bluuebunny/crossref_metadata_2025 huggingface dataset:
Controlling rotation and migration of rings in a simple shear flow through geometric modifications
Authors: Borker Neeraj S. , Stroock Abraham D. , Koch Donald L.
Published: February 2018

A ring with a cross-section that has a blunt inner and sharper outer edge can attain an equilibrium orientation in a Newtonian fluid subject to a low Reynolds number simple shear flow. This may be contrasted with the continuous rotation exhibited by most rigid bodies. Such rings align along an orientation when the rotation due to fluid vorticity balances the counter-rotation due to the extensional component of the simple shear flow. While the viscous stress on the particle tries to rotate it, the pressure can generate a counter-vorticity torque that aligns the particle. Using boundary integral computations, we demonstrate ways to effectively control this pressure by altering the geometry of the ring cross-section, thus leading to alignment at moderate particle aspect ratios. Aligning rings that lack fore–aft symmetry can migrate indefinitely along the gradient direction. This differs from the periodic spatial trajectories of fore–aft asymmetric axisymmetric particles that rotate in periodic orbits. The mechanism for migration of aligned rings along the gradient direction is elucidated in this work. The migration speed can be controlled by varying the cross-sectional shape and size of the ring. Our results provide new insights into controlling motion of individual particles and thereby open new pathways towards manipulating macroscopic properties of a suspension.
Simultaneous and temporal autoregressive network models
Authors: SEWELL DANIEL K.
Published: February 2018

While logistic regression models are easily accessible to researchers, when applied to network data there are unrealistic assumptions made about the dependence structure of the data. For temporal networks measured in discrete time, recent work has made good advances (Almquist & Butts, 2014), but there is still the assumption that the dyads are conditionally independent given the edge histories. This assumption can be quite strong and is sometimes difficult to justify. If time steps are rather large, one would typically expect not only the existence of temporal dependencies among the dyads across observed time points but also the existence of simultaneous dependencies affecting how the dyads of the network co-evolve. We propose a general observation-driven model for dynamic networks that overcomes this problem by modeling both the mean and the covariance structures as functions of the edge histories using a flexible autoregressive approach. This approach can be shown to fit into a generalized linear mixed model framework. We propose a visualization method that provides evidence concerning the existence of simultaneous dependence. We describe a simulation study to determine the method's performance in the presence and absence of simultaneous dependence, and we analyze both a proximity network from conference attendees and a world trade network. We also use this last data set to illustrate how simultaneous dependencies become more prominent as the time intervals become coarser.
Compulsory Acquisition as a Constitutional Matter: The Case in Africa
Authors: Alden Wily Liz
Published: February 2018

Compulsory acquisition of land by the state for public purposes is an entrenched feature of national constitutions. Yet the scope of private property is rarely defined. This is problematic in agrarian economies where millions own land under non-statutory arrangements that were historically excluded from recognition as property. This study examines the case in Africa where more than 650 million people are untitled customary landowners. Despite vibrant constitutional change, protection of these rights remains disappointing, while the grounds for taking land have expanded. However, this article concludes that reining in the scope of public purpose is not the most useful way forward. It would be more productive to persist in bringing constitutional force to bear on the standing of customary rights, along with democratizing procedures towards full community participation in deciding how public purpose acquisitions should proceed. The result would be greater tenure security, good governance and more peaceful relations between the state and people regarding land.
Prediction Intervals and Empirical Bayes Confidence Intervals
Authors: Cox D. R.
Published: February 2018

Approximate parametric prediction intervals are obtained for an unobserved random variable when the amount of data on which to base the estimation is large. Applications include the construction of approximate confidence intervals in empirical Bayes estimation.
The role of sleep difficulties in the vasomotor menopausal symptoms and depressed mood relationships: an international pooled analysis of eight studies in the InterLACE consortium
Authors: Chung Hsin-Fang , Pandeya Nirmala , Dobson Annette J. , Kuh Diana , Brunner Eric J. , Crawford Sybil L. , Avis Nancy E. , Gold Ellen B. , Mitchell Ellen S. , Woods Nancy F. , Bromberger Joyce T. , Thurston Rebecca C. , Joffe Hadine , Yoshizawa Toyoko , Anderson Debra , Mishra Gita D.
Published: February 2018

Background

Many women experience both vasomotor menopausal symptoms (VMS) and depressed mood at midlife, but little is known regarding the prospective bi-directional relationships between VMS and depressed mood and the role of sleep difficulties in both directions.

Methods

A pooled analysis was conducted using data from 21 312 women (median: 50 years, interquartile range 49−51) in eight studies from the InterLACE consortium. The degree of VMS, sleep difficulties, and depressed mood was self-reported and categorised as never, rarely, sometimes, and often (if reporting frequency) or never, mild, moderate, and severe (if reporting severity). Multivariable logistic regression models were used to examine the bi-directional associations adjusted for within-study correlation.

Results

At baseline, the prevalence of VMS (40%, range 13–62%) and depressed mood (26%, 8–41%) varied substantially across studies, and a strong dose-dependent association between VMS and likelihood of depressed mood was found. Over 3 years of follow-up, women with often/severe VMS at baseline were more likely to have subsequent depressed mood compared with those without VMS (odds ratios (OR) 1.56, 1.27–1.92). Women with often/severe depressed mood at baseline were also more likely to have subsequent VMS than those without depressed mood (OR 1.89, 1.47–2.44). With further adjustment for the degree of sleep difficulties at baseline, the OR of having a subsequent depressed mood associated with often/severe VMS was attenuated and no longer significant (OR 1.13, 0.90–1.40). Conversely, often/severe depressed mood remained significantly associated with subsequent VMS (OR 1.80, 1.38–2.34).

