/IVB, 3/75/22/31. Multivariable analyses indicated only esophageal stenosis as a common factor for poor prognosis. In addition, overall survival tended to decrease according to the GPS subgroups (median survival time (months): GPS0/GPS1/GPS2 16.1/14.9/8.7).

Conclusions

Esophageal stenosis was identified as a candidate stratification factor for randomized trials of unresectable LAESCC patients. Furthermore, GPS represents a prognostic factor for LAESCC patients treated with chemoradiotherapy.

Clinical Trial Information

UMIN000000861.
Antioxidant Activity and Kinetics Studies of Quercetin, Epicatechin and Naringenin in Bulk Methyl Linoleate
Authors: Palma Manuel , Robert Paz , Holgado Francisca , Velasco Joaquín , Márquez‐Ruiz Gloria
Published: July 2017

The objective of this work was to evaluate the antioxidant action of flavonoids with specific differences in chemical structure, namely, quercetin (Q), epicatechin (E) and naringenin (N), in bulk methyl linoleate (ML) under different oxidation conditions at 60 °C, in an oven and in a Rancimat apparatus. The oxidation kinetics were studied by direct and concomitant analysis of primary and secondary oxidation compounds. Addition of 200 mg/kg of E or Q to ML increased about tenfold the oxidative stability of ML. The protective effect was significantly higher for E, independent of the oxidation conditions used. However, N showed no effect. Results obtained were attributed to differences in structural features and polarity. Thus, the presence of the ortho‐dihydroxy structure in the B ring and the 3‐hydroxyl group in the C ring of E and Q seemed to be determinant and the comparatively higher polarity of E may have enhanced its antioxidant efficiency.
Impacts of Sensation, Perception, and Motor Abilities of the Ipsilesional Upper Limb on Hand Functions in Unilateral Stroke: Quantifications From Biomechanical and Functional Perspectives
Authors: Hsu Hsiu‐Yun , Ke Chia‐Wen , Kuan Ta‐Shen , Yang Hsiu‐Ching , Tsai Ching‐Liang , Kuo Li‐Chieh
Published: July 2017

Background

The presence of subtle losses in hand dexterity after stroke affects the regaining of independence with regard to activities of daily living. Therefore, awareness of ipsilesional upper extremity (UE) function may be of importance when developing a comprehensive rehabilitation program. However, current hand function tests seem to be unable to identify asymptomatic UE impairments.

Objectives

To assess the motor coordination as well as the sensory perception of an ipsilesional UE using biomechanical analysis of performance‐oriented tasks and conducting a Manual Tactile Test (MTT).

Design

Case‐controlled study.

Setting

A university hospital.

Participants

A total of 21 patients with unilateral stroke, along with 21 matched healthy control subjects, were recruited.

Methods

Each participant was requested to perform a pinch−holding‐up activity (PHUA) test, object‐transport task, and reach‐to‐grasp task via motion capture, as well as the MTT.

Main Outcome Measurements

The kinetic data of the PHUA test, kinematics analysis of functional movements, and time requirement of MTT were analyzed.

Results

Patients with ipsilesional UE had an inferior ability to scale and produce pinch force precisely when conducting the PHUA test compared to the healthy controls (P < .05). The movement time was statistically longer and peak velocity was significantly lower (P < .05) in the performance‐oriented tasks for the ipsilesional UE patients. The longer time requirement in 3 MTT subtests showed that the ipsilesional UE patients experienced degradation in sensory perception (P < .001).

Conclusion

Comprehensive sensorimotor assessments based on functional perspectives are valid tools to determine deficits in the sensation‐perception‐motor system in the ipsilesional UE. Integration of sensorimotor training programs for ipsilesional UE in future neuro‐rehabilitation strategies may provide more beneficial effects to regain patients' motor recovery and to promote daily living activity independence than focusing on paretic arm motor training alone.

Level of Evidence

III
Ultrasonographic Assessment of Femoral Cartilage Thickness in Patients With Cerebral Palsy
Authors: Adiguzel Emre , Tok Fatih , Ata Emre , Yaşar Evren , Yılmaz Bilge
Published: July 2017

Background

Cerebral palsy (CP) is one of the most disabling syndromes in children. To our knowledge, there has not yet been any reported evaluation by ultrasonography of the effect of CP on distal femoral cartilage. The value of understanding this effect on cartilage is that sonographic evaluation of cartilage thickness may help physicians to predict the joint health of these children.

Objective

To determine whether femoral cartilage thickness in patients with CP is different from that in healthy control subjects.

Design

Cross‐sectional study.

Setting

National tertiary rehabilitation center.

Patients

The study included 40 patients with diplegic CP (23 male and 17 female) and 51 healthy control subjects (29 male and 22 female).

Methods

Demographic and clinical characteristics were recorded. Cartilage thicknesses were measured.

Main Outcome Measure

Cartilage thickness measurements were taken from the medial and lateral condyles, and intercondylar areas of both knees.

