bluuebunny/crossref_metadata_2025 huggingface dataset:
Childhood Adversity and Pain Facilitation
Authors: You Dokyoung S. , Meagher Mary W.
Published: October 2018

Objective

This study investigated whether childhood adversity would be associated with hypersensitivity on two measures of central pain facilitation: area of secondary allodynia and temporal summation of second pain (TSSP), and whether pain facilitation would be explained by adult posttraumatic stress disorder (PTSD) symptoms.

Method

Participants endorsing high (n = 31) and low (n = 31) childhood adversity underwent capsaicin-induced secondary allodynia and TSSP testing. The tests were conducted a week apart with test order counterbalanced.

Results

Larger areas of secondary allodynia were observed in the high adversity group compared with the low adversity group (F(1,60) = 4.81, p = .032). This group difference was largely (62%) explained by greater PTSD symptoms in the high adversity group. Although no overall difference was found in TSSP slopes (p = .886), this was attributed to an order by group interaction (F(1,58) = 5.07, p = .028) and low power. Subsequent analyses revealed positive TSSP slopes in the high adversity group when TSSP testing was performed first, and this order effect was associated with blunted sympathetic responses to TSSP on the first visit. The two facilitation measures were unrelated (p = .631).

Conclusions

Larger areas of secondary allodynia were observed in the high adversity group, which was explained largely by PTSD symptoms. This suggests that adversity-related changes in pain facilitation may underlie the association between childhood adversity and generalized widespread pain. Although TSSP was affected by previous testing, adversity-related pain facilitation was observed when TSSP testing occurred first. Finally, adversity was not associated with a consistent pattern of hypersensitivity across the two measures of central pain facilitation.
HIV Vaccine Trials: Ethical, Psychological, and Psychological-Social Aspects (1991–1996)
Authors: Giami Alain , Linard Françoise
Published: October 2018

The authors, who took part in designing and conducting the first phase-1 clinical trials of the HIV vaccine between 1991 and 1996, discuss the history of this innovative program, in particular, the conditions under which volunteers were recruited. They recall its multidisciplinary aspects; the team included, along with clinicians who were used to performing such trials, epidemiologists, psychiatrists, psychoanalysts, social psychologists, and a philosopher specialized in ethics. When forming this team, officials at France's National Research Agency on AIDS (ANRS) were careful to identify the volunteers social characteristics and pay heed to their subjective motivations for participating, given the context, namely a rising incidence of HIV infection and the challenges that were undermining confidence in medicine. Important in this context was the application of the Huriet-Sérusclat Act (1988) with its provisions for protecting participants. These clinical trials led to reformulating several ethical questions, for instance, the tension between the need of such trials and the necessity to not expose volunteers to poorly known risks; the importance of precise scientific information for delivering free, informed consent; and the possibility for volunteers to take part on the basis of their autonomy and “risk choice.” The network of volunteers, which operated on this basis for nearly 25 years, is a rare example of collaboration between basic research in biomedicine, medical doctors, psychologists, psychoanalysts, and ethicists.
Postface: Meaning of the Experiment and Implications of the Experience
Authors: Le Marcis Frederic
Published: October 2018

Discussing specifically on the involvement of social sciences in and on the issue of recruitment in HIV vaccine trials, the postface of this special issue reasserts the importance of social science engagement in clinical research. Three entry themes are underlying the discussion: the relationship between the individual and society in consent, the analysis of consent as a transaction, the examination of the basis, and the context of trust within trials.
Recruitment and Engagement in Preventive Clinical Trials: Interdependencies and Mediation
Authors: Ollivier-Yaniv Caroline
Published: October 2018

This article takes a standpoint based in the human and social sciences to examine a decisive time in any research related to HIV-AIDS, ie, when healthy, seronegative individuals agree to take part in preventive clinical trials. The context of recruitment for such trials has been changing over the past several decades: the normalization of the epidemic after a period of sensationalism, the change in focus of social communities to other causes, the changes in the disease from a therapeutic point of view (new drug treatments and preventive drugs), the absence of compensation for participation in trials, the absence of any direct health benefits for the participants, and the fear of volunteers or the people in their lives of the idea of transforming their healthy body into a postexperimental body. Research on the prevention of HIV seems to be dependent on the consent of a limited number of people and groups because their reasons for taking part in such experiments, which are just as much personal as they are for the sake of science, are necessarily very particular. How can healthy individuals be recruited for preventive HIV trials? What is the social basis and what kind of mediation is involved in a mutual understanding between trial participants and investigators? Such questions are answered by the authors in this book, who approach the issues from a multidisciplinary and diachronic perspective.
Temporary Ectopic Implantation of an Amputated Leg Using the Distal Runoff Vessel of the Anterolateral Thigh Flap Followed by Subsequent Prefabricated Chimeric Replantation
Authors: Wang Kuan-Chih , Hung Kuo-Shu , Chang Tzu-Yen , Wu Po-Ting , Lee Yao-Chou
Published: October 2018

Aim

Infrapopliteal replantation is indicated in selected patients. When the patient is hemodynamically unstable or the amputation site is severely contaminated, temporary ectopic implantation of the amputated limb is an option. To the best of our knowledge, this is the first case report using the distal runoff vessel of the anterolateral thigh flap for temporary ectopic implantation of an amputated leg followed by replantation with the prefabricated anterolateral thigh flap.