Conclusions

Difficulty in sleeping largely explained the relationship between VMS and subsequent depressed mood, but it had little impact on the relationship between depressed mood and subsequent VMS.
Association between alcohol and substance use disorders and psychiatric service use in patients with severe mental illness: a nationwide Danish register-based cohort study
Authors: Jørgensen Kirstine Bro , Nordentoft Merete , Hjorthøj Carsten
Published: February 2018

Background

Substance use disorder is highly prevalent in people with psychiatric disorders, and known to impede the psychiatric treatment. Some studies show increased rates of service use, while others show a decrease. These conflicting results are further hampered by a lack of large-scale studies. The aim of this study was to investigate the association between substance use disorder and psychiatric service use in psychiatric patients.

Methods

The study was a prospective registry-based cohort study including patients with severe mental illness. The primary outcome was the number of hospitalisations, bed days and the number of psychiatric emergency department contacts. The association was calculated with incidence rate ratio with 95% confidence intervals.

Results

The study included all psychiatric patients born since 1955. In total, 21 558 patients with schizophrenia (47.54% with substance use disorder), 80 778 patients with depression (28.78% with substance use disorder), 10 560 patients with bipolar affective disorder (40.08% with substance use disorder) and 69 252 patients with a personality disorder (39.18% with substance use disorder) were included. Patients with comorbid substance use disorder had significantly increased rates of hospitalisations, bed days and psychiatric emergency department contacts (p < 0.001) for the majority of the included substances, compared with patients without such disorders.

Conclusion

Substance use disorder was associated with an increased number of hospitalisations, bed days and increased number of psychiatric emergency department contacts for the majority of the included substances.
THE SANCTUARIES OF APOLLO MALEATAS AND APOLLO TYRITAS IN LACONIA: RELIGION IN SPARTAN–PERIOIKIC RELATIONS
Authors: Pavlides Nicolette
Published: February 2018

This article examines how religion contributed to the interconnectivity of the large geographical region of Laconia which was under Spartan control for most of the Archaic and Classical periods. With a particular focus on two Laconian sanctuaries, that of Apollo Maleatas and that of Apollo Tyritas, located in the area of the Thyreatis/Kynouria, which had traditionally been a disputed region between Sparta and Argos, it considers how sanctuaries played a part in Spartan–perioikic relations. The votives from the two sanctuaries vary: the sanctuary of Apollo Maleatas is rich in weapon dedications, while that of Apollo Tyritas has a diverse array of offerings, including bronzes, pottery and weapons. I argue that the sanctuary of Apollo Maleatas served as a central gathering place that united the Lakedaimonians, both Spartans and perioikoi, and where they celebrated the military qualities of Apollo. The sanctuary of Apollo Tyritas may reflect Spartan interests in the disputed region from the late seventh/early sixth century, and it too presents evidence for the military preoccupations affecting the area. The warrior-god Apollo, prominently worshipped in Sparta and Laconia, was appropriately offered offensive weapons of spears and arrowheads, both real size and miniature. The Spartans and perioikoi celebrated the Maleateia festival, at the sanctuary of Apollo Maleatas, which presented an opportunity for Spartans and perioikoi to gather together. A Laconian sacred landscape was formed through the celebration of common cults and festivals, thus uniting the centre (Sparta) with the Laconian (and Messenian) countryside.
Reliability and validity of food portion size estimation from images using manual flexible digital virtual meshes
Authors: Beltran Alicia , Dadabhoy Hafza , Ryan Courtney , Dholakia Ruchita , Baranowski Janice , Li Yuecheng , Yan Guifang , Jia Wenyan , Sun Mingui , Baranowski Tom
Published: February 2018

Objective

The eButton takes frontal images at 4s intervals throughout the day. A three-dimensional manually administered wire mesh procedure has been developed to quantify portion sizes from the two-dimensional images. The present paper reports a test of the inter-rater reliability and validity of use of the wire mesh procedure.

Design

Seventeen foods of diverse shapes and sizes served on plates, bowls and cups were selected to rigorously test the portion assessment procedure. A dietitian not involved in inter-rater reliability assessment used standard cups to independently measure the quantities of foods to generate the ‘true’ value for a total of seventy-five ‘served’ and seventy-five smaller ‘left’ images with diverse portion sizes.

Setting

The images appeared on the computer to which the digital wire meshes were applied.

Subjects

Two dietitians and three engineers independently estimated portion size of the larger (‘served’) and smaller (‘left’) images for the same foods.

Results

The engineers had higher reliability and validity than the dietitians. The dietitians had lower reliabilities and validities for the smaller more irregular images, but the engineers did not, suggesting training could overcome this limitation. The lower reliabilities and validities for foods served in bowls, compared with plates, suggest difficulties with the curved nature of the bowls.