Results

Both groups were similar in terms of age, gender, and weight (P > .05). The mean cartilage thickness measurements of the medial condyle and intercondylar area of knees in the CP group were significantly less than those in the healthy control group (all P < .05). There was moderate negative correlation between age and all femoral cartilage thickness measurements in the CP group. There was no correlation between age and femoral cartilage thickness measurements in the healthy group. There was a negative correlation between Gross Motor Functional Classification System levels and cartilage thickness in the CP group. The highest cartilage thickness measurements were detected in level 1 patients, and the lowest measurements were detected in level 5 patients.

Conclusion

This study showed that patients with CP have a thinner femoral cartilage than healthy control subjects. Management of patients with CP should include close surveillance.

Level of Evidence

III
Using Global Migration Law to Prevent Human Trafficking
Authors: Chuang Janie A.
Published: July 2017

Our understanding of human trafficking has changed significantly since 2000, when the international community adopted the first modern antitrafficking treaty—the UN Protocol to Prevent, Suppress and Punish Trafficking in Persons, Especially Women and Children (Trafficking Protocol). Policy attention has expanded beyond a near-exclusive focus on sex trafficking to bring long-overdue attention to nonsexual labor trafficking. That attention has helped surface how the lack of international laws and institutions pertaining to labor migration can enable—if not encourage—the exploitation of migrant workers. Many migrant workers throughout the world labor under conditions that do not qualify as trafficking yet suffer significant rights violations for which access to protection and redress is limited. Failing to attend to these “lesser” abuses creates and sustains vulnerability to trafficking.
Discrepancy between information provided and information required by emergency physicians for long-term care patients
Authors: Parashar Richa , McLeod Shelley , Melady Don
Published: July 2017

Objectives

The primary objective of this study was to identify information included in long-term care (LTC) transfer documentation and to compare it to the information required by local emergency department (ED) physicians to provide optimal care and make decisions for LTC patients.

Methods

A retrospective chart review was conducted for a sample of LTC residents transferred by ambulance to the ED of an academic, tertiary care hospital over a 1-year period. All emergency physicians working at the institution were invited to complete an online questionnaire about information included in LTC transfer documentation and information required by emergency physicians to provide care for LTC patients.

Results

Of the 200 charts reviewed, the most common information transferred to the ED with the LTC patient was the patient’s past medical history (n=184, 92.0%), name of family physician (n=182, 91.0%), a list of known allergies (n=179, 89.5%), the reason for transfer to the ED (n=155, 77.5%), the patient’s emergency contact information (n=152, 76.0%), and medication administration record (n=150, 75.0%). From a physician’s perspective, the most frequently requested pieces of information included reason for transfer, past medical history, cognitive status, advanced directives for level of care and resuscitation, and the patient’s emergency contact information. This information was provided 77.5% (n=155), 92.0% (n=184), 24.0% (n=48), 62.0% (n=124), and 76.0% (n=152) of the time, respectively.

Conclusions

Our study demonstrates a clear discrepancy between information provided and information required by emergency physicians for LTC patients. Quality improvement initiatives at the local level may help reduce this discrepancy.
Communities ready for takeoff
Authors: Rijkhoff Sanne A. M. , Hoard Season A. , Gaffney Michael J. , Smith Paul M.
Published: July 2017

Although much of the social science literature supports the importance of community assets for success in many policy areas, these assets are often overlooked when selecting communities for new infrastructure facilities. Extensive collaboration is crucial for the success of environmental and economic projects, yet it often is not adequately addressed when making siting decisions for new projects. This article develops a social asset framework that includes social, creative, and human capital to inform site-selection decisions. This framework is applied to the Northwest Advanced Renewables Alliance project to assess community suitability for biofuel-related developments. This framework is the first to take all necessary community assets into account, providing insight into successful site selection beyond current models. The framework not only serves as a model for future biorefinery projects but also guides tasks that depend on informed location selection for success.
Geochemistry and petrogenesis of the early Palaeozoic appinite-granite complex in the Western Kunlun Orogenic Belt, NW China: implications for Palaeozoic tectonic evolution
Authors: ZHU JIE , LI QIUGEN , CHEN XU , TANG HAOSHU , WANG ZONGQI , CHEN YANJING , LIU SHUWEN , XIAO BING , CHEN JUNLU
Published: July 2017

The Datong pluton, the largest early Palaeozoic granitoid in the Western Kunlun Orogenic Belt (WKOB) in NW China, is a typical appinite-granite complex. It consists of diorites, quartz diorites, monzodiorites, quartz monzodiorites, monzonites, quartz monzonites, syenites, granodiorites and monzogranites. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) zircon U–Pb dating yielded crystallization ages of 459 ± 3 Ma for the quartz monzonites and 452 ± 5 Ma for the monzogranites (Late Ordovician). The rocks possess a wide range of SiO2 (56.0–73.4 wt %), MgO (0.17–4.55 wt %) and Mg no. (25–60), with high K2O (2.83–5.29 wt %) contents, exhibiting high-K calc-alkaline to shoshonitic traits. They are characterized by enrichments in large-ion lithophile elements (LILEs) and light rare Earth elements (LREEs), as well as depletions in high-field-strength elements (HFSEs). The rocks have initial 87Sr/86Sr ratios of 0.7086–0.7185, negative εNd(t) values of –3.72 to –1.79 and εHf(t) values vary from –1.6 to +4.7. These features are modelled to show that they were most likely derived from an enriched lithospheric mantle source and that fractional crystallization with minor crustal contamination was involved in their petrogenetic process. Considering the distribution and chronology of the Palaeozoic intrusions – such as Kegang, Bulong, Qiukesu, Yierba, North Kudi, Dongbake, Buya, Ayilixi and Warengzilafu granitoid plutons with ages of c. 420–530 Ma – in conjunction with the Palaeozoic metamorphic overprinting in the WKOB, we propose a divergent double-subduction model to explain the destruction of the Proto-Tethys Ocean and suggest that the Datong pluton was likely emplaced in a post-collisional setting following the termination of subduction in response to slab break-off.
DRIPs and the Dividend Pay Date Effect
Authors: Berkman Henk , Koch Paul D.
Published: July 2017