Patient and Methods

A 28-year-old male driver had left leg avulsion amputation after a car accident. Because of concerns about the high-energy trauma mechanism and extensive trauma zone, temporary ectopic implantation was planned to avoid a lengthy replantation procedure and to enable future replantation. The amputated leg was implanted to the thigh using the distal runoff vessel of the descending branch of the lateral circumflex femoral system in the preservation of proximal cutaneous perforator. When the patient became hemodynamically stable and the amputated stump was relatively clean and healthy, we replanted the amputated leg with the prefabricated anterolateral thigh flap on day 7.

Results

The replanted leg and anterolateral thigh flap survived well after the procedure. At the 15-month follow-up, the patient could walk independently. There was no need for custom-made shoes because there was no obvious leg length discrepancy and the flap was not bulky.

Conclusions

We believe that the distal runoff vessel of the descending branch of the lateral circumflex femoral system can not only serve as a recipient site for temporary ectopic implantation but also enable the harvest of a prefabricated anterolateral thigh flap with the amputated part at the replantation stage. This prefabricated tissue containing the anterolateral thigh flap and the amputated part needs only 1 set of vascular anastomosis to accomplish replantation and simultaneous revascularization of the anterolateral thigh flap. Most importantly, this ectopically prefabricated chimeric tissue minimizes the need for extensive bone shortening after radial debridement by providing sufficient soft tissue coverage at the replantation stage.
Alteration of Sciatic Nerve Histology and Electrical Function After Compression and After Neurolysis in a Diabetic Rat Model
Authors: Hu Junda , Tu Yiji , Ding Zuoyou , Chen Zenggan , Lee Dellon A. , Lineaweaver William C. , Zhang Feng
Published: October 2018

Background

Diabetic rats are more sensitive to nerve entrapment. This study was conducted to evaluate nerve function and histological changes in diabetic rats after nerve compression and subsequent decompression.

Methods

A total of 35 Wistar rats were included. The experimental group was divided into diabetic sciatic nerve compression group (DSNC, n = 5) and diabetic sciatic nerve decompression group (DSND, n = 20). The DSNC model was created by wrapping a silicone tube circumferentially around the nerve for 4 weeks, and then the DSND group accepted nerve decompression and was followed up to 12 weeks. The DSND group was equally divided into DSND 3 weeks (DSND3), 6 weeks (DSND6), 9 weeks (DSND9), and 12 weeks (DSND12) groups. Five rats were taken as normoglycemic control group (CR, n = 5), and another 5 rats as diabetic control group (DM, n = 5). The mechanical hyperalgesia of rats was detected by Semmes-Weinstein nylon monofilaments (SWMs) and by motor nerve conduction velocity (MNCV). These 2 physiological indicators and histology of sciatic nerves were compared among different groups.

Results

The SWM measurements improved toward normal values after decompression. The SWM value was significantly lower (more normal) in the DSNC groups than in the DSND group (P < 0.05). The MNCV was 53.7 ± 0.8 m/s in the CR group, whereas it was 28.4 ± 1.0 m/s in the DSNC group (P < 0.001). Six weeks after decompression, the MNCV was significantly faster than that in the DSNC group (P < 0.001). Histological examination demonstrated chronic nerve compression, which responded toward normal after decompression, but with degree of myelination never recovering to normal.

Conclusions

Chronic compression of the diabetic sciatic nerve has measureable negative effects on sciatic nerve motor nerve function, associated with a decline of touch/pressure threshold and degeneration of myelin sheath and axon. Nerve decompression surgery can reverse these effects and partially restore nerve function.
A New Method for Double-Eyelid Blepharoplasty Using Orbital Septum
Authors: Li Gaofeng , Ding Wei , Tan Jun , Zhang Bo , Chen Xin , He Bin
Published: October 2018

Background

This article presents a new method using orbital septum for double-eyelid blepharoplasty.

Methods

During double-eyelid blepharoplasty, we incised the orbital septum horizontally. Using the attachment site of the levator aponeurosis as a pedicle, the lower part of the dissected orbital septum was turned downward and then sutured to the upper border of the lower orbicularis oculi muscle and posterior pretarsal fascia. We evaluated the efficacy of this double-eyelid surgical procedure in patients undergoing the procedure from December 2015 to October 2017.