Conclusions

The wire mesh procedure is an important step forward in quantifying portion size, which has been subject to substantial self-report error. Improved training procedures are needed to overcome the identified problems.
Moving beyond depression screening: integrating perinatal depression treatment into OB/GYN practices
Authors: Terrazas Christina , Segre Lisa S. , Wolfe Cheryl
Published: February 2018

In 2015, the American College of Obstetricians and Gynecologists issued a recommendation to screen women for depression and anxiety symptoms at least once during the perinatal period. Nevertheless, many identified women will not receive care from a behavioral health specialist. Listening Visits (LV), developed for delivery by nurses and validated in the United Kingdom, have recently been evaluated in a US-based randomized controlled trial (RCT) which recruited research participants from three home-visiting programs and an urban OB/GYN practice. RCT results indicated clinically and significant improvement in depression symptoms. To bridge the gap between evidence and practice, and based on experiences garnered at the OB/GYN site during the RCT, this development paper proposes a strategy for implementing depression screening and LV into routine clinical care in this practice setting.
Linking small fruit and vegetable farmers and institutional foodservice operations: marketing challenges and considerations
Authors: Boys Kathryn A. , Fraser Angela M.
Published: February 2018

The centralized nature of the United States food production, processing and distribution system makes it difficult for small fruit and vegetable farmers to serve as suppliers to institutional foodservice operations (IFOs), such as schools and hospitals. Due to age, economic and/or health status, it is often the clients of these foodservice operations who would benefit from increasing their consumption of locally grown fruits and vegetables. Unfortunately, institutions are often limited in their resources and food preparation infrastructure, and lack market-based incentives to incorporate locally grown foods into their menus. This study identifies and suggests solutions to barriers that limit the ability of small fruit and vegetable farmers to serve as suppliers to IFOs. Data were collected through an extensive series of focus group meetings held with small-scale fruit and vegetable farmers in three South-Atlantic states. From these meetings, practical marketing considerations, such as payment terms, and processing, packaging and delivery requirements of supplying institutional foodservice buyers, were identified as obstacles to the efficient function of this market channel. Food safety challenges, including the related issues of obtaining (food) products liability insurance and food safety certifications, were also acknowledged among top concerns. A majority of the identified challenges were similar to those reported in other studies, but several were complicated by characteristics of farm production, limited food system infrastructure and marketing experiences in the study region. Several practical solutions to overcoming some of these marketing constraints are offered.
National security and the right to liberty in armed conflict: The legality and limits of security detention in international humanitarian law
Authors: Teferra Zelalem Mogessie
Published: February 2018

This paper examines the legality and limits of security detention in armed conflict situations. It particularly investigates the issues of whether the protection of national security is a legitimate ground to restrict the right to liberty of persons in situations of international or non-international armed conflict, and if so, what are the limits to a State's prerogative to restrict the right to liberty of individuals suspected of threatening its national security. On the basis of a thorough analysis of the relevant extant rules of international law regulating warfare, the paper concludes that security detention is permissible in armed conflict situations regardless of whether the nature of the conflict is international or non-international. However, the prerogative of a State to impose security detention is circumscribed by a plethora of fundamental substantive and procedural safeguards against arbitrariness that are provided in the different rules of international humanitarian law and international human rights law. These safeguards affirm that the search for absolute security is neither desirable nor attainable and that the mere invocation of security concerns does not grant an absolute power to restrict or suspend the liberty of individuals in armed conflict situations. Whenever it is imposed, security detention should be preventive in nature, and must aim at safeguarding the basic national security interests of a State from serious, future, direct and imminent threats related to the armed conflict situation. Detainees should also be able to challenge its legality before a competent organ at the initial or later stage of the detention through a system of periodic review.
Efficient DNA-assisted synthesis of trans-membrane gold nanowires
Authors: Guo Maoxiang , Hernández-Neuta Iván , Madaboosi Narayanan , Nilsson Mats , van der Wijngaart Wouter
Published: February 2018

Whereas electric circuits and surface-based (bio)chemical sensors are mostly constructed in-plane due to ease of manufacturing, 3D microscale and nanoscale structures allow denser integration of electronic components and improved mass transport of the analyte to (bio)chemical sensor surfaces. This work reports the first out-of-plane metallic nanowire formation based on stretching of DNA through a porous membrane. We use rolling circle amplification (RCA) to generate long single-stranded DNA concatemers with one end anchored to the surface. The DNA strands are stretched through the pores in the membrane during liquid removal by forced convection. Because the liquid–air interface movement across the membrane occurs in every pore, DNA stretching across the membrane is highly efficient. The stretched DNA molecules are transformed into trans-membrane gold nanowires through gold nanoparticle hybridization and gold enhancement chemistry. A 50 fM oligonucleotide concentration, a value two orders of magnitude lower than previously reported for flat surface-based nanowire formation, was sufficient for nanowire formation. We observed nanowires in up to 2.7% of the membrane pores, leading to an across-membrane electrical conductivity reduction from open circuit to <20 Ω. The simple electrical read-out offers a high signal-to-noise ratio and can also be extended for use as a biosensor due to the high specificity and scope for multiplexing offered by RCA.
Stigma and self-management: an Interpretative Phenomenological Analysis of the impact of chronic recurrent urinary tract infections after spinal cord injury
Authors: Hearn Jasmine Heath , Selvarajah Sen , Kennedy Paul , Taylor Julian
Published: February 2018

Study design

Qualitative, phenomenological design.

Objectives

Neurogenic bladder dysfunction and urinary tract infection (UTI) are common secondary consequences to neurological damage to the spinal cord. This study sought to establish the impact of chronic, recurrent UTIs on people with spinal cord injury (SCI).