On the day that dividends are paid, we find a significant positive mean abnormal return that is completely reversed over the following days. This dividend pay date effect has strengthened since the 1970s and is consistent with the temporary price pressure hypothesis. The pay date effect is concentrated among stocks with dividend reinvestment plans (DRIPs) and is larger for stocks with a higher dividend yield, greater DRIP participation, and greater limits to arbitrage. Over time, profits from a trading strategy that exploits this behavior are positively related to the dividend yield and spread and negatively associated with aggregate liquidity.
The role of language production mechanisms in children's sentence repetition: Evidence from an inflectionally rich language
Authors: NAG SONALI , SNOWLING MARGARET J. , MIRKOVIĆ JELENA
Published: July 2017

We examine the role of language production mechanisms in sentence repetition, a task widely used as a diagnostic tool in developmental disorders. We investigate sentence repetition in 5- to 8-year-old native speakers of Kannada, an inflectionally rich language of India. The inflectional characteristics of the language make it an ideal testing ground for exploring the engagement of grammatical and phonological encoding processes. We presented active, passive, and embedded sentences and, in a subset of the material, we also manipulated sentence length. Using accuracy and speech error analyses at the sentence, word, and affix levels, we provide evidence that individual differences in task performance are influenced by the linguistic properties of the material. These findings clarify the role of key language production mechanisms involved in sentence repetition. We propose that it is the versatility to develop a profile across several language production mechanisms that makes sentence repetition particularly useful as a clinical tool.
Prospects for Cross-Strait Political Negotiation: Exploring Win-Sets
Authors: Wenger Josh , Chen Ming-tong
Published: July 2017

This study adopts a pre-negotiation approach based on Robert Putnam's win-set concept to examine domestic constraints on cross-Strait political negotiation. Survey research of elite opinion in both China and Taiwan and of public opinion in Taiwan is used to estimate each side's win-set (that is, the set of political negotiation outcomes that could win majority approval domestically) during Ma Ying-jeou's second presidential term in Taiwan (2012–2016). The possibility for overlap in win-sets that could provide a zone of possible agreement and the potential for coalitions in favour of negotiation are analysed. The study finds no win-set overlap and limited potential for coalitions favouring negotiation outcomes with the least distance from overlap, concluding that domestic conditions for formal political negotiations between Beijing and Taipei are unlikely to be ripe in the near term.
Parthenogenetic activation and somatic cell nuclear transfer of porcine oocytes activated by an electric pulse and AZD5438 treatment
Authors: Li Xiao-Chen , Guo Qing , Zhu Hai-Ying , Jin Long , Zhang Yu-Chen , Zhang Guang-Lei , Xing Xiao-Xu , Xuan Mei-Fu , Luo Qi-Rong , Luo Zhao-Bo , Wang Jun-Xia , Cui Cheng-Du , Li Wen-Xue , Cui Zheng-Yun , Yin Xi-Jun , Kang Jin-Dan
Published: July 2017

We examined the in vitro developmental competence of parthenogenetic activation (PA) oocytes activated by an electric pulse (EP) and treated with various concentrations of AZD5438 for 4 h. Treatment with 10 µM AZD5438 for 4 h significantly improved the blastocyst formation rate of PA oocytes in comparison with 0, 20, or 50 µM AZD5438 treatment (46.4% vs. 34.5%, 32.3%, and 24.0%, respectively; P < 0.05). The blastocyst formation rate was higher in the group treated with AZD5438 for 4 h than in the groups treated with AZD5438 for 2 or 6 h (42.8% vs. 38.6% and 37.2%, respectively; P > 0.05). Furthermore, 66.67% of blastocysts derived from these AZD5438-treated PA oocytes had a diploid karyotype. The blastocyst formation rate of PA and somatic cell nuclear transfer (SCNT) embryos was similar between oocytes activated by an EP and treated with 2 mM 6-dimethylaminopurine for 4 h and those activated by an EP and treated with 10 µM AZD5438 for 4 h (11.11% vs. 13.40%, P > 0.05). In addition, the level of maturation-promoting factor (MPF) was significantly decreased in oocytes activated by an EP and treated with 10 µM AZD5438 for 4 h. Finally, the mRNA expression levels of apoptosis-related genes (Bax and Bcl-2) and pluripotency-related genes (Oct4, Nanog, and Sox2) were checked by RT-PCR; however, there were no differences between the AZD5438-treated and non-treated control groups. Our results demonstrate that porcine oocyte activation via an EP in combination with AZD5438 treatment can lead to a high blastocyst formation rate in PA and SCNT experiments.
FINANCIAL SHOCKS, JOB DESTRUCTION SHOCKS, AND LABOR MARKET FLUCTUATIONS
Authors: Zanetti Francesco
Published: July 2017