Results

We included 462 eyes of 231 patients in the final analysis. Sutures were removed 7 days after surgery. All double-eyelid creases were well formed, and the eyelids closed well. Six-month follow-up results revealed that the double-eyelid shape was natural looking, and no patients experienced upper eyelid retraction or incomplete eye closure. Notched scars did not occur, and patient satisfaction was achieved in all cases. Two hundred eleven patients were fully satisfied with the surgical results, and 20 were basically satisfied with the surgical results.

Conclusions

Using the orbital septum is a good approach for double-eyelid blepharoplasty.
Immunosuppression is Inappropriately Qualifying the Immune Status of Septic and SIRS Patients
Authors: Cavaillon Jean-Marc , Giamarellos-Bourboulis Evangelos J.
Published: October 2018

Immunosuppression is the most commonly used concept to qualify the immune status of patients with either sterile systemic inflammatory response syndrome (SIRS) or sepsis. In this review we attempt to demonstrate that the concept of immunosuppression is an oversimplification of the complex anti-inflammatory response that occurs in patients dealing with a severe sterile or infectious insult. Particularly, the immune status of leukocytes varies greatly depending on the compartment from where they are derived from. Furthermore, although certain functions of immune cells present in the blood stream or in the hematopoietic organs can be significantly diminished, other functions are either unchanged or even enhanced. This juxtaposition illustrates that there is no global defect. The mechanisms called reprogramming or trained innate immunity are probably aimed at preventing a generalized deleterious inflammatory reaction, and work to maintain the defense mechanisms at their due levels.
The Influence of Culture on Teamwork and Communication in a Simulation-Based Resuscitation Training at a Community Hospital in Honduras
Authors: Perry Madeline F. , Seto Teresa L. , Vasquez Juan Carlos , Josyula Srirama , Rule Amy R.L. , Rule David W. , Kamath-Rayne Beena D.
Published: October 2018

Summary Statement

Communication and teamwork are important aspects of medicine and have been a recent focus of resuscitation. Culture can influence communication and teamwork, and these effects have not been studied in low-resource settings. Using a case study and the TEAM scale, we evaluated how culture influences teamwork and communication during resuscitation simulations, in addition to examining other challenges of simulation research in low-resource settings. We observed lower scores in leadership and communication skills than have been seen in other studies using the TEAM scale, which led us to evaluate the possible role of culture in influencing these skills. The high power distance and collectivism in Latin America can make communication difficult, especially during debriefing. Furthermore, in a male-biased medical hierarchy, female nurses may be less likely to voice concerns. Ultimately, this commentary provides advice for taking the influences of culture into account when planning future simulation training in low-resource settings.
Validation of the FAST Workstation as an Objective Evaluator of Hand-Tied Surgical Knots
Authors: Schneider Andrew M. , Pedowitz Robert A. , Evans Douglas A.
Published: October 2018

Introduction

Hand-tying surgical knots is an important skill that is applicable across all surgical disciplines. Knot quality is traditionally assessed in the operating room by visual inspection, which is inherently subjective. With the increasing prevalence of simulation training, surgical trainees having access to objective feedback of their knot-tying skills are paramount for skill evaluation. Our study aimed to validate a mechanical suture loop security tester as an objective evaluation method of hand-tied surgical knot quality.

Methods

Seventy-three subjects were recruited and categorized based on surgical expertise into one of the following three groups: medical students, surgical residents, and attending surgeons. They hand-tied five surgical knots consecutively using 0 Vicryl sutures. The knots were tested using the suture loop security workstation with 10 lbs of linear force for 10 seconds. Success of the suture loop was set at less than 3 mm of loop expansion. This protocol was based on previous research showing that 3 mm of loop expansion would represent clinical failure of the knot in vivo.

Results

The students, residents, and attending surgeons tied a median of two, three, and four successful knots, respectively. Post hoc pairwise comparisons revealed that residents tied more successful knots than students (p < 0.001), and attending physicians tied more successful knots than students (p < 0.001). However, there was no statistically significant difference in the number of successes between residents and attending physicians (p = 0.24).

Conclusions

Using the mechanical loop security workstation demonstrates construct validity as a reliable objective evaluation tool of hand-tied surgical knots.
Leonardo da Vinci's discovery of the dynamic soaring by birds in wind shear
Authors: Richardson Philip L.
Published: October 2018

Although Leonardo da Vinci (1452–1519) is well known to have studied bird flight, few people realize that he was the first to document flight manoeuvres now called dynamic soaring. Birds use these manoeuvres to extract energy from the gradient of wind velocity (wind shear) for sustained flight. In his Manuscript E (
ca
1513–1515) Leonardo described land birds performing flight manoeuvres that match those of albatrosses and other seabirds when they are engaged in dynamic soaring over the ocean. His description pre-dates by almost 400 years the first generally accepted explanation of the physics of this soaring technique by Lord Rayleigh in 1883. Leonardo's early description of dynamic soaring is one of his major aerodynamic discoveries.
Phase transition and switchable dielectric behaviours in an organic–inorganic hybrid compound: (3-nitroanilinium)
2
(18-crown-6)
2
(H
2
PO
4
)
2
(H
3
PO
4
)
3
(H
2
O)
Authors: Liu Yang , Zhu Chun-li , Zheng Xiao-yuan , Qin Liu-lei , Yang Shuang-xi , Liu Zun-qi
Published: October 2018