Setting

Community sample, United Kingdom.

Methods

Twelve participants with SCI, aged between 28 and 68 years, who had experienced at least three recurrent UTI events within the previous 12 months were recruited. Detailed qualitative information was obtained from semi-structured interviews, which lasted between 30 and 60 min. Interpretative Phenomenological Analysis was performed to explore the lived experience of UTIs.

Results

Interview findings identified a range of factors related to the experience of recurrent UTIs in people with SCI. These were classified into the following themes: (1) Symptom Management Precedence, (2) Stigma-Motivated Risk Management and (3) Exhaustive Exploration of Treatment Options. Participants discussed management of acute exacerbations. Distress arose from perceptions of UTIs as potentially stigmatizing and fear of relying on antibiotics. Arising from this fear, many participants sought alternative prevention and management strategies.

Conclusions

These results suggest that chronic recurrent UTIs act as major barriers to social participation, with adverse effects on quality of life of people with a neurogenic bladder after SCI. People with SCI would benefit from additional assessment of the impact of recurrent UTIs, so that healthcare professionals can address specific concerns, such as the psychosocial impact of urinary incontinence and stigmatizing views. Additional support to enhance self-management and facilitate social participation should be provided.
BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis
Authors: Dong Xingchen , Hu Xiangming , Chen Jinjing , Hu Dan , Chen Lin-Feng
Published: February 2018

Small molecules targeting bromodomains of BET proteins possess strong anti-tumor activities and have emerged as potential therapeutics for cancer. However, the underlying mechanisms for the anti-proliferative activity of these inhibitors are still not fully characterized. In this study, we demonstrated that BET inhibitor JQ1 suppressed the proliferation and invasiveness of gastric cancer cells by inducing cellular senescence. Depletion of BRD4, which was overexpressed in gastric cancer tissues, but not other BET proteins recapitulated JQ1-induced cellular senescence with increased cellular SA-β-Gal activity and elevated p21 levels. In addition, we showed that the levels of p21 were regulated at the post-transcriptional level by BRD4-dependent expression of miR-106b-5p, which targets the 3′-UTR of p21 mRNA. Overexpression of miR-106b-5p prevented JQ1-induced p21 expression and BRD4 inhibition-associated cellular senescence, whereas miR-106b-5p inhibitor up-regulated p21 and induced cellular senescence. Finally, we demonstrated that inhibition of E2F suppressed the binding of BRD4 to the promoter of miR-106b-5p and inhibited its transcription, leading to the increased p21 levels and cellular senescence in gastric cancer cells. Our results reveal a novel mechanism by which BRD4 regulates cancer cell proliferation by modulating the cellular senescence through E2F/miR-106b-5p/p21 axis and provide new insights into using BET inhibitors as potential anticancer drugs.
Actin nucleator Spire 1 is a regulator of ectoplasmic specialization in the testis
Authors: Wen Qing , Li Nan , Xiao Xiang , Lui Wing-yee , Chu Darren S. , Wong Chris K. C. , Lian Qingquan , Ge Renshan , Lee Will M. , Silvestrini Bruno , Cheng C. Yan
Published: February 2018

Germ cell differentiation during the epithelial cycle of spermatogenesis is accompanied by extensive remodeling at the Sertoli cell–cell and Sertoli cell–spermatid interface to accommodate the transport of preleptotene spermatocytes and developing spermatids across the blood–testis barrier (BTB) and the adluminal compartment of the seminiferous epithelium, respectively. The unique cell junction in the testis is the actin-rich ectoplasmic specialization (ES) designated basal ES at the Sertoli cell–cell interface, and the apical ES at the Sertoli–spermatid interface. Since ES dynamics (i.e., disassembly, reassembly and stabilization) are supported by actin microfilaments, which rapidly converts between their bundled and unbundled/branched configuration to confer plasticity to the ES, it is logical to speculate that actin nucleation proteins play a crucial role to ES dynamics. Herein, we reported findings that Spire 1, an actin nucleator known to polymerize actins into long stretches of linear microfilaments in cells, is an important regulator of ES dynamics. Its knockdown by RNAi in Sertoli cells cultured in vitro was found to impede the Sertoli cell tight junction (TJ)-permeability barrier through changes in the organization of F-actin across Sertoli cell cytosol. Unexpectedly, Spire 1 knockdown also perturbed microtubule (MT) organization in Sertoli cells cultured in vitro. Biochemical studies using cultured Sertoli cells and specific F-actin vs. MT polymerization assays supported the notion that a transient loss of Spire 1 by RNAi disrupted Sertoli cell actin and MT polymerization and bundling activities. These findings in vitro were reproduced in studies in vivo by RNAi using Spire 1-specific siRNA duplexes to transfect testes with Polyplus in vivo-jetPEI as a transfection medium with high transfection efficiency. Spire 1 knockdown in the testis led to gross disruption of F-actin and MT organization across the seminiferous epithelium, thereby impeding the transport of spermatids and phagosomes across the epithelium and perturbing spermatogenesis. In summary, Spire 1 is an ES regulator to support germ cell development during spermatogenesis.
MiR-22 suppresses epithelial–mesenchymal transition in bladder cancer by inhibiting Snail and MAPK1/Slug/vimentin feedback loop
Authors: Xu Mingjie , Li Jiangfeng , Wang Xiao , Meng Shuai , Shen Jiaying , Wang Song , Xu Xin , Xie Bo , Liu Ben , Xie Liping
Published: February 2018

MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of bladder cancer (BCa). MiR-22 was previously reported to act as a tumor suppressor or oncomiRNA in various types of cancer. However, its accurate expression, function, and mechanism in BCa remain unclear. Here, we find that miR-22 is frequently downregulated in BCa tissues compared with adjacent non-cancerous tissues. Overexpression of miR-22 significantly inhibits proliferation, migration, and invasion of BCa cells both in vitro and in vivo. Importantly, miR-22 is found to suppress cell proliferation/apoptosis by directly targeting MAPK1 (mitogen-activated protein kinase 1, ERK2) and inhibit cell motility by targeting both MAPK1 and Snail. Further statistical analysis shows that low-expression of MAPK1 or Snail is an independent prognostic factor for a better overall survival in patients with BCa (n = 401). Importantly, we describe an important regenerative feedback loop among vimentin, Slug and MAPK1 in BCa cells. MAPK1-induced Slug expression upregulates vimentin. Vimentin in turn activates MAPK1. By inhibiting Snail and MAPK1/Slug/vimentin feedback loop, miR-22 suppresses epithelial–mesenchymal transition (EMT) of BCa cells in vitro as well as in vivo. Taken together, this study reveals that miR-22 is critical to the proliferation, apoptosis and EMT progression in BCa cells. Targeting the pathway described here may be a novel approach for inhibiting proliferation and metastasis of BCa.
Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson’s disease
Authors: Tozzi Alessandro , Tantucci Michela , Marchi Saverio , Mazzocchetti Petra , Morari Michele , Pinton Paolo , Mancini Andrea , Calabresi Paolo
Published: February 2018

Parkinson’s disease (PD) is a neurodegenerative disorder in which genetic and environmental factors synergistically lead to loss of midbrain dopamine (DA) neurons. Mutation of leucine-rich repeated kinase2 (Lrrk2) genes is responsible for the majority of inherited familial cases of PD and can also be found in sporadic cases. The pathophysiological role of this kinase has to be fully understood yet. Hyperactivation of Lrrk2 kinase domain might represent a predisposing factor for both enhanced striatal glutamatergic release and mitochondrial vulnerability to environmental factors that are observed in PD. To investigate possible alterations of striatal susceptibility to mitochondrial dysfunction, we performed electrophysiological recordings from the nucleus striatum of a G2019S Lrrk2 mouse model of PD, as well as molecular and morphological analyses of G2019S Lrrk2-expressing SH-SY5Y neuroblastoma cells. In G2019S mice, we found reduced striatal DA levels, according to the hypothesis of alteration of dopaminergic transmission, and increased loss of field potential induced by the mitochondrial complex I inhibitor rotenone. This detrimental effect is reversed by the D2 DA receptor agonist quinpiroleviathe inhibition of the cAMP/PKA intracellular pathway. Analysis of mitochondrial functions in G2019S Lrrk2-expressing SH-SY5Y cells revealed strong rotenone-induced oxidative stress characterized by reduced Ca2+buffering capability and ATP synthesis, production of reactive oxygen species, and increased mitochondrial fragmentation. Importantly, quinpirole was able to prevent all these changes. We suggest that the G2019S-Lrrk2 mutation is a predisposing factor for enhanced striatal susceptibility to mitochondrial dysfunction induced by exposure to mitochondrial environmental toxins and that the D2 receptor stimulation is neuroprotective on mitochondrial function,viathe inhibition of cAMP/PKA intracellular pathway. We suggest new possible neuroprotective strategies for patients carrying this genetic alteration based on drugs specifically targeting Lrrk2 kinase domain and mitochondrial functionality.
Preconditioning, induced by sub-toxic dose of the neurotoxin L-BMAA, delays ALS progression in mice and prevents Na+/Ca2+ exchanger 3 downregulation
Authors: Anzilotti Serenella , Brancaccio Paola , Simeone Giuseppe , Valsecchi Valeria , Vinciguerra Antonio , Secondo Agnese , Petrozziello Tiziana , Guida Natascia , Sirabella Rossana , Cuomo Ornella , Cepparulo Pasquale , Herchuelz Andrè , Amoroso Salvatore , Di Renzo Gianfranco , Annunziato Lucio , Pignataro Giuseppe
Published: February 2018

Preconditioning (PC) is a phenomenon wherein a mild insult induces resistance to a later, severe injury. Although PC has been extensively studied in several neurological disorders, no studies have been performed in amyotrophic lateral sclerosis (ALS). Here we hypothesize that a sub-toxic acute exposure to the cycad neurotoxin beta-methylamino-L-alanine (L-BMAA) is able to delay ALS progression in SOD1 G93A mice and that NCX3, a membrane transporter able to handle the deregulation of ionic homeostasis occurring during ALS, takes part to this neuroprotective effect. Preconditioning effect was examined on disease onset and duration, motor functions, and motor neurons in terms of functional declines and severity of histological damage in male and female mice. Our findings demonstrate that a sub-toxic dose of L-BMAA works as preconditioning stimulus and is able to delay ALS onset and to prolong ALS mice survival. Interestingly, preconditioning prevented NCX3 downregulation in SOD1 G93A mice spinal cord, leading to an increased number of motor neurons associated to a reduced astrogliosis, and reduced the denervation of neuromuscular junctions observed in SOD1 G93A mice. These protective effects were mitigated in ncx3+/− mice. This study established for the first time an animal model of preconditioning in ALS and candidates NCX3 as a new therapeutic target.
Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells
Authors: Mauro-Lizcano Marta , López-Rivas Abelardo
Published: February 2018