This paper investigates the effect of financial shocks using a general equilibrium model that links the firm's flows of financing with labor market variables. The results show that financial shocks have sizeable effects on debt, dividend payout, and wages. Shocks to the job destruction rate are important in explaining fluctuations in unemployment. The analysis also investigates the underlying driving forces of some key comovements in the data and finds shocks to the job destructions rate important.
ACCEPTING THE OMEN: EXTERNAL REFERENCE IN GREEK DECLAMATION
Authors: Guast William
Published: July 2017

Traditional accounts of Greek declamation paint this important imperial genre as a flight from the alleged impotence of Greek cities under Roman rule into a nostalgic fantasy of the autonomy of the classical past. But there is clear evidence of declaimers using their works to refer to the world outside the fiction, often to the immediate performance context, and above all to themselves. This paper examines examples from Aelius Aristides, Philostratus’Lives of the Sophistsand Polemo, and shows that such a practice facilitated vigorous and eloquent communication, while also allowing for any external message to be plausibly denied.
Repeated Applications of Mesotrione and Napropamide on New Cranberry Plantings
Authors: Sandler Hilary A.
Published: July 2017

To evaluate the weed control provided by various combinations of PRE applications of napropamide (Nap) and POST applications of mesotrione (Mes) in newly planted and 1-yr-old cranberry vines, six 2-yr experiments were conducted during 2009-2012. Three sites were treated in the year of planting plus the subsequent year (called “new plantings”) and three sites were treated in their second year of growth plus the subsequent year (called “second-year plantings”). Ten treatments, delivered in 3,735 L ha−1 water, were administered each year: Nap at 3.36 kg ai ha−1 applied once, twice, thrice or once followed by (fb) one application of Mes at 210 g ai ha−1; Nap at 5.04 kg ha−1applied once, twice or once fb one application of Mes at 210 g ha−1; Mes at 210 g ha−1 applied once or twice; and nontreated. At new planting sites, plots receiving treatments other than a single Nap application had less total weed biomass compared to nontreated plots. At second-year plantings, all herbicide-treated plots had less total weed biomass than nontreated plots; in addition, plots receiving Mes-only treatments had less total weed biomass than Nap-only treatments. Correlation analysis indicated that monocot biomass production was the primary positive predictor for total weed biomass. Herbicides did not adversely affect cranberry biomass production but overall vine colonization was poor for four of the six sites indicating that other factors, including cultivar choice, planting method, and water management, may play a larger role in rapid cranberry vine colonization than the suppression of initial weed biomass. Given the complementary range of efficacy for Nap and Mes, a combination PRE-POST herbicide program of a low rate of Nap fb Mes may be the most cost-beneficial program in many instances. If cost is a limiting factor, applying a single application of Mes to a new planting should be included as a component of cranberry bed establishment since this practice consistently resulted in significantly less initial weed biomass compared to areas left nontreated.
The development of activatable lytic peptides for targeting triple negative breast cancer
Authors: Zhao Hui , Qin Xuan , Yang Dan , Jiang Yanhong , Zheng Weihao , Wang Dongyuan , Tian Yuan , Liu Qisong , Xu Naihan , Li Zigang
Published: July 2017

Cytolytic peptides are an emerging class of promising cancer therapeutics shown to overcome drug resistance. They eliminate cancer cells via disruption of the phospholipid bilayer of cell membranes, a mechanism that differentiates it from traditional treatments. However, applications of lytic peptides via systematic administration are hampered by nonspecific toxicity. Here, we describe activatable, masked lytic peptides that are conjugated with anionic peptides via a cleavable linker sensitive to matrix metalloproteinases (Ac-w-βA-e8-XPLG*LAG-klUklUkklUklUk-NH2; lower case letters in the sequences represent D-amino-acids, U=Aib, α-aminoisobutyric acid, *cleavage site). The peptides were activated upon being introduced into the triple negative breast cancer cell line MDA-MB-231, which overexpresses secreted matrix metalloproteinases, to selectively cleave the peptide linker. Our results indicate that the activatable design could be applied to improve the targeting ability of lytic peptides.
High-aspect-ratio nanoimprint process chains
Authors: Cadarso Víctor J. , Chidambaram Nachiappan , Jacot-Descombes Loïc , Schift Helmut
Published: July 2017