An organic–inorganic hybrid compound with an extensive three-dimensional (3D) crystal structure, (3-nitroanilinium)
2
(18-crown-6)
2
(H
2
PO
4
)
2
(H
3
PO
4
)
3
(H
2
O) (
1
), was synthesized under slow evaporation conditions. Differential scanning calorimetry measurements indicated that
1
underwent a reversible phase transition at
ca
231 K with a hysteresis width of 10 K. Variable-temperature X-ray single-crystal diffraction revealed that the phase transition of
1
can be ascribed to coupling of pendulum-like motions of its nitro group with proton transfer in O–H···O hydrogen bonds of the 3D framework. The temperature dependence of its dielectric permittivity demonstrated a step-like change in the range of 150–280 K with remarkable dielectric anisotropy, making
1
a promising switchable dielectric material. Potential energy calculations further supported the possibility of dynamic motion of the cationic nitro group. Overall, our findings may inspire the development of other switchable dielectric phase transition materials by introducing inorganic anions into organic–inorganic hybrid systems.
Enrichment of lithium from salt lake brine by forward osmosis
Authors: Li Jinli , Wang Min , Zhao Youjing , Yang Hongjun , Zhong Yuan
Published: October 2018

Forward osmosis (FO) is a concentration process based on the natural phenomena of osmosis. It is considered a breakthrough technology that can be potentially used for concentrating solutions and suspensions. The diluted nature of brine restricts the treatment technologies that can be applied. Then, brine concentration by FO could represent a new emerging technology enabling the application of a wider range of treatment alternatives. The performance of concentrated brine depending upon FO membranes was studied at normal temperature and pressure in this research. Cellulose triacetates on radio-frequency-weldable non-woven support (CTA-NW) and a thin-film composite with embedded polyester screen support (TFC-ES) were compared; and their orientations were considered. The brine was from Chaerhan Salt Lake after extracting potassium as the feed solution, NaCl solution or MgCl
2
solution as the draw solution. The results indicated that CTA-NW exhibited better concentration performance than TFC-ES, while the water fluxes of the two membranes were exactly the opposite. In the case of CTA-NW in active layer facing feed solution orientation with MgCl
2
as the draw solution, the concentration factor of Li
+
was nearly 3.0. Quantitative structure–activity relationship of FO membranes and concentration characteristics was correlated, based on results of SEM, FTIR and contact angles studies. The concentration performance could be mainly attributed to the porosity and the thickness of FO membranes; while the water flux was dependent on the hydrophily of FO membrane surface.
Microstructural patterns with tunable mechanical anisotropy obtained by simulating anisotropic spinodal decomposition
Authors: Vidyasagar A. , Krödel S. , Kochmann D. M.
Published: October 2018

The generation of mechanical metamaterials with tailored effective properties through carefully engineered microstructures requires avenues to predict optimal microstructural architectures. Phase separation in heterogeneous systems naturally produces complex microstructural patterns whose effective response depends on the underlying process of spinodal decomposition. During this process, anisotropy may arise due to advection, diffusive chemical gradients or crystallographic interface energy, leading to anisotropic patterns with strongly directional effective properties. We explore the link between anisotropic surface energies during spinodal decomposition, the resulting microstructures and, ultimately, the anisotropic elastic moduli of the resulting medium. We simulate the formation of anisotropic patterns within representative volume elements, using recently developed stabilized spectral techniques that circumvent further regularization, and present a powerful alternative to current numerical techniques. The interface morphology of representative phase-separated microstructures is shown to strongly depend on surface anisotropy. The effective elastic moduli of the thus-obtained porous media are identified by periodic homogenization, and directionality is demonstrated through elastic surfaces. Our approach not only improves upon numerical tools to simulate phase separation; it also offers an avenue to generate tailored microstructures with tunable resulting elastic anisotropy.
The socially mediated recovery of a fearful fish paired with periodically replaced calm models
Authors: Crane Adam L. , Bairos-Novak Kevin R. , Sacco Laurel H. , Ferrari Maud C. O.
Published: October 2018