Glutamine plays an important role in the metabolism of tumor cells through its contribution to redox homeostasis, bioenergetics, synthesis of macromolecules, and signaling. Triple-negative breast cancers (TNBC) are highly metastatic and associated with poor prognosis. TNBC cells show a marked dependence on extracellular glutamine for growth. Herein we demonstrate that TNBC cells are markedly sensitized to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis upon glutamine deprivation. Upregulation of pro-apoptotic TRAIL receptor 2 (TRAIL-R2/DR5) and downregulation of FLICE-inhibitory protein (FLIP) are observed in glutamine-deprived TNBC cells. Activation of the amino-acid-sensing kinase general control nonderepressible 2 (GCN2) upon glutamine deprivation is responsible for TRAIL-R2 upregulation through a signaling pathway involving ATF4 and CHOP transcription factors. In contrast, FLIP downregulation in glutamine-deprived TNBC occurs by a GCN2-independent mechanism. Importantly, silencing FLIP expression by RNA interference results in a marked sensitization of TNBC cells to TRAIL-induced apoptosis. In addition, pharmacological or genetic inhibition of transaminases increases TRAIL-R2 expression and downregulates FLIP levels, sensitizing TNBC cells to TRAIL. Interestingly, treatment with l-asparaginase markedly sensitizes TNBC cells to TRAIL through its glutaminase activity. Overall, our findings suggest that targeting the glutamine addiction phenotype of TNBC can be regarded as a potential antitumoral target in combination with agonists of proapoptotic TRAIL receptors.
Cadherin-26 (CDH26) regulates airway epithelial cell cytoskeletal structure and polarity
Authors: Lachowicz-Scroggins Marrah E. , Gordon Erin D. , Wesolowska-Andersen Agata , Jackson Nathan D. , MacLeod Hannah J. , Sharp Louis Z. , Sun Matthew , Seibold Max A. , Fahy John V.
Published: February 2018

Polarization of the airway epithelial cells (AECs) in the airway lumen is critical to the proper function of the mucociliary escalator and maintenance of lung health, but the cellular requirements for polarization of AECs are poorly understood. Using human AECs and cell lines, we demonstrate that cadherin-26 (CDH26) is abundantly expressed in differentiated AECs, localizes to the cell apices near ciliary membranes, and has functional cadherin domains with homotypic binding. We find a unique and non-redundant role for CDH26, previously uncharacterized in AECs, in regulation of cell–cell contact and cell integrity through maintaining cytoskeletal structures. Overexpression of CDH26 in cells with a fibroblastoid phenotype increases contact inhibition and promotes monolayer formation and cortical actin structures. CDH26 expression is also important for localization of planar cell polarity proteins. Knockdown of CDH26 in AECs results in loss of cortical actin and disruption of CRB3 and other proteins associated with apical polarity. Together, our findings uncover previously unrecognized functions for CDH26 in the maintenance of actin cytoskeleton and apicobasal polarity of AECs.
Publisher Correction: Network inference from glycoproteomics data reveals new reactions in the IgG glycosylation pathway
Authors: Benedetti Elisa , Pučić-Baković Maja , Keser Toma , Wahl Annika , Hassinen Antti , Yang Jeong-Yeh , Liu Lin , Trbojević-Akmačić Irena , Razdorov Genadij , Štambuk Jerko , Klarić Lucija , Ugrina Ivo , Selman Maurice H. J. , Wuhrer Manfred , Rudan Igor , Polasek Ozren , Hayward Caroline , Grallert Harald , Strauch Konstantin , Peters Annette , Meitinger Thomas , Gieger Christian , Vilaj Marija , Boons Geert-Jan , Moremen Kelley W. , Ovchinnikova Tatiana , Bovin Nicolai , Kellokumpu Sakari , Theis Fabian J. , Lauc Gordan , Krumsiek Jan
Published: February 2018

Correction to:Nature Communications (2017) 8:1231. doi:10.1038/s41467-017-01525-0
Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration
Authors: Huang Wei , Feng Yuliang , Liang Jialiang , Yu Hao , Wang Cheng , Wang Boyu , Wang Mingyang , Jiang Lin , Meng Wei , Cai Wenfeng , Medvedovic Mario , Chen Jenny , Paul Christian , Davidson W. Sean , Sadayappan Sakthivel , Stambrook Peter J. , Yu Xi-Yong , Wang Yigang
Published: February 2018

The goal of replenishing the cardiomyocyte (CM) population using regenerative therapies following myocardial infarction (MI) is hampered by the limited regeneration capacity of adult CMs, partially due to their withdrawal from the cell cycle. Here, we show that microRNA-128 (miR-128) is upregulated in CMs during the postnatal switch from proliferation to terminal differentiation. In neonatal mice, cardiac-specific overexpression of miR-128 impairs CM proliferation and cardiac function, while miR-128 deletion extends proliferation of postnatal CMs by enhancing expression of the chromatin modifier SUZ12, which suppresses p27 (cyclin-dependent kinase inhibitor) expression and activates the positive cell cycle regulators Cyclin E and CDK2. Furthermore, deletion of miR-128 promotes cell cycle re-entry of adult CMs, thereby reducing the levels of fibrosis, and attenuating cardiac dysfunction in response to MI. These results suggest that miR-128 serves as a critical regulator of endogenous CM proliferation, and might be a novel therapeutic target for heart repair.
Localization of adaptive variants in human genomes using averaged one-dependence estimation
Authors: Sugden Lauren Alpert , Atkinson Elizabeth G. , Fischer Annie P. , Rong Stephen , Henn Brenna M. , Ramachandran Sohini
Published: February 2018