Different methods capable of developing complex structures and building elements with high-aspect-ratio nanostructures combined with microstructures, which are of interest in nanophotonics, are presented. As originals for subsequent replication steps, two families of masters were developed: (i) 3.2 μm deep, 180 nm wide trenches were fabricated by silicon cryo-etching and (ii) 9.8 μm high, 350 nm wide ridges were fabricated using 2-photon polymerization direct laser writing. Both emerging technologies enable the vertical smooth sidewalls needed for a successful imprint into thin layers of polymers with aspect ratios exceeding 15. Nanoridges with high aspect ratios of up to 28 and no residual layer were produced in Ormocers using the micromoulding into capillaries (MIMIC) process with subsequent ultraviolet-curing. This work presents and balances the different fabrication routes and the subsequent generation of working tools from masters with inverted tones and the combination of hard and soft materials. This provides these techniques with a proof of concept for their compatibility with high volume manufacturing of complex micro- and nanostructures.
Acylated heptapeptide binds albumin with high affinity and application as tag furnishes long-acting peptides
Authors: Zorzi Alessandro , Middendorp Simon J. , Wilbs Jonas , Deyle Kaycie , Heinis Christian
Published: July 2017

The rapid renal clearance of peptides in vivo limits this attractive platform for the treatment of a broad range of diseases that require prolonged drug half-lives. An intriguing approach for extending peptide circulation times works through a ‘piggy-back’ strategy in which peptides bind via a ligand to the long-lived serum protein albumin. In accordance with this strategy, we developed an easily synthesized albumin-binding ligand based on a peptide-fatty acid chimera that has a high affinity for human albumin (Kd=39 nM). This ligand prolongs the elimination half-life of cyclic peptides in rats 25-fold to over seven hours. Conjugation to a peptide factor XII inhibitor developed for anti-thrombotic therapy extends the half-life from 13 minutes to over five hours, inhibiting coagulation for eight hours in rabbits. This high-affinity albumin ligand could potentially extend the half-life of peptides in human to several days, substantially broadening the application range of peptides as therapeutics.
Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells
Authors: Muto Yoshiharu , Nishiyama Masaaki , Nita Akihiro , Moroishi Toshiro , Nakayama Keiichi I.
Published: July 2017

Hematopoietic stem cells (HSCs) are maintained in a hypoxic niche to limit oxidative stress. Although iron elicits oxidative stress, the importance of iron homeostasis in HSCs has been unknown. Here we show that iron regulation by the F-box protein FBXL5 is required for HSC self-renewal. Conditional deletion of Fbxl5 in mouse HSCs results in cellular iron overload and a reduced cell number. Bone marrow transplantation reveals that FBXL5-deficient HSCs are unable to reconstitute the hematopoietic system of irradiated recipients as a result of stem cell exhaustion. Transcriptomic analysis shows abnormal activation of oxidative stress responses and the cell cycle in FBXL5-deficient mouse HSCs as well as downregulation of FBXL5 expression in HSCs of patients with myelodysplastic syndrome. Suppression of iron regulatory protein 2 (IRP2) accumulation in FBXL5-deficient mouse HSCs restores stem cell function, implicating IRP2 as a potential therapeutic target for human hematopoietic diseases associated with FBXL5 downregulation.
Aspartate β-hydroxylase disrupts mitochondrial DNA stability and function in hepatocellular carcinoma
Authors: Tang C , Hou Y , Wang H , Wang K , Xiang H , Wan X , Xia Y , Li J , Wei W , Xu S , Lei Z , Pawlik T M , Wang H , Wu M , Shen F
Published: July 2017

The mechanism of aberrant mitochondrial genome and function in hepatocellular carcinoma (HCC) remains largely unknown. Our previous study demonstrated an increased expression of aspartate β-hydroxylase (ASPH) in HCC tissues, which was associated with tumor invasiveness and a worse prognosis. Currently, we unexpectedly observed the presence of ASPH in purified mitochondrial protein fraction. In addition, immunostaining of both exogenously and endogenously expressed ASPH showed a colocalization with mitochondrial biomarkers. This study aimed to investigate whether the mitochondrial ASPH is involved in mitochondrial malfunction in HCC. Our results showed that ASPH overexpression in HCC tissues was correlated with decreased copy numbers of displacement loop (D-loop) and NADH dehydrogenase subunit 1 (ND-1) and enhanced D-loop mutation, suggesting the disrupted mitochondrial DNA (mtDNA) stability. The reduced mtDNA copy numbers were associated with aggressive clinicopathological features of HCC. The loss of mtDNA integrity induced by enforced expression of ASPH was accompanied with mitochondrial dysfunction, which was characterized by the aberrant mitochondrial membrane potential, decreased ATP generation and enhanced reactive oxygen species. In contrast, knocking down ASPH by siRNA in HCC cell lines showed the opposite impact on mtDNA integrity and function. Mass spectrometry and co-immunoprecipitation further identified that ASPH interacted with histone H2A member X (H2AX). ASPH overexpression diminished the interaction between H2AX and mitochondrial transcription factor A (mtTFA), an important DNA-binding protein for mtDNA replication, which then reduced the binding of mtTFA to D-loop region. Collectively, our results demonstrate that ASPH overexpression disrupts the mtDNA integrity through H2AX–mtTFA signal, thereby affecting mitochondrial functions in HCC.
Piezomagnetism and magnetoelastic memory in uranium dioxide
Authors: Jaime M. , Saul A. , Salamon M. , Zapf V. S. , Harrison N. , Durakiewicz T. , Lashley J. C. , Andersson D. A. , Stanek C. R. , Smith J. L. , Gofryk K.
Published: July 2017