Social learning is an important mechanism for acquiring knowledge about environmental risk. However, little work has explored the learning of safety and how such learning outcomes are shaped by the social environment. Here, we exposed minnows,Pimephales promelas, to a high-risk environment to induce behavioural responses associated with fear (e.g. neophobia). We then used the presence of calm conspecific models (low-risk individuals) to weaken these responses. When observers (individuals from the high-risk environment) and models were paired consistently in a one-on-one setting, the observers showed no recovery (i.e. no weakening of the fear responses), and instead the models indirectly acquired those responses (i.e. a socially transmitted state of fear). However, observers paired with models that were periodically replaced with new calm models showed a significant recovery, and each new model showed diminished socially transmitted fear. We argue that our understanding of predation-related fear and social information transfer can prove fruitful in understanding problems with fear and stress across animal taxa, including among humans who experience post-traumatic stress and secondary trauma. Our findings indicate that the periodic replacement of models can promote fear recovery in observers and reduce socially transmitted fear in models.
Spatial heterogeneity contributes more to portfolio effects than species variability in bottom-associated marine fishes
Authors: Thorson James T. , Scheuerell Mark D. , Olden Julian D. , Schindler Daniel E.
Published: October 2018

Variance of community abundance will be reduced relative to its theoretical maximum whenever population densities fluctuate asynchronously. Fishing communities and mobile predators can switch among fish species and/or fishing locations with asynchronous dynamics, thereby buffering against variable resource densities (termed ‘portfolio effects’, PEs). However, whether variation among species or locations represent the dominant contributor to PE remains relatively unexplored. Here, we apply a spatio-temporal model to multidecadal time series (1982–2015) for 20 bottom-associated fishes in seven marine ecosystems. For each ecosystem, we compute the reduction in variance over time in total biomass relative to its theoretical maximum if species and locations were perfectly correlated (total PE). We also compute the reduction in variance due to asynchrony among species at each location (species PE) or the reduction due to asynchrony among locations for each species (spatial PE). We specifically compute total, species and spatial PE in 10-year moving windows to detect changes over time. Our analyses revealed that spatial PE are stronger than species PE in six of seven ecosystems, and that ecosystems where species PE is constant over time can exhibit shifts in locations that strongly contribute to PE. We therefore recommend that spatial and total PE be monitored as ecosystem indicators representing risk exposure for human and natural consumers.
Rhythmic motor behaviour influences perception of visual time
Authors: Tomassini Alice , Vercillo Tiziana , Torricelli Francesco , Morrone Maria Concetta
Published: October 2018

Temporal processing is fundamental for an accurate synchronization between motor behaviour and sensory processing. Here, we investigate how motor timing during rhythmic tapping influences perception of visual time. Participants listen to a sequence of four auditory tones played at 1 Hz and continue the sequence (without auditory stimulation) by tapping four times with their finger. During finger tapping, they are presented with an empty visual interval and are asked to judge its length compared to a previously internalized interval of 150 ms. The visual temporal estimates show non-monotonic changes locked to the finger tapping: perceived time is maximally expanded at halftime between the two consecutive finger taps, and maximally compressed near tap onsets. Importantly, the temporal dynamics of the perceptual time distortion scales linearly with the timing of the motor tapping, with maximal expansion always being anchored to the centre of the inter-tap interval. These results reveal an intrinsic coupling between distortion of perceptual time and production of self-timed motor rhythms, suggesting the existence of a timing mechanism that keeps perception and action accurately synchronized.
Accurate peptide fragmentation predictions allow data driven approaches to replace and improve upon proteomics search engine scoring functions
Authors: C. Silva Ana Sílvia , Martens Lennart , Degroeve Sven
Published: October 2018

The use of post-processing tools to maximize the information gained from a proteomics search engine is widely accepted and used by the community, with the most notable example being Percolator - a semi-supervised machine learning model which learns a new scoring function for a given dataset. The usage of such tools is however bound to the search engine's scoring scheme, which doesn't always make full use of the intensity information present in a spectrum. We aim to show how this tool can be applied in such a way that maximizes the use of spectrum intensity information by leveraging another machine learning-based tool, MS2PIP. MS2PIP predicts fragment ion peak intensities. We show how comparing these intensities to annotated experimental spectra by calculating direct similarity metrics provides enough information for a tool such as Percolator to accurately separate two classes of PSMs. This approach allows using more information out of the data (compared to simpler intensity based metrics, like peak counting or explained intensities summing) while maintaining control of statistics such as the false discovery rate.
Cooperation of partially-transformed clones: an invisible force behind the early stages of carcinogenesis
Authors: Esposito Alessandro
Published: October 2018

Most tumours exhibit significant heterogeneity and are best described as communities of cellular populations competing for resources. Growing experimental evidence also suggests, however, that cooperation between cancer clones is important as well for the maintenance of tumour heterogeneity and tumour progression. However, a role for cell communication during the earliest steps in oncogenesis is not well characterised despite its vital importance in normal tissue and clinically manifest tumours. By modelling the interaction between the mutational process and cell-to-cell communication in three-dimensional tissue architecture, we show that non-cell-autonomous mechanisms of carcinogenesis could support and accelerate pre-cancerous clonal expansion through the cooperation of different, non- or partially- transformed mutants. We predict the existence of a ‘cell-autonomous time-horizon’, a time before which cooperation between cell-to-cell communication and DNA mutations might be one of the most fundamental forces shaping the early stages of oncogenesis. The understanding of this process could shed new light on the mechanisms leading to clinically manifest cancers.
FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis
Authors: Turunen S. Pauliina , von Nandelstadh Pernilla , Öhman Tiina , Gucciardo Erika , Martins Beatriz , Rantanen Ville , Li Huini , Höpfner Katrin , Varjosalo Markku , Lehti Kaisa
Published: October 2018