Statistical methods for identifying adaptive mutations from population genetic data face several obstacles: assessing the significance of genomic outliers, integrating correlated measures of selection into one analytic framework, and distinguishing adaptive variants from hitchhiking neutral variants. Here, we introduce SWIF(r), a probabilistic method that detects selective sweeps by learning the distributions of multiple selection statistics under different evolutionary scenarios and calculating the posterior probability of a sweep at each genomic site. SWIF(r) is trained using simulations from a user-specified demographic model and explicitly models the joint distributions of selection statistics, thereby increasing its power to both identify regions undergoing sweeps and localize adaptive mutations. Using array and exome data from 45 ‡Khomani San hunter-gatherers of southern Africa, we identify an enrichment of adaptive signals in genes associated with metabolism and obesity. SWIF(r) provides a transparent probabilistic framework for localizing beneficial mutations that is extensible to a variety of evolutionary scenarios.
Identifying noncoding risk variants using disease-relevant gene regulatory networks
Authors: Gao Long , Uzun Yasin , Gao Peng , He Bing , Ma Xiaoke , Wang Jiahui , Han Shizhong , Tan Kai
Published: February 2018

Identifying noncoding risk variants remains a challenging task. Because noncoding variants exert their effects in the context of a gene regulatory network (GRN), we hypothesize that explicit use of disease-relevant GRNs can significantly improve the inference accuracy of noncoding risk variants. We describe Annotation of Regulatory Variants using Integrated Networks (ARVIN), a general computational framework for predicting causal noncoding variants. It employs a set of novel regulatory network-based features, combined with sequence-based features to infer noncoding risk variants. Using known causal variants in gene promoters and enhancers in a number of diseases, we show ARVIN outperforms state-of-the-art methods that use sequence-based features alone. Additional experimental validation using reporter assay further demonstrates the accuracy of ARVIN. Application of ARVIN to seven autoimmune diseases provides a holistic view of the gene subnetwork perturbed by the combinatorial action of the entire set of risk noncoding mutations.
Physical basis of amyloid fibril polymorphism
Authors: Close William , Neumann Matthias , Schmidt Andreas , Hora Manuel , Annamalai Karthikeyan , Schmidt Matthias , Reif Bernd , Schmidt Volker , Grigorieff Nikolaus , Fändrich Marcus
Published: February 2018

Polymorphism is a key feature of amyloid fibril structures but it remains challenging to explain these variations for a particular sample. Here, we report electron cryomicroscopy-based reconstructions from different fibril morphologies formed by a peptide fragment from an amyloidogenic immunoglobulin light chain. The observed fibril morphologies vary in the number and cross-sectional arrangement of a structurally conserved building block. A comparison with the theoretically possible constellations reveals the experimentally observed spectrum of fibril morphologies to be governed by opposing sets of forces that primarily arise from the β-sheet twist, as well as peptide–peptide interactions within the fibril cross-section. Our results provide a framework for rationalizing and predicting the structure and polymorphism of cross-β fibrils, and suggest that a small number of physical parameters control the observed fibril architectures.
Structural determinants of the SINE B2 element embedded in the long non-coding RNA activator of translation AS Uchl1
Authors: Podbevšek Peter , Fasolo Francesca , Bon Carlotta , Cimatti Laura , Reißer Sabine , Carninci Piero , Bussi Giovanni , Zucchelli Silvia , Plavec Janez , Gustincich Stefano
Published: February 2018

Pervasive transcription of mammalian genomes leads to a previously underestimated level of complexity in gene regulatory networks. Recently, we have identified a new functional class of natural and synthetic antisense long non-coding RNAs (lncRNA) that increases translation of partially overlapping sense mRNAs. These molecules were named SINEUPs, as they require an embedded inverted SINE B2 element for their UP-regulation of translation. Mouse AS Uchl1 is the representative member of natural SINEUPs. It was originally discovered for its role in increasing translation of Uchl1 mRNA, a gene associated with neurodegenerative diseases. Here we present the secondary structure of the SINE B2 Transposable Element (TE) embedded in AS Uchl1. We find that specific structural regions, containing a short hairpin, are required for the ability of AS Uchl1 RNA to increase translation of its target mRNA. We also provide a high-resolution structure of the relevant hairpin, based on NMR observables. Our results highlight the importance of structural determinants in embedded TEs for their activity as functional domains in lncRNAs.
Step-wise evolution of complex chemical defenses in millipedes: a phylogenomic approach
Authors: Rodriguez Juanita , Jones Tappey H. , Sierwald Petra , Marek Paul E. , Shear William A. , Brewer Michael S. , Kocot Kevin M. , Bond Jason E.
Published: February 2018