The thermal and magnetic properties of uranium dioxide, a prime nuclear fuel and thoroughly studied actinide material, remain a long standing puzzle, a result of strong coupling between magnetism and lattice vibrations. The magnetic state of this cubic material is characterized by a 3-k non-collinear antiferromagnetic structure and multidomain Jahn-Teller distortions, likely related to its anisotropic thermal properties. Here we show that single crystals of uranium dioxide subjected to strong magnetic fields along threefold axes in the magnetic state exhibit the abrupt appearance of positive linear magnetostriction, leading to a trigonal distortion. Upon reversal of the field the linear term also reverses sign, a hallmark of piezomagnetism. A switching phenomenon occurs at ±18 T, which persists during subsequent field reversals, demonstrating a robust magneto-elastic memory that makes uranium dioxide the hardest piezomagnet known. A model including a strong magnetic anisotropy, elastic, Zeeman, Heisenberg exchange, and magnetoelastic contributions to the total energy is proposed.
Flexible interlocked porous frameworks allow quantitative photoisomerization in a crystalline solid
Authors: Zheng Yongtai , Sato Hiroshi , Wu Pengyan , Jeon Hyung Joon , Matsuda Ryotaro , Kitagawa Susumu
Published: July 2017

Photochromic molecules have shown much promise as molecular components of stimuli-responsive materials, but despite recent achievements in various photoresponsive materials, quantitative conversion in photochemical reactions in solids is hampered by the lack of intrinsic structural flexibility available to release stress and strain upon photochemical events. This issue remains one of the challenges in developing solid-state photoresponsive materials. Here, we report a strategy to realize photoresponsive crystalline materials showing quantitative reversible photochemical reactions upon ultraviolet and visible light irradiation by introducing structural flexibility into crystalline porous frameworks with a twofold interpenetration composed of a diarylethene-based ligand. The structural flexibility of the porous framework enables highly efficient photochemical electrocyclization in a single-crystal-to-single-crystal manner. CO2 sorption on the porous crystal at 195 K is reversibly modulated by light irradiation, and coincident X-ray powder diffraction/sorption measurements clearly demonstrate the flexible nature of the twofold interpenetrated frameworks.
PLATE-Seq for genome-wide regulatory network analysis of high-throughput screens
Authors: Bush Erin C. , Ray Forest , Alvarez Mariano J. , Realubit Ronald , Li Hai , Karan Charles , Califano Andrea , Sims Peter A.
Published: July 2017

Pharmacological and functional genomic screens play an essential role in the discovery and characterization of therapeutic targets and associated pharmacological inhibitors. Although these screens affect thousands of gene products, the typical readout is based on low complexity rather than genome-wide assays. To address this limitation, we introduce pooled library amplification for transcriptome expression (PLATE-Seq), a low-cost, genome-wide mRNA profiling methodology specifically designed to complement high-throughput screening assays. Introduction of sample-specific barcodes during reverse transcription supports pooled library construction and low-depth sequencing that is 10- to 20-fold less expensive than conventional RNA-Seq. The use of network-based algorithms to infer protein activity from PLATE-Seq data results in comparable reproducibility to 30 M read sequencing. Indeed, PLATE-Seq reproducibility compares favorably to other large-scale perturbational profiling studies such as the connectivity map and library of integrated network-based cellular signatures.
Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation
Authors: Cosin-Roger Jesus , Simmen Simona , Melhem Hassan , Atrott Kirstin , Frey-Wagner Isabelle , Hausmann Martin , de Vallière Cheryl , Spalinger Marianne R. , Spielmann Patrick , Wenger Roland H. , Zeitz Jonas , Vavricka Stephan R. , Rogler Gerhard , Ruiz Pedro A.
Published: July 2017

Hypoxia regulates autophagy and nucleotide-binding oligomerization domain receptor, pyrin domain containing (NLRP)3, two innate immune mechanisms linked by mutual regulation and associated to IBD. Here we show that hypoxia ameliorates inflammation during the development of colitis by modulating autophagy and mammalian target of rapamycin (mTOR)/NLRP3 pathway. Hypoxia significantly reduces tumor necrosis factor α, interleukin (IL)-6 and NLRP3 expression, and increases the turnover of the autophagy protein p62 in colon biopsies of Crohn’s disease patients, and in samples from dextran sulfate sodium-treated mice and Il-10−/− mice. In vitro, NF-κB signaling and NLRP3 expression are reduced through hypoxia-induced autophagy. We also identify NLRP3 as a novel binding partner of mTOR. Dimethyloxalylglycine-mediated hydroxylase inhibition ameliorates colitis in mice, downregulates NLRP3 and promotes autophagy. We suggest that hypoxia counteracts inflammation through the downregulation of the binding of mTOR and NLRP3 and activation of autophagy.
Activation of LXRα improves cardiac remodeling induced by pulmonary artery hypertension in rats
Authors: Gong Yibo , Yang Yifeng , Wu Qin , Gao Ge , Liu Yin , Xiong Yaoyao , Huang Can , Wu Sijie
Published: July 2017