Cancer cells balance with the equilibrium of cell death and growth to expand and metastasize. The activity of mammalian sterile20-like kinases MST1/2 has been linked to apoptosis and tumor suppression via YAP/Hippo pathway dependent and independent mechanisms. With a kinase substrate screen we identified here MST1 and MST2 among the top substrates for fibroblast growth factor receptor 4 (FGFR4). In COS-1 cells, MST1 was phosphorylated at Y433 residue in an FGFR4 kinase activity-dependent manner, as assessed by mass spectrometry. Blockade of this phosphorylation by Y433F mutation induced MST1 activation, as reflected by increased autophosphorylation at T183 in FGFR4 overexpressing MDA-MB-231 cells. Importantly, the specific short-term inhibition or knockdown of FGFR4 also led to MST1/2 activation in conjunction with induction of MST1/2-dependent apoptosis in an endogenous model of HER2+breast cancer cells. Moreover, FGFR4 knockdown increased the level of active nuclear MST1 coincidentally with cell polarization and membrane-association of YAP in three-dimensional breast cancer cell spheres. Consistently, FGFR4 overexpression correlated with reduced Hippo pathway-mediated, nuclear translocation-inhibiting YAP phosphorylation, and abysmal HER2+breast carcinoma patient outcome in TCGA cohort. Our results reveal a novel mechanism for FGFR4 oncogenic activity via suppression of the stress-associated MST1/2-dependent apoptosis machinery in the tumor cells with prominent HER/ERBB signaling driven proliferation.
Length asymmetry and heterozygosity strongly influences the evolution of poly-A microsatellites at meiotic recombination hotspots
Authors: Heissl Angelika , Betancourt Andrea J. , Hermann Philipp , Povysil Gundula , Arbeithuber Barbara , Futschik Andreas , Ebner Thomas , Tiemann-Boege Irene
Published: October 2018

Meiotic recombination has strong, but poorly understood, effects on short tandem repeat (STR) instability. Here, we screened thousands of single recombinant products to characterize the transmission and evolution of polymorphic poly-A repeats at a human recombination hotspot. We show that length asymmetry between heterozygous poly-As plays a key role in the recombination outcome and their transmission. A difference of 10 As (9A/19A) elevates the frequency of non-crossovers, complex recombination products, and long conversion tracts. Moreover, asymmetry also influences STR transmission: the shorter allele is transmitted more frequently (deletion bias) at the asymmetric STR (9A/19A), while the longer allele is favored (insertion bias) at the site with a small STR length difference (6A/7A). Finally, potentially due to this opposing insertion/deletion driven evolution, we find that poly-As are enriched at human recombination hotspots predominantly with short poly-As, possibly influencing open chromatin regions that in turn can activate hotspots.
Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma
Authors: Stafford James M. , Lee Chul-Hwan , Voigt Philipp , Descostes Nicolas , Saldaña-Meyer Ricardo , Yu Jia-Ray , Leroy Gary , Oksuz Ozgur , Chapman Jessica R. , Suarez Fernando , Modrek Aram S. , Bayin N. Sumru , Placantonakis Dimitris G. , Karajannis Matthias A. , Snuder Matija , Ueberheide Beatrix , Reinberg Danny
Published: October 2018

A methionine substitution at lysine 27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits PRC2 in a dominant negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found this interaction on chromatin is transient with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-chromatin suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to K27M leading to a failure to spread H3K27me3 at distinct foci. In turn, levels of Polycomb antagonists such as H3K36me2 are elevated suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.
Type 1 Diabetes: an Association Between Autoimmunity the Dynamics of Gut Amyloid-producing E. coli and Their Phages
Authors: Tetz George , Brown Stuart M. , Hao Yuhan , Tetz Victor
Published: October 2018

The etiopathogenesis of type 1 diabetes (T1D), a common autoimmune disorder, is not completely understood. Recent studies suggested the gut microbiome plays a role in T1D. We have used public longitudinal microbiome data from T1D patients to analyze amyloid-producing bacterial composition and found a significant association between initially high amyloid-producing Escherichia coli abundance, subsequent E. coli depletion prior to seroconversion, and T1D development. In children who presented seroconversion or developed T1D, we observed an increase in the E. coli phage/E. coli ratio prior to E. coli depletion, suggesting that the decrease in E. coli was due to prophage activation. Evaluation of the role of phages in amyloid release from E. coli biofilms in vitro suggested an indirect role of the bacterial phages in the modulation of host immunity. This study for the first time suggests that amyloid-producing E. coli, their phages, and bacteria-derived amyloid might be involved in pro-diabetic pathway activation in children at risk for T1D.
CSNAP, the smallest CSN subunit, modulates proteostasis through cullin-RING ubiquitin ligases
Authors: Füzesi-Levi Maria G. , Enchev Radoslav Ivanov , Ben-Nissan Gili , Levin Yishai , Kupervaser Meital , Friedlander Gilgi , Salame Tomer Meir , Nevo Reinat , Peter Matthias , Sharon Michal
Published: October 2018