With fossil representatives from the Silurian capable of respiring atmospheric oxygen, millipedes are among the oldest terrestrial animals, and likely the first to acquire diverse and complex chemical defenses against predators. Exploring the origin of complex adaptive traits is critical for understanding the evolution of Earth’s biological complexity, and chemical defense evolution serves as an ideal study system. The classic explanation for the evolution of complexity is by gradual increase from simple to complex, passing through intermediate “stepping stone” states. Here we present the first phylogenetic-based study of the evolution of complex chemical defenses in millipedes by generating the largest genomic-based phylogenetic dataset ever assembled for the group. Our phylogenomic results demonstrate that chemical complexity shows a clear pattern of escalation through time. New pathways are added in a stepwise pattern, leading to greater chemical complexity, independently in a number of derived lineages. This complexity gradually increased through time, leading to the advent of three distantly related chemically complex evolutionary lineages, each uniquely characteristic of each of the respective millipede groups.
Altered immunity in crowded Mythimna separata is mediated by octopamine and dopamine
Authors: Kong Hailong , Dong Chuanlei , Tian Zhen , Mao Nian , Wang Cheng , Cheng Yunxia , Zhang Lei , Jiang Xingfu , Luo Lizhi
Published: February 2018

Similar to pathogenic infection, high population density alters insects’ prophylactic immunity. Density-dependent prophylaxis has been reported in many polyphenic insects, but the regulatory mechanism underlying this phenomenon remains unclear. The biogenic monoamines are known to play critical roles in mediating insect immune responses. In the current study, the immune capacity and the levels of three biogenic monoamines were investigated in the polyphenic larvae of Mythimna separata, reared at the densities of 1, 2, 5, 10, and 30 larvae per 650-mL jar. Concomitant with the increased phenoloxidase (PO) activity and total haemocyte count in the larvae at high densities (5, 10, 30 larvae/jar), the octopamine level was also increased. In contrast, the dopamine level was decreased, and the 5-hydroxytryptamine level was not significantly affected. Injection of octopamine induced significant increases in the total haemocyte count and PO activity. Conversely, epinastine, a specific antagonist of octopamine, decreased the total haemocyte count and PO activity. Another octopamine antagonist, phentolamine, inhibited the activity of PO and lysozymes. In addition, injection of dopamine induced a significant increase in PO activity and decreased the total haemocyte count and lysozyme activity. These results suggested that both octopamine and dopamine mediate the increases in total haemocyte count and PO activity in the crowded larvae.
Cardiovascular and renal protective role of angiotensin blockade in hypertension with advanced CKD: a subgroup analysis of ATTEMPT-CVD randomized trial
Authors: Kim-Mitsuyama Shokei , Soejima Hirofumi , Yasuda Osamu , Node Koichi , Jinnouchi Hideaki , Yamamoto Eiichiro , Sekigami Taiji , Ogawa Hisao , Matsui Kunihiko
Published: February 2018

The ATTEMPT-CVD study was prospective randomized active-controlled trial and the main findings had been reported. According to baseline GFR and albuminuria categories, we divided the patients of the ATTEMPT-CVD study into 2 subgroups: (Group 1) the patients with at least one of eGFR of <45 ml/min per 1.73 m2 and UACR of ≥300 mg/g creatinine, defined as G3b and/or A3; (Group 2) the patients except for Group 1, defined as the other patients. In patients with G3b and/or A3, the incidence of cardiovascular events was significantly less in ARB group than in non-ARB group (11 vs 22, respectively) (HR = 0.465: 95%CI = 0.224–0.965; P = 0.040). UACR was significantly less in ARB group than in non-ARB group during follow-up period in patients with G3b and/or A3 (P = 0.0003), while eGFR, plasma BNP levels, and blood pressure were comparable between ARB and non-ARB groups. Allocation to ARB therapy was a significant independent prognostic factor for cardiovascular events in patients with G3b and/or A3 (P = 0.0268). On the other hand, in the other patients, the occurrence of cardiovascular events was comparable between ARB and non-ARB groups. In patients with advanced CKD, ARB-based therapy may confer greater benefit in prevention of cardiovascular events than non-ARB therapy.
Rational Construction of Uniform CoNi-Based Core-Shell Microspheres with Tunable Electromagnetic Wave Absorption Properties
Authors: Chen Na , Jiang Jian-Tang , Xu Cheng-Yan , Yan Shao-Jiu , Zhen Liang
Published: February 2018

Core-shell particles with integration of ferromagnetic core and dielectric shell are attracting extensive attention for promising microwave absorption applications. In this work, CoNi microspheres with conical bulges were synthesized by a simple and scalable liquid-phase reduction method. Subsequent coating of dielectric materials was conducted to acquire core-shell structured CoNi@TiO2 composite particles, in which the thickness of TiO2 is about 40 nm. The coating of TiO2 enables the absorption band of CoNi to effectively shift from Ku to S band, and endows CoNi@TiO2 microspheres with outstanding electromagnetic wave absorption performance along with a maximum reflection loss of 76.6 dB at 3.3 GHz, much better than that of bare CoNi microspheres (54.4 dB at 17.8 GHz). The enhanced EMA performance is attributed to the unique core-shell structures, which can induce dipole polarization and interfacial polarization, and tune the dielectric properties to achieve good impedance matching. Impressively, TiO2 coating endows the composites with better microwave absorption capability than CoNi@SiO2 microspheres. Compared with SiO2, TiO2 dielectric shells could protect CoNi microspheres from merger and agglomeration during annealed. These results indicate that CoNi@TiO2 core-shell microspheres can serve as high-performance absorbers for electromagnetic wave absorbing application.