Inflammatory factors regulated by NF-κB play a significant role in PAH and myocardial hypertrophy. LXR activation may inhibit myocardial hypertrophy via suppressing inflammatory pathways; it is unknown whether LXR is also involved in PAH-induced myocardial hypertrophy or remodeling. To further explore the protective effect of LXR in PAH-induced cardiac hypertrophy and remodeling, a PAH model was developed, and T0901317, an agonist of LXR, was used to examine the effect of LXR activation. PAH rats demonstrated obvious cardiac hypertrophy and remodeling in the right ventricle, but significant improvement of cardiac hypertrophy and remodeling was observed in PAH rats treated with T0901317. Through RT-PCR, Western blot and ELISA examination, NF-κB, IL-6, TNF-α, and iNOS were found to be significantly reduced in PAH rats treated with T0901317 compared to PAH rats treated with DMSO. Apoptosis was also significantly reduced in PAH rats treated with T0901317. Thus, LXR activation may inhibit PAH-induced cardiac hypertrophy and remodeling by inhibiting NF-κB-mediated inflammatory pathways.
Metabolomic characteristics of cholesterol-induced non-obese nonalcoholic fatty liver disease in mice
Authors: Tu Lan N. , Showalter Megan R. , Cajka Tomas , Fan Sili , Pillai Viju V. , Fiehn Oliver , Selvaraj Vimal
Published: July 2017

Nonalcoholic fatty liver disease (NAFLD) in non-obese patients remains a clinical condition with unclear etiology and pathogenesis. Using a metabolomics approach in a mouse model that recapitulates almost all the characteristic features of non-obese NAFLD, we aimed to advance mechanistic understanding of this disorder. Mice fed high fat, high cholesterol, cholate (HFHCC) diet for three weeks consistently developed hepatic pathology similar to NAFLD and nonalcoholic steatohepatitis (NASH) without changes to body weight or fat pad weights. Gas- and liquid chromatography/mass spectrometry-based profiling of lipidomic and primary metabolism changes in the liver and plasma revealed that systemic mechanisms leading to steatosis and hepatitis in this non-obese NAFLD model were driven by a combination of effects directed by elevated free cholesterol, cholesterol esters and cholic acid, and associated changes to metabolism of sphingomyelins and phosphatidylcholines. These results demonstrate that mechanisms underlying cholesterol-induced non-obese NAFLD are distinct from NAFLD occurring as a consequence of metabolic syndrome. In addition, this investigation provides one of the first metabolite reference profiles for interpreting effects of dietary and hepatic cholesterol in human non-obese NAFLD/NASH patients.
Structural determinants at the M2 muscarinic receptor modulate the RGS4-GIRK response to pilocarpine by impairment of the receptor voltage sensitivity
Authors: Chen I-Shan , Furutani Kazuharu , Kurachi Yoshihisa
Published: July 2017

Membrane potential controls the response of the M2 muscarinic receptor to its ligands. Membrane hyperpolarization increases response to the full agonist acetylcholine (ACh) while decreasing response to the partial agonist pilocarpine. We previously have demonstrated that the regulator of G-protein signaling (RGS) 4 protein discriminates between the voltage-dependent responses of ACh and pilocarpine; however, the underlying mechanism remains unclear. Here we show that RGS4 is involved in the voltage-dependent behavior of the M2 muscarinic receptor-mediated signaling in response to pilocarpine. Additionally we revealed structural determinants on the M2 muscarinic receptor underlying the voltage-dependent response. By electrophysiological recording in Xenopus oocytes expressing M2 muscarinic receptor and G-protein-gated inwardly rectifying K+ channels, we quantified voltage-dependent desensitization of pilocarpine-induced current in the presence or absence of RGS4. Hyperpolarization-induced desensitization of the current required for RGS4, also depended on pilocarpine concentration. Mutations of charged residues in the aspartic acid-arginine-tyrosine motif of the M2 muscarinic receptor, but not intracellular loop 3, significantly impaired the voltage-dependence of RGS4 function. Thus, our results demonstrated that voltage-dependence of RGS4 modulation is derived from the M2 muscarinic receptor. These results provide novel insights into how membrane potential impacts G-protein signaling by modulating GPCR communication with downstream effectors.
Modulation of water diffusion by activation-induced neural cell swelling in Aplysia Californica
Authors: Abe Yoshifumi , Van Nguyen Khieu , Tsurugizawa Tomokazu , Ciobanu Luisa , Le Bihan Denis
Published: July 2017