The cullin-RING ubiquitin E3 ligase (CRL) family consists of ~250 complexes that catalyze ubiquitylation of proteins to achieve cellular regulation. All CRLs are inhibited by the COP9 signalosome complex (CSN) through both enzymatic (deneddylation) and non-enzymatic (steric) mechanisms. The relative contribution of these two mechanisms is unclear. Here, we decouple the mechanisms using CSNAP, the recently discovered ninth subunit of the CSN. We find that CSNAP reduces the affinity of CSN toward CRL complexes. Removing CSNAP does not affect deneddylation, but leads to global effects on the CRL, causing altered reproductive capacity, suppressed DNA damage response, decreased viability, and delayed cell cycle progression. Thus, although CSNAP is only 2% of the CSN mass, it plays a critical role in the steric regulation of CRLs by the CSN.
Dorsal Hippocampus Not Always Necessary in a Radial Arm Maze Delayed Win-shift Task
Authors: Layfield Dylan , Sidell Nathan , Abdullahi Afnan , Newman Ehren L.
Published: October 2018

Spatial working memory is important for foraging and navigating the environment. However, its neural underpinnings remain poorly understood. The hippocampus, known for its spatial coding and involvement in spatial memory, is widely understood to be necessary for spatial working memory when retention intervals increase beyond seconds into minutes. Here, we describe new evidence that the dorsal hippocampus is not always necessary for spatial working memory for retention intervals of 8 minutes. Rats were trained to perform a delayed spatial win shift radial arm maze task (DSWS) with an 8-minute delay between study and test phases. We then tested whether bilateral inactivation of the dorsal hippocampus between the study and test phases impaired behavioral performance at test. Inactivation was achieved through a bilateral infusion of lidocaine. Performance following lidocaine was compared to control trials, in which, sterile phosphate buffered saline (PBS) was infused. Test performance did not differ between the lidocaine and PBS conditions, remaining high in each. To explore the possibility that this insensitivity to inactivation was a result of overtraining, a second cohort of animals received substantially less training prior to the infusions. In this second cohort, lidocaine infusions did significantly impair task performance. These data indicate that successful performance of a spatial win-shift task on the 8-arm maze need not always be hippocampally dependent.
NetTCR: sequence-based prediction of TCR binding to peptide-MHC complexes using convolutional neural networks
Authors: Jurtz Vanessa Isabell , Jessen Leon Eyrich , Bentzen Amalie Kai , Jespersen Martin Closter , Mahajan Swapnil , Vita Randi , Jensen Kamilla Kjærgaard , Marcatili Paolo , Hadrup Sine Reker , Peters Bjoern , Nielsen Morten
Published: October 2018

Predicting epitopes recognized by cytotoxic T cells has been a long standing challenge within the field of immuno- and bioinformatics. While reliable predictions of peptide binding are available for most Major Histocompatibility Complex class I (MHCI) alleles, prediction models of T cell receptor (TCR) interactions with MHC class I-peptide complexes remain poor due to the limited amount of available training data. Recent next generation sequencing projects have however generated a considerable amount of data relating TCR sequences with their cognate HLA-peptide complex target. Here, we utilize such data to train a sequence-based predictor of the interaction between TCRs and peptides presented by the most common human MHCI allele, HLA-A*02:01. Our model is based on convolutional neural networks, which are especially designed to meet the challenges posed by the large length variations of TCRs. We show that such a sequence-based model allows for the identification of TCRs binding a given cognate peptide-MHC target out of a large pool of non-binding TCRs.
Probing the flavin transfer mechanism in alkanesulfonate monooxygenase system
Authors: Dayal PV , Ellis HR
Published: October 2018

Bacteria acquire sulfur through the sulfur assimilation pathway, but under sulfur limiting conditions bacteria must acquire sulfur from alternative sources. The alkanesulfonate monooxygenase enzymes are expressed under sulfur-limiting conditions, and catalyze the desulfonation of wide-range of alkanesulfonate substrates. The SsuE enzyme is an NADPH-dependent FMN reductase that provides reduced flavin to the SsuD monooxygenase. The mechanism for the transfer of reduced flavin in flavin dependent two-component systems occurs either by free-diffusion or channeling. Previous studies have shown the presence of protein-protein interactions between SsuE and SsuD, but the identification of putative interaction sights have not been investigated. Current studies utilized HDX-MS to identify protective sites on SsuE and SsuD. A conserved α-helix on SsuD showed a decrease in percent deuteration when SsuE was included in the reaction. This suggests the role of α-helix in promoting protein-protein interactions. Specific SsuD variants were generated in order to investigate the role of these residues in protein-protein interactions and catalysis. Variant containing substitutions at the charged residues showed a six-fold decrease in the activity, while a deletion variant of SsuD lacking the α-helix showed no activity when compared to wild-type SsuD. In addition, there was no protein-protein interactions identified between SsuE and his-tagged SsuD variants in pull-down assays, which correlated with an increase in theKdvalue. The α-helix is located right next to a dynamic loop region, positioned at the entrance of the active site. The putative interaction site and dynamic loop region located so close to the active site of SsuD suggests the importance of this region in the SsuD catalysis. Stopped-flow studies were performed to analyze the lag-phase which signifies the stabilization and transfer of reduced flavin from SsuE to SsuD. The SsuD variants showed a decrease in lag-phase, which could be because of a downturn in flavin transfer. A competitive assay was devised to evaluate the mechanism of flavin transfer in the alkanesulfonate monooxygenase system. A variant of SsuE was generated which interacted with SsuD, but was not able to reduce FMN. Assays that included varying concentrations of Y118A SsuE and wild-type SsuE in the coupled assays showed a decrease in the desulfonation activity of SsuD. The decrease in activity could be by virtue of Y118A SsuE competing with the wild-type SsuE for the putative docking site on SsuD. These studies define the importance of protein-protein interactions for the efficient transfer of reduced flavin from SsuE to SsuD leading to the desulfonation of alkanesulfonates.
Phosphorylation of the α2 glycine receptor induces an extracellular conformational change and slows the rise and decay rates of glycinergic synaptic currents
Authors: Islam Sharifun , Chen Xiumin , Estrada-Mondragon Argel , Lynch Joseph. W.
Published: October 2018

The α2 glycine receptor (GlyR) is a pentameric ligand-gated anion channel that plays a key role in cortical interneuron migration and in the differentiation of cortical progenitor cells into functional neurons. It also mediates tonic inhibitory chloride currents in adult forebrain neurons. Disruption of α2 GlyR gene expression or receptor function results in the aberrant functioning of neuronal circuits which contributes to the pathophysiology of schizophrenia, autism and epilepsy. This implicates the α2 GlyR as a possible therapeutic target for a range of neurological disorders. However, despite its therapeutic potential, little is known about the mechanisms by which α2 GlyRs are functionally modulated. To address this, we investigated whether the α2 GlyR is modulated by phosphorylation at a serine residue (S341) within the same PKA consensus sequence (R-E-S-R) that houses the α3 GlyR S346 residue that is known to be phosphorylated by PKA. Resolving this question might uncover a novel means of physiologically, pathologically or therapeutically modulating α2 GlyRs. We show using voltage-clamp fluorometry that forskolin-induced phosphorylation of S341 induces a conformational change in the glycine binding site. We also employed glycinergic artificial synapses to demonstrate that the S341E phospho-mimetic mutation slows the rise and decay rates of α2-mediated glycinergic inhibitory postsynaptic currents. These results suggest that PKA phosphorylation alters the structural and functional properties of the α2 GlyR. This information may help to identify new mechanisms by which α2 GlyRs may be pathologically modified or therapeutically targeted for the treatment of neurological disorders.
Different temporal windows for contextual fear memory destabilisation in the amygdala and hippocampus
Authors: Lee Jonathan L. C. , Amorim Felippe E. , Cassini Lindsey F. , Amaral Olavo B.
Published: October 2018

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-re-exposure interventions, while those in the hippocampus have performed them after re-exposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory re-exposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after re-exposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.
Hfq-assisted RsmA regulation is central to Pseudomonas aeruginosa biofilm polysaccharide PEL expression
Authors: Irie Yasuhiko , Murina Victoriia , Hauryliuk Vasili , Shingler Victoria
Published: October 2018

Expression of biofilm-associated genes is controlled by multiple regulatory elements, allowing bacteria to appropriately switch between sessile and motile lifestyles. In Pseudomonas aeruginosa, the post-transcriptional regulator RsmA has been implicated in the control of various genes including those related to biofilms, but much of the evidence for these links is limited to transcriptomic and phenotypic studies. RsmA binds to target mRNAs to modulate translation by affecting ribosomal access and/or mRNA stability. Here we trace a global regulatory role of RsmA to the inhibition of Vfr – a transcription factor that controls a transcriptional regulator FleQ. FleQ directly controls biofilm-associated genes that encode the PEL polysaccharide biosynthesis machinery. Furthermore, we show that RsmA cannot bind vfr mRNA alone, but requires the RNA chaperone protein Hfq. This is the first example where a RsmA protein family member is demonstrated to require another protein for RNA binding.