Diffusion functional magnetic resonance imaging (DfMRI) has been proposed as a method for functional neuroimaging studies, as an alternative to blood oxygenation level dependent (BOLD)-fMRI. DfMRI is thought to more directly reflect neural activation, but its exact mechanism remains unclear. It has been hypothesized that the water apparent diffusion coefficient (ADC) decrease observed upon neural activation results from swelling of neurons or neuron parts. To elucidate the origin of the DfMRI response at cellular level we performed diffusion MR microscopy at 17.2 T in Aplysia californica buccal ganglia and compared the water ADCs at cellular and ganglia levels before and after neuronal activation induced by perfusion with a solution containing dopamine. Neural cell swelling, evidenced from optical microscopy imaging, resulted in an intracellular ADC increase and an ADC decrease at ganglia level. Furthermore, the intracellular ADC increase was found to have a significant positive correlation with the increase in cell size. Our results strongly support the hypothesis that the ADC decrease observed with DfMRI upon neuronal activation at tissue level reflects activation-induced neural cell swelling.
Identification and analysis of mtDNA genomes attributed to Finns reveal long-stagnant demographic trends obscured in the total diversity
Authors: Översti Sanni , Onkamo Päivi , Stoljarova Monika , Budowle Bruce , Sajantila Antti , Palo Jukka U.
Published: July 2017

In Europe, modern mitochondrial diversity is relatively homogeneous and suggests an ubiquitous rapid population growth since the Neolithic revolution. Similar patterns also have been observed in mitochondrial control region data in Finland, which contrasts with the distinctive autosomal and Y-chromosomal diversity among Finns. A different picture emerges from the 843 whole mitochondrial genomes from modern Finns analyzed here. Up to one third of the subhaplogroups can be considered as Finn-characteristic, i.e. rather common in Finland but virtually absent or rare elsewhere in Europe. Bayesian phylogenetic analyses suggest that most of these attributed Finnish lineages date back to around 3,000–5,000 years, coinciding with the arrival of Corded Ware culture and agriculture into Finland. Bayesian estimation of past effective population sizes reveals two differing demographic histories: 1) the ‘local’ Finnish mtDNA haplotypes yielding small and dwindling size estimates for most of the past; and 2) the ‘immigrant’ haplotypes showing growth typical of most European populations. The results based on the local diversity are more in line with that known about Finns from other studies, e.g., Y-chromosome analyses and archaeology findings. The mitochondrial gene pool thus may contain signals of local population history that cannot be readily deduced from the total diversity.
Suppression of HBV replication by the expression of nickase- and nuclease dead-Cas9
Authors: Kurihara Takeshi , Fukuhara Takasuke , Ono Chikako , Yamamoto Satomi , Uemura Kentaro , Okamoto Toru , Sugiyama Masaya , Motooka Daisuke , Nakamura Shota , Ikawa Masato , Mizokami Masashi , Maehara Yoshihiko , Matsuura Yoshiharu
Published: July 2017

Complete removal of hepatitis B virus (HBV) DNA from nuclei is difficult by the current therapies. Recent reports have shown that a novel genome-editing tool using Cas9 with a single-guide RNA (sgRNA) system can cleave the HBV genome in vitro and in vivo. However, induction of a double-strand break (DSB) on the targeted genome by Cas9 risks undesirable off-target cleavage on the host genome. Nickase-Cas9 cleaves a single strand of DNA, and thereby two sgRNAs are required for inducing DSBs. To avoid Cas9-induced off-target mutagenesis, we examined the effects of the expressions of nickase-Cas9 and nuclease dead Cas9 (d-Cas9) with sgRNAs on HBV replication. The expression of nickase-Cas9 with a pair of sgRNAs cleaved the target HBV genome and suppressed the viral-protein expression and HBV replication in vitro. Moreover, nickase-Cas9 with the sgRNA pair cleaved the targeted HBV genome in mouse liver. Interestingly, d-Cas9 expression with the sgRNAs also suppressed HBV replication in vitro without cleaving the HBV genome. These results suggest the possible use of nickase-Cas9 and d-Cas9 with a pair of sgRNAs for eliminating HBV DNA from the livers of chronic hepatitis B patients with low risk of undesirable off-target mutation on the host genome.
Crystal structure of a low molecular weight activator Blm-pep with yeast 20S proteasome – insights into the enzyme activation mechanism
Authors: Witkowska Julia , Giżyńska Małgorzata , Grudnik Przemysław , Golik Przemysław , Karpowicz Przemysław , Giełdoń Artur , Dubin Grzegorz , Jankowska Elżbieta
Published: July 2017

Proteasomes are responsible for protein turnover in eukaryotic cells, degrading short-lived species but also removing improperly folded or oxidatively damaged ones. Dysfunction of a proteasome results in gradual accumulation of misfolded/damaged proteins, leading to their aggregation. It has been postulated that proteasome activators may facilitate removal of such aggregation-prone proteins and thus prevent development of neurodegenerative disorders. However, the discovery of pharmacologically relevant compounds is hindered by insufficient structural understanding of the activation process. In this study we provide a model peptidic activator of human proteasome and analyze the structure-activity relationship within this novel scaffold. The binding mode of the activator at the relevant pocket within the proteasome has been determined by X-ray crystallography. This crystal structure provides an important basis for rational design of pharmacological compounds. Moreover, by providing a novel insight into the proteasome gating mechanism, our results allow the commonly accepted model of proteasome regulation to be revisited.